Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][Mg]Br>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: C[Mg]Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Product: Cc1nc(Cl)nc(Cl)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a 5-L reactor was added 2,4,6-trichloro-1,3,5-triazine (180 g, 976 mmol) and DCM (180 mL). To the solution cooled at 0° C. in a dry ice bath was added methylmagnesium bromide (390 mL, 1171 mmol) over 30 min while the reaction temperature was kept below rt. After the addition, the reaction mixture was placed in an ice-water bath to keep the internal temperature stable at 20° C. After the mixture was stirred overnight at rt, it was cooled to −20° C. and was slowly quenched with ice water (500 mL) (internal temperature was controlled below 0° C.). The mixture was allowed to warm to rt and was transferred to a separation funnel. The organic layer was washed with water (500 mL), and concentrated to afford 2,4-dichloro-6-methyl-1,3,5-triazine (127 g, 774 mmol, 79% yield) as a solid that was carried to the next step.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[CH:7]=1>C(O)(=O)C>[NH2:5][C:6]1[N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:10](=[O:20])[NH:9][C:8](=[O:21])[C:7]=1[N:1]=[O:3]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1cccc(Cl)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1cccc(Cl)c1

Procedure:
6.4 ml of 4N sodium nitrite was added at 65-70° C. to a suspension of 6.29 g (25 mM) of 6-amino-1-(3-chlorobenzyl)-uracil in 92 ml of acetic acid. After 30 minutes the mixture was cooled, the solid collected and washed with the acetic acid and water to give the title compound (5.21 g) as a pink solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.C([O:29][CH2:30][CH2:31][N:32]1[C:36]([CH:37]([CH3:39])[CH3:38])=[C:35]([CH:40]=[O:41])[C:34]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[N:33]1)(=O)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH2:43]([O:42][C:34]1[C:35]([CH:40]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:41])=[C:36]([CH:37]([CH3:38])[CH3:39])[N:32]([CH2:31][CH2:30][OH:29])[N:33]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)c1c(C=O)c(OCc2ccccc2)nn1CCOC(=O)c1ccccc1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1c(C(O)c2ccccc2OCc2ccccc2)c(OCc2ccccc2)nn1CCO
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a solution of 2-benzyloxybromobenzene (1.66 g) in tetrahydrofuran (50 mL) was added tert-butyllithium (1.6 mol/L pentane solution, 4.33 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added a solution of 1-(2-benzoyloxyethyl)-3-benzyloxy-4-formyl-5-isopropyl-1H-pyrazole (620 mg) in tetrahydrofuran (5 mL), and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1–2/1) to give 2-{3-benzyloxy-4-[(2-benzyloxyphenyl)hydroxymethyl]-5-isopropylpyrazol-1-yl}ethanol (448 mg). To a solution of 2-{3-benzyloxy-4-[(2-benzyloxyphenyl)hydroxymethyl]-5-isopropylpyrazol-1-yl}ethanol (448 mg) in methanol (5 mL) was added 10% palladium-carbon powder (448 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (220 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[C:24]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][C:4]1[C:5]2[C:10]([CH:11]=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:32][C:31]1[CH:34]=[CH:35][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=1
Reactant: CNCc1c2ccccc2cc2ccccc12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(C(C)(C)C)cc1)Cc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 91 %

Procedure:
2.2 g (0.01 mole) of N-methyl-9-anthrylmethylamine was dissolved in 40 ml of toluene, and 1.7 g (0.012 mole) of anhydrous potassium carbonate was added. With continued stirring at room temperature, 2.49 g (0.011 mole) of p-t-butylbenzylbromide was added, and the mixture was reacted at 40° to 50° C. for 4 hours. The reaction mixture was mixed with ice water, and distributed. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on a silica gel column, and eluted with 4% ethyl acetate/n-hexane. The eluate was concentrated to give 3.3 g (yield 91%) of an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1cccc2c1CCN2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4c(Cl)cccc43)c2cc1OC
Yield: 92 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 92% yield from 4-chloro-indoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 172°-179° C. (dec); LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.60 min.).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>ClCCl.C(OCC)(=O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14](=[CH:13][NH:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccccc1=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1cccccc1=O)C(=O)OCC

Procedure:
A mixture of 2-amino-2,4,6-cycloheptatrien-1-one (2 g), described by W. Von E. Doering and L. H. Knox, J. Amer. Chem. Soc., 73, 828 (1951), and diethyl ethoxymethylenemalonate (20 ml) was heated at 140° C. for 2 hr. The reaction was cooled and subjected to chromatography on silica gel using dichloromethane-ethyl acetate (4:1) as the eluant. The pure fractions were pooled to give 4.13 g of 2-[(7-oxo-1,3,5-cycloheptatrien-1-yl)aminomethylene]-propanedioic acid diethyl ester; mp 66°-68° C.; nmr (CDCl3) δ1.35 (m, 6H), 4.35 (m, 2H), 7.35 (m, 5H), 8.4 (d, 1H), 11.4 (broad, 1H); ir (CHCl3) 3230, 1700, 1665, 1580 cm-1 ; uv λ max (MeOH) 356 nm (ε13,770), 292 (9,880), 277 (10,680), 213 (17,020) with shoulders at 338 and 236 nm.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:15])([CH3:14])[C:9]=2[C:8]=1[C:19](O)=[O:20])=[O:5].[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[C:3]=1[C:4]([NH:6][C:7]1[S:18][C:10]2[C:11]([CH3:17])([CH3:16])[O:12][C:13]([CH3:14])([CH3:15])[C:9]=2[C:8]=1[C:19]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:20])=[O:5]
Reactant: COCCN
Reactant: CC1(C)OC(C)(C)c2c1sc(NC(=O)c1c(F)cccc1C(F)(F)F)c2C(=O)O
Product: COCCNC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 45A and 2-methoxyethylamine using the procedure described for Example 2B. 1H NMR (DMSO-d6, 300 MHz) δ 1.45 (s, 6H), 1.48 (s, 6H), 3.18 (s, 3H), 3.31-3.41 (m, 4H), 7.68-7.82 (m, 3H), 7.99 (t, J=5.3 Hz, 1H), 11.51 (br s, 1H). MS (ESI+) m/z 489 (M+H)+. Anal. calcd. for C22H24F4N2O4S: C, 54.09; H, 4.95; N, 5.73. Found: C, 53.88; H, 4.65; N, 5.71.
Reaction SMILES: [C:1]1([C:7](=[O:23])[CH:8]=[CH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([O:21]C)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl.Cl>ClCCl>[C:1]1([C:7](=[O:23])[CH:8]=[CH:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[C:13]([OH:20])=[C:12]([OH:21])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C=CC(=O)c2ccccc2)cc(C(F)(F)F)c1O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=C(C=Cc1cc(O)c(O)c(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution containing 0.32 g of the above product obtained in Example 85 in 10 ml of dichloromethane 3 ml of 1 molar BBr3 -CH2Cl2 was added. The mixture was stirred for 20 min at room temperature, acidified with 10 ml 2 N hydrochloric acid and extracted with dichloromethane. The solvent was evaporated in reduced pressure and the residue crystallized from acetone-dichloromethane. Yield 0.07 g (23%), m.p. 196°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][N:12]([CH2:23][OH:24])[C:13](=[O:22])[C:14]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)=[C:8]3[NH:7][C:6]=2[CH:25]=1.[C:26](Cl)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][N:12]([CH2:23][O:24][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:13](=[O:22])[C:14]([C:15]4[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=4)=[C:8]3[NH:7][C:6]=2[CH:25]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccc(Cl)cc1N2
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1cc(Cl)ccc1S2
Reaction time: 0.58 h
Yield: 78 %

Procedure:
To 1.0 g. of 7-chloro-4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (2.6 mmol.) in 15 ml. of pyridine at 0° C. was added dropwise 0.9 ml. of hexadecanoyl chloride (3.9 mmol.). After stirring for 35 minutes, the mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in the formation of a yellow precipitate. The precipitate was collected, washed with water and air-dried, then purified using flash chromatography on silica gel, employing a mixture of 2% ethyl acetate: 98% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 7-chloro-4-(4-chlorophenyl)-2-[(1-oxohexadecyloxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a pale yellow crystalline solid (1.25 g; 78% yield) having the structural formula, ##STR21## a melting point in the range of 120°-122° C. and the following elemental analysis:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[F:7][C:8]([F:23])([S:19](Cl)(=[O:21])=[O:20])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].[F:24][C:25]([F:29])([F:28])[CH2:26][OH:27].C(N(CC)CC)C>ClCCl>[F:7][C:8]([F:23])([S:19]([O:27][CH2:26][C:25]([F:29])([F:28])[F:24])(=[O:21])=[O:20])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: OCC(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
The process according to claim 12, wherein the perfluorobutanesulphonate alkaline salts are solubilised in methanol and treated with gaseous hydrochloric acid to give the corresponding perfluorobutanesulphonic acid which, after treatment with PCl5 is transformed into the corresponding perfluorobutanesulphonyl chloride, the latter reacts with 2,2,2-trifluoroethanol and triethylamine in dichloromethane to give 2,2,2-trifluoroethanol perfluorobutanesulphonate, which is recycled in the reaction at phase a).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12](C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[C@H:11]([CH2:27][OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>[OH-].[OH-].[Pd+2].CO>[Si:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH2:27][OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN[C@H](CO)C1

Procedure:
A mixture of (2S, 4R)-4-t-butyldimethylsilyloxy-2-hydroxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (10.0 g), methanol (100 ml) and 20% palladium hydroxide on carbon (0.5 g) was stirred under atmospheric pressure of hydrogen at ambient temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S,4R)-4-t-butyldimethylsilyloxy-2-hydroxymethylpyrrolidine. To a solution of the compound obtained above in a mixture of tetrahydrofuran (100 ml) and water (100 ml) was dropwise added a solution of chloroacetyl chloride (5.0 ml) in tetrahydrofuran (10 ml) under ice-cooling with stirring, keeping the pH between 8-9 with 4N aqueous sodium hydroxide. The mixture was stirred at the same condition for 2 hours and extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1 V/V) (100 ml ×5). The solution was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (200 g) and eluted with a mixture of methanol and dichloromethane (1:99 V/V) to give (2S,4R)-4-t-butyldimethylsilyloxy-1-chloroacetyl-2-(hydroxymethyl)pyrrolidine (4.22 g).
Reaction SMILES: FC1C=CC(C2C3C(=CC([S:18][C:19]4[S:20][C:21]([C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH2:25][CH3:26])=[CH:22][N:23]=4)=CC=3)OC(=O)C=2)=CC=1>CCO.CCCCCC>[F:30][C:27]([F:28])([F:29])[C:24]([C:21]1[S:20][C:19]([SH:18])=[N:23][CH:22]=1)([OH:31])[CH2:25][CH3:26]
Reactant: CCC(O)(c1cnc(Sc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)s1)C(F)(F)F
Solvent: CCO
Solvent: CCCCCC
Product: CCC(O)(c1cnc(S)s1)C(F)(F)F

Procedure:
A solution of (±)-1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol (1.2 g) from step 2 of example 1 in EtOH/hexane (20 ml, 1:4) was injected (1×1.2 g) onto a CHIRALPAK AD preparative (5 cm×50 cm) HPLC column (eluting with hexane/EtOH, 4:1; at 75 ml/min with UV detection at 280 nm). The enantiomers were separated with the faster eluting enantiomer having a retention time of ˜19 min (enantiomer #1, (2S)-1,1,1-trifluoro-2-(2-mercapto-1,3-thiazol-5-yl)butan-2-ol) and the slower eluting enantiomer having a retention time of ˜34 min (enantiomer #2, (2R)-1,1,1-trifluoro-2-2-mercapto-1,3-thiazol-5-yl)butan-2-ol). The eluants were concentrated to provide enantiomer #1 (0.468 g, 99% ee) and enantiomer #2 (0.426 g, 98% ee).
Reaction SMILES: C(O)(C)C.[O:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[C:21](Cl)[N:20]=1>O>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:19]([NH2:18])=[N:20][C:21]([N:15]3[CH2:14][CH2:13][N:12]([C:10]([CH:6]4[O:5][CH2:9][CH2:8][CH2:7]4)=[O:11])[CH2:17][CH2:16]3)=[N:22][C:23]2=[CH:24][C:25]=1[O:31][CH3:32]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)O
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 108.1 %

Procedure:
To a solution of iso-propanol (290 ml), water (50 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 35 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 12 hours. The crystals were collected by filtration, washed with iso-propanol and dried in vacuo at 40° C. to yield 38.8 g (94%) of Terazosin.HCl dihydrate. See Trial K in Table I. Trial L was performed using a 5% percent volume of water.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][N:14]=[C:15]=[O:16].O>CS(C)=O>[CH3:13][NH:14][C:15](=[O:16])[NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CN=C=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1csc(NC(=O)NC)n1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of ethyl 2-aminothiazol-4-ylacetate (27.4 g.) in dimethylsulfoxide (135 ml.) was dropwise added methylisocyanate (13.05 g.) with stirring at room temperature, and the mixture was stirred for 3 hours at 40° C. After the reaction, the reaction mixture was poured into water (500 ml.), and then extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride in turn and then dried over magnesium sulfate. After distillation of the solvent from the extract, the residue was pulverized in diethyl ether, collected by filtration and then dried to give colorless crystals of ethyl 2-(3-methylureido)thiazol-4-ylacetate (25.7 g.), mp 158° to 159° C.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[N:15]1([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)C>[O:14]=[C:5]1[NH:4][C:3]([NH:25][C:24]2[CH:23]=[CH:22][C:21]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:27][CH:26]=2)=[N:8][CH:7]=[C:6]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Reactant: Nc1ccc(N2CCCCC2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccc(N3CCCCC3)cc2)[nH]c1=O
Temperature: 80 °C

Procedure:
Ethyl 2-(methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxylate (200 mg, 0.934 mmol) was added to 4-(piperidin-1-yl)aniline (158 mg, 0.934 mmol) dissolved in ethanol. The solution was heated in an oil bath to 80° C., while stiffing, in reflux, for 72 hours. The sample was filtered and dried. 1H-NMR confirmed the product (HGN-0034) (15 mg, 0.447 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:12]([CH3:16])=[C:13]([CH3:15])[N:14]=2)[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.[CH2:17]([C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:20]=1[CH2:21]Cl)[CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)Cl.C(#N)C>[CH3:15][C:13]1[N:14]=[C:3]2[C:2]([NH:1][CH2:21][C:20]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:19]=3[CH2:17][CH3:18])=[CH:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]2[C:12]=1[CH3:16]
Reactant: CCc1cccc(C)c1CCl
Reactant: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)OC)cn2c(C)c(C)nc12
Yield: 37.3 %

Procedure:
Methyl 8-amino-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylate (0.7 g, 3.2 mmol), 2-ethyl-6-methylbenzylchloride (0.54 g, 3.2 mmol), potassium carbonate (0.9 g, 6.4 mmol) and a cat. amount of potassium iodide were added to acetonitrile (20 ml) and were refluxed for 6 h. Following filtration, the acetonitrile was evaporated under reduced pressure to give an oil. The oily residue was solved in methylene chloride and washed with water. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give a solid. Purification by column chromatography on silica gel using methylene chloride:ethylacetate (10:1) as eluent gave 0.42 g (38%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([F:20])[CH:10]=1.[Br:21]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:21])=[CH:4][C:3]=1[NH:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([F:20])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(Nc2ccccc2N)cc1F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Nc2cc(Br)ccc2N)cc1F
Reaction time: 2 h
Yield: 68.2 %

Procedure:
179 mg ethyl 4-(2-amino-phenylamino)-2-fluoro-benzoate (compound in Production Example 332) was dissolved in 4 mL N,N-dimethylformamide, and 116 mg N-bromosuccinimide was added thereto under ice-cooling and stirred for 2 hours. An aqueous sodium thiosulfate solution and an aqueous sodium bicarbonate solution were added thereto and stirred for 1 hour, and the reaction mixture was extracted with ethyl acetate. The extract was purified by NH silica gel chromatography (ethyl acetate/hexane), to give 157 mg of the title compound as a red oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40]I)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:38][CH2:37][C:36]2[C:31](=[CH:32][C:33]([CH2:39][CH2:40][N:12]3[C:11](=[O:15])[CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:14]=[N:13]3)=[CH:34][CH:35]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCI)cc2C1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccccc4)cc3=O)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 245 mg (1.21 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) in 1.2 mL DMF is added 791 mg (2.43 mmol) cesium carbonate and after 15 min 470 mg (1.21 mmol) 7-(2-iodoethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 8). The reaction mixture is stirred overnight at RT and the precipitate is removed by filtration. The solvent is evaporated, the residue is dissolved in DMF and purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: O[CH:2]([C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:15]([CH2:18][CH2:19][CH3:20])[C:16]=2[CH3:17])=[O:11])=[CH:5][CH:4]=1>C(O)=O.C(OCC)(=O)C.[Zn]>[CH3:39][O:38][C:34]1[CH:33]=[C:32]2[C:37]([C:28]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]4[C:13](=[O:27])[N:14]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:15]([CH2:18][CH2:19][CH3:20])[C:16]=4[CH3:17])=[O:11])=[CH:7][CH:8]=3)=[CH:29][CH:30]=[N:31]2)=[CH:36][CH:35]=1
Reactant: CCCn1c(C)c(C(=O)Nc2ccc(C(O)c3ccnc4cc(OC)ccc34)cc2)c(=O)n1-c1ccccc1
Agent: [Zn]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCCn1c(C)c(C(=O)Nc2ccc(Cc3ccnc4cc(OC)ccc34)cc2)c(=O)n1-c1ccccc1
Temperature: 60 °C
Yield: 24.8 %

Procedure:
In a 25 mL round bottom flask was dissolved N-(4-(hydroxy(7-methoxyquinolin-4-yl)methyl)phenyl)-5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxamide (104 mg, 199 μmol) in 4 mL of formic acid and the resultant was then treated with zinc dust (325 mg, 4975 μmol) and heated at 60° C. After 6 h the reaction mixture was diluted with ethyl acetate, filtered over Celite and neutralized with aqueous NaHCO3 (sat.). The aqueous phase was extracted with ethyl acetate, and then the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by MPLC (ISCO, dichloromethane: 1% NH4OH in MeOH, 100:0 to 90:10) to afford N-(4-((7-methoxyquinolin-4-yl)methyl)phenyl)-5-methyl-3-oxo-2-phenyl-1-propyl-2,3-dihydro-1H-pyrazole-4-carboxamide (25 mg, 25% yield) as an off-white solid. MS (ESI pos. ion) m/z: 507 (MH+). Calc'd exact mass for C31H30N4O3: 506. 1H NMR (400 MHz, DMSO-d6) 10.65 (s, 1H), 8.74 (d, J=4.42 Hz, 1H), 8.10 (d, J=9.22 Hz, 1H), 7.57 (t, J=7.52 Hz, 2H), 7.46-7.52 (m, 3H), 7.35-7.44 (m, 3H), 7.14-7.28 (m, 4H), 4.38 (s, 2H), 3.90 (s, 3H), 3.79 (t, J=7.14 Hz, 2H), 2.72 (s, 3H), 1.32-1.41 (m, 2H), 0.66 (t, J=7.39 Hz, 3H).