Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:4])[O:18][CH:15]1[CH2:16][CH2:17][N:12]([CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:13][CH2:14]1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)OC1CCN(Cc2ccccc2)CC1

Procedure:
Methyl isocyanate (8.94 g, 157 mmol) was added to a solution of 1-benzyl-4-piperidinol (10 g, 52.3 mmol) in chloroform (80 ml), and the reaction stirred under reflux for 16 hours. The cooled mixture was concentrated under reduced pressure, the residual solid was triturated from 40–60 petroleum ether, and the product filtered and dried to afford the title compound as a white solid, 1 g. m.p.—106–108° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[CH:3]\[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[F:12][C:13]([F:23])([F:22])[C:14]1[C:15](=[O:21])[CH:16]=[CH:17][C:18](=O)[CH:19]=1.C(Cl)Cl>CCO>[OH:21][C:15]1[C:14]([C:13]([F:12])([F:22])[F:23])=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:1][C:2]([CH3:11])=[C:3]2[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: O=C1C=CC(=O)C(C(F)(F)F)=C1
Reactant: C/C(N)=C/C(=O)OC(C)(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1[nH]c2ccc(O)c(C(F)(F)F)c2c1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 66 %

Procedure:
A stirred solution of 1,1-dimethylethyl (2Z)-3-amino-2-butenoate (47.6 g, 0.3 mol) in EtOH (100 mL) was treated dropwise at ambient temperature with a 1.2 M solution of 2-(trifluoromethyl)-2,5-cyclohexadiene-1,4-dione in CH2Cl2 (300 mL, 0.35 mol) (internal temperature rose to +35° C. during the addition). The reaction was stirred 1 h and concentrated at reduced pressure. Stirring the resulting material with CHCl3 at ice-bath temperature afforded 1,1-dimethylethyl 5-hydroxy-2-methyl-4-(trifluoromethyl)-1H-indole-3-carboxylate as an off-white solid which was collected by filtration (62 g, 66% yield): 1H NMR (DMSO-d6) δ 11.55 (s, 1H), 9.68 (bs, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 2.37 (s, 3H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:33]([O:35][CH3:36])=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (288 mg, 1.1 mmol) was dissolved in dichloromethane (3 mL) at -78° C. and treated with 4-methylmorpholine (0.25 mL, 2.27 mmol, 2.eq.) and 2,4-dimethoxy-benzoyl chloride (220 mg, 1.1 mmol, 1 eq.) dissolved in 3 mL of dichloromethane. The solution was allowed to warm to 0° C. and stirred for 1 hour. The solution was washed with 1N HCl, and 5% sodium bicarbonate. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 324 mg (69%) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:14])[NH:4][CH:3]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(O)CO.O>[OH:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[CH:3][N:4]=1
Reactant: COc1ccc2c(=O)[nH]cc(Br)c2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: OCCO
Product: COc1ccc2c(O)ncc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 145 °C
Yield: 42.4 %

Procedure:
To a solution of 4-bromo-6-methoxyisoquinolin-1(2H)-one (0.5 g, 1.968 mmol) and tert-butyl piperazine-1-carboxylate (0.916 g, 4.92 mmol) in ethylene glycol (5 ml) was added DIPEA (1.0.31 ml, 5.90 mmol) and heated to 145° C. for overnight in sealed tube. The reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound (0.3 g, 29.4%). The crude compound was taken for the next step without further purification. MS: MS m/z 260.20 (M++1).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[N:15]([O-])=O.[Na+]>Cl.O>[ClH:1].[ClH:1].[N:3]1([C:8]2[CH:14]=[CH:13][C:11]([NH:12][NH2:15])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(-n2ccnc2)cc1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 119.2 %

Procedure:
To a cooled (-15° C.) and stirred suspension of 4-(imidazol-1-yl)aniline, dihydrochloride (20 g, 86.2 mmol) in concentrated hydrochloric acid (100 ml) was added dropwise, over 1 hour, a solution of sodium nitrite (6.25 g, 90.6 mmol) in water (40 ml). After a further 10 minutes of stirring at -12° C., the mixture was quickly filtered to remove a solid, and the filtrate was added portionwise to a cooled (-20° C.) and stirred solution of tin (II) chloride dihydrate (100 g) in concentrated hydrochloric acid (50 ml) at such a rate as to maintain the internal temperature below -10° C. (15 minutes). The mixture was allowed to warm to 5° C. over 30 minutes, and the solid was collected and washed with diethyl ether (4×100 ml). The above solid was suspended in water (200 ml) and basified with 4N sodium hydroxide solution and extracted with ethyl acetate (5×500 ml). The combined organic solutions were dried (Na2SO4) and filtered. The filtrate was vigorously stirred while hydrogen chloride was being bubbled through the solution until a deep red mixture was obtained. Stirring was continued for a further 20 minutes to give a cream solid which was collected by filtration and dried over phosphorus pentoxide-potassium hydroxide under high vacuum to leave 12.7 g (60%) of the title compound; δH (360 MHz, DMSO-d6) 7.20 (2H, d, J=9.0 Hz), 7.73 (2H, d, J=9.0 Hz), 7.91 (1H, t, J=1.5 Hz), 8.23 (1H, t, J=1.7 Hz), 9.71 (1H, t, J=1.3 Hz).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[Cl:28][C:29]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:29]=1[Cl:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1cc(F)ccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(CNc1cc(F)ccc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
10.0 g of sodium triacetoxyborohydride (47.2 mmol) was added to a solution of 6.0 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (32.0 mmol), 4.6 g of 2-chloro-5-fluoroaniline (32.0 mmol) and 1.8 ml of acetic acid (32.0 mmol) in methylene chloride (320 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 5.36 g of the title compound (yield: 53%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21](Br)=[CH:20][C:19]=1[C:33]1[O:37][N:36]=[C:35]([CH3:38])[C:34]=1[C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[CH:48]=[CH2:49]>C(O)CCC.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:52]([O:51][C:47](=[O:50])[CH:48]=[CH:49][C:21]1[CH:20]=[C:19]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[C:34]=2[C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:18]([O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:23][C:22]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:55])([CH3:54])[CH3:53]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(C)noc2-c2cc(C=CC(=O)OC(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Temperature: 140 °C
Yield: 52.2 %

Procedure:
Diisopropylethyl amine (1 ml, 5.7 mmol) was added to a suspension of 5-(2,4-Bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (0.56 g, 1.0 mmol) in tert-butyl acrylate (1 ml, 6.8 mmol) and 1-butanol (8 ml) under a nitrogen atmosphere. Dichlorobis(tri-o-tolylphosphine)palladium (II) (cat.) was added and the suspension heated, 140° C. for ˜18 hrs., to give a yellow/green solution. The solution was allowed to cool and concentrated to a yellow/green gum. The crude product was purified by column chromatography, silica, eluting with ethyl acetate/hexane (1:9), to give 3-{2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-phenyl}-acrylic acid tert-butyl ester as a yellow/green gum (315 mg). Starting material (170 mg) was recovered.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[N:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([N:26]1[CH2:25][CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=3)=[N:22][CH:21]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(Br)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(Br)c(C(F)(F)F)c3)nc2)CC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a mixture of 2-(4-bromo-3-(trifluoromethyl)phenyl)acetic acid 46-6 (564 mg, 2.0 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (440 mg, 2.0 mmol) and HATU (798 mg, 2.1 mmol) in DMF (6 mL) was added DIEA (1.04 mL, 6.0 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4 and the solvent was evaporated. The residue was subject to silica gel flash chromatography to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-bromo-3-(trifluoromethyl)phenyl)acetamide 192-1 (920 mg, 95%). MS m/z 485.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][NH2:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH:3]=[CH:4]3)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: COc1cccc(OC)c1C=O
Reactant: Cn1ccc2cc(CN)ccc21
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(ccn2C)c1

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (1-methyl-1H-indol-5-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.76 min.; [M+H]+: 379.12 g/mol.
Reaction SMILES: [CH3:1][C:2]1[C:7](=O)[NH:6][C:5]([NH2:9])=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:12]>>[Cl:12][C:7]1[C:2]([CH3:1])=[CH:3][N:4]=[C:5]([NH2:9])[N:6]=1
Reactant: Cc1cnc(N)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cnc(N)nc1Cl
Yield: 29 %

Procedure:
A mixture of 5-methylisocytosine (3 g, 24.0 mmol) and POCl3 (20 mL) was refluxed for 45 minutes. Excess of POCl3 was removed under reduced pressure and the residue was poured over ice. The resulting mixture was made basic with ammonia at 10° C. The precipitate was filtrated and crystallized from ethanol to give 4-chloro-2-amino-5-methylpyrimidine (1 g 29.0% yield). 1H NMR (400 MHz, DMSO): δ 8.11 (s, 1H), 6.81 (br s, 2H), 2.04 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8](=[N:21][NH2:22])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.O>ClCCl>[C:8](=[N:21][NH:22][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(CCCCl)NN=C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
4-Chlorobutyryl chloride (57 mL, 510 mmol) is added to a solution of benzophenone hydrazone (100 g, 510 mmol) and pyridine (41 mL, 510 mmol) in anhydrous dichloromethane (520 mL) under nitrogen at a rate that maintains a gentle reflux throughout the addition. The mixture is stirred for 0.5 h and poured into water (1 L). The layers are separated and the organic layer washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo to yield 4-chloro-butyric acid benzhydrylidene-hydrazide as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8](=[O:17])(=[O:16])[CH2:7][C:6]=2[CH:18]=1.[H-].[Na+].[N:21]1([CH2:27][CH2:28][CH2:29]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[S:8](=[O:16])(=[O:17])[CH:7]([CH2:29][CH2:28][CH2:27][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[CH:18]=1
Reactant: ClCCCN1CCCCC1
Reactant: O=S1(=O)Cc2cc(Cl)ccc2Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=S1(=O)c2ccccc2Oc2ccc(Cl)cc2C1CCCN1CCCCC1
Temperature: 70 °C
Reaction time: 4.5 h

Procedure:
A solution of 4.18 g 2-chloro-11H-dibenz (b,f)-1,4-oxathiepin 10,10-dioxide in 40 ml of dimethylformamide was treated with 0.65 g of sodium hydride and the mixture stirred for 4.5 hours at 70° C. Thereafter, 10 ml of 3-piperidinopropyl chloride were added and the mixture stirred for 3.5 hours at 70° C. It was then decomposed by dropwise addition of 4 ml of ethanol and diluted with 700 ml of water and extracted with benzene. From the benzene solution the base was extracted with 100 ml of 3M-HCl. The separated acid aqueous solution was made alkaline with aqueous ammonia and the base extracted with chloroform. The extract was dried with potassium carbonate and evaporated. The residue was chromatographed on a column of 400 g of neutral aluminum oxide (activity II). The less polar impurities were eluted with benzene and 4.37 g of homogeneous oily base were eluted with benzene and 4.37 g of homogeneous oily base were eluted with chloroform. Neutralization with hydrogen chloride in a mixture of ethanol and ether yielded the hydrochloride. By crystallization from a mixture of ethanol and ether the pure product was obtained, m.p. 177°-179° C.
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.[C:13](Cl)(=[O:15])[CH3:14].C(N(CC)CC)C>ClC(Cl)C>[C:13]([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)(=[O:15])[CH3:14]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cc1csc(NC(C)=O)n1

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)acetate was reacted with acetyl chloride in dichloroethane in the presence of triethylamine, and then the reaction mixture was worked up and purified in a usual manner to obtain ethyl 2-(2-acetylaminothiazol-4-yl)acetate as a colorless solid. MS: 229.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH2:12].[Cl:14][C:15]1[S:19][C:18]([CH2:20][C:21](Cl)=[O:22])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([I:10])[C:7]([Cl:11])=[CH:6][C:5]=1[NH:12][C:21](=[O:22])[CH2:20][C:18]1[S:19][C:15]([Cl:14])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cc1ccc(Cl)s1
Reactant: COC(=O)c1cc(I)c(Cl)cc1N
Product: COC(=O)c1cc(I)c(Cl)cc1NC(=O)Cc1ccc(Cl)s1
Yield: 74.1 %

Procedure:
Prepared essentially as described in EXAMPLE 1, Step A from 5.0 g 2-amino-4-chloro-5-iodobenzoic acid methyl ester and 2.8 g (5-chlorothiophen-2-yl)acetyl chloride (also prepared essentially as described in EXAMPLE 1) to give the title compound (5.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4].[Cu](C#N)[C:27]#[N:28].ClCCl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:27]#[N:28])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH3:24])[CH:9]=2)=[O:4]
Reactant: N#C[Cu]C#N
Reactant: CCc1ccccc1Oc1ccc2c(O)c(C(=O)OC)nc(I)c2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc2c(O)c(C(=O)OC)nc(C#N)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.5 %

Procedure:
A mixture of 7-(2-Ethyl-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (1.5 g, 3.34 mmole) and copper cyanide (598 ml, 6.68 mmole) in anhydrous dimethylformamide (13 ml) was refluxed for 5 minutes before it was cooled to room temperature and dichloromethane was added and stirred for 5 minutes. The suspension was filtered. The filtrate was washed with 0.1 N HCl, twice with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was recrystallized with acetonitrile. The crystal was filtered and dried to give the title compound as a white solid (902 mg): MS: (+) m/z 349.08 (M+1), (−) m/z 347.10 (M−1).
Reaction SMILES: C(O[C:4]1[CH2:9][CH:8]([CH3:10])[CH2:7][CH2:6][N:5]=1)C.[CH3:11][C:12]1([CH3:20])[CH2:19][C:17](=[O:18])[CH2:16][C:14](=[O:15])[CH2:13]1>C(OCC)C>[CH3:11][C:12]1([CH3:20])[CH2:13][C:14](=[O:15])[C:16](=[C:4]2[CH2:9][CH:8]([CH3:10])[CH2:7][CH2:6][NH:5]2)[C:17](=[O:18])[CH2:19]1
Reactant: CCOC1=NCCC(C)C1
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCOCC
Product: CC1CCNC(=C2C(=O)CC(C)(C)CC2=O)C1
Yield: 17 %

Procedure:
A mixture of 2-ethoxy-4-methyl-3,4,5,6-tetrahydropyridine (9.27 grams, 0.066 mole) and dimedone (9.20 grams, 0.066 mole) is heated at 112°-113° C. for a 3-hour period. The cooled residue is dissolved in ethyl ether and extracted with three portions of 3N HCl. A solution of 6N sodium hydroxide is added to the strongly acidic solution causing the product to separate as a white solid, with precipitation complete at a final pH of 1. The crude product weighs 4.32 grams on drying and melts at 172°-175° C. Recrystallization from a large volume of cyclohexane gives 2.64 grams of pure material, m.p. 174° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:18]([NH2:20])=[CH:17][C:16]([CH3:21])=[N:15][C:14]=3[S:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([CH3:21])=[CH:17][C:18]=3[NH:20][S:28]([C:26]3[N:25]=[CH:24][N:23]([CH3:22])[CH:27]=3)(=[O:30])=[O:29])[S:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(-c2csc3nc(C)cc(N)c23)cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2csc3nc(C)cc(NS(=O)(=O)c4cn(C)cn4)c23)cc1OC

Procedure:
Following general method outlined in Example 1, starting from 3-[3,4-bis(methyloxy)phenyl]-6-methylthieno[2,3-b]pyridin-4-amine (62 mg, 0.150 mmol) (Description 24) and 1-methyl-1H-imidazole-4-sulfonyl chloride (54.0 mg, 0.299 mmol), the title compound (26 mg) was isolated as a TFA salt. LCMS (B) m/z: 445 [M+1]+, Rt 2.41 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1cccc(C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1cccc(C(F)(F)F)c1
Yield: 97.5 %

Procedure:
To a stirred solution of 2.99 g (8.90 mmole) of 2-chloro-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 27 mL of acetone and 27 mL of water was added 2.97 g (45.15 mmole) of sodium azide. The mixture was heated at 70 degrees for 11 hours. The mixture was partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 60 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.97 g of 2-azido-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH:11]=[O:12])[C:8]([CH3:13])=[CH:7][C:6]=1[S:14][C:15](=[O:19])[N:16]([CH3:18])[CH3:17])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Li+].C1(C)C=CC=CC=1.Cl>C1COCC1.O>[C:1]([C:5]1[CH:10]=[C:9]([CH2:11][OH:12])[C:8]([CH3:13])=[CH:7][C:6]=1[S:14][C:15](=[O:19])[N:16]([CH3:17])[CH3:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(SC(=O)N(C)C)c(C(C)(C)C)cc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(SC(=O)N(C)C)c(C(C)(C)C)cc1CO
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
Dimethylthiocarbamic acid S-(2-tert-butyl-4-formyl-5-methylphenyl) ester (4a) (6.0 gm, 21 mmol) was dissolved in THF and treated with lithium borohydride (0.8 gm) in portions. The mixture was cooled in an ice bath and stirring continued for 1.5 hours. Toluene (25 mL) and water (10 mL) were added followed by cautious addition of 37% hydrochloric acid (2.8 gm) to destroy excess borohydride and adjust the pH to 6.5. The aqueous layer was separated and the organic layer extracted with 1 N NaOH (2×10 mL) and water (10 mL) and concentrated to a solid. This was recrystallized from toluene and heptane and the crystals vacuum dried at 40° C. to give dimethylthiocarbamic acid S-(2-tert-butyl-4-hydroxymethyl-5-methylphenyl) ester (5a) (5.6 gm): mp: 135.9-136.4° C.; HPLC: 99.1%.