Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:15])[CH:3]=1.[Cl-].[CH3:17][O:18][C:19](=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:6]2[N:5]=[C:4]([NH:15][C:24]([C:23]2[CH:27]=[CH:28][C:20]([C:19]([O:18][CH3:17])=[O:29])=[CH:21][CH:22]=2)=[O:25])[CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1cc(Cl)n2nc(C(F)(F)F)cc2n1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc(Cl)n3nc(C(F)(F)F)cc3n2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 10 %

Procedure:
7-chloro-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-5-amine (0.5 g, 1.0 equivalent) was suspended in pyridine (0.2 M) in a round bottom flask. At 0° C. was added a solution of terephthalic acid monomethylester chloride (2.0 equivalents) pre-dissolved in pyridine (0.8M), and followed by addition of N,N-dimethylpyridin-4-amine (0.1 equivalent). The mixture was stirred vigorously at 0° C. for 48 h. The reaction was quenched with saturated NaHCO3; pyridine was removed in vacuo and the residue was extracted with EtOAc twice and the combined organic layers were dried over Na2SO4. The organic layers were concentrated in vacuo and the crude mixture was purified using chromatography (SiO2, gradient of 10 to 50% EtOAc/hexanes) to afford the titled compound (10%) as a solid. Melting point (191.0-195.0° C.). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 7.20 (s, 1 H) 8.06-8.11 (m, 2 H) 8.12-8.18 (m, 2 H) 8.32 (s, 1 H) 11.88 (s, 1 H); ESI-MS: m/z 399.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[O:15])[C:9](=[O:27])[CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:32](O)[CH3:33]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([O:24][CH2:32][CH3:33])=[O:23])=[CH:18][CH:17]=3)=[O:15])[C:9](=[O:27])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: O=C(O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2=O)cc1

Procedure:
A crude sample of the product of Example 62 (3.4 g) was treated with a solution, at 0° C., made by adding thionyl chloride (2.25 g) dropwise to ethanol (45 ml) with stirring at below 0° C. The mixture was stirred at room temperature for 2 hours, heated at gentle reflux for 21/2 hours, and evaporated. The residue was treated with water and adjusted to pH6 with aqueous sodium bicarbonate solution. The gum which precipitated was separated and the aqueous solution was adjusted to pH8 and extracted with dichloromethane (2×50 ml). The combined extracts were washed with brine, dried and evaporated. The residue was purified by chromatography using a 10 g. Mega Bond Elut silica gel column, eluting with 5% methanol/dichloromethane/0.5% triethylamine to give the title product as a solid (0.2 g); m.p. 163°-165° C.; NMR(CDCl3) δ 8.34(2H,m), 7.97(2H,m), 6.98(2H,m), 6.63(2H,m), 4.89(2H,s), 4.7(2H,s), 4.29(2H,q), 4.1(2H,s), 3.7(2H,m), 3.6(2H,m), 1.31(3H,t); m/e 398(M+H)+ ; calculated for C21H23N3 O5 : C, 63.5; M, 5.83; N, 10.6. Found: C, 61.5; H, 5.9; N, 10.5%.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:13])=[C:9]([CH:12]=1)[CH2:10][OH:11])(=[O:3])[CH3:2].O=[CH:15][C:16]([Cl:19])([Cl:18])[Cl:17]>C(OCC)C>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[NH:13][CH:15]([C:16]([Cl:19])([Cl:18])[Cl:17])[O:11][CH2:10][C:9]=2[CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(N)c(CO)c1
Solvent: CCOCC
Product: CC(=O)Oc1ccc2c(c1)COC(C(Cl)(Cl)Cl)N2
Reaction time: 0.08 h

Procedure:
5-Acetoxy-2-aminobenzyl alcohol (8.8 g.) was dissolved in dry diethyl ether (150 ml.), anhydrous chloral (9.6 ml.) was added with stirring over 5 minutes, and the mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue crystallised on stirring with a mixture of methanol (50 ml.) and water (25 ml.) to give 6-acetoxy-1,2-dihydro-2-trichloromethyl-4H-benzo[d]-[1,3]-oxazine, m.p. 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>O1CCCC1>[OH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:23][CH:22]=1)(=[O:26])=[O:25]
Reactant: Nc1ccccc1O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
A flask with a stirrer was charged with 8.18 g of 2-aminophenol, 7.58 g of triethylamine and 100 ml of tetrahydrofuran, and a solution of 15.50 g of 4-methoxybenzenesulfonyl chloride in 30 ml of tetrahydrofuran was dropwise added with cooling with ice over 10 minutes. After completion of the addition, the reaction mixture was stirred at room temperature for 2 hours and then poured into 500 ml of ice water. A precipitated crystal was recovered by filtration and washed with water. The obtained crystal was recrystallized from ethanol/n-hexane mixed solvents, to give 9.8 g of an end product. Melting point 89° C.
Reaction SMILES: [C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]2C(CC(O)C)=CC=C3C([NH:14][C:15](=O)[C:10]=23)=O)[CH2:5][CH2:4]1)#[N:2].NN.C[OH:33]>>[C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([CH2:9][CH:10]([OH:33])[CH2:15][NH2:14])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO
Reactant: CC(O)Cc1ccc2c(c1N1CCC(C#N)(c3ccccc3)CC1)C(=O)NC2=O
Agent: NN
Product: N#CC1(c2ccccc2)CCN(CC(O)CN)CC1
Yield: 94 %

Procedure:
A mixture of 3-(4-cyano-4-phenylpiperidin-1-yl)-(2-hydroxypropyl)phthalimide (10 g, 23.48 mmol) and hydrazine (6.01 g, 188 mmol, 8 eq.) in methanol (100 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (5.53 g, 94%).
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=O.C([CH2:22][C:23]([NH:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([OH:30])=[O:29])=[O:24])(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:22]/[C:23]([NH:25][C:26]2[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([OH:30])=[O:29])=[O:24])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 74.6 %

Procedure:
Piperidine (0.96 mL, 9.7 mmol) was added to a suspension of 3,4-dimethoxybenzaldehyde (1.6 g, 9.7 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.9 g, 8.6 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (tranilast) (2.1 g, 74%) was obtained as a yellow crystalline solid; mp 208-209° C., lit. [22] 206° C.; δH (500 MHz, DMSO-d6) 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 6.79 (d, J=15.5 Hz, 1H, CH═CHCO), 6.99 (d, J5′,6′=8.5 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=7.9 Hz, 1H, H4), 7.25 (d, J5′,6′=8.5 Hz, 1H, H6′), 7.38 (s, 1H, H2′), 7.56 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=7.9 Hz, 1H, H5), 8.00 (d, J3,4=7.9 Hz, 1H, H3), 8.62 (d, J5,6=7.9 Hz, 1H, H6), 11.30 (s, 1H, NH), 13.61 (br s, 1H, CO2H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1.B(F)(F)F.CCOCC.C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:17](=[O:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1
Reactant: Oc1cccc(O)c1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1O
Temperature: 108 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
Resorcinol (1,3-dihydroxybenzene) (62.000 g, 563.1 mmol, 1.0 equiv.) and 4-Hydroxyphenylacetic acid (94.237 g, 619.4 mmol, 1.1 equiv.) were added to a 3 neck 2 L round bottomed flask fitted with a paddle, a pressure equalizing addition funnel and a thermometer and a heating mantle. Toluene (350 mL) was added to the flask to give a suspension. The reaction purged with nitrogen and the addition funnel filled with Boron trifluoride etherate (198.201 ml, 1578.0 mmol, 2.8 equiv.) via canula. The reaction was stirred at 150 rpm and boron trifluoride etherate was added in portions of 3-4 mL and the reaction heated. During addition the internal temperature rose to 100° C. The reaction went through various changes in color from yellow to dark red. After complete addition of boron trifluoride etherate the addition funnel was removed and replaced with a condenser. The reaction was stirred for 1.5 h at an internal temperature of 108° C. A sample was taken and HPLC analysis indicated the reaction was complete. The reaction was cooled and stirring stopped to give a biphasic solution. A 12% aqueous solution of sodium acetate (41 g, 336 mL) was slowly added to the reaction with stirring. The reaction was stirred for 16 hours. A precipitate formed overnight and was collected in a sintered glass funnel. The solid was dried on a vacuum oven for 16 h to give the product as a white powder (119.67 g, 87.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][CH:21]([F:25])[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:20][CH:21]([F:25])[C:22]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:23]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)C(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C(F)F)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol), 2,2-difluoroacetic acid (171 mg, 1.78 mmol), 4-(Dimethylamino)pyridine (18 mg, 0.15 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (676 mg, 1.78 mmol) were dissolved in pyridine (20 mL). After the reaction mixture was stirred at room temperature overnight, water (1 mL) was added and it was extracted with ethyl acetate. It was concentrated and purified by prep-HPLC to give the desired product (59.6 mg). LCMS (ESI): RT (min)=1.161, M+H+=330.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 11.48 (s, 1H), 9.22 (s, 1H), 8.50 (s, 1H), 8.08 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 1H), 7.16 (d, J=8.8 Hz, 2H), 6.44 (t, J=54.0 Hz, 1H), 2.22 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:27])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH3:26])=[CH2:25])[C:5]2=[CH:4][CH:3]=1.O.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:22][C:18]1[CH:17]=[C:16]([CH:15]2[CH2:14][C:13](=[O:23])[NH:12][CH:11]([C:24]([CH3:26])=[CH2:25])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([CH:29]4[CH2:31][CH2:30]4)=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:27])[CH:21]=[CH:20][CH:19]=1
Reactant: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(C3CC3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
Under nitrogen atmosphere, to a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-isopropenyl-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxyl acid tert-butyl ester (0.050 g) prepared in Example 172b in toluene (5 mL) was added water (0.1 mL), cyclopropyl boronic acid (0.020 g, 0.23 mmol), K3PO4 (0.098 g, 0.46 mmol), and Pd(PPh3)4 (0.018 g, 0.016 mmol). The mixture was irradiated at 130° C. by microwave for 0.5 h. Then cooled to room temperature and filtered through a short pad of silica gel, the silica gel was washed with ethyl acetate. The filtrate was concentrated. To the residue was added trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 0.5 h, then partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with NaHCO3 aqueous solution, dried over MgSO4 and concentrated. The residue was purified with Prep.LC to give title compound as a white solid (Yield: 8 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][NH2:16])=[CH:13][C:12]([C:17]([F:20])([F:19])[F:18])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9].[F:21][C:22]1[CH:23]=[C:24]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>C(#N)C>[F:2][C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][NH:16][C:34]([NH:33][C:24]3[CH:25]=[CH:26][C:27]([N:28]4[CH2:29][CH:30]([OH:32])[CH2:31]4)=[C:22]([F:21])[CH:23]=3)=[O:35])=[CH:13][C:12]([C:17]([F:20])([F:18])[F:19])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: NCc1cc(C(F)(F)F)nn1-c1ccc(F)c(F)c1
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1ccc(F)c(F)c1)Nc1ccc(N2CC(O)C2)c(F)c1
Yield: 87.9 %

Procedure:
To a stirred solution of ((1-(3,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (75 mg, 0.239 mmol, 1.0 eq) in acetonitrile (5.5 mL) was added TEA (0.13 mL, 0.96 mmol, 4.0 eq.) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (73 mg, 0.244 mmol, 1.02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (4:1) as eluent) to get 1-((1-(3,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)urea (102 mg, 88%).
Reaction SMILES: Br.Br.Br.[NH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[N:9]=1.[Br:26][C:27]1[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1>>[CH3:25][N:22]1[CH2:23][CH2:24][CH:19]([N:16]2[CH2:15][CH2:14][N:13]([C:11](=[O:12])[CH2:10][C:8]3[N:9]=[C:5]([NH:4][C:32]([C:30]4[S:31][C:27]([Br:26])=[CH:28][CH:29]=4)=[O:33])[S:6][CH:7]=3)[CH2:18][CH2:17]2)[CH2:20][CH2:21]1
Reactant: O=C(O)c1ccc(Br)s1
Reactant: CN1CCC(N2CCN(C(=O)Cc3csc(N)n3)CC2)CC1
Agent: Br
Product: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Br)s4)n3)CC2)CC1

Procedure:
47.3 Using general procedure D, 2-(2-amino-thiazol-4-yl)-1-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-ethanone trihydrobromide was coupled with 5-bromothiophene-2-carboxylic acid to give 5-bromo-thiophene-2-carboxylic acid (4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-amide. Yellow solid. MS 514.3 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][NH:12][C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])[C:4]=2[O:3]1.[C:19](Cl)([Cl:21])=[O:20]>C1C=CC=CC=1>[Cl:21][C:19]([N:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)[NH:12][C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[O:20]
Reactant: CON(C)C(=O)NNc1cccc2c1OC(C)C2
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CON(C)C(=O)NN(C(=O)Cl)c1cccc2c1OC(C)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g of 1E was added to a stirred solution of 75 ml of 12.5% phosgene in benzene. The resulting mixture was stirred for 2 hours at room temperature, then the solvent was evaporated to give 1-(chlorocarbonyl)-1-(2,3-dihydro-2-methylbenzofuran-7-yl)-4-methoxy-4-methylsemicarbazide (1F), as an amber syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2C3C(=CC=CC=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](O)C[N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@H:18]2[C@@H:19]([O:27][CH2:28][CH3:29])[CH2:20][N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl (cis)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.40-7.25, 5.20-5.13, 4.73, 4.10, 3.98, 3.77-3.59, 3.53-3.30, 2.70, 2.46, 1.27, 1.15; HRMS (FAB) calcd for C28H32Cl2N4O3+H 543.1929, found 543.1913. Anal. Calcd for C28H32Cl2N4O3: C, 61.88; H, 5.93; N, 10.31. Found: C, 62.07; H, 6.14; N, 10.16.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:15])([C:10]([O:12]CC)=[O:11])[CH2:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)#[N:2].Cl>C(O)(=O)C>[C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:15])([C:10]([OH:12])=[O:11])[CH2:5][C:4]=1[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=1)#[N:2]
Reactant: CCOC(=O)C1(C)CC(c2ccc(C)cc2)=C(C#N)C(=O)N1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(C2=C(C#N)C(=O)NC(C)(C(=O)O)C2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Intermediate 108B (1.211 g, 4.06 mmol) was dissolved in acetic acid (95 mL) in a 250 mL 1 neck pear shaped flask that was equipped with a magnetic stirrer. HCl (11.67 mL, 142 mmol) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was concentrated in vacuo to give the desired product as a pale yellow solid. LCMS Anal. Calc'd for C15H14N2O3 270.1, found [M+H] 271.0. 1H NMR (500 MHz, CDCl3) δ 7.48 (d, J=8.3 Hz, 2H), 7.23 (d, J=7.7 Hz, 2H), 3.39 (d, J=18.2 Hz, 1H), 2.83 (d, J=18.2 Hz, 1H), 2.35 (s, 3H), 1.54 (s, 3H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20](=[O:22])[CH3:21])/[C:15]([OH:17])=[O:16])[N:13]=1.C(OC(C)C)(C)C>C(O)=O>[CH:1]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20](=[O:22])[CH3:21])/[C:15]([OH:17])=[O:16])[N:13]=1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O/N=C(\C(=O)O)c1csc(N)n1
Solvent: O=CO
Solvent: CC(C)OC(C)C
Product: CC(=O)O/N=C(\C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (20.6 ml) was added formic acid (16.6 ml) at 15° C. The mixture was stirred at room temperature for 30 minutes. To the mixture was 2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetic acid (10 g) under ice-cooling, and the reaction mixture was stirred at room temperature for 20 hours. To the mixture was added isopropyl ether (37.2 ml) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The resulting precipitate was collected by filtration to give 2-(2-formylaminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetic acid (9.39 g).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH2:14][NH:13][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCCN1CCCC1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Yield: 72.4 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (5 g, 29.9 mmol) reacted with 1-(2-aminoethyl)pyrrolidine (4.1 g, 35.9 mmol) to give 5.7 g (73%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH2:26][CH3:27])[C:22]=4[NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH2:26][CH3:27])[C:22]=4[NH:28][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(-c2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-ethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: C([N:8]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:15]2[C:10](=[C:11]([Cl:30])[C:12]([O:28][CH3:29])=[CH:13][CH:14]=2)[CH2:9]1)C1C=CC=CC=1.Cl>C(O)C>[Cl:30][C:11]1[C:12]([O:28][CH3:29])=[CH:13][CH:14]=[C:15]2[C:10]=1[CH2:9][NH:8][CH2:17][CH:16]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: COc1ccc(C2CN(Cc3ccccc3)Cc3c2ccc(OC)c3Cl)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1ccc(C2CNCc3c2ccc(OC)c3Cl)cc1OC
Yield: 65.2 %

Procedure:
1.13 g of 2-benzyl-8-chloro-7-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 28 ml of ethanol, and after adding thereto 0.22 ml of 12N hydrochloric acid, hydrogenation reaction was performed by addition of 0.1 g of 10%-paradium-carbon. After the hydrogenation reaction was over, the reaction solution was filtered, and concentrated. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-n-hexane, giving 580 mg of 8-chloro-7-methoxy-4-(3,4,-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, m.p. 130°-132° C. ##STR59##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C([Cl:14])=O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([Cl:14])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Br)cn1
Temperature: 40 °C

Procedure:
The acid from step 1 (0.702 g, 3.475 mmol) was suspended in DCM (40 mL) under argon, DMF (1 drop) was added and the mixture was cooled in an ice-bath. Oxalyl chloride was added portion-wise over 5 minutes and the mixture was then heated to 40° C. for 90 minutes. On cooling, the solvent was removed to produce 5-bromo-2-pyridinecarbonyl chloride (0.801 g) as a brown solid which was used in step 3.