Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[O:8][CH2:7]2.[BH4-].[Li+].Cl.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:7][OH:8])[C:10]=1[CH2:9][OH:11]
Reactant: Cc1cccc2c1C(=O)OC2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(CO)c1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A solution of the 7-methyl-1(3H)-isobenzofuranone obtained above in tetrahydrofuran (80 ml) was cooled to 0° C., and lithium borohydride (1.90 g, 87.2 mmol) was added thereto. The mixture was stirred at 60° C. for 2 hours, then cooled to 0° C., and a 2N aqueous solution of hydrochloric acid (50 ml) was added dropwise. The product was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure to give an oily residue. The residue was subjected to chromatography on a silica gel (75 g) column (eluent; ethyl acetate:hexane=2:1˜1:0) to afford the title compound (4.17 g, 19% total yield from methyl 2,6-dimethylbenzoate) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[C:7]([O:13][CH3:14])=[N:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]2=[N:4][N:3]=1.C[O-].[Na+]>CO.O>[NH2:1][C:2]1[N:6]=[C:5]2[N:4]([C:7]([O:13][CH3:14])=[N:8][CH:9]=[C:10]2[O:11][CH3:12])[N:3]=1
Reactant: COc1cnc(OC)n2c(N)nnc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cnc(OC)n2nc(N)nc12
Yield: 92.9 %

Procedure:
3-Amino-5,8-dimethoxy[1,2,4]triazolo[4,3-c]-pyrimidine (9.762 g, 0.050 mole) was loaded into a 500 mL three necked flask equipped with an overhead stirrer, condenser, addition funnel, and thermocouple temperature probe. Methanol (70 mL) was added and the mixture was stirred to form a slurry. Sodium methoxide (16.716 g of a 25% solution in methanol) was added dropwise over 28 min, after which the mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with water (135 mL) and stirred for an additional 1.5 h. The product solids were recovered by filtration through Whatman #54 paper using a Buchner funnel and aspirator vacuum. After washing with water, the solids were dried in vacuo at room temperature to give 9.064 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (yield=92.8%): 1H NMR (300 MHz, DMSO-d6) 3.88 (s, 3H), 4.04 (s, 3H), 6.38 (br s, 2H), 7.48 (s, 1H); MS(GC, 70eV) 195 (M+, 85%), 194 (100%)
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC=CC=3C(O)=O)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1[C:32]2[CH:33]=[CH:34][C:35]([C:43]#[C:44][C:45]3[CH:55]=[CH:54][C:48]([C:49]([O:51]CC)=[O:50])=[CH:47][CH:46]=3)=[CH:36][C:37]=2[C:38]([CH3:42])([CH3:41])[CH2:39][CH:40]=1>>[CH3:30][C:31]1[C:32]2[CH:33]=[CH:34][C:35]([C:43]#[C:44][C:45]3[CH:55]=[CH:54][C:48]([C:49]([OH:51])=[O:50])=[CH:47][CH:46]=3)=[CH:36][C:37]=2[C:38]([CH3:41])([CH3:42])[CH2:39][CH:40]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3C)cc1
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccccc3C(=O)O)cc21
Product: CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 37 mg (0.11 mmol) of ethyl 4-[(7,8-dihydro-5,8,8-trimethylnaphth-2-yl)ethynyl]benzoate (Compound 95) was converted to the title compound (white solid) using 23 mg (1.1 ml, 0.54 mmol) of LiOH (0.5 M aqueous solution).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:20]([CH3:22])=O)[C:18]=2[OH:19])[CH:10]=[CH:11][C:12]=1[Cl:13].[NH:23]([C:25]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]1)=[S:26])[NH2:24].Cl>O>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2[S:15][CH:16]=[C:17]([C:20](=[N:24][NH:23][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:28]3)=[S:26])[CH3:22])[C:18]=2[OH:19])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)C1CCN(C(=S)NN)CC1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=S)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a dimethylformamide solution (600 μL) of 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (30 mg, 0.10 mmol) and methyl 1-hydrazinothiocarbonyl-piperidine-4-carboxylate (46 mg, 0.20 mmol) prepared in Reference Synthetic Example 2, concentrated hydrochloric acid (9 μL, 0.1 mmol) was added at room temperature, and the resulting solution was stirred at room temperature for 8 hours, then mixed with water and extracted with ethyl acetate. The extract was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) and recrystallized from chloroform to give the desired product (yield 55%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C:25](=[O:28])[N:24]([CH:29]([C:33]([O:35][CH3:36])=[O:34])[CH2:30][CH2:31][OH:32])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.P([O-])(O)(O)=O.[K+]>ClCCl>[CH2:11]([O:18][C:19]([N:21]1[CH2:27][CH2:26][C:25](=[O:28])[N:24]([CH:29]([C:33]([O:35][CH3:36])=[O:34])[CH2:30][CH:31]=[O:32])[CH2:23][CH2:22]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(CCO)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(CC=O)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.31 ml (3.60 mmol) of oxalyl chloride in 7.7 ml dichloromethane at −50 to −60° C. was added a solution of 0.53 ml (7.51 mmol) dimethylsulfoxide in 1.6 ml of dichloromethane within 10 min. The solution was stirred for 5 min and a solution of 1.14 (3.13 mmol) (rac)-4-(3-hydroxy-1-methoxycarbonyl-propyl)-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester in 6.8 ml dichloromethane was added within 10 min. The mixture was stirred for 15 min and 2.18 ml (15.64 mmol) of triethylamine were added within 20 min. The suspension was stirred for 1¼ h and slowly warmed to 0° C. The reaction was neutralized with cold 10% aq. potassium dihydrogenphosphate solution (adjusted with 10% aq. potassium hydrogensulfate solution to pH 4-5) and extracted with diethyl ether (3×). The organic phases were washed with 10% aq. potassium dihydrogenphosphate solution, sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated to yield 1.25 g (quantitative) of the title compound as yellow oil. MS: 363.2 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][C:21]3=[O:22])[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:45][C:34]([F:33])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:40][CH2:39]1)=[O:36]
Reactant: O=C(c1ccc(OCCCCCBr)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCCCCN2CCC(NC(=O)C(F)(F)F)CC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
1-{1-[4-(5-Bromopentyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) and 4-trifluoroacetylaminopiperidine (2 g) are dissolved in dimethylformamide (40 ml), and thereto is added potassium carbonate (2 g) and the mixture is stirred overnight. The reaction mixture is poured into water, and the mixture is extracted with toluene/ethyl acetate (1:1), dried over magnesium sulfate, and purified by silica gel column chromatography (eluent; dichloromethane: methanol=50:1) to give 1-[1-{4-[5-(4-trifluoroacetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2 g) as colorless oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:11][C:12]2[C:13]([Cl:19])=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.O[C:46]1[CH:54]=[CH:53][C:49]([C:50]([NH2:52])=[O:51])=[CH:48][CH:47]=1>CN(C)C=O.C(Cl)(Cl)Cl>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[NH:11][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][C:8]([O:10][C:46]1[CH:54]=[CH:53][C:49]([C:50](=[O:51])[NH2:52])=[CH:48][CH:47]=1)=[O:9]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: NC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: NC(=O)c1ccc(OC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
To the solution of 1 (diclofenac, 890 mg, 3.0 mmol) in 50 mL of N,N-dimethylformamide, hydroxybenzotriazole (445 mg, 3.3 mmol) and DCC (680 mg, 3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture 4-hydroxybenzamide (4, 616 mg, 4.5 mmol) was added and stirred for 1 h at 0° C. and 3 hs at room temperature. After filtration, the filtrate was evaporated under reduced pressure and the oily residue thus obtained was dissolved in chloroform; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude product 5 was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (9/1), from which 4-carbamoylphenyl 2-(2-(2,6-dichlorophenylamino)phenyl)acetate (5) was obtained (212 mg, 17% yield).
Reaction SMILES: B.[CH2:2]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl>O1CCCC1.O>[CH2:2]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:20][CH:21]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCOc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To 100 ml. of 1.0 M borane in tetrahydrofuran cooled in an ice bath under nitrogen is added dropwise, 27.8 g. of p-decyloxybenzoic acid in 300 ml. of tetrahydrofuran over a period of 45 minutes. The mixture is stirred at room temperature for 6 hours and poured onto ice, diluted with water and 10 ml. of concentrated hydrochloric acid. The mixture is filtered and the solid washed with water to give white crystals. Recrystallization from ethanol gives white plates, m.p. 57.5°-59° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([OH:31])=[C:26]([F:32])[CH:25]=1)=[O:19])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:31][C:27]3[C:26]([F:32])=[CH:25][C:24]([CH2:23][CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:29][C:28]=3[F:30])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: CCOC(=O)C1CC1Cc1cc(F)c(O)c(F)c1
Product: O=C(O)C1CC1Cc1cc(F)c(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 88.2 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.023 g, 0.10 mmol) obtained in Step C of Preparation Example 27 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.026 g, 0.10 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.037 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:20][CH2:19]2)=[O:14])=[C:6]([CH:12]=1)[O:7][CH2:8][C:9](O)=[O:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:45][CH:46]([CH3:49])[CH2:47][OH:48].O>CN(C)C=O.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:20][CH2:19]2)=[O:14])=[C:6]([O:7][CH2:8][C:9]([NH:45][CH:46]([CH3:49])[CH2:47][OH:48])=[O:10])[CH:12]=1
Reactant: CC(N)CO
Reactant: O=C(O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(CO)NC(=O)COc1cc(Cl)ccc1C(=O)NCCN1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Temperature: 60 °C

Procedure:
The product of Example 2 (0.3 g) was dissolved in N,N-dimethylformamide (3 ml). 1,1′-Carbonyldiimidazole (0.1 g) and 2-amino-1-propanol (5 molar equivalents) were added, the solution heated at 60° C. for 1.5 hours and cooled. Water and ether were added, the organic phase separated and concentrated to a gum which was purified by chromatography (dichloromethane:methanol, 9:1) to give the product as a solid (0.15 g), m.p. 115-116° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](O)=[C:23]([CH2:32][CH2:33][CH2:34][OH:35])[N:22]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:20][C:21]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[O:35][CH2:34][CH2:33][CH2:32][C:23]=2[N:22]=1
Reactant: OCCCc1nc(Cl)c2ccccc2c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc2c(c3ccccc13)OCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of triphenylphosphine (1.03 g, 3.94 mmol) and 1-chloro-3-(3-hydroxypropyl)isoquinolin-4-ol (520 mg, 2.18 mmol) in THF (2 mL) at 0° C. was added diisopropyl azodicarboxylate (0.85 mL, 4.38 mmol) dropwise. The resulting solution was stirred for 4 h at rt. After concentration of solvent, the residue was purified by silica gel chromatography eluting with 0%-20% ethyl acetate in hexane to give the desired product 6-chloro-3,4-dihydro-2H-pyrano[3,2-c]isoquinoline (350 mg, 73%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27-8.20 (m, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.73 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.67-7.60 (m, 1H), 4.45-4.31 (m, 2H), 3.07 (t, J=6.5 Hz, 2H), 2.29-2.15 (m, 2H); MS: MS m/z 220.0 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13](=[O:19])[CH:12]=1.[CH3:20][C:21]1[N:25]([CH2:26][CH2:27][O:28][CH2:29][C:30](=O)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:24]2[CH:38]=[CH:39][CH:40]=[CH:41][C:23]=2[N:22]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:12]2[C:13](=[O:19])[C:14]([CH3:18])([CH3:17])[CH2:15][CH2:16][C:11]=2[NH:10][C:30]([CH2:29][O:28][CH2:27][CH2:26][N:25]2[C:24]3[CH:38]=[CH:39][CH:40]=[CH:41][C:23]=3[N:22]=[C:21]2[CH3:20])=[C:31]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: O=Cc1ccccc1Cl
Reactant: CCOC(=O)CC(=O)COCCn1c(C)nc2ccccc21
Reactant: CC1(C)CCC(N)=CC1=O
Product: CCOC(=O)C1=C(COCCn2c(C)nc3ccccc32)NC2=C(C(=O)C(C)(C)CC2)C1c1ccccc1Cl
Yield: 11.5 %

Procedure:
The title compound (63 mg) was prepared from 2-chlorobenzaldehyde (202 mg), 3-amino-6,6-dimethyl-2-cyclohexene-1-one (200 mg) and ethyl 4-[2-(2-methylbenzimidazol-1-yl)ethoxy]-3-oxobutanoate (304 mg) by the method of Example 1. M.p. 118°-120° C.
Reaction SMILES: [C:1]([C:3](=[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)SC)[C:4]([NH2:6])=[O:5])#[N:2].O.[NH2:27][NH2:28]>CCO>[NH2:2][C:1]1[NH:28][N:27]=[C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CSC(Nc1ccc(N2CCN(C(C)C)CC2)cc1)=C(C#N)C(N)=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(c2ccc(Nc3n[nH]c(N)c3C(N)=O)cc2)CC1
Temperature: 75 °C

Procedure:
2-cyano-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-3-(methylthio)acrylamide was then suspended in 10 mL EtOH and hydrazine hydrate (1 eq.) was added dropwise. Reaction was heated at 75° C. until intermediate was absent (HPLC). Once intermediate was absent (18 hrs), reaction was brought to room temperature and filtered to obtain 5-amino-3-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-1H-pyrazole-4-carboxamide as a purple powder. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=O)C.[OH-].[Na+].[ClH:34]>C(Cl)Cl.CO.CO>[ClH:34].[OH:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccsc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 66 %

Procedure:
To a solution of 4-(3-acetoxy4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline (200 mg, 0.45 mmol) in methylene chloride/methanol (1/1) (20 ml) was added, a 2M aqueous sodium hydroxide solution (0.67 ml, 1.35 mmol). The mixture was stirred for 35 minutes at ambient temperature, the solvents were evaporated, water was added to the residue and the solution was extracted with ethyl acetate. The organic layer was washed with water, brine, then dried (MgSO4) and evaporated to give a white solid. This solid was then dissolved into a saturated solution of hydrochloric acid in methanol (10 ml) and stirred for 10 minutes. The solid product was filtered and dried under a vacuum, to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline hydrochloride (127 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:12](S(C)(=O)=O)=[CH:11][N:10]=1.[CH3:29][O-:30].[Na+].CO>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:12]([O:30][CH3:29])=[CH:11][N:10]=1
Reactant: C[O-]
Reactant: CS(=O)(=O)c1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: COCCOC
Solvent: CO
Product: COc1cnc(-c2ccc(F)cc2F)nc1-c1cccc(C(F)(F)F)c1
Yield: 83.5 %

Procedure:
2.1 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methanesulfonylpyrimidine, 0.3 g of sodium methoxide and 20 ml of methanol were added to 120 ml of ethylene glycol dimethyl ether and the resulting mixture was heated under reflux for 5 hours. The solvent was distilled away under reduced pressure. The residue was washed with water and then dried to obtain 1.55 g of 2-(2,4-difluorophenyl)-4-(3-trifluoromethylphenyl)-5-methoxypyrimidine (Compound 77).
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([F:12])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C-:13]#[N:14].[Na+].O>CS(C)=O>[F:12][C:11]1[C:3]([CH2:2][C:13]#[N:14])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: [C-]#N
Reactant: Fc1cc2c(cc1CCl)OCO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cc2c(cc1F)OCO2
Temperature: 30 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A mixture of 5-chloromethyl-6-fluoro-benzo[1,3]dioxole (640 mg, 3.4 mmol) and NaCN (340 mg, 6.8 mmol) in DMSO (20 mL) was stirred at 30° C. for 1 h and then poured into water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford (6-fluoro-benzo[1,3]dioxol-5-yl)-acetonitrile (530 mg, 70%). 1H-NMR (300 MHz, CDCl3) δ 6.82 (d, J=4.8, 1H), 6.62 (d, J=5.4, 1H), 5.99 (s, 2H), 3.65 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[S:16][CH2:15][CH2:14][CH2:13][S:12]2)=[CH:9][S:8][C:7]=1[NH2:24])=[O:5])[CH3:2].[C:25]1(=O)[O:30][C:28](=[O:29])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[S:12][CH2:13][CH2:14][CH2:15][S:16]2)=[CH:9][S:8][C:7]=1[N:24]1[C:28](=[O:29])[C:27]2[C:26](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]1=[O:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C2(c3cccc(Cl)c3)SCCCS2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-Amino-4-[2-(3-chlorophenyl)-1,3-dithian-2-yl]thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 27 & 28, Part C) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1>>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:34]5[CH2:35][CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: CC1CCCNC1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCCC(C)C3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 3-methylpiperidine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue chromatographed on an SPE (C18) eluting with a water/acetonitrile gradient, to give, after evaporation of the solvents under vacuum N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(3-methylpiperidin-1-yl)isonicotinamide (16 mg). NMR; δH [2H6]—DMSO includes 10.28,(1H, s), 8.62,(1H, t), 8.21,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.20,(1H, s), 6.98,(1H, d), 4.26,(2H, m), 3.16,(2H, t), 2.80,(1H, m), 2.20,(3H, s), 1.78,(1H, m), 1.68,(1H, m), 1.57,(1H, m), 1.45,(1H, m), 1.15,(1H, m), 1.04,(1H, m),0.91,(2H, d), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.54 min, MH+483.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:21])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2Br)c2ccccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Product: S=C1CN=C(c2ccccc2Br)c2ccccc2N1

Procedure:
A mixture of 1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepin-2-one and P2S5 can be reacted in the same manner as in Preparation I to produce 1,3-dihydro-5-(o-bromophenyl)-2H-1,4-benzodiazepine-2-thione. This latter compound can then be substituted in the procedure of Example 1 to produce 6-(o-bromophenyl)-1-methyl-4H-s-triazolo[4,3-a] [1,4]benzodiazepine.