Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12]C(=O)OC(C)(C)C)[CH2:5]2.C(C1C=C2C(=CC=1)NC[C@@H](N[S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])C2)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH:6]([NH:12][S:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:5]2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Cl)cc2C1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Product: O=S(=O)(NC1CNc2ccc(Cl)cc2C1)c1ccccc1

Procedure:
Compound 21B was prepared from 21A by procedures analogous to those described in Example 1D and 1G.
Reaction SMILES: Cl.[C:2]([NH:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:5])([CH3:4])[CH3:3].[N:13]([O-])=[O:14].[Na+]>O>[N:13]([N:6]([C:2]([CH3:5])([CH3:3])[CH3:4])[CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:14]
Reactant: O=N[O-]
Reactant: CC(C)(C)NC1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)N(N=O)C1CCCCC1
Temperature: 90 °C

Procedure:
A mixture consisting of 13.2 ml of 10N hydrochloric acid, 50 ml of water, 18.8 g of tert.-butyl-cyclohexyl-amine and 17.9 g of sodium nitrite is heated at 90° C. for 3 hours. On cooling, a solid precipitates and is filtered off with suction. Yield: 16.3 g melting point: 87° C.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2].[H-].[Na+].C(O)(=O)[CH2:35][C:36](CC(O)=O)([C:38](O)=O)[OH:37]>C(O)(C)C>[C:1]([C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:37][CH:36]([CH3:38])[CH3:35])[N:12]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:7]1=[O:27])#[N:2]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CS(=O)c1nccc(-c2cn(Cc3ccccc3C#N)c(=O)n2-c2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1nccc(-c2cn(Cc3ccccc3C#N)c(=O)n2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In 5 ml of isopropanol was suspended 100 mg of 1-(2-cyano-benzyl)-3-(4-fluorophenyl)-4-(2-methylsulfinylpyrimidin-4-yl)-4-imidazolin-2-one (Compound of Reference example 6(2) or Reference example 7(2)), 26.3 mg of sodium hydride was added to the mixture and the resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture were successively added an aqueous citric acid solution and an aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed, dried and concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 68 mg of the title compound as powder.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>ClCCl>[N:11]1([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1nc2ccccc2o1
Solvent: ClCCl
Product: c1ccc2oc(N3CCNCC3)nc2c1

Procedure:
A 3.07 g portion of 2-chlorobenzoxazole was dissolved in 10 ml of dichloromethane. Under cooling with ice, to this was added dropwise 3.45 g of anhydrous piperazine which has been dissolved in 30 ml of dichloromethane, followed by 1 hour of reaction. The reaction solution was concentrated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (dichloromethane:methanol=20:1), followed by concentration of the eluate under a reduced pressure. Thereafter, the resulting residue was dissolved in 30 ml of water, neutralized with 1N hydrochloric acid, extracted with dichloromethane, washed with water, dehydrated with Na2SO4 and then concentrated under a reduced pressure to obtain 1.77 g of 2-(1-piperazinyl)benzoxazole.
Reaction SMILES: C[O:2][C:3](=[O:44])[C@@H:4]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C:18]=3[CH:17]=2)=[CH:8][CH:7]=1.[OH-].[Na+]>C(O)C.C1COCC1>[C:36]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:29][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:28]=[CH:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][C:18]=3[CH:17]=2)=[CH:8][CH:7]=1)[C:3]([OH:44])=[O:2])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc3c(c2)Cc2ccccc2-3)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1ccccc1)c1ccccc1N[C@@H](Cc1ccc(OC/C=C/c2ccc3c(c2)Cc2ccccc2-3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
(E)-(S)-2-(2-Benzoyl-phenylamino)-3-{4-[3-(9H-fluoren-2-yl)-allyloxy]-phenyl}-propionic acid methyl ester (example 3) (600 mg, 1.0 mmol) was dissolved in a mixture of ethanol (20 ml) and THF (10 ml). 1N NaOH (5 ml) was added and the mixture was stirred for 16 h at room temperature. The mixture was concentrated in vacuo. Water (5 ml) and ethyl acetate (10 ml) was added. The mixture was neutralised with 1N HCl. The aqueous phase was isolated and extracted with ethyl acetate (×2) The organic layers were combined, washed with water, dried (MgSO4) and evaporated to give 500 mg of the title compound.
Reaction SMILES: [CH3:1][NH:2]/[C:3](/[NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[CH:4]\[N+:5]([O-:7])=[O:6].[ClH:22]>C(O)(C)C>[CH3:1][NH:2][C:3]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[O:17][C:16]([CH2:18][N:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6].[ClH:22]
Reactant: CN/C(=C\[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Agent: Cl
Solvent: CC(C)O
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 30 °C

Procedure:
Ranitidine base (31.44 g, 0.1 mol) was dissolved in anhydrous isopropyl alcohol (isopropanol) (160 mL) by warming to 30° C., filtering through celite and washing the cake with anhydrous isopropyl alcohol (68 mL). The solution was warmed to 43° C., seeds (Form #1, 0.2g) were added and anhydrous hydrogen chloride in anhydrous isopropyl alcohol (15.19 g, 24%, 1 equivalent) was added all at once. The temperature rose to 51° C. and the temperature was maintained at 45°-50° C. for 5 hours while the product crystallized. The mixture was allowed to cool to 25° C. The precipitate was filtered and washed with anhydrous isopropyl alcohol (2×30 mL) to yield damp Ranitidine Hydrochloride. Vacuum drying at 40° C. overnight yields 34.26 g (0.0977 mol, 97.7%) of pure Ranitidine Hydrochloride (Form #1). The I.R. in KBr of the crystals conformed to Form #1.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3].[F:7][CH:8](C)[CH:9](O)CO>[OH-].[K+]>[F:7][CH:8]([CH:3]1[CH2:5][O:4][C:1](=[O:6])[O:2]1)[CH3:9]
Reactant: COC(=O)OC
Reactant: CC(F)C(O)CO
Agent: [K+]
Agent: [OH-]
Product: CC(F)C1COC(=O)O1
Temperature: 60 °C
Reaction time: 12 h
Yield: 136 %

Procedure:
2.0 g of potassium hydroxide and 50 g of dimethyl carbonate were added to 108.0 g (1.00 mol) of 3-fluoro-1,2-butanediol, and the resulting mixture was stirred at 60° C. for 12 hours. After filtering off potassium hydroxide, the mixture was distilled to obtain 101.2 g of 4-(1-fluoroethyl) -1,3-dioxolan-2-one (yield 75.5%). An elemental analysis was performed and the following values were observed:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=O)=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.ClC(OCC(C)C)=O.[CH:40]1([NH2:46])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>O1CCCC1>[CH:40]1([NH:46][C:18](=[O:20])[C@@H:17]2[CH2:21][CH2:22][CH2:23][N:16]2[C:14](=[O:15])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: NC1CCCCC1
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
3.2 g (0.01 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline were dissolved in 50 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 1.27 ml (0.01 mol) of N-ethylmorpholine were added followed by 1.31 ml (0.01 mol) of isobutyl chloroformate and the solution was stirred at -10° C. for 20 minutes. 1.21 ml (0.01 mol) of cyclohexylamine were then added and the mixture was stirred at 0° C. for 1 hour and then left to stand at room temperature for 16 hours. The mixture was evaporated and the residue was treated with 100 ml of ethyl acetate, washed with 80 ml of 1-N hydrochloric acid, 80 ml of water and 80 ml of 5% sodium bicarbonate solution, dried over sodium sulphate and evaporated to an oil. The product crystallised from ethyl acetate/ethyl to yield 2.36 g of N-benzyloxycarbonyl-L-alanyl-L-proline cyclohexylamide of melting point 130.5°-131.5° C. A second crop (0.95 g; melting point 130.5°-131.5° C.) was obtained on leaving the mother liquor to stand overnight. The total yield was 83%, [α]D20 =-96.3° (c=1.175% in methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:29][CH2:30][CH:31]=[C:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[N:42][C:37]=2[CH2:36][O:35][C:34]2[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:29][CH2:30][CH:31]=[C:32]3[C:38]4[CH:39]=[CH:40][CH:41]=[N:42][C:37]=4[CH2:36][O:35][C:34]4[CH:43]=[CH:44][C:45]([C:47]([OH:50])([CH3:49])[CH3:48])=[CH:46][C:33]3=4)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: O=[N+]([O-])c1cc(C2(O)CCNCC2)ccc1Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)c([N+](=O)[O-])c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 14 h
Yield: 30.3 %

Procedure:
To a solution of the 4-(4-Chloro-3-nitro-phenyl)-piperidin-4-ol (0.295 g, 1.2 mmol) in isopropanol was added 2,6-lutidine (0.225 mL, 2.1 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.224 g, 0.6 mmol), added in portions over 1 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by Isco flash chromatography (15% methanol/85% methylene chloride) to yield the title compound (0.100 g, 30%). 1H-NMR (CDCl3): δ 1.53 (s, 6H), 1.70 (d, 2H), 1.81–2.18 (m, 4H), 2.3–2.44 (m, 4H), 2.56 (t, 2H), 2.69 (d, 2H), 5.32 (bs, 2H), 6.16 (t, 1H), 6.81 (d, 1H), 7.28 (t, 2H), 7.48 (t, 2H), 7.58 (t, 2H), 8.06 (s, 1H). ESI-MS m/z: 550 (M+1), retention time 1.51.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].Cl.CN(C)CCCN=C=NCC>ClCCl>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([C:18]([N:1]2[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]2)=[O:19])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CC[C@@H](O)C2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
(R)-Pyrrolidin-3-ol (0.276 g, 3.17 mmol) was added to a mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (0.4 g, 2.11 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.61 g, 3.17 mmol) in dichloromethane (7 mL). The resulting reaction mixture was stirred at RT under nitrogen atmosphere for 18 h. The mixture was diluted with DCM (10 mL) and washed with water (1×15 mL), 10% aqueous citric acid solution (2×15 mL) and brine (2×15 mL), and dried over sodium sulfate. The solvents were reduced in vacuo to afford the title compound as colourless oil (0.42 g, 74%). 1H NMR (400 MHz, CDCl3): δ 4.54-4.52 (1 H, m), 4.11-4.09 (4 H, m), 3.50-3.48 (5 H, m), 2.01-2.00 (2 H, m), 1.43 (9 H, d, J=0.78 Hz)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10](SC)[C:11]3[C:12](=[CH:14][S:15][CH:16]=3)[NH:13][C:7]=2[CH:6]=1)(=[O:4])=[O:3].O.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)(=O)C>[CH3:1][S:2]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:11]3[C:12](=[CH:14][S:15][CH:16]=3)[NH:13][C:7]=2[CH:6]=1)(=[O:3])=[O:4]
Reactant: C1CNCCN1
Reactant: CSC1=Nc2ccc(S(C)(=O)=O)cc2Nc2cscc21
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)Nc1cscc1C(N1CCNCC1)=N2

Procedure:
A solution of 6-methylsulfonyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess piperazine and glacial acetic acid is heated in a bomb at 150° C. for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=2[S:4][CH:3]=1.[H][H]>[Pd].O1CCCC1.C(N(CC)CC)C>[S:4]1[C:5]2[C:10]([CH:11]=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=2[CH:2]=[CH:3]1
Reactant: [H][H]
Reactant: O=Cc1cccc2c(Br)csc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=Cc1cccc2ccsc12

Procedure:
2 g of 5% palladium-on carbon catalyst are added to a solution of 10.4 g (43.15 mmoles) of 3-bromo-7-benzothiophene-carbaldehyde in 130 ml of tetrahydrofuran and 5.6 ml of triethylamine and the mixture is hydrogenated with hydrogen in a hydrogenating apparatus for 45 hours at 20°-22° C. under atmospheric pressure. The catalyst is then filtered off and the solvent is evaporated in vacuo from the filtrate. The residue is dissolved with 50 ml each of water and ethyl acetate, and 5.2 g (67.5% of the theoretical amount) of 7-benzothiophene-carbaldehyde are obtainable as residue from the separated organic phase after evaporation of the solvent in vacuo.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O=[CH:26][C:27]1[CH:35]=[CH:34][C:32]([OH:33])=[C:29]([O:30][CH3:31])[CH:28]=1>C1(C)C=CC=CC=1>[OH:33][C:32]1[CH:34]=[CH:35][C:27](/[CH:26]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
6.5 g (19.5 mmol, 3 eq) of methyl triphenylphosphoranylideneacetate are added to a solution of 1.0 g (6.5 mmol, 1 eq) of vanillin in 15 ml of toluene. The reaction mixture is stirred for 1 hour at 90° C. The solvent is evaporated off and the residual oil is then chromatographed on silica gel (8/2 heptane/ethyl acetate). 1.12 g of methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate are obtained in oil form. Yield=83%
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[SH:9].Br[C:12]1[S:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>>[Cl:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:10])[C:8]=1[S:9][C:12]1[S:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: Sc1c(Cl)cncc1Cl
Reactant: CS(=O)(=O)c1cc([N+](=O)[O-])c(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Product: CS(=O)(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
3,5-dichloropyridine-4-thiol sodium salt prepared as in example 17 (0.160 g, 0.39 mmol) and 2-bromo-5-methylsulfonyl-3-nitro-thiophene (0.1 g, 0.36 mmol) were dissolved in N,N-dimethylformide (3 mL). To the above mixture, potassium carbonate (0.192 g, 1.39 mmol) was added. The resulting reaction mixture was stirred at ambient temperature for 5 hours. After this time, the reaction mixture was quenched with ice water and stirred at ambient temperature for 20 minutes and the resulting precipitate was collected by filtration, washed with water (10 mL) and dried in vacuo at 40° C. overnight. The solid was triturated with dichloromethane and diethyl ether to afford the title product as an off-white solid (35 mg, 9% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (1H, s), 8.66 (1H, s), 3.56 (3H, s). MS m/z: 383.09 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1.[C:24]([NH:27][NH2:28])(=O)[CH3:25]>C(O)C>[Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11]3[N:12]([C:24]([CH3:25])=[N:27][N:28]=3)[C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(C2=NCC(=S)Nc3c(Cl)ccc(Cl)c32)cc1
Reactant: CC(=O)NN
Solvent: CCO
Product: Cc1nnc2n1-c1c(Cl)ccc(Cl)c1C(c1ccc(C(C)C)cc1)=NC2
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6,9-dichloro-1,3-dihydro-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with acetic acid hydrazide and the resulting product heated to 250° C. to give 7,10-dichloro-1-methyl-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([CH2:16][NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:17]([CH2:16][C:14]1[S:15][C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:12][CH:13]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])(=[O:20])=[O:19]
Reactant: Fc1ccccc1CBr
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(Cc3ccccc3F)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1

Procedure:
In analogy to example 10, step 3, N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (example 27, step 1) was reacted with 2-fluorobenzyl bromide and cesium carbonate in N,N-dimethylacetamide to give N-(2-fluoro-benzyl)-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide as a light yellow oil. MS: 600.6 ([M+NH4]+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1I.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Cu]I>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:23]#[C:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1I
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N)c1C#Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
2-iodo-3-nitro-benzoic acid methyl ester (0.79 g, 2.84 mmol), 1-chloro-4-ethynylbenzene (0.41 g, 2.99 mmol), palladium tetrakis(triphenylphosphine) (0.16 g, 0.14 mmol), copper (I) iodide (0.03 g, 0.14 mmol), and triethylamine (1.44 g, 14.19 mmol) were dissolved in 15 mL toluene. Argon was bubbled through the resulting solution for 15 min. The reaction was stirred under argon at 80° C. for 2 h and 20 min. The reaction mixture was then washed once with water, dried (MgSO4), and concentrated in vacuo. The orange oil was purified by flash chromatography eluting with 50 to 100% CHCl3/hexanes to yield 3-amino-2-(4-chloro-phenylethynyl)-benzoic acid methyl ester, 0.76 g (94%) as a yellow oil. 1H NMR (300 MHz, d6-DMSO) δ 3.84 (s, 3H), 5.84 (br s, 2H), 6.97 (dd, J=8.1, 1.3 Hz, 1H), 7.05 (dd, J=7.5, 1.2 Hz, 1H), 7.17 (app t, J=7.5 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H). MS (electrospray, MH+) 286.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:13][C:12]=1[O:21][CH3:22].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([N:29]2[CH2:30][C@@H:26]([O:25][CH3:24])[CH2:27][C@H:28]2[CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[O:20])=[CH:13][C:12]=1[O:21][CH3:22]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Cl)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.6 %

Procedure:
A mixture of 4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetic acid (398 mg, 1.19 mmol), methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-1-[4-[N′-(2-chlorophenyl)ureido]-3-methoxyphenylacetyl]-4-methoxy-2-pyrrolidinyl]methoxybenzoate (600 mg, 87%) as a colorless amorphous solid 1H-NMR (CDCl3) δ1.99-2.06 (m, 1H), 2.34 (d, J=13.9 Hz, 1H), 3.30 (s, 3H), 3.59 (d, J=7.4 Hz, 1H), 3.62 (d, J=3.2 Hz, 2H), 3.83 (s, 3H), 3.88 (s, 3H), 4.00-4.18 (m, 3H), 4.42-4.51 (m, 2H), 6.82-7.07 (m, 7H), 7.28 (d, J=8.3 Hz, 1H), 7.35 (dd, J=7.9, 1.5 Hz, 1H), 7.94-8.00 (m, 3H), 8.18 (d, J=8.3 Hz, 1H); MS (ESI) m/z 582 (M++1), 5.84 (M++3).
Reaction SMILES: Br[C:2]1[CH:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:6][CH:5]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].Cl[Pd]Cl>[CH:9]1([O:8][C:7]2[C:2]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[CH:3][C:4]([C:14]([O:16][CH3:17])=[O:15])=[CH:5][N:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C1=CNC(OC2CCCC2)C(Br)=C1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cnc(OC2CCCC2)c(-c2ccncc2)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 30.8 %

Procedure:
Methyl 5-bromo-6-(cyclopentyloxy)-1,6-dihydropyridine-3-carboxylate (2.50 g, 7.94 mmol) was dissolved in DME (10 mL) and pyridin-4-ylboronic acid (813 mg, 6.61 mmol), DPPF-PdCl2 (108 mg, 0.13 mmol, Strem) and water (0.5 mL, 28 mmol) were added. The mixture was stirred at 40° C. for 4 h. The reaction mixture was cooled to RT, diluted with H10 and extracted 3× with EtOAc. The combined organic extracts were washed 1× with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40 g pre-packed column, elution 0-30% EtOAc:hexanes) to give the title compound (608 mg, 31%). MS m/z: 299 (M+1).