Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=O)(C)(C)C.Br[CH2:22][C:23]1[NH:28][C:27]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:26][C@@H:25]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[F:41])[C:24]=1[C:42]([O:44][CH2:45][CH3:46])=[O:43]>>[NH2:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:10][CH:11]2[N:17]([CH2:22][C:23]3[NH:28][C:27]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[N:26][C@@H:25]([C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=4[F:41])[C:24]=3[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC2COCC(C1)N2
Product: CCOC(=O)C1=C(CN2C3COCC2CC(N)(C(=O)O)C3)NC(c2nccs2)=N[C@H]1c1cccc(F)c1F
Yield: 8.4 %

Procedure:
The title compound was prepared in analogy to Example 133 by using 7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid 139a (49 mg) and ethyl (4R)-6-(bromomethyl)-4-(2,3-difluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 140a (48 mg). 5 mg of the title compound was isolated.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH2:7])[CH2:2][CH3:3].[NH:10](C(OCC1C=CC=CC=1)=O)[C@H:11]([C:23](O)=[O:24])[CH2:12][C:13](=[O:22])[O:14]CC1C=CC=CC=1>>[CH2:1]([O:4][C:5](=[O:9])[C@@H:6]([CH3:8])[NH:7][C:23](=[O:24])[C@H:11]([CH2:12][C:13](=[O:14])[OH:22])[NH2:10])[CH2:2][CH3:3]
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCCOC(=O)[C@@H](C)N
Product: CCCOC(=O)[C@@H](C)NC(=O)[C@@H](N)CC(=O)O

Procedure:
This compound was prepared from 1.7 g D-alanine propyl ester and 3.6 g Z-Asp(OBzl) in a manner similar to Example 11 (A). Yield: 1.6 g.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][N+:13]=1[O-].CCN(CC)CC.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:14]1[N:13]=[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[CH:17]=[C:16]([CH3:18])[C:15]=1[CH3:19]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(N2C(=O)c3ccccc3C2=O)[n+]([O-])cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1cc(N2C(=O)c3ccccc3C2=O)nc(Cl)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of 2-(1,3-dioxoisoindolin-2-yl)-4,5-dimethylpyridine 1-oxide (1.5 g, 0.01 mol) in POCl3 (50 mL) was added Et3N (680 mg, 0.01 mol) at room temperature. The mixture was stirred at 80□ for 2 hr, and then carefully poured into the mixture of saturation NaHCO3 solution and ice water. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give a crude residue that was purified by column chromatography on silica gel (10-15% ethyl acetate in petroleum ether) to give 2-(6-chloro-4,5-dimethylpyridin-2-yl)isoindoline-1,3-dione (650 mg, 41%). 1H NMR (300 MHz, CDCl3) δ 7.97-7.92 (m, 2H), 7.82-7.78 (m, 2H), 7.16 (s, 1H), 2.41 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12]>C(O)(=O)C.C(OCC)C.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:9])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Br)c(C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccc(Br)c(C)c1N
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of crude 1-bromo-2,4-dimethyl-3-nitrobenzene (0.58 g, 2.9 mmol) in glacial acetic acid (12 mL) was added iron powder (0.65 g, 11.6 mmol). The mixture was stirred rapidly at 80° C. under nitrogen for 2 hours. Upon completion, the mixture was cooled, diluted with diethyl ether and extracted with aqueous sodium hydroxide solution (2N). The organic layer was dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-bromo-2,6-dimethylphenylamine as a yellow oil which was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:13])[C:5]1=[O:14].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:13])[C:5]1=[O:14]
Reactant: Cn1c(=O)n(CCO)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(CCCl)c2ccccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 30 parts of 1,3-dihydro-1-(2-hydroxyethyl)-3-methyl-2H-benzimidazol-2-one and 600 parts of trichloromethane are added dropwise 200 parts of thionyl chloride. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is allowed to cool and the solvent is evaporated. The residue is crystallized from 2-propanol (activated charcoal), yielding 18.2 parts of 1-(2-chloroethyl)-1,3-dihydro-3-methyl-2H-benzimidazol-2-one.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][N:5]([CH:14]([CH3:16])[CH3:15])[C:4]=2[N:3]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21]([OH:23])=[O:22].Cl>O.O1CCOCC1>[CH:14]([N:5]1[C:4]2[N:3]=[C:2]([NH:17][C:18]3[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=3)[C:21]([OH:23])=[O:22])[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7](=[O:13])[CH2:6]1)([CH3:16])[CH3:15]
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(C(=O)O)cc(C(F)(F)F)c3)nc21
Temperature: 25 °C
Yield: 80 %

Procedure:
2-Chloro-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (3.5 g; 14.54 mmol) and 3-amino-5-(trifluoromethyl)-benzoic acid (2.98 g; 14.54 mmol) were diluted in 15 ml of water and 15 ml of 1,4-dioxane, 2 ml of HCl 37% were added. The reaction mixture was refluxed 24 h, then cooled to room temperature. The desired product precipitated from the reaction mixture, it was filtered, washed with water and dried in vacuo. 4.77 g (0.012 mol; 80% yield) were obtained as white powder.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:16]=[CH:17][C:18]=2[CH3:19])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]=2
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
Potassium thiocyanate (1.23 g, 12.7 mmol) was suspended in acetic acid (25 mL), and the mixture was stirred at room temperature for 10 min. A solution of tert-butyl {3-[(5-aminopyridin-2-yl)oxy]-4-methylphenyl}carbamate (1.00 g, 3.17 mmol) in acetic acid (25 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (531 mg, 3.32 mmol) in acetic acid (20 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 22 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate (50 mL), and the solution was washed with water (50 mL), 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (0.97 g, 82%) as a colorless powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][OH:13])([O-:3])=[O:2].Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19]>C(=O)([O-])[O-].[Na+].[Na+]>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][O:14][C:6]1[CH:7]=[CH:8][C:9]([NH:10][CH2:11][CH2:12][OH:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: OCC(O)CCl
Reactant: O=[N+]([O-])c1cc(O)ccc1NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(OCC(O)CO)ccc1NCCO
Temperature: 90 °C

Procedure:
0.2 mol (39.6 g) of 3-nitro-4-[N-(β-hydroxyethyl)-amino]-phenol is dissolved in 125 ml of 2N sodium carbonate solution. 0.25 mol (27.5 g) of 1-chloropropane-2,3-diol is added to this solution, heated beforehand to about 90° C. Heating is maintained for a further 2 hours. After cooling, the reaction medium is extracted with ethyl acetate. After the solvent has been evaporated off to dryness, 29 g of the desired product are obtained in the form of orange crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]2([O:15][CH:14]2[CH3:16])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.[OH-].[NH4+:26]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:18][CH2:17][C:13]([CH:14]([NH2:26])[CH3:16])([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(N)C1(O)CCN(C(=O)OCc2ccccc2)C1

Procedure:
A solution of 2-methyl-1-oxa-5-azaspiro[2,4]heptane-5-carboxylic acid benzyl ester (Example A9, 0.31 g, 1.25 mmol) in methanol (10 mL) and ammonium hydroxide (7 mL) is heated in a sealed tube at 100° C. for 16 hours. After cooling, the reaction mixture is dissolved ethyl acetate, washed with water, dried over Na2SO4 and evaporated to afford the title compound (0.340 g). 1H NMR (200 MHz, CDCl3): δ 7.33-7.26 (m, 5H), 5.28 (bs, 2H), 5.07 (s, 2H), 3.56-3.16 (m, 5H), 2.03-1.76 (m, 2H), 1.15 (d, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([F:15])[CH:5]=1.[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:18]=1>>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([F:15])[C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:8][CH:9]=2)=[O:26])=[C:19]([C:28]([F:31])([F:29])[F:30])[CH:18]=1
Reactant: O=C(O)C=Cc1cnc(Cl)cc1C(F)(F)F
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: Cl
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2cnc(Cl)cc2C(F)(F)F)cc1F
Yield: 68.1 %

Procedure:
N-(4-Aminomethyl-2-fluoro-phenyl)-methanesulfonamide HCl salt (56 mg, 0.22 mmol) was reacted with 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-acrylic acid (54 mg, 1.0 eq) to give 3-(6-chloro-4-trifluoromethyl-pyridin-3-yl)-N-(5-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (66 mg, 65.7%) after purification by column chromatography (Hex EtOAc=3/2).
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25]O>>[C:19]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:15][C:14]3[C:10](=[C:11]([C:16]([O:18][CH3:25])=[O:17])[NH:12][N:13]=3)[CH:9]=[CH:8]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CO
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Product: COC(=O)c1[nH]nc2c1C=CC(c1ccccc1)(c1ccccc1)C2

Procedure:
56 mg of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid and 10 cm3 of methanol are treated as in Example 2-1 to give 39 mg of methyl 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylate, in the form of a white foam, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10]CC2C=CC=CC=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].Br[CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>CN(C=O)C>[CH2:18]([C:6]1[CH:7]=[C:8]([OH:10])[CH:9]=[C:4]([CH2:1][CH:2]=[CH2:3])[C:5]=1[O:21][CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25])[CH:19]=[CH2:20]
Reactant: COC(=O)C(Br)c1ccc(Cl)cc1
Reactant: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCc1cc(O)cc(CC=C)c1OC(C(=O)OC)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2,6-diallyl-4-benzyloxyphenol (200 mg, 1.0 eq) in DMF (8 mL) were added methyl α-bromo-4-chlorobenzeneacetate (190 mg, 1.0 eq) and Cs2CO3 (285 mg, 1.2 eq). The reaction mixture was stirred at room temperature for 15 h, poured into ether, washed with water and brine, dried over MgSO4, filtered, and concentrated in vac. Purification by chromatography (SiO2, EtOAc/Hexanes 1:20) afforded the desired methyl α-(2,6-diallyl-4-hydroxyphenoxy)4-chlorobenzeneacetate.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:29]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][NH:28][C:2]2[N:10]=[C:9]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Clc1nc(NCCN2CCCCC2)nc2[nH]cnc12
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(C(CNc2nc(NCCN3CCCCC3)nc3[nH]cnc23)c2ccccc2)cc1

Procedure:
A mixture of Intermediate 38 (5.000 g, 17.8 mmol), 2,2-diphenylethylamine (5.200 g, 27 mmol) and N,N-diisopropylethylamine (6.2 ml, 36 mmol) in isopropanol (100 ml) was heated to reflux overnight. Upon cooling the solvent was removed in vacuo and the residue was purified using flash column chromatography with a Biotage column (90 g, SiO2) eluting with 5% methanol/chloroform/1% ammonia gave the title compound as an off white solid (4.500 g).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(Cc2ccccc2)CC1
Yield: 103.9 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (34.5 g, 102 mmol), 4-amino-1-benzyl piperidine (21.4 g, 112 mmol), diisopropylethylamine (245 ml, 143 mmol) in propan-2-ol (1 L) was heated at reflux for 2 hours. The mixture was concentrated under vacuum and the residues partitioned between ethyl acetate and water. The organics were washed with water, dried with sodium sulfate and concentrated under vacuum affording 52.1 g of (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-(1-benzyl-piperidin-4-yl)amine as an orange residue which was used for the next step without further purification. 1H NMR (400 MHz, DMSO) δ: 9.10 (s, 1H), 8.19 (m, 2H), 7.63-7.58 (m, 2H), 7.51 (t, 3H), 7.33 (d, 4H), 6.69 (d, 1H), 4.00 (s, 1H), 3.57 (br s, 2H), 2.84 (br s, 2H), 2.31 (br s, 2H), 2.11 (s, 3H), 2.04 (s, 1H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:32])=[O:31])=[CH:26][CH:25]=1)[C:18]([CH3:33])=[C:17]2[CH2:34][C:35]([OH:37])=[O:36])#[N:13]>CC(C)=O>[C:12]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[C:19](=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:32])(=[O:9])=[O:31])=[CH:26][CH:25]=1)[C:18]([CH3:33])=[C:17]2[CH2:34][C:35]([OH:37])=[O:36])#[N:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)=O)cc1
Solvent: CC(C)=O
Product: CC1=C(CC(=O)O)c2cc(C#N)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1

Procedure:
5-Cyano-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenylacetic acid is prepared by the addition of 1.0 mole of m-chloroperbenzoic acid per mole of 5-cyano-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenylacetic acid in an acetone solution.
Reaction SMILES: O1CCCC1.COP([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(OC)=O.[H-].[Na+].[CH:22]1([C:27]2[CH2:28][CH:29]3[CH:32]([CH:33]=2)[C:31](=O)[CH2:30]3)[CH2:26][CH2:25][CH2:24][CH2:23]1>O>[CH:22]1([C:27]2[CH2:33][C@@H:32]3[C@H:29]([CH:28]=2)[C:30](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:31]3)[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: O=C1CC2CC(C3CCCC3)=CC12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C=C1C[C@@H]2CC(C3CCCC3)=C[C@H]12
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
A tetrahydrofuran (15 mL) solution of tert-butyl dimethylphosphonoacetate (3.21 g, 14.4 mmol) was added dropwise at 0° C. over 15 minutes to a tetrahydrofuran (15 mL) suspension of sodium hydride (0.59 g, 63%, 15.7 mmol), and the mixture was stirred at 0° C. for 25 minutes. To this solution, a tetrahydrofuran (15 mL) solution of 3-cyclopentylbicyclo[3.2.0]hept-3-en-6-one (2.30 g, 13.1 mmol) was added dropwise at 0° C. over 10 minutes, and the mixture was stirred at room temperature for 16 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the compound of interest as a yellow oil substance (3.30 g, 92%).
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([NH2:27])=[O:26])[CH:18]=1>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:27][C:25]([NH:24][CH2:23][C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)=[O:26])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NCc1cccnc1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Product: O=C(NCc1cccnc1)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and 1-(3-pyridylmethyl)urea.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=[N:22][C:19]2=[N:20][CH:21]=1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:16]1[N:17]=[C:18]2[CH:25]=[CH:24][CH:23]=[N:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CNc1cnc2ncccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2ncc(NCC3CCCCN3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butyl ester (0.48 g) was dissolved in dichloromethane (3 ml), cooled (ice bath) and treated with trifluoroacetic acid (2 ml). The mixture was stirred for 3 hours at room temperature, solvent removed at reduced pressure and the residue co-evaporated with toluene to give the title compound (0.45 g).
Reaction SMILES: C(N(CCCC)CCCC)CCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=O)[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1.Cl.[NH2:34][OH:35]>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[C:30]3[C:29](=[N:34][OH:35])[CH2:28][CH2:27][CH2:26][C:25]=3[NH:24][C:23]=2[CH3:32])=[CH:17][CH:16]=1
Reactant: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=O)CCC2
Reactant: NO
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: CCO
Product: Cc1[nH]c2c(c1Sc1ccc(Cl)cc1)C(=NO)CCC2
Temperature: 65 °C
Reaction time: 8 h

Procedure:
Tributylamine (6.6 mL 28 mmol) was added to a stirred suspension of 3-(4-chlorophenylsulfanyl)-2-methyl-4,5,6,7-tetrahydro-1H-indol-4-one (8.0 g, 27 mmol) and hydroxylamine hydrochloride (1.9 g, 27 mmol) in ethanol (40 mL). The mixture was heated to 65° C. and maintained at this temperature for 4 h then allowed to cool to r.t. and left overnight. Additional hydroxylamine hydrochloride (0.15 g, 2.2 mmol) and tributylamine (1.0 mL, 4.2 mmol) were added and the mixture was re-heated to 65° C. for a further 2 h. After cooling to r.t., the solid product was collected by filtration, washed with ethanol (2×10 mL) then dried in a vacuum oven at 40° C. to give the title compound as an off-white solid; 5.71 g (68%); purity: 96.3 area % by HPLC; m/z: 307/309 (MH+); 1H-NMR: 11.26 (1H, s), 10.20 (1H, s), 7.23 (2H, m), 6.92 (2H, m), 2.62-2.58 (2H, m), 2.56-2.52 (2H, m), 2.12 (3H, s), 2.83-1.76 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].[C:11]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:10]=[CH:11][NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C([O-])O
Reactant: Cc1cc(C)c(N)c(N)c1
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cc1cc(C)c2nc[nH]c2c1

Procedure:
Intermediate 179.1 (275 mg) in 3 mL formic acid was irradiated in a microwave reactor at 150° C. for 5 min. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc (3×). The organic phase was washed with water and brine, dried (Na2SO4) and concentrated to afford 245 mg of Intermediate 179.2 as an orange solid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH2:22]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH2:25][CH3:26]>>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:28][CH:29]=2)[N:8]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Product: CCCCCc1ccc(C(=O)NC2N=C(c3ccccc3F)c3ccccc3N(C)C2=O)cc1

Procedure:
The procedure of Example 134 was carried out using equivalent amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-n-pentylbenzoyl chloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo to give the title compound which was dried at 65° C.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].BrBr.[CH3:14][OH:15]>C(O)(=O)C>[CH3:14][O:15][CH2:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: CO
Reactant: Cc1[nH]c2ncccc2c1C
Agent: BrBr
Solvent: CC(=O)O
Product: COCc1[nH]c2ncccc2c1C

Procedure:
2,3-dimethylpyrrolo[2,3-b]pyridine 0,5 g (0.0034 mol) was treated in 7 ml acetic acid with an equimolecular amount of bromine and after 5 min a yellow precipitate was formed. The solid was filtred off and treated with 20 ml methanol. The mixture was refluxed for 30 min. and was then evaporated. The residue was partitioned between methylene chloride and bicarbonate solution. The organic layer was separated dried over Na2SO4 and evaporated. The residue was treated with boiling petroleumether (60-80) which was decantated and allowed to cool. The precipitated product was filtred off affording 0,13 g (22%) as white solid.