Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[C:22]1([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:28]2[CH:29]=[CH:30][C:31]([CH2:32][S:16][C:14]3[S:15][C:11]4[CH2:10][CH2:9][C:8]5[C:17](=[CH:18][CH:19]=[CH:20][C:7]=5[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=4[N:13]=3)=[CH:34][CH:35]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: BrCc1ccc(-c2ccccc2)cc1
Product: O=C(O)COc1cccc2c1CCc1sc(SCc3ccc(-c4ccccc4)cc3)nc1-2
Yield: 68 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy)acetate and 4-phenylbenzyl bromide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 68%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:56][CH2:57][CH:58]([OH:65])[CH2:59][N:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:56][CH2:57][CH:58]([OH:65])[CH2:59][N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11]
Reactant: NCC(O)CN1CCCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCC(O)CN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (300 mg, 0.578 mmol), HOBt (78 mg, 1 eq.) and EDAC (222 mg, 2 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-amino-3-pyrrolidin-1-yl-propan-2-ol (170 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the reaction was concentrated and purified on a silica gel column to give 169 mg (45%) of the titled compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][N:35]3[CH2:39][CH:38]=[CH:37][CH2:36]3)[CH2:24][CH:23]2[OH:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][N:35]3[CH2:36][CH:37]=[CH:38][CH2:39]3)[CH2:24][C:23]2=[O:40])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: O=C(NC1(C(=O)NC2CCN(c3ccccc3NN3CC=CC3)CC2O)CCCCC1)c1cc2ccccc2o1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3NN3CC=CC3)CC2=O)CCCCC1)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-[N-(2,5-dihydropyrrol-1-yl)amino]phenyl]piperidin-3-ol (0.7 g) obtained in Step 1 in 6 ml of dimethylsulfoxide (DMSO), was added 0.8 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.75 g) was added slowly to the reaction mixture, which was then stirred for about 2 hours at room temperature. The reaction mixture was diluted with 50 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was filtered and dried to give 0.6 g of the titled compound as white color.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[C@@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](O[C:26](=[O:28])[CH3:27])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[C@H:10]([NH:11][CH2:14][C:12]1[CH:13]=[CH:27][C:26]2[O:28][CH2:1][O:8][C:9]=2[CH:10]=1)[CH:12]([CH3:13])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](N)C(=O)OCc1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](NCc1ccc2c(c1)OCO2)C(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 170.1 %

Procedure:
To a solution of D-valine benzyl ester free base (12.92 g, 62 mmol) in dry methylene chloride (120 mL) was added 3,4-(methylenedioxy)phenyl methanol (9.45 g, 62 mmol) and sodium triacetoxyborohydride (18.50 g, 86.8 mmol). After 15 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (120 mL) and the aqueous layer was separated and extracted with methylene chloride. The combined methylene chloride layers were washed with brine, dried over magnesium sulfate, and concentrated. The residue was chromatographed (300 g SiO2, 5% ethyl acetate-hexanes) to afford 2(R)-(3,4-methylenedioxy-benzylamino)-3-methylbutyric acid benzyl ester (18 g) as a colorless oil.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18]C(C#N)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].[OH-:20].[K+].Cl.C(O)CO[CH2:26][CH2:27][OH:28]>>[CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:26]([C:27]([OH:28])=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: [OH-]
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: OCCOCCO
Agent: Cl
Agent: [K+]
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1

Procedure:
A mixture of 100 mg of p-[trans-4-(trans-1-pentenyl)cyclohexyl]benzonitrile and 10 ml of a 10% solution of potassium hydroxide in diethylene glycol was boiled at 180° C. for 1 hour while gassing with argon in a round flask provided with a magnetic stirrer and a reflux condenser. After cooling the brown reaction mixture was made acid with 25% hydrochloric acid and partitioned between 70 ml of dichloromethane and 70 ml of water. The aqueous phase was back-extracted three times with 70 ml of dichloromethane each time. The organic phases were washed twice with 70 ml of water each time and dried over magnesium sulphate and active carbon. After separating the solvent in a rotary evaporator there were obtained 99 mg (92%) of p-[trans-4-(trans-1-pentenyl)cyclohexyl]benzoic acid as white, intensively smelling crystals; Rf-value 0.44 (ethyl acetate/petroleum ether, vol. 3:7).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])C.[OH-].[Li+]>CO.O>[C:15]([N:9]1[C:10]([C:11]([F:13])([F:14])[F:12])=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)n1ncc(C(=O)O)c1C(F)(F)F
Temperature: 25 °C
Yield: 91.7 %

Procedure:
To a stirred mixture of 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.000 g; 11.4 mmol) in methanol/water (1:1 ratio, 50 mL) was added lithium hydroxide (0.383 g; 16.0 mmol) at room temperature. The mixture was heated to reflux for 2 hr, then allowed to cool to room temperature and concentrated to approximately half of the original volume. The resulting mixture was acidified with 1N HCl to ˜pH 1 and extracted with methylene chloride. The extracts were dried over sodium sulfate, filtered and concentrated to provide 1-tert-butyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (2.47 g, 92%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:15][CH2:16]Cl)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([NH2:27])[CH3:26])=[CH:21][CH:20]=1.CCO.O>CCN(C(C)C)C(C)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]([N:27]2[CH2:16][CH2:15][N:4]([S:5]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)(=[O:7])=[O:6])[CH2:3][CH2:2]2)[CH3:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCN([C@H](C)c3ccc(Br)cc3)CC2)cc1
Temperature: 125 °C
Yield: 81.9 %

Procedure:
N,N-Bis(2-chloroethyl)-4-methylbenzenesulfonamide (4.0 g, 13.50 mmol) and (R)-1-(4-bromophenyl)ethanamine (2.57 g, 12.83 mmol) in DIPEA (5 mL) were stirred and heated at 125° C. for 32 hours. The resulting dark mixture was cooled to 80° C. then a mixture of EtOH/water (70/30, 20 mL) added slowly to give a brown precipitate. The precipitate was collected by filtration, washed with EtOH/water (70/30) and iso-hexane and air dried to afford (R)-1-[1-(4-bromophenyl)ethyl]-4-tosylpiperazine (4.45 g, 78%) as a brown solid, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.[Br:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>O>[Br:34][C:35]1[CH:36]=[C:37]([S:41]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:16](=[O:21])[CH2:17]2)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cccc(Br)c3)CC2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a mixture of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone (1.19 g), sodium carbonate (848 mg), ethyl acetate (40 ml) and water (20 ml) was added 3-bromobenzenesulfonyl chloride (1.02 g), and the mixture was stirred at room temperature for 1 hour. The organic layer was separated, washed with saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:2) to give colorless crystals of the title compound (1.05 g).
Reaction SMILES: [CH3:1][C:2]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:9]2[C:4](=[N:5][C:6]([N:20](C(OC(C)(C)C)=O)[NH:21][C:22](OC(C)(C)C)=O)=[CH:7][CH:8]=2)[CH:3]=1.[CH3:36]C(O)=O>>[CH3:36][C:22]1[N:5]2[C:4]3[CH:3]=[C:2]([CH3:1])[N:10]([S:11]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)(=[O:12])=[O:13])[C:9]=3[CH:8]=[CH:7][C:6]2=[N:20][N:21]=1
Reactant: Cc1cc2nc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(=O)O
Product: Cc1cc2c(ccc3nnc(C)n32)n1S(=O)(=O)c1ccccc1
Temperature: 25 °C

Procedure:
di-tert-Butyl 1-[2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (9.4 g, 19 mmol, from Step 3) in AcOH (150 mL) was heated in the range of 115-120° C. for 20 hours. Upon cooling to room temperature, the solvent was removed in vacuo. After this cyclization, purification via HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded 1,7-dimethyl-6-(phenylsulfonyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]2)=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: Oc1ccncc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 10.1 g Pyridin-4-ol and 10 g 1-Fluoro-4-nitro-benzene and 46.1 g Cs2CO3 in 30 mL DMF was stirred at RT for 2 h. This solution was poured on to 300 mL of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried in vacuo. Yield: 11.2 g.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S([O:38][C:39]1[CH2:44][CH2:43][CH2:42][C:41](=O)[C:40]=1[CH3:46])(=O)=O>C(OCC)C>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:41]4[CH2:42][CH2:43][CH2:44][C:39](=[O:38])[C:40]=4[CH3:46])=[CH:19][C:18]=3[Cl:32])=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1=O
Reactant: CC1(C)OB(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)OC1(C)C
Solvent: CCOCC
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)CCCC1=O
Yield: 53.6 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 10, Step B (0.350 g, 0.780 mmol) and 2-methyl-3-oxo-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.222 g, 0.858 mmol) were reacted by the procedure described in Example 1, Step F. The crude product was purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate in hexane to afford an orange oil. The oil was dissolved in diethyl ether and precipitated with petroleum ether to afford orange solid (0.180 g).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:11]([C:10]2[CH:9]=[N:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[OH:12])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Reactant: Br[Mg]c1ccccc1
Product: OC(c1ccccc1)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (300 mg, 1.73 mmol) and phenylmagnesium bromide (1.73 mL, 3.46 mmol, 2 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Yellow solid. Yield: 138 mg, 42%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=5.91 (s, 1H), 7.29-7.34 (m, 1H), 7.35-7.50 (m, 7H), 7.68 (dd, J=8.2, 0.6 Hz, 1H), 7.73-7.78 (m, 1H), 7.94-7.99 (m, 2H), 8.68 (dd, J=1.6, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=74.1, 120.3, 126.5, 126.9, 128.0, 128.7, 128.7, 128.9, 135.0, 137.6, 139.0, 143.0, 148.2, 156.7; (ESI): m/z=261.97 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[C@H:5]([C:18]([O:20]CC2C=CC=CC=2)=[O:19])[C@@H:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.[H][H]>CCO.[Pd]>[C:31]([O:30][C:28]([C@H:4]1[CH2:3][C:2]([F:1])([F:35])[CH2:7][NH:6][C@@H:5]1[C:18]([OH:20])=[O:19])=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1CC(F)(F)CN[C@@H]1C(=O)O

Procedure:
A solution of 1,2-dibenzyl 3-tert-butyl (2S,3S)-5,5-difluoropiperidine-1,2,3-tricarboxylate (0.370 g, 0.000756 mol) in EtOH (7.0 mL) was hydrogenated in the presence of 10% Pd/C, under a ballon pressure of hydrogen, for 2 h. After filtered off the catalyst, the filtration was evaporated to dry. The residue was used directly in next step (190 mg, 94.77%). LC MS (M−Bu+1) 210.0.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:8]3[C:13]4[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C(S)(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[C:8]3[C:13]4[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc2sc3c(c2c1)C(N1CCN(C)CC1)=Nc1ccc(F)cc1N3
Agent: CC(S)S
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN1CCN(C2=Nc3ccc(F)cc3Nc3sc4ccc(O)cc4c32)CC1

Procedure:
In the same manner as in Example 62 and using 8-fluoro-2-methoxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine, dichloromethane, ethanedithiol and aluminium chloride, 8-fluoro-2-hydroxy-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][C:12]([CH3:17])([CH3:16])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:18].[C:19]([NH:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([NH:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:33])[C:12]([CH3:16])([CH3:17])[CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:18]
Reactant: CC(C)(C)NC(=O)c1cccc(CCl)c1
Reactant: CC1(C)CN(C(=O)c2ccc(N)c(F)c2)CCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2(C)C)c1
Yield: 39.2 %

Procedure:
To (4-amino-3-fluorophenyl)(3,3-dimethylpiperazin-1-yl)methanone (0.521 mmol, 131 mg) in acetonitrile (5.213 mL) was added N-tert-butyl-3-(chloromethyl)benzamide (0.573 mmol, 129 mg), and triethylamine (1.040 mmol, 145 μl, 105 mg). A catalytic amount of sodium iodide was added. The mixture was heated to reflux for 3 hours. The mixture was allowed to cool and ethyl acetate was added. The organic mixture was washed with water, dried with sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica chromatography (eluting with 5% methanol in dichloromethane) to yield the title compound (90 mg). MS (ESI) m/z 441.4 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].[C:21]1([CH3:31])[CH:26]=CC(S(Cl)(=O)=O)=C[CH:22]=1.C(O)(C)(C)C.N1C=CC=CC=1>CCOCC>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([O:16][C:21]([CH3:31])([CH3:26])[CH3:22])=[O:15]
Reactant: Cc1ccc2oc(-c3ccccc3C(=O)O)c(Br)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: Cc1ccc2oc(-c3ccccc3C(=O)OC(C)(C)C)c(Br)c2c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
A mixture of 2-(3-bromo-5-methyl-2-benzofuranyl)benzoic acid (described in EP-A-0434249) (2.0 g), p-toluenesulphonyl chloride (2.5 g), tert-butanol (10 ml) and pyridine (3 ml) was stirred at 0° C. and allowed to warm to room temperature. Stirring was continued for 72 hours. The mixture was then diluted with ether (100 ml) and washed with 2M hydrochloric acid (75 ml) followed by an aqueous solution of 1M sodium bicarbonate (75 ml). The aqueous solutions were further extracted with ethyl acetate (100 ml) and the combined organic extracts were dried and evaporated in vacuo. Purification by flash column chromatography eluting with dichloromethane:hexane (3:7) gave the title compound (0.6 g) as a colourless gum.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[N+](C1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1)([O-])=O.[CH3:42][O:43]C1C=CC=C(N)C=1>>[CH3:42][O:43][C:4]1[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][S:10]([C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)(=[O:11])=[O:12]
Reactant: COc1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Reactant: COc1cccc(N)c1
Agent: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 73 %

Procedure:
N-(3-methoxy-phenyl)-4-nitro-benzenesulfonamide (RK1-1-27D) I This compound was prepared according to the procedure described for compound 11a except using m-anisidine. Recrystallization from DCM/Hexanes obtained the required product as brown-yellow needles (202 mg, 73%). Mp=96-98° C.; 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=9.0 Hz, 2H), 7.94 (d, J=9.0 Hz, 2H), 7.16 (t, J=8.0 Hz, 1H), 6.73-6.70 (m, 2H), 6.60-6.58 (m, 2H), 3.76 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1N.Cl.N([O-])=O.[Na+].[BrH:17]>O>[Br:17][C:3]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Br
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-methyl-6-nitroaniline (75.0 g, 0.493 mole) and 40 ml of hydrochloric acid (48% solution) in 135 ml of water was cooled to 0°. During a one hour period a solution of sodium nitrite (36.2 g, 0.51 mole) in 60 ml of water was added to the reaction mixture. The mixture was suction filtered through a sintered glass funnel, collecting the filtrate in a flask cooled by a dry ice-acetone bath. The filtrate was placed in a jacketed addition funnel cooled by a dry ice-acetone bath. During a five minute period this solution was added to a stirred mixture of cuprous bromide (77.8 g, 0.51 mole) in 165 ml of hydrobromic acid (48% solution). After complete addition, the mixture was stirred at room temperature for approximately 18 hours, heated at reflux for two hours, then steam distilled. The distillate was extracted with methylene chloride and the extract washed with 2 N aqueous sodium hydroxide, followed by several portions of saturated aqueous sodium chloride solution. The organic phase was passed through phase separation filter paper and evaporated under reduced pressure to give 1-bromo-2-methyl-6-nitrobenzene (17 g) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([OH:25])=O)=[CH:14]3)=[O:10])[CH2:4]1.[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:26][N:2]([CH3:1])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH:20]([CH3:22])[CH3:21])[C:15]([C:23]([N:27]2[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]2)=[O:25])=[CH:14]3)=[O:10])[CH2:4]1
Reactant: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21
Reactant: O=S1(=O)CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)n1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(C(=O)N3CCCC(N(C)C)C3)ccc21

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid, thiomorpholine 1,1-dioxide and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (15%).
Reaction SMILES: N[CH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.C(Cl)CCl.ON1C2C=CC=CC=2N=N1.C[N:23]([CH:25]=[O:26])C>ClCCl>[NH:7]1[C:3]([CH2:2][C:25]([NH2:23])=[O:26])=[N:4][N:5]=[N:6]1
Reactant: CN(C)C=O
Reactant: NCc1nnn[nH]1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: NC(=O)Cc1nnn[nH]1

Procedure:
Carboxylic acid 14.4 can be coupled with 5-aminomethyltetrazole 19.1 (available commercially from Dynamit Nobel GmbH, Leverkusen, Germany) using any of a variety of peptide coupling reagents, including EDC and 1-hydroxybenzotriazole in dichloromethane or DMF, to give 1H-tetraazol-5-ylmethyl carboxamide 19.2. Under similar reaction conditions, 14.4 can be coupled with 5-aminotetrazole 19.3 to afford 1H-tetraazol-5-yl carboxamide 19.4.