Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[C:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:8])[CH3:5].[OH-].[Na+]>CO.C1COCC1>[CH3:29][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]#[C:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:8])([CH3:5])[C:3]([OH:30])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1C#CCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1C#CCCc1ccccc1)C(=O)O

Procedure:
20 mg 2-methyl-2-{[1-(4-phenyl-but-1-ynyl)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester were reacted with 60 μl of 2 M sodium hydroxide in 0.5 ml methanol and 0.5 ml THF for 48 h room temperature and for 4 h at 60° C. The organic solvents were then removed in vacuo, and the residue was treated with water, acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate, and concentrated. After chromatography on silica (ethyl acetate/heptane) 11 mg of 2-methyl-2-{[1-(4-phenyl-but-1-ynyl)-naphthalene-2-carbonyl]-amino}-propionic acid were obtained.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[CH3:30][CH:31]([OH:34])[CH:32]=[CH2:33]>[Cu]I.C1(C)C=CC=CC=1>[CH3:30][CH:31]([O:34][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH:32]=[CH2:33]
Reactant: COc1ccc(I)cc1
Reactant: C=CC(C)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: C=CC(C)Oc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 38 h
Yield: 53.9 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), 1,10-phenanthroline (36 mg, 0.20 mmol, 0.20 equiv), Cs2CO3 (652 mg, 2.0 mmol, 2.0 equiv), 4-iodoanisole (234 mg, 1.0 mmol, 1.0 equiv), 3-buten-2-ol (180 μL, 2.0 mmol, 2.0 equiv) and toluene (0.5 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 38 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with diethyl ether. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane:diethyl ether 30:1) provided 96 mg (54% yield) of the known title compound as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][C:4]=1[CH3:14])=O.[BH4-].[Na+].[NH3:17]>CO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH2:17][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[CH:5][C:4]=1[CH3:14]
Reactant: N
Reactant: Cc1cc(C(C)(C)C#N)ccc1C=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(C)(C)C#N)ccc1CN
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
2-(4-formyl-3-methylphenyl)-2-methylpropanenitrile 1.89 g, 10.2 mmol) is dissolved in 50 ml of 7M NH3 in MeOH. Ti(OiPr)4 (6 mmol, 20 mmol) is added and the mixture stirred for 3 hours at room temperature. NaBH4 (0.6 g, 15 mmol) is added and the reaction left at room temperature overnight. The mixture is quenched by the addition of 25 ml of NH4OH 2 M. The resulting precipitate is filtered off and washed with EtOAc. Phases are separated, the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness, giving 2-[4-(aminomethyl)-3-methylphenyl]-2-methylpropanenitrile (1.325 g, 7.09 mmol, 87%). The crude product is used without further purification. 1H NMR (400 MHz, DMSO-D6) δ 1.64 (s, 6H, first rotamer) 1.65 (s, 6H, second rotamer) 2.28 (s, 3H, first rotamer) 2.29 (s, 3H, second rotamer) 3.32 (broad s, 2 H) 3.67 (s, 2H, first rotamer) 3.68 (s, 2H, second rotamer) 7.24-7.27 (m, 1H) 7.28 (s, 1H) 7.36-7.40 (m, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=O)/[Cl:5])/[Cl:3].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[Cl:3][C:2]1[C:1](=[O:9])[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[CH:6][C:4]=1[Cl:5]
Reactant: NNc1ccccc1
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Solvent: CCO
Product: O=c1c(Cl)c(Cl)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mucochloric acid (9.3 g, 0.055 moles) was dissolved in ethanol (60 ml) and phenyl hydrazine (5.4 g, 0.05 moles) was added. The reaction mixture was stirred at room temperature for 2 hours. Evaporated to a low bulk and the residue was suspended in glacial acetic acid (60 ml). Refluxed with stirring for 3 hours. Evaporated to dryness and triturated with methanol to give the required product as a pale brown solid. (11.0 g, 91%)
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:18]1([O:1][C:2]2[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrC1CCCC1
Reactant: COC(=O)c1ccc(OC)c(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OC)c(OC2CCCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of methyl 3-hydroxy-4-methoxy-2-nitrobenzoate (1.14 g, 5.0 mmol), bromocyclopentane (0.7 mL, 6.5 mmol), potassium carbonate (2.0 g, 14 mmol), and anhydrous acetonitrile (15 mL) was refluxed under N2. After 19 h, the reaction was allowed to cool to room temperature, concentrated, and purified by silica gel chromatography (4:1→3:2; hexanes:ethyl acetate) to give methyl 3-(cyclopentyloxy)-4-methoxy-2-nitrobenzoate: MS (ESI): 296.5.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9].[CH3:15][O:16][CH2:17]Cl>>[CH3:1][O:2][CH2:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[N:6]([CH2:15][O:16][CH3:17])[C:7](=[O:10])[CH2:8][Cl:9]
Reactant: COCCl
Reactant: COCc1ccccc1NC(=O)CCl
Product: COCc1ccccc1N(COC)C(=O)CCl

Procedure:
Following the above procedure, but using 2'-(methoxymethyl)-2-chloroacetanilide as the sec-amide starting material and chloromethyl methyl ether as the alkylating agent, the product 2'-(methoxymethyl)-N-(methoxymethyl)-2-chloroacetanilide was obtained.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:18]=[N:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28]OC(OC)N(C)C>>[CH:1]1([N:7]2[C:8]3[C:9]4[N:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:10]=4[N:11]=[CH:12][C:13]=3[C:14](=[O:16])[CH:15]=[CH:28]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1cnc2c(ncn2COCC[Si](C)(C)C)c1NC1CCCCC1
Reactant: COC(OC)N(C)C
Product: C[Si](C)(C)CCOCn1cnc2c1ncc1c(=O)ccn(C3CCCCC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1-[7-(Cyclohexylamino)-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-6-yl]ethanone (88.9 mg, 0.229 mmol) in N,N-dimethylformamide dimethyl acetal (2.0 mL) was stirred at 180° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (5 mL) and stirred with 1 M hydrochloric acid (2 mL) at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol=1/1/0→0/10/1 (v/v/v)) to give the title compound as a yellow solid (57.5 mg, yield 63%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.C(O[CH2:15][N:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:22]([N:16]1[CH2:17][CH:6]2[CH:7]([C:2]([CH3:9])([CH3:1])[CH2:3][CH2:4][C:5]2=[O:8])[CH2:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC1(C)C=CC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC(=O)C2CN(Cc3ccccc3)CC21
Reaction time: 3 h

Procedure:
To a solution of 5 g of 4,4-dimethylcyclohex-2-enone and 12.4 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 100 cm3 of dichloromethane are added, at a temperature of 10° C., 5 drops of trifluoroacetic acid. The reaction mixture is stirred at this temperature for 3 hours, then potassium carbonate is added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 5.2 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (85/15 by volume) and collecting 100 cm3 fractions. Fractions 39 to 63 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 3.64 g of (3aRS,7aRS)-2-benzyl-7,7-dimethyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Br.Br.Br.[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][NH:37][CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]>>[CH2:13]([C:15]1[C:16]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([C:32]4[NH:33][C:34]5[CH2:39][CH2:38][N:37]([CH2:6][C:5]6[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=6)[CH2:36][C:35]=5[N:40]=4)=[N:28][NH:29]3)=[CH:25][CH:24]=2)=[CH:17][C:18]([F:22])=[C:19]([OH:21])[CH:20]=1)[CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccc(O)cc3)C4)n[nH]c2c1
Yield: 49.2 %

Procedure:
The title compound was prepared from 4-hydroxy-benzaldehyde (24.2 mg, 198 μmol) and 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) using the method of Example 18. The crude material was purified by HPLC Method A to afford 31.4 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)O)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Cl:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C(O)c2ccc(Br)cc2)c1
Solvent: ClCCl
Product: COc1cccc(C(Cl)c2ccc(Br)cc2)c1
Reaction time: 8 h

Procedure:
The crude alcohol from above (6.5 g, 22 mmole) was dissolved in 50 ml of dichloromethane, and 2.4 ml (33 mmole) of thionyl chloride was added dropwise at room temperature. The reaction was allowed to stir overnight and the solvent was removed under vacuum. The crude product was redissolved in 50 ml of toluene and the solvent was again removed under vacuum in order to eliminate excess thionyl chloride, providing 6.85 g of crude 4-bromo-3'-methoxybenzhydryl chloride as a dark oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:22]3[NH:23][C:24]4[CH:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2].CO[CH:36](OC)[N:37]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(CC)CC)C.Br>O1CCOCC1.CO>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:20]([NH:21][C:22]3[NH:23][C:24]4[CH:30]=[C:29]([CH2:31][N:32]=[CH:36][N:37]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:28]=[CH:27][C:25]=4[N:26]=3)[C:19](=[O:33])[N:10]2[C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:3])[CH3:2]
Reactant: COC(OC)N1CCCCCC1
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3nc4ccc(CN)cc4[nH]3)[C@H]2SC1
Agent: Br
Solvent: CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3nc4ccc(CN=CN5CCCCCC5)cc4[nH]3)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
To a solution of t-butyl 3-acetoxymethyl-7-(5-aminomethylbenzimidazol-2-yl)aminoceph-3-em-4-carboxylate (93 mg.) in dioxane (2 ml.) and methanol (3 ml.) at 20° was added dimethoxyhexahydro-1H-azepin-1-ylmethane (30 mg.) and then triethylamine. The mixture was cooled to 0° and stirred for 30 minutes. Two equivalents of HBr in methanol were added and the solvent evaporated. The residue was dissolved in the minimum CH2Cl2 and triethylamine hydrobromide precipitated by addition of ether. The product was purified by chromatography on magnesium silicate using CH2Cl2 /MeOH 98:2 v/v as eluant to give t-butyl 3-acetoxymethyl-7-(5-hexahydro-1H-azepin-1-ylmethyleneaminomethylbenzimidazol-2-yl)aminoceph-3-em-4-carboxylate having the following n.m.r. in d6DMSO: 1.63 (s, 9H); 1.7 (s, 8H); 2.17 (s, 3H); 3.3-4.0 (br, 6H); 4.67 (s, 2H); 4.75 (d, 1H); 5.1 (d, 1H); 5.38 (d, 1H); 6.0 (d, 1H); 6.8-7.5 (m, 3H); 8.43 (s, 1H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Br:31])[C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.C([O:43][C:44](=[O:48])[C@H:45]([CH3:47])[NH2:46])C>CCOCC>[Br:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:46][C@H:45]([C:44]([OH:48])=[O:43])[CH3:47])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCCCCCCCCCBr)C(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)[C@H](C)N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C[C@H](NC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)C(=O)O

Procedure:
A solution of 4.75 g. of N-trifluoroacetyl-4-(16-bromohexadecylamino)benzoyl chloride and 1.2 g. of triethylamine in 200 ml. of warm ether is treated with 1.55 g. alanine ethyl ester and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields the product as a white, crystalline solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8]Cl)(=O)C.[OH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CN(C=O)C>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1
Reactant: CC(=O)OCCCCCl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(OCCCCO)cc1
Temperature: 90 °C
Reaction time: 11 h
Yield: 89.5 %

Procedure:
276.6 g of 4-chlorobutyl acetate (1.8 mol) were added to a solution of 249 g of ethyl 4-hydroxybenzoate (1.5 mol), 3 g of potassium iodide (0.018 mol) and 248 g of potassium carbonate (1.8 mol) in 21 of DMF, and the mixture was stirred at 90° C. for 11 hours. The reaction mixture was poured into 5 l of ice-water, and the precipitate was filtered off with suction and washed with 41 of ice-water. The crude product was dissolved in 3 l of ethanol, potassium hydroxide (400 g) was added, and the mixture was refluxed for 3 hours. The reaction mixture was poured into 6 l of ice-water and acidified using concentrated hydrochloric acid, and the precipitate was filtered off. The precipitate was washed with water until neutral and subsequently dried, giving 282.1 g of 4-(4′-hydroxybutoxy)benzoic acid (yield 89%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21](COCC[Si](C)(C)C)[N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:14])=[O:13])(=[O:5])=[O:4].[OH-].[Na+]>C(O)C.C(OC(C)C)(C)C>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[C:19]2[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:14])=[O:13])(=[O:5])=[O:4]
Reactant: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(CCc3ccccc3)c2c1
Temperature: 20 °C
Yield: 29.9 %

Procedure:
2-Methylsulfonyl-N-(3-phenethyl-1H-indazol-5-yl)benzenesulfonamide can be obtained in the following way: 5.6 ml of an aqueous 5N hydrochloric acid solution are added dropwise to a suspension of 0.56 g of 2-methylsulfonyl-N-[3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]benzenesulfonamide in 17 ml of absolute ethanol. The reaction mixture is then refluxed for 30 minutes and then cooled to a temperature in the region of 20° C. 6.8 ml of an aqueous 5N sodium hydroxide solution are then added and the mixture is stirred. The mixture is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and the residue is taken up in a mixture of 35 ml of ethyl acetate and of 50 ml of water. After settling out, the aqueous phase is extracted with 2 times 30 ml of ethyl acetate. The organic extracts are pooled, washed with 2 times 20 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is purified by chromatography under argon pressure (50 kPa) on a column of 75 g of silica (particle size 40-63 μm), eluting with a dichloromethane/methanol (98/2 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is repurified by chromatography under argon pressure (50 kPa), on a column of silica (particle size 40-63 μm), eluting with a cyclohexane/ethyl acetate (70/30 by volume) mixture. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 30° C. The residue thus obtained is taken up in 15 ml of diisopropyl ether, triturated, filtered and then dried. 130 mg of 2-methylsulfonyl-N-(3-phenethyl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a white solid melting at 192° C. (CI mass analysis: m/z 456 (M+H)+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]4[C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:27]([C:29]6[N:30]=[CH:31][N:32](C(C7C=CC=CC=7)(C7C=CC=CC=7)C7C=CC=CC=7)[CH:33]=6)O)[CH:25]=5)[NH:20][CH:19]=4)[CH2:12][CH2:11]3)[C:4]=2[CH:3]=[CH:2]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].Cl>ClCCl>[NH:30]1[C:29]([CH2:27][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[C:18]3[CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:5]3[C:4]4[CH:3]=[CH:2][NH:1][C:9]=4[CH:8]=[CH:7][N:6]=3)[CH2:11][CH2:12]2)=[CH:33][N:32]=[CH:31]1
Reactant: OC(c1ccc2[nH]cc(CCN3CCN(c4nccc5[nH]ccc45)CC3)c2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2[nH]ccc2c(N2CCN(CCc3c[nH]c4ccc(Cc5cnc[nH]5)cc34)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution, cooled to −5° C., of 1.9 mmol of the compound obtained in Step 1 and 9.5 mmol of triethylsilane in dichloromethane, is treated with a solution of 19 mmol of trifluoroacetic acid. After stirring at ambient temperature for 18 hours, the reaction mixture is treated with a saturated solution of NaHCO3, and then the organic phase is treated with a 2N HCl solution. The aqueous phase is rendered basic with 20% sodium hydroxide solution, and extraction with dichloromethane enables the expected product to be isolated after drying and concentrating the organic phase.
Reaction SMILES: O[C:2]1([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:10]=[C:9]2[CH2:11][NH:12][CH:13]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:14][N:7]3[C:8]2=[C:4]([CH:5]=[CH:6]3)[CH:3]1[C:24]([F:27])([F:26])[F:25].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:28]([C:2]1[C:3]([C:24]([F:26])([F:27])[F:25])=[C:4]2[C:8]3=[C:9]([CH2:11][NH:12][CH:13]([C:15]([NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[O:16])[CH2:14][N:7]3[CH:6]=[CH:5]2)[CH:10]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Nc1ccccc1)C1Cn2ccc3c2C(=CC(O)(CCc2ccccc2)C3C(F)(F)F)CN1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccc1)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1

Procedure:
The 6-hydroxy-6-phenethyl-N-phenyl-7-(trifluoromethyl)-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide was further processed with thionyl chloride and pyridine as described in Example 1, above to yield 6-phenethyl-N-phenyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indole-2(1H)-carboxamide (5 mg).
Reaction SMILES: [Mg].II.C(Br)C.[CH3:7][N:8]1[CH2:13][CH2:12][CH:11](Cl)[CH2:10][CH2:9]1.[CH:15]12[C:27](=[O:28])[CH:19]3[C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[CH:22]1[CH:16]2[C:17]1[CH:32]=[CH:31][CH:30]=[CH:29][C:18]=13.[Cl-].[NH4+]>O1CCCC1>[OH:28][C:27]1([CH:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)[CH:19]2[C:18]3[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=3[CH:16]3[CH:15]1[CH:22]3[C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=12
Reactant: O=C1C2c3ccccc3C3C1C3c1ccccc12
Reactant: CN1CCC(Cl)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CN1CCC(C2(O)C3c4ccccc4C4C(c5ccccc53)C42)CC1
Reaction time: 0.5 h

Procedure:
In a reaction vessel, 1.95 g (0.08 mole) of magnesium chips under dry nitrogen is covered with 12 ml of abs. tetrahydrofuran, and corroded with a trace of iodine and 0.1 ml of ethylbromide. While stirring is maintained, 10.7 g (0.08 mole) of 1-methyl-4-chloropiperidine, dissolved in 30 ml of abs. tetrahydrofuran, is added dropwise at 60° in such a manner that the reaction mixture remains boiling. Refluxing is performed for a further 30 minutes until all the magnesium is dissolved. To this Grignard solution cooled to 5° is then added dropwise at 5-10° in the course of 30 minutes, with stirring, 4.46 g (0.02 mole) of 1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-one dissolved in 20 ml of abs. tetrahydrofuran. The reaction mixture is subsequently heated to ca. 20° and then stirred into 350 ml of a 3% ammonium chloride solution. The reaction product precipitated in crystalline form is filtered off with suction, washed with water and dried in a water-jet vacuum at ca. 50° to obtain 4-(11-hydroxy-1,1a,6,10b-tetrahydro-1,6-methano-dibenzo[a,e]cyclopropa[c]cyclohepten-11-yl)-1-methyl-piperidine; M.P. 239°-242°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][NH:13][CH3:14])=[CH:5][N:6]2[CH3:11].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[N:6]([CH3:11])[CH:5]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: CNCc1cn(C)c2cccc(F)c12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2cccc(F)c12)C(=O)/C=C/c1ccc(N)nc1
Yield: 31.3 %

Procedure:
According to the procedure of Example 24, except substituting 4-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.11 g, 37%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.