Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C(N(CC)CC)C.[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>ClCCl>[S:47]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=1)[C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])([C:44]1[CH:45]=[CH:46][C:41]([CH3:40])=[CH:42][CH:43]=1)(=[O:49])=[O:48]
Reactant: O=C(OCc1ccccc1)c1cccc(C#CCOCCOCCOCCOCCO)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCC#Cc2cccc(C(=O)OCc3ccccc3)c2)cc1
Temperature: 0 °C

Procedure:
Into a 500-mL 3 neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 3-(1-hydroxy-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (25.2 g, 56.88 mmol, 1.00 equiv) in dichloromethane (300 mL), triethylamine (17.2 g, 170.30 mmol, 3.00 equiv). This was followed by the addition of a solution of 4-methylbenzene-1-sulfonyl chloride (16.3 g, 85.34 mmol, 1.50 equiv) in dichloromethane (100 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether/ethyl acetate (5:1-1:1). This resulted in 31 g (91%) of benzyl 3-(1-(tosyloxy)-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:12]1(=[O:21])[N:11]([CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Oc1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1ccncc1
Temperature: 25 °C
Reaction time: 32 h
Yield: 3.1 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 13.97 g (55 mmol) of N-(2-bromoethyl)phthalimide in 80 ml of DMF, 80 ml (55 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added. The mixture was stirred at room temperature for 32 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 0.41 g of the desired compound (yield: 3.1%, colorless crystal).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[CH:16]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH:16]2[C:15]3[N:11]([C:12]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:13][N:14]=3)[C:10]3[CH:35]=[CH:36][CH:37]=[CH:38][C:9]=3[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]2=[O:18])=[CH:21]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester (4.26 g, 8.19 mmol) in CH2Cl2 (27 mL) was added TFA (9.5 mL, 0.123 mmol). The reaction was stirred at room temperature for 8 hours and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and Et2O (15 mL) and was stirred for 24 hours. The precipitate was filtered and was washed with Et2O to provide 2.33 g of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid. 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 7.70 (d, 1H), 7.54-7.38 (m, 7H), 7.26 (d, 1H), 7.17 (m, 2H), 6.98 (t, 1H), 6.88 (m, 2H), 4.90 (d, 1H), 4.49 (d, 1H), 3.82 (t, 1H), 3.59 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH2:12])=[CH:2]1.CCN(CC)CC.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](Cl)=[O:26]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:25](=[O:26])[C:24]2[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=[C:22]([C:21]([F:20])([F:35])[F:36])[CH:23]=2)=[CH:2]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccccc12)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
To a solution of 2-(1H-indol-3-yl)-ethylamine (1.0 g) in CH2Cl2 was added at 22° C. NEt3 (1.74 ml) and 3,5-bis-trifluoromethyl-benzoyl chloride (1.24 ml) and stirring was continued at 22° C. for 16 h. The mixture was washed with aqueous NaHCO3 and brine and the organic layer was dried and evaporated to give the title compound as a brown solid. MS: 401.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2-:14].[Na+]>CN(C)C1C=CC=CC=1>[NH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: [NH2-]
Reactant: Cc1ccc(-c2ccncc2)cc1
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(-c2ccnc(N)c2)cc1
Temperature: 110 °C
Reaction time: 48 h
Yield: 46.9 %

Procedure:
Under an argon gas, 4-(4-methylphenyl)pyridine (2.74 g) was dissolved in N,N-dimethylaniline (10 ml), followed by the addition of sodium amide (1.40 g) at room temperature. After the resulting mixture was stirred at 110° C. for 2 days, the reaction mixture was cooled to room temperature. Brown powder precipitated by the addition of water was collected by filtration. The powder was further purified by chromatography on a silica gel column (ethyl acetate:toluene=1:1). After concentration of the resulting fraction, hexane was added and powder thus precipitated was collected by filtration and dried, whereby the title compound (1.40 g, 47%) was obtained.
Reaction SMILES: COC1C=CC(C[O:8][C:9](=[O:37])[C@@H:10]2[CH2:14][C@@H:13]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][N:11]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)=[O:25])=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N+:34]([C:31]1[CH:32]=[CH:33][C:28]([CH2:27][O:26][C:24]([N:11]2[CH2:12][C@H:13]([O:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][C@H:10]2[C:9]([OH:37])=[O:8])=[O:25])=[CH:29][CH:30]=1)([O-:36])=[O:35]
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1

Procedure:
Trans-1-(p-Nitrobenzyloxycarbonyl)-4-benzoyloxy-L-proline p-methoxybenzyl ester (61.3 g) and anisole (12.8 ml) were stirred together with 70 ml of trifluoroacetic acid at room temperature for 30 minutes. The reaction mixture was distilled to remove tri-fluoroacetic acid, and the residue was diluted with ethyl acetate and a saturated sodium bicarbonate solution. The precipitated crystals were separated by filtration and dissolved in methanol. The solution was acidified with 6N hydrochloric acid to pH 1.0, diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation to give trans-1-(p-nitrobenzyloxycarbonyl)-4-benzoyloxy-L-proline.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][Br:10])[CH:4]=1.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].O>CN(C=O)C>[Br:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOP(OCC)OCC
Reactant: BrCc1cccc(CBr)c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1cccc(CBr)c1)OCC
Temperature: 150 °C
Yield: 72.3 %

Procedure:
To a solution of α,α′-Bisbromo-m-xylene (10.02 g, 37.95 mmol) in DMF (20 mL) was added triethyl phosphite (3.15 g, 3.3 mL, 19.98 mmol) via syringe. The mixture was heated to 150° C. for 2 minutes in a microwave. The reaction mixture was poured into water and product extracted with diethyl ether (3×25 mL). The combined organics were washed with water (2×50 mL) and brine (50 mL), and dried over Na2SO4. Reduced volume in vacuo and purified product by flash column eluting 30-100% ethyl acetate in hexanes to give 4.64 g (76%) 60 as a colorless oil. LCMS: m/z for C12H18BrO3P++H observed 321.0 and 323.0 at 2.29 minutes of a 3.5 minute run, gradient 5-95% CH3CN in H2O.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16]N1C(C)(C)C(=O)N(Br)C1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: COC(=O)Cc1ccc(C(C)(C)C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(C(C)(C)C)cc1

Procedure:
A solution of methyl 4-tert-butylphenylacetate (3.0 g), 1,3-dibromo-5,5-dimethylhydantoin (3.28 g) and azobisisobutyronitrile (AIBN, 0.01 g) in carbon tetrachloride (100 ml) was stirred in a 70° oil bath for hours. After cooling the mixture was filtered through Celite® and the filtrate was evaporated to give an oily residue of methyl α-bromo-4-tert-butylphenylacetate.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([NH:40][C@H:41]([C:46](O)=O)[C:42]([CH3:45])([CH3:44])[CH3:43])=O)(C)(C)C>>[ClH:28].[NH2:40][C@@H:41]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:46][N-:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[C@H](N)C[N-]c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-L-tert-butylglycine by using the same method as in Example 96.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:16]([N:18]2[CH2:23][CH:22]=[C:21]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1>[CH:7]1([CH2:16][N:18]2[CH2:19][CH:20]=[C:21]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[CH2:22][CH2:23]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C(C1CCc2ccccc21)N1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2CCc3ccccc32)C1
Temperature: 25 °C

Procedure:
To a solution of LiAlH4 (1.6 g) in dry THF (100 ml) kept at 0° C. was added drop-wise a solution of 3-[1-(1-indanylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole 4a (4.7 g) in dry THF (200 ml). The mixture was left stirring over-night at room temperature. Excess LiAlH4 was destroyed by cautiously adding 10% water in THF. The precipitated inorganic salts were filtered off. The solvents were evaporated leaving crude title compound (5.2 g). Recrystallization from 2-propanol afforded 2.8 g of pure 5a. Mp 168-170° C. 1H NMR (CDCl3): δ1.85-2.00 (m, 1H); 2.30-2.45 (m, 1H); 2.60 (dd, 1H); 2.60-2.70 (m, 2H); 2.70-3.00 (m, 5H); 3.30 (broad t, 2H); 3.45 (quin, 1H); 6.25 (broad t, 1H); 7.10-7.25 (m, 6H); 7.30-7.40 (m, 2H); 7.90 (d, 1H); 8.10 (broad s, 1H). MS m/z (%): 329 (MH+, 2%), 160 (10%), 131 (100%), 91 (19%).
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]([CH:13]([OH:16])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]([CH:13]([O:16][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCC(O)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(F)cc1[N+](=O)[O-])C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h

Procedure:
To 14.8 g (47.3 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-hydroxy-pentanoic acid in 90 ml dimethylformamide were added at 0° C. 8.26 g (189 mmol) sodium hydride (55%). The suspension was stirred for 2 hours and then 10.4 ml (94.6 mmol) 2,5-difluoro-nitrobenzene in 10 ml dimethylformamide were added. After stirring overnight the mixture was poured under cooling on aqueous 2M citric acid solution. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane (3:7) yielded 12.9 g (61%) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-pentanoic acid as orange solid, MS m/e (%): 453.0 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:24])=[O:23])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2.[Na+:30].[Na+].[Na+].[C:33](OC(=O)C)(=[O:35])[CH3:34].C([O-])(=O)C.[Na+]>CN(C)C=O>[Na+:30].[Na+:30].[Na+:30].[C:33]([O:1][C:2]1[CH:15]=[C:14]2[C:16]3=[C:17]4[C:3]=1[C:4]([S:26]([O-:29])(=[O:28])=[O:27])=[C:5]([S:22]([O-:25])(=[O:23])=[O:24])[C:6]([S:18]([O-:21])(=[O:20])=[O:19])=[C:7]4[CH:8]=[CH:9][C:10]3=[CH:11][CH:12]=[CH:13]2)(=[O:35])[CH3:34]
Reactant: O=S(=O)([O-])c1c(S(=O)(=O)[O-])c2ccc3cccc4cc(O)c(c1S(=O)(=O)[O-])c2c34
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cccc3ccc4c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c(S(=O)(=O)[O-])c1c4c32

Procedure:
10 grams of trisodium hydroxypyrenetrisulfonate, 50 mls of acetic anhydride and 1.6 grams of sodium acetate are added to 200 mls of dimethylformamide in a 500 ml flask. The flask is equipped with a condenser having a drying tube and a stirring bar. The contents of the flask are stirred at 50° to 70° C. for one to two hours. The reaction mixture is filtered and the filtrate collected. The filtrate is vacuum evaporated to yield a crude solid product. This crude solid product is extracted into boiling methanol. The volume of the methanol is reduce to 100 mls and cooled. The first batch of product crystallizes out and is filtered. The methanol is again reduced to approximately 20 mls to yield a second crop of product. This is filtered and combined with the first batch and dried for twenty to forty minutes at 60° C.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[C:19]([O:18][C:16]([N:6]1[CH2:7][C@H:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:9][C@H:5]1[CH2:3][OH:2])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](c2ccccc2)C[C@H]1CO
Reaction time: 14 h

Procedure:
4.2 g of (2S,4S)-4-Phenyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (13.75 mmol) in 30 ml tetrahydrofuran were slowly added to a suspension of 0.27 g of lithium aluminium hydride in 50 ml tetrahydrofurane. Stirring was continued for 5 h at 0-5° C. and for 14 h at room temperature. For workup, a mixture of tetrahydrofurane/water (1:1) was slowly added to the reaction mixture at 0° C. The solvent was then evaporated under reduced pressure, water was added and the pH was adjusted to about 5 with 20% aqueous citric acid. The aqueous phase was extracted four times with ethyl acetate, the organic layers were combined, dried over magnesium sulphate, filtered, and the solvent was removed under reduced pressure to yield 3.85 of product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7](Br)[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4].[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].C(NCC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH2:15])=[C:7]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:8]=[C:9]2[C:13]=1[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1c(N)c(Br)cc2cn[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)c(C#C[Si](C)(C)C)cc2cn[nH]c12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 60.3 %

Procedure:
To a solution of 1.5 g (5.6 mmol) of 6-amino-5-bromo-1H-indazole-7-carboxylic acid methyl ester, prepared as in step a in example 16, in 3 mL of N,N-dimethylformamide under an atmosphere of argon is added 785 μL (5.6 mmol) of trimethylsilylacetylene, 8.65 mL of diethylamine (83.2 mmol), 194 mg (0.28 mmol) of dichlorobis(triphenylphosphine)palladium II and 53 mg (0.28 mmol) of copper iodide. The reaction mixture is stirred in a microwave oven at 150° C. for 5 minutes, filtrated over Celite (washing with ethyl actetate) and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, hexane/ethyl acetate 2:1) to afford 970 mg of the product (61%) as a yellowish solid; LC/MS:288/289 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][CH:6]=[CH:5]2.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].[OH-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:7][CH:6]=[CH:5]2
Reactant: Clc1nccc2cc(Br)ccc12
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: Brc1ccc2c(Oc3ccccc3)nccc2c1
Temperature: 140 °C
Yield: 98.6 %

Procedure:
A mixture of 10 g of 1b, 31 g of phenol and 4 g of KOH was heated at 140° C. for 2 hours. After cooling to room temperature aqueous 3N NaOH was added and the mixture was extracted with dichloromethane. The dichloromethane extract was washed with aqueous 2N NaOH, washed with water, dried (MgSO4) and concentrated to yield 12.2 g of 1c. 1H-NMR 200 MHz (CDCl3) δ: 7.1-7.6 (6H, m), 7.70 (1H, dd, J=9 Hz and J=2 Hz), 7.95-8.10 (2H, m), 8.31 (1H, d, J=9 Hz).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29](Cl)(=[O:31])=[O:30])[CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:33])=[C:27]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH:28]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1S(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 5-fluoro-2-methylbenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 5-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-methyl-benzenesulfonamide as a colorless oil. MS: 513.0 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([CH:13]=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([O:20]C)[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([OH:20])[C:8](=[O:22])[NH:7][C:6]=2[CH:23]=1
Reactant: CCOC(=O)C=Cc1c(OC)c(=O)[nH]c2cc(Cl)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1c(O)c(=O)[nH]c2cc(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 68 h
Yield: 83.1 %

Procedure:
A solution of 8-Chloro-4-[2-(ethoxycarbonyl)ethenyl]-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.1009 g) in tetrahydrofuran (2.3 mL) was treated with a solution of lithium hydroxide monohydrate (0.0126 g) in tetrahydrofuran (2.3 mL) and water (0.5 mL) at room temperature. The solution was stirred at room temperature under argon for 68 hours. It was then added to 0.05N hydrochloric acid (10 mL). The resulting solid was filtered off, washed with water, and air-dried to give a light tan solid (0.0803 g). The solid was dissolved in hot ethanol (5 mL). The solution was filtered and treated with water (2 mL). The crystals were filtered off at room temperature, washed with aqueous ethanol (1:1, v:v) and dried under vacuum to give a light tan solid (0.054 g); mp 177.5°-178.4° C.; 1H NMR (d6 -DMSO) 7.74 (d,1, J=16), 6.74 (d,1, J=16) for trans olefin protons; MS: m/z=276 (base peak), 322 (M+1). Analysis for C15 H12ClNO5 : Calculated: C, 56.00; H, 3.78; N, 3.99; Found: C, 56.55; H, 3.78; N, 3.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH3:30])[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:21][C:22]2[CH:23]=[C:24]([CH3:30])[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=2)[C:9]2[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][N:12]([CH3:14])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(C)cc1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nn(C)cc1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1
Reaction time: 0.33 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-1H-pyrazole-3-carboxylate (Step 10.2) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). After purification by silica gel column chromatography, the resulting residue was further purified by preparative HPLC (Gilson gx-281; column: Sunfire C18, 30×100 mm, 5 μm; flow: 30 mL/min; gradient: 5% to 100% B in 20 min; A=0.1% TFA in H2O, B=CH3CN. detection: UV). tR: 3.91 min (HPLC 1); tR: 0.90 min (LC-MS 2); ESI-MS: 415 [M+H]+ (LC-MS 2); Rf=0.46 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[CH3:18][S:19](OCCN1CCC(NC(OC(C)(C)C)=O)CC1)(=[O:21])=[O:20]>>[CH3:18][S:19]([O:1][CH2:2][CH2:3][C@H:4]1[CH2:5][CH2:6][C@H:7]([NH:10][C:11]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:17])[CH2:8][CH2:9]1)(=[O:21])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCO)CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1

Procedure:
Commercially available tert-butyl [trans-4-(2-hydroxyethyl)cyclohexyl]carbamate (500 mg, 2.05 mmol) was reacted according to the procedure described for Intermediate 6 to give the product as a white solid (yield 92%).