Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:15][C:16]1[O:20][N:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[C:17]=1[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>O1CCCC1>[F:27][C:23]1[CH:22]=[C:21]([C:18]2[C:17]([C:28]3[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:1](=[O:3])[CH3:2])(=[O:36])=[O:35])=[CH:32][CH:33]=3)=[C:16]([CH3:15])[O:20][N:19]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1ccc(S(N)(=O)=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)noc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
Acetic anhydride (1.01 g, 9.39 mmol) and triethylamine (0.401 g, 3.97 mmol) were added to a solution of 4-[5-methyl-3-(3-fluorophenyl)isoxazol-4-yl]benzenesulfonamide (1.10 g, 3.31 mmol) and N,N-dimethylpyridine (0.202 g) in dry tetrahydrofuran. After stirring for 18 hours at room temperature, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid and brine, dried over anhydrous MgSO4 and concentrated to afford 1.0 g (81%) of the desired product as a crystalline product: mp 144-145° C. 1H NMR (CDCl3) 8.00 (d, 2H, J=7.3 Hz), 7.30-7.27 (m, 4H), 7.10-7.06 (m, 3H), 2.46 (s, 3H), 1.99 (s, 3H). Anal. Calc'd for C18H15FN2O4S: C, 57.75; H, 4.04; N, 7.48. Found: C, 57.84; H, 4.06; N, 7.49.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1[C:9]([NH:34][C@@H:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][S:37](O)(=[O:39])=[O:38])=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)=[N:12][CH:13]=1.CN(C=O)C>ClCCl>[F:7][C:8]1[C:9]([NH:34][C@@H:35]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:36][S:37]([Cl:4])(=[O:39])=[O:38])=[CH:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([F:23])[CH:21]=3)[N:16]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)=[N:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)Cl)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.7 %

Procedure:
Oxalyl chloride (3.5 mL, 38.7 mmol) was added to a solution of (S)-2-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3yl)pyridin-4- lamino)-3,3-dimethylbutane-1-sulfonic acid, 57a, (7.3 g, 12.9 mmol) in dichloromethane (130 mL), followed by the slow, dropwise addition of DMF (2 mL). The yellow colored solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford 8.4 g of the desired product as a foamy yellow solid: LC/MS (60-90% ACN/water 5 min with 0.9% FA) m/z 585.72 (M+H) RT =2.30 minutes.
Reaction SMILES: [CH:1]1([N:4]2[C:13]([CH3:15])([CH3:14])[CH:12](O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:17])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:37][O:38][C:39]([C:41]1[N:42]=[CH:43][NH:44][CH:45]=1)=[O:40].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH3:37][O:38][C:39]([C:41]1[N:42]([CH:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[N:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]2([CH3:15])[CH3:14])[CH:43]=[N:44][CH:45]=1)=[O:40]
Reactant: COC(=O)c1c[nH]cn1
Reactant: CC1(C)C(O)c2ccccc2C(=O)N1C1CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)N(C2CC2)C1(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-cyclopropyl-4-hydroxy-3,3-dimethyl-3,4-dihydro-2H-isoquinolin-1-one (2.25 g, 9.72 mmol) in THF (100 mL) is added triphenylphosphine (4.3 g, 16.5 mmol), and methyl-4-imidazolecarboxylate (2.08 g, 16.5 mmol). The heterogeneous reaction mixture is cooled to 0° C. and di-tert-butyl azodicarboxylate (3.81 g, 16.5 mmol) is added. The reaction is allowed to warm to room temperature and stirred for 45 min, and then heated at 44° C. for an additional 75 min, at which time the reaction is cooled to 0° C. and 4M HCl in dioxane (20 mL, 80 mmol) is added. The reaction is brought to room temperature and allowed to stir for 1 h. The reaction mixture is then basified to a pH of ca. 9 via the cautious addition of saturated aqueous NaHCO3. The resulting mixture is further diluted with ethyl acetate and saturated aqueous NaHCO3, and the layers are separated. The aqueous layer is extracted three times with ethyl acetate and the organic layers are combined, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue is adsorbed onto silica gel and submitted to silica gel flash chromatography (ethyl acetate-dichloromethane, 1:24 to 1:4) to provide 3-(2-cyclopropyl-3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester as an off-white solid; HRMS (ESI) m/z 340.1668 [(M+H)+; calculated for C19H22N3O3: 340.1661]; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.34-0.45 (m, 1 H), 0.78-0.88 (m, 1 H), 0.90-0.99 (m, 1 H), 1.05-1.16 (m, 1 H), 1.31 (s, 3 H), 1.45 (s, 3 H), 2.29-2.43 (m, 1 H), 3.94 (s, 3 H), 6.55 (s, 1 H), 7.28-7.33 (m, 2 H), 7.44-7.55 (m, 2 H), 7.78 (s, 1 H), 8.17-8.29 (m, 1 H)
Reaction SMILES: [C:1]([C:3]([CH2:15][Si:16]1([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])C(OCC)=O)#[N:2].O.[Br-].[Li+]>CN(C)C=O>[CH3:21][Si:16]1([CH2:15][CH:3]([C:1]#[N:2])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)CC(C#N)(C[Si]1(C)CCCC1)C(=O)OCC
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C#N)C[Si]1(C)CCCC1
Yield: 88.3 %

Procedure:
Diethyl 2-cyano-2-[(1-methyl-1-silacyclopentan-1-yl)methyl]succinate (1.943 g, 6.25 mmol) was treated with water and lithium bromide in dimethylformamide in the same manner as that of Example 15. The reaction mixture was treated in a conventional manner, and the residue was purified by silica gel column chromatography [hexane/ethyl acetate (14:1)] to obtain ethyl 4-(1-methyl-1-silacyclopentan-1-yl)-3-cyanobutanoate (1.321 g, 88%) mentioned in the title was obtained as colorless oil.
Reaction SMILES: [C:1]([N:4]([CH2:14][CH3:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([N:4]([CH2:14][CH3:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCN(C(C)=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCN(C(C)=O)c1ccc(N)cc1

Procedure:
N-acetyl-N-ethyl-4-nitroaniline (9a) (1.8 g, 8.64 mmol) is hydrogenated in THF (30 ml), over 10%Pd on carbon (100 mg) for 1.5 hours. The catalyst is removed by filtration and the solvent removed evaporation. The product crystalises on standing in hexane, and following filtration, is dried under vacuum; ES+ (M+1) 178.88.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][N:10]=[C:9]1[CH:13]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[CH3:25])[CH2:14][CH:15]=[CH2:16])=O)(C)(C)C.[OH-].[Na+].CCOC(C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:25][C:19]1[C:20]([CH3:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH:13]([C:9]1[NH:10][CH2:11][CH2:12][N:8]=1)[CH2:14][CH:15]=[CH2:16]
Reactant: C=CCC(Oc1cccc(C)c1C)C1=NCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C=CCC(Oc1cccc(C)c1C)C1=NCCN1

Procedure:
2-[1-(2,3-dimethyl-phenoxy)-but-3-enyl]-4,5-dihydro-imidazole-1-carboxylic acid tert-butyl ester (120 mg) was dissolved in a solution of 10% trifluoroacetic acid in dichloromethane (5 ml). After 24 hours the mixture was shaken between NaOH (2M) and EtOAc and the organic phase dried with Na2SO4 and evaporated to yield 2-[1-(2,3-Dimethyl-phenoxy)-but-3-enyl]-4,5-dihydro-1H-imidazole as crystals m.p. 72-74° C.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:33])[NH2:32])[C:20]([CH2:34][CH3:35])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN[C@H](C(N)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>ClCCl>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([NH2:32])=[O:33])[C:20]([CH2:34][CH3:35])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CC)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: C=CCON([C@@H]1C=C(CC)[C@@H](C(N)=O)NC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 75.2 %

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3-ethyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 212, 1.44 g, 2.82 mmol) following the procedure described for Intermediate 21, except the reaction mixture was stirred over the weekend at room temperature. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. An emulsion formed and the aqueous was extracted three to four more times with DCM. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound (0.870 g, 75%) as a yellow foam.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.C(=O)=O.[Br:13]N1C(=O)CCC1=O.[Cl-].[Na+]>O1CCCC1>[Br:13][C:9]1[S:8][CH:7]=[C:5]2[C:4]=1[S:3][C:2]([CH3:1])=[N:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cscc2s1
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2csc(Br)c2s1

Procedure:
1 mmol of 2-methylthieno[3,4-d][1,3]thiazole represented by formula (12) was dissolved in 10 ml of tetrahydrofuran and kept at −78° C. in a methanol-bath cooled by dry ice. Into this solution, a solution comprised of 1.05 mmol of N-bromosuccinimide and 5 ml of tetrahydrofran was gradually added dropwise. After two hours reaction, an excess amount of a saturated sodium chloride aqueous solution was added to stop the reaction. The reacted liquid was washed with water, and the organic layer was recovered and dried under sodium sulfate. The solvent was evaporated out and then purification was carried out using column separation method with solvents of ethylacetate and hexane, obtaining 6-bromo-2-methylthieno[3,4-d][1,3]thiazole represented by formula (13).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)(OCC1C=CC=CC=1)=O.C(OC[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[NH:30][CH3:31])C1C=CC=CC=1>O1CCCC1>[CH3:31][N:30]1[C:29]2[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=2[CH2:1][N:11]2[CH2:18][CH2:17][CH2:16][CH:12]2[C:13]1=[O:15]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CNc1ccccc1COCc1ccccc1
Solvent: C1CCOC1
Product: CN1C(=O)C2CCCN2Cc2ccccc21

Procedure:
A mixture of 2.5 g. of N-carbobenzoxyproline, 1.7 g. of N,N'-carbonyldiimidazole and 25 ml. of tetrahydrofuran is stirred for 1 hour at room temperature and 2.2 g. of o-(benzyloxymethyl)-N-methylaniline is added. The mixture is heated at reflux temperature for 4 hours and concentrated to remove the solvent. The residue is mixed with 200 ml. of ethanol and 2 g. of 10% palladium-on-carbon catalyst and shaken in a Parr hydrogenator under about 3 atmospheres of hydrogen pressure until uptake is complete. The catalyst is filtered off and the mother liquor is concentrated to remove volatile materials. The residue is extracted into methylene chloride. This solution is washed twice with water, dried over magnesium sulfate, and heated at reflux temperature for 6 hours with 5 ml. of thionyl chloride. The reaction mixture is washed twice with sodium carbonate solution, once with water and concentrated. The residue is purified by partition chromatography on a diatomaceous earth column using a heptane/ methyl cellosolve solvent system and 1,2,3,5,10,11a-hexahydro- 10-methyl-11H-pyrrolo[2,1-c] [1,4]benzodiazepin-11-one is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2].CC[N:23](C(C)C)[CH:24]([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18](=[O:20])[NH:23][CH:24]([CH3:26])[CH3:25])=[CH:16][CH:17]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnn(Cc2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: ClCCl
Product: CCOC(=O)c1cnn(Cc2ccc(C(=O)NC(C)C)cc2)c1
Temperature: 23 °C

Procedure:
To a solution of 1-(4-carboxy-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (50 mg, 0.153 mmol) in DCM (1 ml) were added DIPEA (40.1 μl, 0.230 mmol), HBTU (63.9 mg, 0.168 mmol) and isopropylamine (13 μl, 0.153 mmol). Reaction mixture was stirred over a weekend at 23° C. The solvent was evaporated, and the residual oil was dissolved in ethyl acetate and washed with 1M hydrochloric acid, saturated sodium bicarbonate solution and brine. Organic layer was dried (sodium sulfate), filtered and evaporated to afford the title compound. HPLC (method G) Rt=1.761 min; UPLC (method F) Rt=0.79 min, MS [M+H]+316.3.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)(=[O:8])=[O:7])[N:3]=[N:2]1.[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:22][N:1]1[CH:5]=[C:4]([S:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)(=[O:8])=[O:7])[N:3]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c[nH]nn2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution tert-butyl 4-(1H-1,2,3-triazol-4-ylsulfonyl)piperazine-1-carboxylate (0.54 g, 1.15 mmol) in DMF (10 mL) at 0° C. was added K2CO3 (0.32 g, 2.30 mmol) followed by MeI (0.09 mL, 1.49 mmol) drop wise. Then the reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was concentrated under reduced pressure and dissolved in CH2Cl2 (20 mL), washed with H2O (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 12 g Redisep column, 9:1 mixture of CH2Cl2/CH3OH) to give tert-butyl 4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazine-1-carboxylate as a white foam (32, 0.30 g, 57%): MS (ESI+) m/z 332.
Reaction SMILES: [C:1]([NH:5][C@H:6]1[CH2:10][CH2:9][C@@H:8]([C:11]([OH:13])=O)[CH2:7]1)(=[O:4])[CH2:2][CH3:3].ClC(N(C)C)=C(C)C.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[N:31]=2)=[CH:26][CH:25]=1.N1C(C)=CC(C)=CC=1C>C1COCC1.C(Cl)Cl>[CH3:22][N:23]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]([CH3:35])[C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[N:31]=2)=[CH:26][CH:25]=1)[C:11]([C@@H:8]1[CH2:9][CH2:10][C@H:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])[CH2:7]1)=[O:13]
Reactant: CNc1ccc(-c2nc3ccccc3n2C)cc1
Reactant: CCC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1CC[C@@H](C(=O)N(C)c2ccc(-c3nc4ccccc4n3C)cc2)C1

Procedure:
100.0 mg (0.54 mmol) (1R,3S)-3-Propionylamino-cyclopentanecarboxylic acid (educt IV.1) and 78.6 μL (0.59 mmol) 1-chloro-N,N,2-trimethyl-propenylamine are stirred in 5 mL dry THF at RT for 1 hour. Then this mixture is given to a mixture of 128.1 mg (0.54 mmol) N-methyl-N-[4-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-amine (educt III.1.a) and 107.0 μL (0.81 mmol) 2,4,6-collidine in DCM at RT. The mixture is stirred over night. The solvent is evaporated. The residue is taken up with water and extracted with DCM. The organic phase is dried and the solvent is evaporated. The residue is triturated with diethyl ether, filtered off and dried.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:31]([Cl:35])=[CH:32][CH:33]=[N:34][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:20]=[CH:21][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH:40]6[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]6)[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)=[CH:16][CH:17]=3)[C:12]3[C:31]([Cl:35])=[CH:32][CH:33]=[N:34][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCC(=O)CC1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-c3ccc(N4CCNCC4)cc3)cc2c2c(Cl)ccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCC(N2CCN(c3ccc(-c4ccc5c(c4)c4c(Cl)ccnc4n5S(=O)(=O)c4ccccc4)cc3)CC2)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
Under an inert atmosphere 9-benzenesulfonyl-4-chloro-6-(4-(piperazin-1-yl)phenyl)-9H-pyrido[2,3-b]indole (30 mg, 0.0596 mmol) was dissolved in anhydrous DCM (1.2 mL, c=0.05M). N-methyl-4-piperidone (22 μL, 3 eq) was added, followed by the addition of two drops of glacial acetic acid. The mixture was stirred for 1 h15 at r.t. and then cooled to 0° C. Sodium triacetoxyborohydride (38 mg, 3eq) was added in portions and the resultant mixture was allowed to warm to room temperature, and then stirred 22 h. The reaction mixture was then quenched with water and saturated aq. NaHCO3. The aqueous layer was extracted with EtOAc (3×7 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield the desired compound (33 mg, 93%) as a white solid that was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>>[Cl:8][C:6]1[CH:5]=[N:4][C:3]2[N:9]3[C:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[N:11][CH:12]=[C:13]3[C:20](=[O:21])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)cnc1-n1ccnc1C1CCCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1[nH]c2cc(Cl)cnc2n2c(C3CCCCC3)ncc12

Procedure:
3-Amino-5-chloro-2-(2-cyclohexyl-1H-imidazol-1-yl)pyridine as synthesized in Production Example 103, 838 mg, 1,1′-carbonyldiimidazole 983 mg and 1,2-chlorobenzene 25 mL were mixed and heated under reflux for 15 hours. Cooling the reaction liquid off, the precipitate was recovered by filtration and washed with methanol. The resulting crystals were dissolved in a liquid mixture of 2N hydrochloric acid and methanol, and the insoluble matter was separated by filtration. The filtrate was made weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, and the precipitate was recovered by filtration. Drying the same in flowing air under heating, 620 mg of the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][C:18]2[C:19]([C:24]([NH2:26])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].I[CH2:32][C:33]1([OH:39])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[OH:39][C:33]1([CH2:32][NH:26][C:24](=[O:25])[C:19]2[C:18]([O:17][CH2:16][C@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([C@H:6]3[CH2:7][CH2:8][C@H:3]([C:2]([F:1])([F:27])[F:28])[CH2:4][CH2:5]3)=[O:10])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: NC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: OC1(CI)CCOCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(NCC1(O)CCOCC1)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinamide (105 mg, 0.263 mmol, EXAMPLE 75 Step 1) in 1-Methyl-2-pyrrolidone (5 mL) was added sodium hydride (60% oil dispersant, 16 mg, 0.394 mmol) at ambient temperature. After being stirred at room temperature for 1 h, 4-(iodomethyl)tetrahydro-2H-pyran-4-ol (76 mg, 0.315 mmol, EXAMPLE 77 Step 1) was added to the mixture. The mixture was heated at 70° C. and stirred for 3 days. After cooling to room temperature, aq. citric acid was added to the mixture. The mixture was extracted with ethyl acetate twice and washed successively with aq. sodium thiosulfate, aq. sodium bicarbonate, and brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to afford 72 mg of crude oil. The residual oil was purified by preparative HPLC purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:11][C:10]=1[O:22][CH3:23])C1C=CC=CC=1.[H][H]>CN(C)C=O.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][C:10]=1[O:22][CH3:23]
Reactant: [H][H]
Reactant: COc1cc(C=CC=CC(=O)O)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc(CCCCC(=O)O)ccc1O

Procedure:
The raw product obtained in Example 21 was dissolved in 500 ml of N,N-dimethylformamide and 22 g of 10% palladium on charcoal catalyst was added. The mixture was hydrogenated at 60° C. and normal pressure until the theoretical amount (3 mole) of hydrogen was consumed. After filtering the solvent was evaporated in vacuo to a great extent and the residue was dissolved in 1 l of dichloromethane and washed with 2 l of water. The product was extracted with 1.5 l of saturated NaHCO3 -solution. After acidification of the aqueous phase with hydrochloric acid the product was extracted with 1 l of dichloromethane. The solvent was distilled off in vacuo and the semisolid residue (180 g) was used to the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].Br[CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH:25]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Reactant: BrC(c1ccccc1)c1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
Ethyl 1-benzhydryl-5-nitro-3-phenyl-1H-indole-2-carboxylate was prepared from ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate and bromodiphenylmethane according to the procedure of Example 1 Step 1 as a yellowish solid: 1H NMR (CDCl3) δ 0.92 (t, J=7.1 Hz, 3H, 4.08 (q, J=7.1 Hz, 2H, 6.86 (d, J=9.4 Hz, 1H, 7.20-7.50 (m, 15H, 7.89 (dd, J=9.3, 2.3 Hz, 1H, 7.97 (s, 1H, 8.47 (d, J=2.3 Hz, 1H, MS (ESI) m/z 477 (MH+); HRMS calcd for C30H25N2O4: 477.1812; found (ESI+): 477.1808.