Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)S[C:5]=2[CH:4]=[CH:3][CH:2]=1.N=CCCC(CC1C=CC=CC=1)(CC1C=CC=CC=1)O.S(Cl)(Cl)=O>C1C=CC=CC=1>[C:12]1([N:13]([C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCCCN1c2ccccc2Sc2ccccc21
Agent: N=CCCC(O)(Cc1ccccc1)Cc1ccccc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: OCCCCN(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To prepare compounds 6a, 6b and 6e, to a solution of 5a (2.03 g, 7.5 mmol), 5b or 5e in 100 ml of dry benzene was added thionyl chloride (2 ml, 10 mmol) and stirred overnight at room temperature. After solvent evaporation, the residue was chromatographed on silica gel column. Elution with 10% ethyl acetate/hexanes afforded the following compounds:
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:12]=[CH:13]\[C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[N:8][C:9]=1[O:10][CH3:11]>C(Cl)(Cl)(Cl)Cl>[Br:1]/[C:12](/[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[C:9]([O:10][CH3:11])[N:8]=1)=[CH:13]\[C@@H:14]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1
Reactant: BrBr
Reactant: COc1nc(/C=C\[C@H]2CCC(=O)N2)ccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(/C(Br)=C/[C@H]2CCC(=O)N2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
Bromine (80 μL) was added to a solution of (5R)-5-[(Z)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]pyrrolidin-2-one (200 mg) in carbon tetrachloride (2 mL) under ice-cooling, and the mixture was stirred at the same temperature (0° C.) for 15 minutes. The reaction solution was concentrated and the residue was dissolved in chloroform. 1,8-Diazabicyclo[5.4.0]undec-7-ene (238 μL) was added under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give the title compound as a colorless powder (164 mg, 62%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClS([N:14]=[C:15]=O)(=O)=O>C(N(CC)CC)C>[C:15]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)#[N:14]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2ccccc12

Procedure:
3-Cyano analogues are synthesized from the precursor indole No. 141 as shown in Scheme 7. Reaction of the precursor indole No. 141 with chlorosulfonyl isocyanate followed by addition of triethylamine yields the 3-Cyanoindole No. 155. The side chain is made by conversion of the benzylic alcohol of CAS No. [111728-87-1] to the benzylic bromide No. 156 using thionyl bromide in THF. The indole is alkylated by the side chain in DMF using sodium hydride to give the intermediate No. 157. This can then be taken to the final product No. 138 in an analogous fashion to that shown in scheme 4.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N+:8]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17]1[CH2:18][CH2:19][N:20](C(OC(C)(C)C)=O)[CH2:21][CH:22]=1)([O-:10])=[O:9]>C(Cl)Cl>[N+:8]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccncc2[N+](=O)[O-])CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1cnccc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
TFA (2 mL, 25.96 mmol) was added to a stirred solution of tert-butyl 4-(3-nitro-4-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (883 mg, 2.892 mmol) in DCM (10 mL) and the reaction stirred at ambient temperature for 15 hours. The solvent was removed in vacuo and the residue azeotroped with DCM (×2) and ether (×2). The residue was passed through a 25 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo to give 3′-nitro-1,2,3,6-tetrahydro-4,4′-bipyridine as an orange oil (523 mg, 88% Yield). MS (ES+) 206.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[O:12][CH:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(-c2ncco2)cc1F
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2ncco2)cc1F
Reaction time: 16 h
Yield: 81.9 %

Procedure:
A stirred solution of 2-(3-fluoro-4-nitro-phenyl)oxazole (500 mg, 2.40 mmol) in methanol (10 mL) was added to stannous chloride (2.7 g, 12.01 mmol) under nitrogen atmosphere and stirred for 16 h. The reaction mixture was diluted with water and filtered through Celite. The filtrate was basified with bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-fluoro-4-oxazol-2-yl aniline (350 mg, 83%) as a yellow colour solid.
Reaction SMILES: C(SP([O-])(OCC)=S)C.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]#[N:45])=[CH:41][CH:42]=4)[N:37]([CH3:46])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1.[CH2:47](N)[CH2:48][NH2:49]>C(O)C.O>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([CH:19]([C:35]3[C:43]4[C:38](=[CH:39][C:40]([C:44]5[NH:49][CH2:48][CH2:47][N:45]=5)=[CH:41][CH:42]=4)[N:37]([CH3:46])[CH:36]=3)[C:20]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=3)(=[O:24])=[O:25])=[O:21])=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: NCCN
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C#N)ccc23)cc1
Agent: CCOP([O-])(=S)SCC
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C4=NCCN4)ccc23)cc1
Reaction time: 14 h

Procedure:
Diethyldithiophosphate (1.3 ml, 7.7 mmol) was added to 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-isopropylphenyl)sulfonamido]-2-oxoethyl}-6-cyano-1-methyl-1H-indole (the product of Example 51, 800 mg, 1.5 mmol) in a mixture of ethanol (10 ml) and water (5 drops). The reaction was heated at reflux with stirring for 14 h. After cooling the solvent was removed in vacuo and the residues purified by flash column chromatography (elution with 98% dichloromethane/2% methanol) to give a brown oil. This residue was dissolved in ethylenediamine and the reaction mixture heated at reflux for 3 h. After cooling the ethylenediamine was removed in vacuo. Hydrochloric acid (10 ml) was added and the resulting precipitate was filtered and washed with dichloromethane and methanol. Flash column chromatography (elution with 80% dichloromethane/20% methanol/5% NH3) gave the product as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[C:3](=[O:46])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([CH3:45])=[N:23][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O>>[CH3:47][N:2]([CH3:1])[C:3](=[O:46])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([CH3:45])=[N:23][NH:24][CH:25]=4)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(CC(=O)N(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(CC(=O)N(C)C)CC3)c2c1
Yield: 16 %

Procedure:
82 mg N,N-dimethyl-2-{4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]piperazin-1-yl}acetamide obtained in Example 191 and 1 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 8 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]([OH:23])=O)=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C(=O)C.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:43][C:44](=[NH:46])[CH3:45]>O>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]2[O:23][N:46]=[C:44]([CH3:45])[N:43]=2)=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=N)NO
Reactant: O=C(O)c1ccc2c(c1)[nH]c(=O)c1cnc(C3CCCCC3)n12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1noc(-c2ccc3c(c2)[nH]c(=O)c2cnc(C4CCCCC4)n23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Cyclohexyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxyic acid as synthesized in Example 58, 300 mg, N,N-dimethylacetamide 5 mL and 1,1′-carbonyldiimidazole 266 mg were mixed and stirred for 30 minutes at room temperature. To the reaction liquid 143 mg of N-hydroxyacetamidine was added, followed by 12 hours' stirring at 110° C. After returning it to the room temperature, water was added thereto and the precipitated matter was recovered by filtration. Drying the precipitate by heating under reduced pressure, 210 mg of the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([C:22](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@@H:9]1[CH2:14][O:15][C:22]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:39][CH:38]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1CO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2C[C@@H](O)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 76.8 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-hydroxymethyl-4-hydroxypyrrolidine 37 (4.4 g, 20.28 mmol) was dissolved in dry pyridine (50 ml) and allowed to stir under argon atmosphere. To this stirred solution was added TEA (2.53 g, 25 mmol) followed by 4,4'-dimethoxytrityl chloride (7.45 g, 22 mmol). The reaction mixture was stirred at room temperature for 12 h and quenched with MeOH (10 ml). The solution was evaporated to dryness and dissolved in EtOAc (200 ml). The EtOAc layer was washed with 5% NaHCO3 solution (100 ml), water (100 ml) and brine. The organic extract was dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The required fractions were pooled together and evaporated to give 8.09 g (100%) of an orange foam. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 3.74 (s, 6H, 2.OCH3), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 6.82 (d, 4H, Ph), and 7.26-8.00 (m, 9H, Ph).
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=2)=[CH:14][CH:13]=1)=O)C1C=CC=CC=1.[BrH:25]>C(O)(=O)C>[BrH:25].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:19]=[CH:20][C:21](=[O:24])[NH:22][CH:23]=2)=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
A solution of 5-(4-benzyloxycarbonylaminophenyl)-2(1H)-pyrazinone (1.1 g) in 15% w/v hydrogen bromide in acetic acid solution (30 ml) was refluxed for 30 min. The yellow precipitate which formed was filtered off and it was washed with a little 1-propanol and then recrystallised from ethanol-water containing 2 drops of concentrated hydrobromic acid to give 5-(4-aminophenyl)-2(1H)-pyrazinone hydrobromide (1.03 g m.p.>300° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C@H:14]1[CH2:15][CH2:16][C@@H:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: NCc1ccccc1
Product: Fc1ccc2[nH]cc([C@H]3CC[C@@H](NCc4ccccc4)CC3)c2c1

Procedure:
This compound was prepared in similar manner as for Intermediate 17, using 4-(5-Fluoro-1-H-indol-3-yl)-cyclohexanone (0.6 g, 2.6 mmol) and benzylamine (0.3 g, 2.8 mmol) to afford 1.0 of the desired product as a mixture of cis and trans isomers. Flash chromatography on silica gel (3% 2M NH3 in methanol/ethyl acetate) afforded 0.41 g (65%) of cis isomer and 0.22 g (33%) of the trans isomer.
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6]Br.Br[C:9]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:12]([N:13]([CH3:15])[CH3:14])=[C:11]([CH2:20][CH3:21])[CH:10]=1.[P:22]([O-:29])(OCC)OCC>O1CCCC1.C(OCC)(=O)C.O>[CH3:14][N:13]([CH3:15])[C:12]1[C:11]([CH2:20][CH3:21])=[CH:10][C:9]([PH:22](=[O:29])[C:9]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:12]([N:13]([CH3:15])[CH3:14])=[C:11]([CH2:20][CH3:21])[CH:10]=2)=[CH:17][C:16]=1[CH2:5][CH3:6]
Reactant: CCOP([O-])OCC
Reactant: BrCCBr
Reactant: CCc1cc(Br)cc(CC)c1N(C)C
Agent: II
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc([PH](=O)c2cc(CC)c(N(C)C)c(CC)c2)cc(CC)c1N(C)C
Temperature: 40 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Under an argon atmosphere, a solution of magnesium (2.8 g, 1.0 equivalent), a small amount of iodine and a small amount of 1,2-dibromoethane in tetrahydrofuran (15 mL) was stirred at room temperature for 30 min. A solution of 4-bromo-2,6-diethyl-N, N-dimethylaniline (29.4 g, 0.115 moL) synthesized in Reference Example 3 in tetrahydrofuran (50 mL) was added to the mixture at 20° C. to 25° C. over 1 hr, and the mixture was stirred at 40° C. for 1 hr. Then, a solution of diethyl phosphite (4.01 g, 0.25 equivalent) in tetrahydrofuran (8 mL) was added at 20° C. to 25° C. over 1 hr. Water (90 mL) was added to the mixture at 5° C. to 10° C., and then ethyl acetate (100 mL) was added to the mixture. The mixture was partitioned, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane/ethyl acetate) to give the title compound (8.34 g, colorless liquid). yield 72%.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][CH:8]([OH:10])[CH3:9]>C(Cl)(Cl)Cl>[CH3:7][C@:8]1([C:3]2[CH:2]=[CH:1][C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:4]=2)[CH2:9][O:10]1
Reactant: CC(C)O
Reactant: CCCCCC
Solvent: ClC(Cl)Cl
Product: C[C@]1(c2ccc3ccccc3c2)CO1
Yield: 85 %

Procedure:
White solid, 85% yield, >99% ee (CHIRALCEL OJ-H, hexane/iPrOH 99.5:0.5); [α]D23 +3.3° (c=1.00, CHCl3); 1H NMR (CDCl3): δ7.85-7.80 (m, 4H), 7.51-7.43 (m, 3H), 3.06-3.04 (d, J=5.6 Hz, 1H), 2.90-2.88 ppm (d, J=5.6 Hz, 1H), 1.82 ppm (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(=O)C([Cl:25])=O.[F:28][C:29]1[CH:30]=[C:31]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[NH2:42].Cl>C(Cl)Cl.N1C=CC=CC=1.O1CCOCC1>[ClH:25].[F:28][C:29]1[CH:30]=[C:31]([CH:43]=[C:44]([F:46])[CH:45]=1)[CH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[NH:38][N:37]=[C:36]2[NH:42][C:19]([C:17]1[CH:16]=[N:15][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:18]=1)=[O:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(=O)O)cn2)CC1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1cnn(C2CCNCC2)c1
Reaction time: 1 h
Yield: 36.2 %

Procedure:
1-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1H-pyrazole-4-carboxylic acid (134 mg, 0.45 mmol) and oxalyl chloride (0.6 mmol) were stirred in DCM dry (5 mL) at room temperature overnight. Volatiles were evaporated and the residue dissolved in dry pyridine (5 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (100 mg, 0.38 mmol) in dry pyridine (2 mL) was added to the cooled reaction mixture. After 1 hour, reaction was quenched with NaHCO3 sat. sol and extracted with ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and evaporated to dryness. Residue was purified by column chromatography over silica gel (DCM/EtOH/NH3 5N in MeOH=1000/50/1) affording 87 mg of Boc-protected derivative which was dissolved in 2 mL of dioxane and treated with 0.4 mL of 4M HCl in dioxane. Volatiles were evaporated affording 65 mg of the title compound.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16]OC1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH:1]1([N:7]2[CH2:16][CH2:17][N:13]([CH2:12][CH2:11][Cl:10])[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: O=C1OCCN1CCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1N(CCCl)CCN1C1CCCCC1
Temperature: 195 °C
Yield: 50 %

Procedure:
A mixture of cyclohexyl isocyanate (50 mmoles), N-(2-chloroethyl)-2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a 50 percent yield of the desired product, m.p. 60° C.-64° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2].[CH:16]([OH:19])([CH3:18])[CH3:17]>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:19][CH:16]([CH3:18])[CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CC(C)O
Reactant: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CCS(=O)(=O)c1ccc(OC(C)C)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A14(c) from 5-ethanesulfonyl-2-fluoro-benzoic acid (Example A17(b)) and isopropanol. MS (m/e): 271.1 ([M−H]−, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CS(O[CH2:27][CH2:28][C:29]1[CH:33]=[CH:32][S:31][CH:30]=1)(=O)=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:27][CH2:28][C:29]3[CH:33]=[CH:32][S:31][CH:30]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)OCCc1ccsc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(CCc3ccsc3)c3cc(F)ccc23)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 4 g (13.8 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 24, part A) and 3.3 g (16 mmol) of 2-thiophen-3-yl-ethyl methansulfonate. The reaction mixture was stirred at 60° C. for 3 hours. After standard work-up, 5.6 g (100% of yield) of 4-[6-fluoro-1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[S:45](=[O:48])(=[O:47])[NH2:46])C(O)=O.C(N(CC)CC)C.CN([C:59]([O:63]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:35][C:36]1[CH:37]=[CH:38][C:42]([C:59]([N:22]2[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]3[CH:14]4[CH2:13][CH2:12][CH:11]3[CH2:10][CH:9]([N:8]3[C:7]5[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=5[N:5]=[C:4]3[CH3:3])[CH2:15]4)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:63])=[CH:43][C:44]=1[S:45]([NH2:46])(=[O:47])=[O:48]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1Cl
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
To a stirred solution of 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (200 mg, 0.4 mmol) in DMF (8 mL) was added 3-chloro-4-sulfamoylbenzoic acid (94 mg, 0.4 mmol), triethylamine (166 μL, 1.2 mmol) and HATU (152 mg, 0.4 mmol). The resulting mixture was stirred at ambient temperature for 3 hours before being diluted with methylene chloride (50 mL). The reaction was then washed with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography on silical gel, eluting with a gradient of 0-10% methanol in ethyl acetate to afford 2-chloro-5-[(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)carbonyl]benzenesulfonamide as amorphous solid (120 mg, 47%). 1H NMR (300 MHz, DMSO-d6) δ 7.87-7.71 (m, 3H), 7.57 (s, 1H), 7.50-7.47 (m, 2H), 7.38-7.33 (m, 4H), 7.24 (s, 1H), 7.14-7.06 (m, 2H), 4.49 (m, 1H), 3.98 (m, 1H), 3.42-3.23 (m, 5H), 3.06-3.00 (m, 1H), 2.43 (s, 3H), 2.39-2.22 (m, 2H), 2.17-2.08 (m, 2H), 1.92-1.76 (m, 10H), 1.58-1.56 (br, 2H). HRMS m/z (M+H)+ calcd: 646.2619; obsd: 646.2610.
Reaction SMILES: [CH2:1]([C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Na+].[CH3:21][O:22]C(Cl)Cl>ClCCl>[CH2:13]([O:12][C:10]([C:9]1[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:21]=[O:22])=[CH:6][CH:7]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1ccccc1Cc1ccccc1
Reactant: COC(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1Cc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 71.8 %

Procedure:
Ethyl 2-benzylbenzoate (54.0 g) was dissolved in 100 ml of dichloromethane, and with stirring, 121.3 g of stannic chloride was added while cooling the solution with a mixture of ice and sodium chloride. The mixture was stirred for 1 hour. Subsequently, 86 g of α,α-dichloromethyl methyl ether was added dropwise over 1 hour, and then the mixture was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was poured into 1 liter of ice water, and stirred. The dichloromethane layer was separated, washed with water, a saturated aqueous solution of sodium carbonate and subsequently with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The dichloromethane was distilled off. To the residue was added 250 ml of a saturated aqueous solution of sodium bisulfite, and the mixture was vigorously stirred. The precipitated crystals were collected by filtration, and washed with 100 ml of a saturated aqueous solution of sodium chloride and then with 100 ml of ether. The crystals were then suspended in 500 ml of water, and with stirring, 120 g of sodium carbonate was added little by little over the course of 15 minutes. The mixture was stirred for 2 hours. The separated oily substance was extracted with 300 ml of ether. The ethereal layer was washed with water and dried over anhydrous magnesium sulfate. The ether was distilled off to afford 43.3 g of 4-(2-ethoxycarbonylbenzyl)benzaldehyde as a red oily substance.