Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH:21]1[CH2:23][CH2:22]1)#[N:6].Cl.C(N(CC)CC)C.Cl>C(OCC)(=O)C.CN(C=O)C>[CH:21]1([N:11]2[C:12]3[C:8](=[C:7]([C:5]4[NH:6][N:3]=[N:2][N:1]=4)[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=3)[CH:9]=[CH:10]2)[CH2:22][CH2:23]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1cc(C#N)c2ccn(C3CC3)c2c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2nnn[nH]2)c2ccn(C3CC3)c2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
In a 100-mL egg plant-type flask, sodium azide (486 mg, 7.48 mmol) was added to a DMF (10 mL) solution of ethyl 4-cyano-1-cyclopropyl-1H-indole-6-carboxylate (475 mg, 1.87 mmol) and triethylamine hydrochloride (1.03 g, 7.48 mmol), and stirred overnight at 110° C. The reaction solution was diluted with ethyl acetate, made acidic with aqueous hydrochloric acid solution added thereto, and the separated organic layer was washed with water and saturated saline water in that order, dried with sodium sulfate, filtered and concentrated. The crude product was washed with hexane to obtain the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([OH:40])[CH:22]=[CH:23][C:24]=1[CH:25]([CH3:39])[C:26]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([Cl:38])[CH:33]=1)([OH:31])[C:27]([F:30])([F:29])[F:28]>CN(C1C=CN=CC=1)C.C(#N)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:24]=1[CH:25]([CH3:39])[C:26]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([Cl:38])[CH:33]=1)([OH:31])[C:27]([F:30])([F:29])[F:28])[O:40][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC(c1ccc(Oc2ccc(C#N)nc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Copper(II)acetate (55 mg), 2-cyanopyridine-5-boronic acid pinacol ester (CAS Reg. No. 741709-63-7, 69 mg), and DMAP (61 mg) were added to a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (Example 19 step 5, 37 mg) in acetonitrile (3 ml). The mixture was stirred with molecular sieves under air atmosphere for 4 h at 80° C., and then filtered over Celite concentrated to an oil. The residue was purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (24 mg) as a white solid. MS (m/e)=468.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:23]=O)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-:25].[CH3:26][NH3+:27].C([BH3-])#N.[Na+]>>[ClH:25].[CH3:26][NH:27][CH2:23][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[N:12]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:14])=[O:15])[CH:11]=1
Reactant: C[NH3+]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2cccc(C)c2)cc1
Reactant: [Cl-]
Agent: [BH3-]C#N
Agent: [Na+]
Product: CNCc1cc(-c2cccc(C)c2)n(S(=O)(=O)c2ccc(C)cc2)c1
Product: Cl
Yield: 53.1 %

Procedure:
Using 5-(3-methylphenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrole-3-carbaldehyde (0.36 g), methylammonium chloride (0.89 g) and sodium cyanoborohydride (0.21 g), a procedure as in Example 4 was performed to give the title compound as white crystals (yield 0.22 g, 52%).
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[CH:6]=[O:7])[CH2:3][CH2:2]1.Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[CH:1]1([C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[C:5]=2[C:6]([OH:15])=[O:7])[CH2:2][CH2:3]1
Reactant: [O-][Cl+][O-]
Reactant: CCc1cccc(C2CC2)c1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1cccc(C2CC2)c1C(=O)O
Temperature: 25 °C

Procedure:
2-Cyclopropyl-6-ethyl-benzaldehyde (CAS 945408-11-7) (500 mg, 2.9 mmol) was dissolved in 3.5 mL tert butanol and 1.7 mL 2-methyl-2-butene. At 0° C. a solution of sodium chlorite (80% purity, 422 mg, 3.8 mmol) and sodium dihydrogenphosphate (452 mg, 3.8 mmol) in 3 mL water was added slowly. The reaction mixture was stirred at room temperature over night. The solvents were evaporated off. The residue was taken up in 1N sodium hydroxide solution and was extracted with tert butyl methylether. The aqueous phase was adjusted at pH 1 with 25% HCl and extracted twice with tert butyl methylether. The combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude product was used without any further purification, white solid (412 mg, 75%), MS: m/e=189.3 [(M−H)−].
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:7][N:6]=1)=[O:4].[OH-].[Li+]>>[CH:13]1([CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=2)[CH2:14][CH2:15]1
Reactant: COC(=O)c1ccc(OCC2CC2)cn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCC2CC2)cn1

Procedure:
In a manner analogous to that described in example 48b) the hydrolysis of 5-cyclopropylmethoxy-pyridine-2-carboxylic acid methyl ester with lithium hydroxide yielded the title compound as a white solid. Mass (calculated) C10H11NO3 [193.201]; (found) [M+H]+=194.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:17][C@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[OH:24]OS([O-])=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([OH:24])[CH:5]=[N:4][C:3]=1[O:17][C@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: C[C@@H](Oc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl)C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a solution of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methylethoxy]pyridine (Preparation 236, 560 mg, 1.59 mmol) in acetone (5 mL) was added an aqueous solution of Oxone® (5 mL, 1.24 g, 1.91 mmol) dropwise with stirring at 0° C. for 15 minutes. The reaction mixture was diluted with water and extracted with EtOAc (3×15 mL), the combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as a brown oil. The crude product was purified by silica gel column chromatography eluting with 0-40% EtOAc in heptane to give the title compound (361 mg, 54%) as yellow oil.
Reaction SMILES: NC1C=CC(OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=NC=1.[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[O:41][CH:40]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-])=O)=[CH:47][CH:46]=2)[CH2:39][CH2:38]3)=[N:32][CH:33]=1)([O-])=O>[Zn]>[NH2:51][C:48]1[CH:49]=[CH:50][C:45]([CH:40]2[CH2:39][CH2:38][C:37]3[C:42](=[CH:43][CH:44]=[C:35]([O:34][C:31]4[N:32]=[CH:33][C:28]([NH2:25])=[CH:29][CH:30]=4)[CH:36]=3)[O:41]2)=[CH:46][CH:47]=1
Reactant: O=[N+]([O-])c1ccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1
Agent: Nc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Agent: [Zn]
Product: Nc1ccc(C2CCc3cc(Oc4ccc(N)cn4)ccc3O2)cc1

Procedure:
6-[2-(4-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 using 100 mg 5-nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine (Example 87(d)) and 665 mg of Zn. 1H NMR (400 MHz, d6-DMSO) δ: 7.50 (d, 1H, J 2.9 Hz), 7.07 (d, 2H, 8.4 Hz), 7.04 (dd, 1H, J 8.6, 2.9 Hz), 6.71 (s, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.56 (d, 2H, J 8.4 Hz), 5.07 (s, 2H), 4.99 (s, 2H), 4.84 (dd, 1H, J 9.7, 2.3 Hz), 2.86-2.95 (m, 1H), 2.66-2.71 (m, 1H), 1.95-2.05 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl.N([O-])=O.[Na+].O.O.O.[C:20]([O-])(=O)[CH3:21].[Na+]>O.C1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([C:21]2[CH:20]=[CH:4][CH:3]=[CH:2][CH:8]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)[O-]
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A mixture of 100 g (0.55 mole) of 97% purity 4-chloro-3-nitroaniline, 200 ml of concentrated hydrochloric acid and 130 ml of water was heated to reflux and then cooled to 0° C. To the resulting slurry was added dropwise a solution of 49 g (0.71 mole)of sodium nitrite in 70 ml of water over a 45 min period while maintaining the temperature at 0°-5° C. To this cold solution was added 1.3 liters of benzene (cooled to 5° C. and the mixture was stirred vigorously while a solution of 190 g sodium acetate trihydrate in 400 ml of water was added over a period of 1 hr. Vigorous stirring was continued first for 3 hr at 5° C. and then for 40 hr at ambient temperature. The organic layer was separated, washed with dilute sodium hydroxide and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with 30% benzene in ligroin. Recrystallization of the isolated solid from cyclohexane-ligroin gave 71.3 g (56%) of the title product as pale yellow crystals, m.p. 43°-44° C.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[NH:27][C:26](=[O:28])[CH:25]=[CH:24][CH:23]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]3[C:4]=2[CH2:3][N:27]2[C:22]([CH3:21])=[CH:23][CH:24]=[CH:25][C:26]2=[O:28])=[CH:15][CH:16]=1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)c(CCl)n2c1
Reactant: Cc1cccc(=O)[nH]1
Agent: Cl
Product: Cc1cccc(=O)n1Cc1c(-c2ccc(Cl)cc2)nc2ccc(F)cn12

Procedure:
The title compound was prepared according to Method B and the experimentals described for compound 91 from 3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridine hydrochloride and 6-methylpyridin-2(1H)-one. 1H-NMR (CDCl3, 400 MHz, δ) 8.75 (dd, J=2.2, 4.6 Hz, 1H), 7.55 (m, 3H), 7.45 (m, 2H), 7.16 (m, 2H), 6.55 (d, J=9.1 Hz, 1H), 5.87 (d, J=6.8 Hz, 1H), 5.84 (s, 2H), 1.74 (s, 3H) ppm; m/e 368 (M+H)+
Reaction SMILES: O[CH:2]([CH2:11][C:12](=[O:28])[C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:27])([CH3:26])[C:15]=2[CH:14]=1)/[C:3](/C)=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C1COCC1>[O:28]=[C:12]([C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:19]([CH3:25])([CH3:24])[CH2:18][CH2:17][C:16]([CH3:26])([CH3:27])[C:15]=2[CH:14]=1)/[CH:11]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C(\C)C(O)CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/C(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 41 (0.33 g, 0.85 mmol) in 8 mL of THF at 0° C. was added triethylamine (0.5 mL, 4 mmol), and a solution of methylsulfonyl chloride (0.106 g, 0.93 mmol) in 2 mL of THF slowly. The mixture was stirred for 1 h at 0° C. and warmed to room temperature for 30 min. The mixture was filtered through a plug of silica gel with 10% ethyl acetate/hexane. The filtrate was concentrated to afford 42 as a light-yellow solid. Recrystallization from dichloromethane/hexane afforded the desired acid 42 as a yellow powder (0.3 g, 95%): m.p. 101°-102° C.; Rf 0.42 (10% ethyl acetate/hexane). The structure of the product was also confirmed using IR, 1H NMR and mass spectroscopy.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].[CH3:18][N:19](C=O)C>>[CH3:18][NH:19][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:6]=1[F:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: -5 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Thionyl chloride (0.15 g, 1.30 mmol) was added slowly to a solution of 2 -fluoro-4-nitrobenzoic acid (Formula 37) (0.20 g, 1.10 mmol) in DMF (5 mL) cooled at −5° C. The mixture was stirred for an additional 1 hour at −5° C. Excess methylamine (freshly distilled from its 40% aqueous solution) was added to the reaction medium. The second mixture was stirred for an additional 1 hour. Ethyl acetate (50 mL) was added to the mixture, which was washed with brine (2×50 ml). The organic layer was dried over MgSO4, and concentrated to yield N-Methyl-2-fluoro-4 -nitrobenzamide (Formula 38) (0.18 g, 85%) as a yellowish solid. 1H NMR (acetone-d6) δ 3.05 (d, 3H, J=4.3), 6.31 (dd, 1H, J=13.5 and 2.1), 6.40 (dd, 1H, J=8.6 and 2.1), 7.64 (dd, 1H, J=8.6 and 8.6).
Reaction SMILES: [F:1][C:2]1[C:12]([SH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([CH:27]=[CH:28][N:29]2[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:13][C:12]3[C:2]([F:1])=[C:3]([CH:9]=[CH:10][CH:11]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:28][N:29]2[C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:25][CH:24]=1
Reactant: Fc1c(Cl)ccc2ccn(-c3cccnc3)c12
Reactant: CCOC(=O)c1cccc(S)c1F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(Sc2cn(-c3cccnc3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a stirred solution of Intermediate A (243 mg, 1.21 mmol) in 1,2-dichloroethane (8 mL) under inert atmosphere was added NCS (163 mg, 1.21 mmol) at RT and stirred for 1 h. To this, compound 2 (200 mg, 0.81 mmol) in 1,2-dichloroethane (2 mL) and NaHCO3 (204 mg, 2.45 mmol) were added at RT. After 24 h stirring at RT, the reaction mixture was diluted with water (15 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 10% EtOAc/Hexanes) to afford compound 3 (50 mg, 9%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.18-8.15 (m, 1H), 7.66-7.762 (m, 2H), 7.36-7.34 (m, 2H), 7.17-7.13 (m, 2H), 4.34 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([C:4]1(O)[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)[CH:2]=[CH2:3].[N:15]([Si](C)(C)C)=[N+:16]=[N-:17].B(F)(F)F.O>C1C=CC=CC=1>[CH2:1]([C:4]1([N:15]=[N+:16]=[N-:17])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH3:13])([CH3:12])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(O)CC(C)(C)CC(C)(C)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: FB(F)F
Solvent: O
Solvent: c1ccccc1
Product: C=CCC1(N=[N+]=[N-])CC(C)(C)CC(C)(C)C1
Temperature: 5 °C
Reaction time: 6 h
Yield: 11.7 %

Procedure:
To a solution of cyclohexanol 8 (1.96 g, 10 mmol) in dry benzene (20 ml) under argon was added azidotrimethylsilane (12 mmol). To this cooled (5° C.) solution was slowly added BF3*OEt2 (12 mmol) via syringe within 20 min. The mixture was stirred for 6 h, then water was slowly added. The organic layer was separated and washed with saturated aqueous NaHCO3, and with brine, and dried over MgSO4. Filtration and evaporation of the solvent keeping the temperature below 25° C. gave an oil which was separated by column chromatography on silica gel (light petroleum ether). A fraction with Rf 0.85 (hexane) was collected. Evaporation of the solvent provided 9 as a colorless oil (0.26 g, 11.7%). 1H NMR (CDCl3, TMS): 0.89 (6H, s, 3,5-CH3eq); 0.90 (1H, d, 14 Hz, 4-CHax); 1.05 (2H, d, 14 Hz, 2,6-CHax); 1.18 (6H, s, 3,5-CH3ax); 1.37 (1H, d, 14 Hz, 4-CHeq); 1.60 (2H, d, 14 Hz, 2,6-CHeq), 2.29 (2H, d, 7 Hz, CH2C═); 4.95-5.25 (2H, m, ═CH2) and 5.65-6.15 ppm (1H, m, ═CH).
Reaction SMILES: Cl.[N:2]1[C:6]2[CH2:7][CH2:8][CH:9]([C:11](N3CCCC3)=[O:12])[CH2:10][C:5]=2[NH:4][CH:3]=1.ClC(Cl)C.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.P(Cl)(Cl)(Cl)=O>C(=O)([O-])[O-].[K+].[K+]>[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:11]([CH:9]2[CH2:8][CH2:7][C:6]3[N:2]=[CH:3][NH:4][C:5]=3[CH2:10]2)=[O:12])=[CH:23]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C(C1CCc2nc[nH]c2C1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C(c1c[nH]c2ccccc12)C1CCc2nc[nH]c2C1
Reaction time: 7 h
Yield: 43.9 %

Procedure:
4 g of N-[(4,5,6,7-tetrahydrobenzimidazol-5-yl)carbonyl]pyrrolidine hydrochloride obtained in Example 5 were added to 40 ml of dichloroethane, and 2.74 g of indole and 4.4 ml of phosphorus oxychloride were added thereto. The mixture was stirred at 80° to 85° C. for 7 hours and then at room temperature overnight. To the mixture was added 40 ml of a cold potassium carbonate aqueous solution, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography using chloroform/methanol as an eluent to obtain 1.82 g of 5-[(indol-3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole as a foam-like substance. In 1 ml of methanol were dissolved 0.16 g of the resulting product and 0.06 g of fumaric acid, and 5 ml of acetonitrile was added to the solution. The formed crystal was collected by filtration to obtain 0.13 g of 5-[(indol- 3-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole fumarate.
Reaction SMILES: C([O-])(=O)C.[Na+].[OH:6][C:7]1[CH:12]=[CH:11][C:10](C(C2OC=CC=2)=O)=[CH:9][CH:8]=1.S1C=CC=C1C(C1C=CC(O)=C(C)C=1C)=O.[Br:36]Br>C(O)(=O)C.O.CO>[Br-:36].[Br-:36].[C:7]1([OH:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(c1ccc(O)cc1)c1ccco1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: Cc1c(O)ccc(C(=O)c2cccs2)c1C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Oc1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
There was introduced into a solution of 28 g sodium acetate and 60 ml methanol 19 g of (2-furyl) (4-hydroxyphenyl) ketone (m.pt.=164° C.) prepared according to the method described in Example 1 (A) and (B), and then there was introduced dropwise 11 ml of bromine dissolved in 14 ml of acetic acid. After 2 hours stirring at ambient temperature, the mixture was poured into three volumes of water and the precipitate isolated. After recrystallisation in dichloroethane there was obtained 22 g of phenol dibromide melting at 164° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=2)[CH2:3]1>C(O)C.O.[Fe]>[CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc([N+](=O)[O-])c2)Nc2ccc(C(F)(F)F)cc21
Agent: [Fe]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Yield: 95.1 %

Procedure:
A mixture of 4,4-dimethyl-2-(3-nitro-phenyl)-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.99 g, 8.53 mmol) and iron powder (11.95 g, 0.21 mol) in ethanol/water/concentrated hydrogen chloride (24 mL/6 mL/0.08 mL) was kept at reflux for 2 h. The mixture was filtered and the mother liquor was concentrated in vacuo to give 2.6 g of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine as off-yellow solid (2.6 g, yield: 95.6%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[CH:33]=O)=[CH:28][CH:27]=1>C(Cl)Cl.[Zn]>[Br:21][C:20]([Br:24])=[CH:36][C:32]([C:29]1[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=1)([CH3:33])[CH3:35]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C=O)c1ccc(Cl)cc1
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C=C(Br)Br)c1ccc(Cl)cc1
Yield: 66.9 %

Procedure:
A solution of triphenyl phosphine (89.34 g, 0.34 mol) in methylene chloride is added dropwise to a mixture of zinc powder (22.27 g, 0.34 mol) and carbon tetrabromide (112.8 g, 0.34 mol) in methylene chloride at 20° C. over one hour. The resultant mixture is stirred at room temperature overnight, treated dropwise with a solution of 2-(p-chlorophenyl)-2-methylpropionaldehyde (31.1 g, 0.17 mol) in methylene chloride over 20 minutes, refluxed for 2 days, and poured into petroleum ether. The organic mixture is filtered through diatomaceous earth and concentrated in vacuo to obtain a residue. The residue is distilled to give the title product as an oil (38.5 g, bp 121-123° C./0.3 mm Hg, 66.8% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:10]2([CH2:15][CH2:14][NH:13][CH:12]([C:16]([NH:18][C:19]3([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)=[O:17])[CH2:11]2)[CH2:9]1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>CC#N>[F:32][C:33]([F:42])([F:43])[C:34]1[CH:41]=[CH:40][C:37]([CH2:38][N:13]2[CH2:14][CH2:15][C:10]3([CH2:9][CH2:8]3)[CH2:11][CH:12]2[C:16]([NH:18][C:19]2([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)=[O:17])=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3Cc3ccc(C(F)(F)F)cc3)CC4)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a solution of methyl 4-(1-(6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate 2,2,2-trifluoroacetate (D89) (27 g, 61.03 mmol) in dry MeCN (900 ml) Cs2CO3 (39.7 g, 122.05 mmol) and a solution of 4-(trifluoromethyl)-benzylbromide (14.6 g, 61.03 mmol) in MeCN (50 ml) were added in sequence. The mixture was stirred at RT for 18 hrs. The solid was filtered off and solvents were evaporated. The residue was ri-dissolved in DCM (200 ml) and washed with H2O (3×100 ml) and NaCl sat. sol (50 ml). The organic phases were dried over Na2SO4 and evaporated to afford a white solid, which was triturated in cyclohexane to afford the title compound (D123) (19.7 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH: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)=[CH:4][CH:3]=1.[CH3:22][S:23]([C:26]1[CH:27]=[C:28]2[CH:34]=[CH:33][NH:32][C:29]2=[N:30][CH:31]=1)(=[O:25])=[O:24]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:32]3[C:29]4=[N:30][CH:31]=[C:26]([S:23]([CH3:22])(=[O:24])=[O:25])[CH:27]=[C:28]4[CH:34]=[CH:33]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)c1cnc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)cnc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-Butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and 5-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (intermediate-25).