Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)([CH2:3][CH3:4])[CH3:2].[C:15]1([C:21]2[O:22][C:23]([C:29]([F:32])([F:31])[F:30])=[C:24]([C:26](O)=[O:27])[N:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]([NH:12][C:26]([C:24]2[N:25]=[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:22][C:23]=2[C:29]([F:31])([F:32])[F:30])=[O:27])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CCC(C)Nc1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Yield: 41 %

Procedure:
sec-Butyl-(5-nitro-pyridin-2-yl)-amine (97.5 mg, 0.5 mmol) was hydrogenated as above and reacted with 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (135 mg, 0.525 mmol), Et3N (352 uL, 2.5 mmol) and BOP (232 mg. 0.525 mmol). Following work-up as above, the crude material was purified by flash chromatography to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-sec-butylamino-pyridin-3-yl)-amide as a light purple solid (83 mg). ES-MS calcd for C20H19F3N4O2 (m/e) 404.40, obsd 405.1 (M+H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH:22]([CH2:29][C:30]1([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH:23]2O>C1(C)C=CC=CC=1>[C:13]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][C:22]([CH2:29][C:30]1([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)=[CH:23]2
Reactant: CC1(CC2Cc3c(-c4ccccc4-c4ccccc4)cccc3C2O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(CC2=Cc3cccc(-c4ccccc4-c4ccccc4)c3C2)CCCCC1
Temperature: 25 °C
Yield: 66.8 %

Procedure:
Mixture of p-toluene-sulfonic acid monohydrate (0.38 g, 2.0 mmol, 0.2 equiv), compound 22 (4.0 g crude, ˜9.88 mmol, 1.0 equiv) and toluene (100 mL) was refluxed for 1 hour. After cooling to room temperature, the mixture was washed sequentially with saturated sodium bicarbonate (100 mL) and saturated brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an AnaLogix (25-80 g) column, eluting with a gradient of 0 to 10% ethyl acetate in heptanes to give compound 23 (2.5 g, 67% yield for 2 steps) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:52])[NH:40][CH2:41][CH2:42][CH:43]([NH2:51])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[NH:21][N:22]=[C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:51][CH:43]([C:44]5[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=5)[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:52])[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCC(N)c1cccc(Cl)c1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2n[nH]c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1cccc(Cl)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 9 supra) (300 mg, 0.64 mmol) and [3-amino-3-(3-chloro-phenyl)-propyl]-carbamic acid tert-butyl ester (from Example 3 supra) (722 mg, 2.6 mmol) was heated at 130° C. with stirring for 2 hours. The resulting oil was purified by chromatography (silica gel, 8 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude [4-(3-{2-[3-tert-butoxycarbonylamino-1-(3-chloro-phenyl)-propylamino]-pyrimidin-4-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester. (Yield 135 mg, 30.6%).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]([C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[CH:27]([CH3:29])[CH3:28])O)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SiH](CC)(CC)CC.OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[CH:27]([CH3:29])[CH3:28])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(Br)cc1C(O)c1ccc2c(c1)N(Cc1ccccc1)CCC2
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(Br)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of (1-benzyl-1,2,3,4-tetrahydro-quinolin-7-yl)-(5-bromo-2-isopropyl-phenyl)-methanol (2.61 g, 5.79 mmol) in TFA (7.0 mL), Et3SiH (4.63 mL, 28.95 mmol) was added followed by triflic acid (1.0 mL, 11.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The reaction was evaporated to dryness and neutralized by adding saturated aqueous NaHCO3 (15 mL). The resulting mixture was extraction with dichloromethane (3×30 mL). Crude product obtained after evaporation solvent was purified by using neutral alumina column chromatography to furnish 1-benzyl-7-(5-bromo-2-isopropyl-benzyl)-1,2,3,4-tetrahydro-quinoline (1.80 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=C)[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18].[O:21]=[O+][O-].O=O.CSC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:21])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: O=[O+][O-]
Reactant: C=Cc1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 2-acetylamino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (708 mg, 2.46 mmol) in DCM (70 mL) was cooled to −68° C. and a flow of ozone was passed through the mixture until it turned dark green. A flow of oxygen was then passed through the mixture for 30 min and dimethyl sulfide (360 μL, 4.86 mmol) was added. This mixture was stirred for 30 min at r.t. and triphenylphosphine (327 mg, 1.23 mmol) was added. The solution was allowed to stand for 60 h at r.t. under argon. It was then concentrated in vacuo and the crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 100:0→80:20) to afford 2-acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (591 mg, 2.04 mmol, 83%) as a beige powder, m.p. 106-108° C., ESI-MS: m/z 290 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[C:18]=1[Cl:25]>CN(C=O)C>[Br:16][C:17]1[C:18]([Cl:25])=[C:19]([CH2:23][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Clc1c(Br)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2cccc(Br)c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (1.21 g, 8.5 mmol) was dissolved in anhydrous DMF (50 mL), and then potassium carbonate (1.76 g, 12.7 mmol) and 1-bromo-3-(bromomethyl)-2-chlorobenzene (3.13 g, 11.0 mmol) in anhydrous DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was filtered, washed with water plus diethyl ether, and dried in vacuo to afford to 2-{[(3-bromo-2-chlorophenyl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (2.28 g, 78% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.03 (s, 3H), 4.39 (s, 2H), 5.67 (s, 1H), 7.17 (t, J=7.9 Hz, 1H), 7.63 (d, J=7.9 Hz, 2H); LRMS (ES+) m/z 345 (75%, M+1), 347 (100%, M+3), 349 (30%, M+5).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[CH2:36][CH2:35][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)=[O:20])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:5][CH:4]=1.[ClH:41].O1CCOCC1>>[ClH:41].[ClH:41].[F:40][C:2]([F:1])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]2[CH2:36][CH2:35][C:11]3[NH:12][C:13]4[CH:14]=[CH:15][C:16]([C:19]([NH:21][CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[O:20])=[CH:17][C:18]=4[C:10]=3[CH2:9]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccc3[nH]c4c(c3c2)CN(Cc2ccc(C(F)(F)F)cc2)CC4)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NC1CCNCC1)c1ccc2[nH]c3c(c2c1)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of tert-butyl 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine-1-carboxylate (9 in Scheme 1(c)), 340 mg, 0.6 mmol) in 4 N HCl/dioxane (10.0 mL) was allowed to stir at room temperature for 2 h. The reaction mixture was then concentrated and the resulting residue was triturated with ethyl ether to give 4-(2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamido)piperidine dihydrochloride salt as a white solid (320 mg, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCCCCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCCCCc1ccccn1

Procedure:
2-Pyridinehexanol (4.88 g), 1,6-dibromohexane (12.6 ml), 12.5M aqueous sodium hydroxide (25 ml) and TAB (0.45 g) were stirred rapidly at room temperature for 7 h. The mixture was diluted with water (60 ml) and extracted with diethyl ether (3×60 ml). The combined organic extracts were washed with water (60 ml) and brine (60 ml), dried and concentrated to give an oil which was purified by FCC eluting with diethyl ether-hexane (0:1→1:1) to give the title compound as a colourless oil (4.52 g), t.l.c. (ether-hexane 1:1) Rf 0.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.Br.Br.[CH2:38]([C:40]1[C:41]([C:48]2[CH:56]=[C:55]3[C:51]([C:52]([C:57]4[NH:58][C:59]5[CH2:64][CH2:63][NH:62][CH2:61][C:60]=5[N:65]=4)=[N:53][NH:54]3)=[CH:50][CH:49]=2)=[CH:42][C:43]([F:47])=[C:44]([OH:46])[CH:45]=1)[CH3:39].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:62]2[CH2:63][CH2:64][C:59]3[NH:58][C:57]([C:52]4[C:51]5[C:55](=[CH:56][C:48]([C:41]6[CH:42]=[C:43]([F:47])[C:44]([OH:46])=[CH:45][C:40]=6[CH2:38][CH3:39])=[CH:49][CH:50]=5)[NH:54][N:53]=4)=[N:65][C:60]=3[CH2:61]2)=[O:10])=[N:6][CH:7]=1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(Cl)cn3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8 %

Procedure:
To a solution of 5-chloro-pyridine-2-carboxylic acid (12 mg, 80 μmol) in DMF (1 mL) was added HBTU (32 mg, 85 μmol) and the resulting reaction mixture was stirred at room temperature for 30 minutes. 5-Ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) and DIPEA (56 μL, 320 μmol) were added and stirring was continued at room temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by reverse phase chromatography (Method C) to afford 3.3 mg of the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]2)=[CH:6][CH:5]=1.[H-].[Na+].CN(C)C=O.CS([C:41]1[S:42][C:43]2[C:48]([N:49]=1)=[CH:47][CH:46]=[CH:45][N:44]=2)(=O)=O>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[C:12]2[NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:29][C:41]3[S:42][C:43]4[C:48]([N:49]=3)=[CH:47][CH:46]=[CH:45][N:44]=4)[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CS(=O)(=O)c1nc2cccnc2s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(NC3CCN(CCOc4nc5cccnc5s4)CC3)nc3ccccc32)cc1
Reaction time: 2 h
Yield: 15 %

Procedure:
To a stirred mixture of 5.3 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol dihydrochloride, 2.8 parts of a sodium hydride dispersion 50% and 90 parts of N,N-dimethylformamide were added 2.55 parts of 2-(methylsulfonyl)thiazolo[5,4-b]pyridine. The whole was stirred for 2 hours. The reaction mixture was poured into water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, hexane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.9 parts (15%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(thiazolo[5,4-b]pyridin-2-yl)oxy]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 151.0° C. (compound 107).
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH2:11])[C:4]([NH2:10])=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:14]=[C:15]([C:20]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=2)=O)=O)[CH:16]=[CH:17][C:18]=1[OH:19].C(OCC)C>CO>[ClH:1].[ClH:1].[OH:12][C:13]1[CH:14]=[C:15]([C:20]2[C:22]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([OH:31])[CH:25]=3)=[N:10][C:4]3[C:3](=[CH:8][CH:7]=[C:6]([NH2:9])[CH:5]=3)[N:11]=2)[CH:16]=[CH:17][C:18]=1[OH:19]
Reactant: Nc1ccc(N)c(N)c1
Reactant: O=C(C(=O)c1ccc(O)c(O)c1)c1ccc(O)c(O)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc2nc(-c3ccc(O)c(O)c3)c(-c3ccc(O)c(O)c3)nc2c1
Temperature: 25 °C
Yield: 169.5 %

Procedure:
98.0 mg (0.5 mmol) of 1,2,4-benzenetriamine dihydrochloride and 137.1 mg (0.5 mmol) of 3,3′,4,4′-tetrahydroxybenzil were dissolved in 3 ml of MeOH. The reaction was refluxed for 6 hours. Then the reaction mixture was cooled to r.t. and added dropwise to 40 ml of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacuo to give 184.0 mg (84.7% yield) of the product. 97.7% purity by LC/MS (230 DAD). Mass-spec [ES+]=362.8. 1H NMR (MeOH-d4) 6.73–6.75 (1H, d), 6.78–6.80 (1H, m), 6.88–6.89 (1H, m), 6.94–6.97 (3H, m), 7.03 (1H, d), 7.49–7.51 (1H, dd), 7.97–7.99 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Sn](CCCC)(CCCC)CCCC)[CH:8]=[N:9][CH:10]=1)=[O:4].Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH3:40].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH3:40][N:36]1[CH2:37][CH2:38][CH2:39][C@@H:35]1[CH2:34][C:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:25]([C:7]3[CH:8]=[N:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=3)[CH:26]=2)[NH:30][CH:29]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(C(=O)OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1cncc(-c2ccc3[nH]cc(C[C@H]4CCCN4C)c3c2)c1

Procedure:
5-Methoxycarbonyl-3-pyridyltri-n-butylstannane (see Preparation and 5-bromo-3-(1-methylpyrrolidin-2(R)-ylmethyl)-1H-indole (see Preparation 36) were reacted together in the presence of tri-o-tolylphosphine, triethylamine and palladium (II) acetate using a procedure similar to that described in Example 1. This yielded the title compound as an oil. The product, which was impure, was used without characterisation in the preparation of Example 49.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+]>C(O)C.ClCCl>[OH:2][CH2:1][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2ncccc2CO)c1
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
To a suspension of 3-(3-formylpyridin-2-yl)nitrobenzene (0.6 g) in ethanol (20 ml) was added sodium borohydride (40 mg), and the mixture was stirred for 5 minutes. The mixture was diluted with dichloromethane and washed with water. The separated aqueous layer was extracted with dichloromethane. The combined organic extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give 3-(3-hydroxymethylpyridin-2-yl)nitrobenzene (606 mg).
Reaction SMILES: Cl.[N:2]([CH2:5][C:6]([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[C:24]([O:25][CH3:26])=[C:23]3[C:18]([C:19](=[O:42])[C:20]([C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])=[O:31])=[CH:21][N:22]3[CH:27]3[CH2:29][CH2:28]3)=[CH:17][C:16]=2[F:43])[CH2:10][CH:9]1[CH3:44])=[O:7])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[ClH:40].[CH:27]1([N:22]2[C:23]3[C:18](=[CH:17][C:16]([F:43])=[C:15]([N:11]4[CH2:10][CH:9]([CH3:44])[N:8]([C:6](=[O:7])[CH2:5][NH2:2])[CH:13]([CH3:14])[CH2:12]4)[C:24]=3[O:25][CH3:26])[C:19](=[O:42])[C:20]([C:30]([NH:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=3[Cl:41])=[O:31])=[CH:21]2)[CH2:28][CH2:29]1
Reactant: COc1c(N2CC(C)N(C(=O)CN=[N+]=[N-])C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1c(N2CC(C)N(C(=O)CN)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Temperature: 0 °C

Procedure:
46.0 mg (0.07 mmol) of the compound of Example 82A are provided in 2 ml of tetrahydrofuran, the solution is cooled to 0° C., 21.1 mg (0.08 mmol) of triphenylphosphine, dissolved in 1 ml of tetrahydrofuran are added dropwise, the reaction mixture is warmed to room temperature and stirred over night at this temperature. For the work-up the solvent is removed completely on a rotary evaporator, the residue is prepurified by preparative RP-HPLC (Method 6) and after fine purification by column chromatography on silica gel 60 (eluent: dichloromethane:ethanol 90:10) and concentrating the fractions with the addition of hydrochloric acid 24 mg of the target compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:21][CH3:22])[C:17]([N+:18]([O-])=O)=[C:13]2[CH:12]=[CH:11][CH:10]=1.O.C(O)(=O)C>C(O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH2:21][CH3:22])[C:17]([NH2:18])=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCc1nn2c(-c3ccc(Cl)cc3Cl)cccc2c1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
7-(2,4-Dichlorophenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (110 mg) was suspended in ethanol (6 mL), and then water (3 mL), acetic acid (1 mL) and zinc powder (220 mg) were added and the mixture was heated and stirred at 60° C. for 1 hour. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain [7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (90 mg) as crude crystals. These were dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.059 mL) and 3 M aqueous sulfuric acid (0.294 mL), sodium borohydride (22.2 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (59 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:19]([O:21]CC)=[O:20])[N:9]2C2C=CC(F)=CC=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:11]=2)[CH:6]=[CH:7][C:8]=1[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)c1cc(=O)c2ccc(Br)cc2n1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2ccccc2n1
Temperature: 2.5 °C
Yield: 203.9 %

Procedure:
A solution of ethyl 7-bromo-1-(4-fluorophenyl)1,4-dihydro-4-oxoquinolinecarboxylate (100 g; 0.256 mole), 400 ml of lN NaOH and 700 ml of THF was refluxed for 2.5 hrs. It was cooled, THF was removed by distillation and the residue cooled to 0-5° C. It was acidified with 2N HCl, the white solid filtered and washed with 1.5 L. of water The product was dried in an oven at 70° C. for 18 hrs. to give 90.4 g (97.5%) of quinolinecarboxylic acid. This product was used in the next step without further purification.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)[CH3:25])[CH:17]=[N:16]3)[CH:10]=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[ClH:32].[Cl:32][C:28]1[CH:27]=[C:26]([C@H:24]([NH:23][C:18]2[CH:17]=[N:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[CH:10]=[N:9][NH:8][CH:12]=4)[CH:14]=3)[N:19]=2)[CH3:25])[CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](Nc1cnc2cc(-c3cnn(C(=O)OC(C)(C)C)c3)ccc2n1)c1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](Nc1cnc2cc(-c3cn[nH]c3)ccc2n1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To an ice cold solution of 4-{2-[(R)-1-(3-Chloro-phenyl)-ethylamino]-quinoxalin-6-yl}-pyrazole-1-carboxylic acid tert-butyl ester (0.1 g,) in 1,4-dioxane (3 mL) was added 14% HCl in dioxane (2 mL). The resulting mixture was stirred at RT for 2 hours. After completion of the reaction, the volatiles were evaporated off completely and the solid was triturated with acetone to afford the title compound as the HCl salt (0.017 g, 20%).