Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][C:22]=1[OH:29])[CH3:16]>C(O)C.Cl.C(OCC)(=O)C.O>[CH2:7]([O:29][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:21]=1[O:20][CH2:19][CH2:18][O:17][CH2:15][CH3:16])[CH:25]=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOCCOc1ccc(C=O)cc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOCCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Potassium carbonate (11.3 g, 81.5 mmol) and benzyl chloride (9.5 mL, 82.6 mmol) were added to a solution of 4-(2-ethoxyethoxy)-3-hydroxybenzaldehyde described in Production Example 24-1 (13.2 g, 62.7 mmol) in ethanol (130 mL) under nitrogen atmosphere at room temperature. The liquid mixture was stirred under a thermal condition of 90° C. for 2 hours. The reaction liquid was cooled to 0° C. and then diluted with 2 M hydrochloric acid, ethyl acetate, and water. The organic layer was washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under vacuum. The resultant residue was dissolved in dichloromethane and the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (13.5 g, 72%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[N:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10][C:11]=2[CH:12]=1)(=[O:3])[CH3:2].[CH3:39][Mg]Br>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[CH2:31][C:30]6[C:25](=[CH:26][C:27]([O:32][CH3:33])=[CH:28][CH:29]=6)[C:24]5=[O:34])[C:18]=4[CH3:35])=[N:15][N:14]=[C:13]([C:36]([NH2:38])=[O:37])[C:9]=3[NH:10][C:11]=2[CH:12]=1)([CH3:39])[CH3:2]
Reactant: C[Mg]Br
Reactant: COc1ccc2c(c1)C(=O)N(c1cccc(-c3nnc(C(N)=O)c4[nH]c5cc(C(C)=O)ccc5c34)c1C)C2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N(c1cccc(-c3nnc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 7-acetyl-1-(3-(6-methoxy-1-oxoisoindolin-2-yl)-2-methylphenyl)-5H-pyridazino[4,5-b]indole-4-carboxamide (36.0 mg, 0.071 mmol) in tetrahydrofuran (8 mL) at 0° C. was added methylmagnesium bromide (0.119 mL, 0.356 mmol). The mixture was stirred at room temperature for 20 min. Additional methylmagnesium bromide (0.119 mL, 0.356 mmol) was added at 0° C. and the mixture was stirred at room temperature for another 20 min. The reaction was quenched with water (15 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. After solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (11.4 mg, 0.021 mmol, 30.1% yield) as a white solid. LCMS (M+H)+=522.20. 1H NMR (500 MHz, DMSO-d6) δ: 12.34 (s, 1H), 8.75 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.73 (d, J=6.9 Hz, 1H), 7.61-7.57 (m, 2H), 7.51 (d, J=6.4 Hz, 1H), 7.35-7.33 (m, 2H), 7.27-7.25 (m, 2H), 5.19 (s, 1H), 4.98 (d, J=16.9 Hz, 1H), 4.90 (d, J=16.9 Hz, 1H), 3.86 (s, 3H), 1.90 (s, 3H), 1.49 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](O)=[O:21])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][NH:24][C@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:21])[N:24]([CH3:23])[CH:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][CH2:27][CH2:26]3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-6,1′-dicarboxylic acid 1′-tert-butyl ester (150 mg, 0.49 mmol), methyl-(R)-1,2,3,4-tetrahydro-naphthalen-1-yl-amine (0.079 g, 0.49 mmol), and diisopropylethylamine (0.50 mL, 0.49 mmol) in DMF (10 mL) was added dropwise BOP (238 mg, 0.49 mmol) at RT. After stirring overnight at RT, the reaction mixture was poured on water (10 mL) and extracted with ethylacetate (20 mL). The aqueous phase was re-extracted with ethylacetate (20 mL). The combined organic layers were washed with aq. sat. sodium bicarbonate solution (30 mL), 1M HCl solution (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/hexane 4:1) to give 6-[methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamoyl]-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (215 mg, 97%). 1H-NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 1.64-2.05 (m, 8H), 2.18-2.22 (m, 1H), 2.72-2.81 (m, 4H), 2.82 (s, 3H), 4.15-4.25 (m, 2H), 5.15-5.20 (m, 1H), 7.18-7.25 (m, 5H), 7.53-7.71 (m, 1H), 7.73-7.74 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([S:8][C:9]([F:12])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: Nc1cc(SC(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc(SC(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 63.3 %

Procedure:
A mixture of 0.60 g of 2-amino-4-(trifluoromethylthio)phenol, 0.45 g of 3-chloroisonicotinic acid, 0.71 g of WSC and 6 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.63 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethylthio)phenyl]isonicotinamide.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=3)(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]>[Pd].C(OCC)(=O)C>[NH2:31][C:27]1[CH:26]=[C:25]([S:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:35])([F:34])[F:1])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=3)[CH2:21][CH2:20]2)(=[O:23])=[O:24])[CH:30]=[CH:29][CH:28]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cccc(S(=O)(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 1 h
Yield: 115.1 %

Procedure:
1,1,1,3,3,3-Hexafluoro-2-(4-((4-(3-nitrophenylsulfonyl)piperazin-1-yl)methyl)phenyl)propan-2-ol (1.660 mmol, 875.3 mg) and palladium on carbon were combined in ethyl acetate (20 mL). The reaction mixture was hydrogenated at 2 bar pressure for 1 hour. The reaction mixture was filtered through dicalite and concentrated under vacuum to afford the title compound (950.5 mg).
Reaction SMILES: C([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])=[CH:8][CH2:7]1)CCCC.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=1
Reactant: CCCCCC1CC=C(c2cccc(F)c2F)CC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: Fc1cccc(-c2ccccc2)c1F

Procedure:
To a mixture of 0.1 mol 4-pentyl-1-(2,3-difluorphenyl)-cyclohex-1-en and 500 ml toluene is added 0.22 mol 2,3-dichlor-5,6-dicyano-p-benzoquinone (DDQ) and refluxed for 2 h. After usual work-up 2',3'-difluorbiphenyl, bp: 125° C. at 0.5 mm Hg is obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH:9]=1)(=O)=O.FC(F)(F)C(O)=O.[CH3:28][C:29]1[S:33][C:32]([C:34]([N:36]2[CH2:41][C:40]3([CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[O:39][CH2:38][CH2:37]2)=[O:35])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(#N)C>[CH2:19]([O:18][CH:14]([O:15][CH2:16][CH3:17])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][CH2:6][N:44]1[CH2:45][CH2:46][C:40]2([O:39][CH2:38][CH2:37][N:36]([C:34]([C:32]3[S:33][C:29]([CH3:28])=[CH:30][CH:31]=3)=[O:35])[CH2:41]2)[CH2:42][CH2:43]1)[CH3:20]
Reactant: CCOC(OCC)c1cccc(CCOS(C)(=O)=O)c1
Reactant: Cc1ccc(C(=O)N2CCOC3(CCNCC3)C2)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(OCC)c1cccc(CCN2CCC3(CC2)CN(C(=O)c2ccc(C)s2)CCO3)c1
Temperature: 70 °C

Procedure:
3-(Diethoxymethyl)phenethyl methanesulfonate (example 20, step d) (0.30 g) in acetonitrile (1.5 mL) was added to a stirred solution of (5-methylthiophen-2-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 9, step b) (0.391 g) and triethylamine (0.415 mL) in acetonitrile (1.5 mL) and the solution heated at 70° C. for 48 h. After cooling, the solution was evaporated in vacuo and applied to a silica gel column for purification, eluting with ethyl acetate:isohexane:triethylamine, 60:40:5 giving the subtitled compound as a gum. Yield 0.2 g.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1.Cl>C(O)C.[Pd]>[NH:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([CH2:4][NH2:3])[CH:13]=2)[CH:9]=[CH:10]1
Reactant: CON=Cc1ccc2cc[nH]c2c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc2cc[nH]c2c1
Reaction time: 3 h
Yield: 87.5 %

Procedure:
An amount of 1H-Indole-6-carbaldehyde O-methyl-oxime (150 mg, 0.86 mmol) is dissolved in ethanol (6.5 mL). Then hydrogen chloride (0.62 mL) is added, followed by 10% Pd/C (15 mg). After hydrogenation at 35 psi for 3 h, the solution is filtered through Celite and evaporated to dryness. The residue is recrystallized from ethyl acetate to give 110 mg of crude product as a yellow solid. MS (ESI) m/z 147.3 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:6]=2[N:7]=1.[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[N:31]=[CH:30][C:29]([NH:32][C:2]3[N:3]=[CH:4][C:5]4[S:10][CH:9]=[C:8]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:21]1
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: O=[N+]([O-])c1cccc(-c2csc3cnc(Cl)nc23)c1
Product: O=[N+]([O-])c1cccc(-c2csc3cnc(Nc4ccc(N5CCOCC5)nc4)nc23)c1
Yield: 80.6 %

Procedure:
N-(6-Morpholinopyridin-3-yl)-7-(3-nitrophenyl)thieno[3,2-d]pyrimidin-2-amine (480 mg, 78% yield) was prepared in the same manner as Step 10 of Example 1 using 2-chloro-7-(3-nitrophenyl)thieno[3,2-d]pyrimidine (400 mg, 1.37 mmol) and 6-morpholinopyridin-3-amine (369 mg, 2.06 mmol).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.Cl.[CH:24]([NH:27][NH2:28])([CH3:26])[CH3:25].[CH3:29][O:30][C:31]([C@@H:33]1[CH2:37][C@@H:36]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][C:42]=2[C:53]([F:56])([F:55])[F:54])(=[O:40])=[O:39])[CH2:35][N:34]1[C:57](=O)[CH2:58][C:59](=O)[CH3:60])=[O:32].COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1C(=O)CC(=O)C)=O.C(OC(C)=O)(C)C.COC([C@@H]1C[C@@H](S(C2C=CC(F)=CC=2C(F)(F)F)(=O)=O)CN1C1N(C(C)C)N=C(C)C=1)=O>O1CCCC1.N1C=CC=CC=1>[CH3:29][O:30][C:31]([C@@H:33]1[CH2:37][C@@H:36]([S:38]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:50])([F:51])[F:52])=[CH:43][C:42]=2[C:53]([F:55])([F:56])[F:54])(=[O:40])=[O:39])[CH2:35][N:34]1[C:57]1[N:27]([CH:24]([CH3:26])[CH3:25])[N:28]=[C:59]([CH3:60])[CH:58]=1)=[O:32]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Reactant: CC(C)NN
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)CC(C)=O
Agent: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1C(C)C
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC(=O)OC(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1c1cc(C)nn1C(C)C
Temperature: 55 °C
Reaction time: 48 h

Procedure:
Lawesson's reagent (39 mg, 106 umol; CAS Reg. No. 19172-47-5) and isopropylhydrazine hydrochloride (12 mg, 106 umol; CAS Reg. No. 16726-41-3) were added to a solution of (2S,4R)-1-(3-oxo-butyryl)-4-[4-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-benzenesulfonyl]-pyrrolidine-2-carboxylic acid methyl ester and (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester (50 mg, 96 umol) in tetrahydrofuran (2.9 ml) and pyridine (0.1 ml) under an argon atmosphere. The mixture was stirred for 16 h at 55° C. and for additional 48 h at ambient temperature. Ice water/0.1 N aqueous HCl solution 1/1 and iPrOAc were added and the layers were separated. The aqueous layer was extracted one more time with iPrOAc, the combined organic layers were washed with ice water/10% aqueous sodium carbonate solution, ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure to give a yellow oil which was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to obtain a mixture of the title compound and (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(2-isopropyl-5-methyl-2H-pyrazol-3-yl)-pyrrolidine-2-carboxylic acid methyl ester (39 mg, 70 umol; 73%) as colorless oil. MS (ESI): m/z=558.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH2:37][OH:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH2:37][OH:38])[C:25](=[O:26])[CH2:24][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[N:20][NH:21]2)=[CH:17][CH:16]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)N(CCO)Cc2ccccc2)c2ccc3cn[nH]c3c2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [C:1]([C:3]1[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1)#[N:2].[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>C(O)(=O)C>[N+:9]([C:6]1[CH:7]=[C:3]([C:1]#[N:2])[N:4]([CH3:8])[CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: Cn1cccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1cc([N+](=O)[O-])cc1C#N
Temperature: 0 °C
Yield: 73.7 %

Procedure:
Compound 22-4 (1 g) was dissolved in anhydrous acetic acid (100 ml), and cooled to 0° C. To the solution was slowly added dropwise nitric acid (380 μl) with stirring, followed by stirring at the same temperature for 1 hour and subsequently at room temperature for 18 hours. After confining the completion of the reaction, to the mixture was added an ice-water (200 ml), followed by slowly adding solid sodium hydroxide (20 g) thereto and stirring for 1 hour. The obtained mixture was extracted with ether (50 ml×3). The obtained organic layer was washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and purified by column-chromatography (ethyl acetate/hexane=1/3) to yield the compound 22-5 (1.05 g, 73.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[NH2:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:30][C:29]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:27]([O:26][CH3:25])[CH:28]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1cc(N)cc(OC)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc(OC)c1
Temperature: 160 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.400 g (2.60 mmol) of 3,5-dimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. At ca. 100° C., 1 mL of glacial acetic acid was added to the melt to dissolve. Water (10 mL) was added to precipitate a gum. Decanted and dissolved gum in 35 mL of methylene chloride. The solution was washed with 2×20 mL of water, dried over magnesium sulfate, charcoaled, filtered, and concentrated. The remaining gum was purified silica gel chromatography eluting with chloroform and then with 2:1 hexane:ethyl acetate to obtain the fraction containing the pure product. The eluent was evaporated to near dryness when crystals separated. The crystals were filtered and washed with 0.5 mL of ether; wt 0.059 g; mp 228°-230° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([CH:13]([OH:21])[CH2:14][NH:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:5][C:4]=1Br>>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:13]([OH:21])[CH2:14][NH:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1c(Br)cc(C(O)CNC2CCCC2)cc1C(F)(F)F
Agent: Cl
Product: Nc1ccc(C(O)CNC2CCCC2)cc1C(F)(F)F

Procedure:
m.p. of the hydrochloride: 144°-145° C., was prepared from 1-(4'-amino-3'-bromo-5'-trifluoromethyl-phenyl)-2-cyclopentylamino-ethanol analogous to Example 51.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[CH:18][C:12]([Br:11])=[C:13]([C:19]([F:22])([F:20])[F:21])[CH:14]=1
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: Clc1nc2ccccc2[nH]1
Product: FC(F)(F)c1cc(Nc2nc3ccccc3[nH]2)ccc1Br

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-bromo-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 262-264° C.). MS(ES+) m/z 356 (M+, 100).
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=1>C1COCC1>[F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:5]
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1cccnc1F
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)c1cccnc1F
Reaction time: 15 h
Yield: 91 %

Procedure:
A homogeneous mixture of 2-fluoronicotinic acid (Aldrich, 0.45 g, 3.2 mmol), in anhydrous THF (12 mL), was treated with oxalyl chloride (0.56 mL, 6.4 mmol) followed by anhydrous DMF (2 drops). After heating at reflux for 1.5 hours, the reaction mixture was concentrated in vacuo to afford 2-fluoronicotinoyl chloride as a residue which was used without further purification. The residue was dissolved in anhydrous THF (8 mL), anhydrous DCM (2 mL), pyridine (1 mL) and DMF (to a total volume of 16 mL). This homogeneous 2-fluoronicotinoyl chloride mixture (2 mL) was then added to a rapidly stirred mixture of o-toluidine (Aldrich, 0.17 mL, 1.6 mmol) in anhydrous THF (2 mL). After 15 hours, the reaction was quenched with water, and then extracted with 10% isopropanol in chloroform. The organic layer was washed once with sat. aq. NaHCO3, once with sat. aq. NaCl, then dried over anhydrous Na2SO4 and concentrated in vacuo to afford the desired product (0.084 g, 91%) as a pale orange solid which was used without further purification. MS(ESI+) m/z 231 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]1N2CCN(CC2)C1>CCOC(C)=O.O>[CH3:14][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: C1CN2CCN1CC2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c2ccccc2c2ccccc21
Temperature: 92.5 °C
Yield: 961.2 %

Procedure:
To a solution of carbazole (1.03 g, 6.16 mmol) in DMC (10 mL), DABCO (0.069 g, 0.62 mmol) is added and the resulting solution is heated to 90-95° C. for 24 h. The reaction is cooled to RT, and diluted with EtOAc (40 mL) and H2O (40 mL). The organic layer is separated and washed in sequence with H2O (50 mL), 10% aqueous citric acid (2×40 mL) and H2O (3×40 mL). The organic layer is dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 9-methylcarbazole (about 1.08 g, 97%) as a beige solid: 1H NMR (CDCl3) δ8.06 (d, 2H), 7.43 (t, 2H), 7.31 (d, 2H), 7.20 (t, 2H), 3.71 (s, 3H); 13C NMR (CDCl3) δ141.0, 125.7, 122.8, 120.3, 118.9, 108.5, 29.0; MS m/z 181 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2.[C-:16]#[N:17].[K+]>CN(C=O)C>[F:15][C:4]1[C:3]([CH2:2][C:16]#[N:17])=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2)=[CH:6][CH:5]=1
Reactant: [C-]#N
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(F)c(CC#N)c2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (20.0 g, 74 mmol; prepared as in WO 2007/081597) in DMF (530 mL) was added KCN (22.1 g, 339 mmol) and the mixture was stirred at 70° C. overnight. The mixture was concentrated, water and EA were added and the aq. layer was extracted with EA. The combined org layers were washed with brine, dried over MgSO4 and concentrated to afford the title intermediate as a beige solid (16.13 g, 100% yield).
Reaction SMILES: [Br:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>C1COCC1>[C:19]1([S:24]([N:13]2[C:14]3[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7]3[C:12]2=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1
Reactant: Brc1cccc2c1[nH]c1ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1I
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c2ccccc2c2cccc(Br)c21
Temperature: 40 °C
Reaction time: 12 h

Procedure:
19.6 g (80 mmol) of 1-bromocarbazole are initially introduced in 1000 ml of THF, and 8.9 g (223.3 mmol) of NaH (60% in oil) are added at 0° C. 24 g (80 mmol) of 2-iodobenzenesulfonyl chloride are subsequently added to the mixture, which is then stirred at 40° C. for 12 h. The organic phase is dried over MgSO4, and the solvent is removed in vacuo. The residue is recrystallised from acetone and finally sublimed in a high vacuum. Yield: 29 g (574 mmol), 72% of theory, purity according to HPLC 99.9%.