Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[CH:4]([CH3:8])[CH2:5][CH2:6][CH:7]=1.[NH3:10]>[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH2:10]
Reactant: CC1=CCCC(C)C1=O
Reactant: N
Agent: [Pd]
Product: Cc1cccc(C)c1N
Reaction time: 4 h
Yield: 63 %

Procedure:
A solution of 19.7 g (0.158 mole) of 2,6-dimethyl-cyclohex-2-en-1-one in 180 ml of conc. ammonia is heated, after the addition of 4.0 g of palladium on charcoal (5%), in a hydrogenating autoclave for 4 hours at 280°-290° C., whereby a pressure of 20 bars is established, and is then maintained under these conditions for 5 hours. Cooling and pressure release are then carried out; the contents are again heated for about 5 hours and the pressure is again released. In order to effect the complete removal of hydrogen, the procedure of heating and pressure release is carried out in all three times. An addition is then made of 150 ml of ether and the catalyst is filtered off. The filter residue is washed three times alternately with 100 ml of ether and water, respectively. The mother liquor is extracted, after separation of the ether phase, five times with 150 ml of ether each time. The combined ether phases are dried over magnesium sulphate. After the ether has been distilled off, there remains 17.0 g of crude 2,6-dimethylaniline, from which is obtained, by distillation in a water-jet vacuum, 12.0 g (63% of theory) of pure 2,6-dimethylaniline; b.p. 103° C./ 18 Torr.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:54])[C@@H:15]([NH:40][S:41]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)(=[O:43])=[O:42])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>O1CCOCC1>[NH2:39]/[C:20](=[N:21]\[S:22]([C:25]1[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]2[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=2[C:35]=1[CH3:36])(=[O:24])=[O:23])/[NH:19][CH2:18][CH2:17][CH2:16][C@H:15]([NH:40][S:41]([C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1)(=[O:43])=[O:42])[C:14](=[O:54])[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCNCC2)c(C)c2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of compound C (36.6 g, 46.2 mmol) in dioxane (60 mL) was added 4M HCl in dioxane (58 mL) dropwise. The reaction mixture was stirred at room temperature for 1.5 h. Et2O (600 mL) was added to the reaction mixture, precipitated product was filtered off, washed with Et2O and finally dried under vacuum to afford compound D (34.5 g, 46.2 mmol). LC-MS [M+H] 685.4 (C33H44N6O6S2+H, calc: 685.9). Compound D was used without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].C(N(CC)CC)C.[C:16](Cl)(=[O:18])[O-:17]>ClCCl>[C:16](=[O:18])([OH:1])[OH:17].[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C([O-])Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of N-hydroxysuccinimide and 1.0 g of triethylamine were dissolved in 20 ml of dichloromethane, and 3.92 g of the chlorocarbonate of Lutensol T03 in 10 ml of dichloromethane were added dropwise over the course of 5 min. The mixture was left to stir at room temperature for 2 h, the solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate. The remaining solid was separated off, and the solvent was removed from the filtrate under reduced pressure to afford 4.3 g of the N-hydroxysuccinimide carbonate of Lutensol T03.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[N:19]1([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:29]([C:28]1[CH:27]=[CH:26][C:25]([N:19]2[CH2:24][CH2:23][N:22]([CH2:1][C:3]3[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]4[C:12]=3[CH:11]=[CH:10][CH:9]=[CH:8]4)[CH2:21][CH2:20]2)=[CH:32][CH:31]=1)#[N:30]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CN2CCN(c3ccc(C#N)cc3)CC2)c2ccccn2c1=O

Procedure:
A mixture of the ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (0.891 g, 3.63 mmol), 4-piperazin-1-ylbenzonitrile (0.952 g, 5.09 mmol), glacial acetic acid (1.25 mL, 21.8 mmol) and 18.2 mL of dichloroethane was stirred vigorously. To the stirring mixture was added sodium triacetoxyborohydride (1.08 g, 5.09 mmol), which was stirred for 18 hours. The mixture was quenched with a 10% sodium carbonate solution, extracted with dichloromethane (1×40 mL), and partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography eluting with EtOAc to yield ethyl 1-{[4-(4-cyanophenyl)piperazin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:5]([CH3:18])[C:4]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20])#[CH:2]>[Pt]=O>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[N:5]([CH3:18])[C:4]=1[C:19]([N:21]1[CH2:22][CH2:23][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH2:26]1)=[O:20])[CH3:2]
Reactant: C#Cc1nc(-c2cccc(C(F)(F)F)c2)n(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: O=[Pt]
Product: CCc1nc(-c2cccc(C(F)(F)F)c2)n(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 14, [5-ethynyl-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 41) was hydrogenated using platinum oxide as catalyst to give the title compound as yellow foam. MS: 435.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:38]([C:29]3[CH:30]=[CH:31][C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:28]=3)=[O:39])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(NC2CCN(C(=O)c3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.5 %

Procedure:
Compound (49) (0.056 g, 0.2 mmol) and triethylamine (0.14 mL, 1 mmol) were added sequentially to a solution of 2-naphthoyl chloride (0.114 g, 0.6 mmol) in CH2Cl2 (5 mL) at 25° C. The mixture was stirred at 25° C. for 12 h, then was concentrated in vacuo to a residue. Purification of the residue by flash column chromatography (gradient elution 5 to 30% EtOAc in hexanes) provided the title compound (0.04 g, 50%): TLC (Rf =0.50; 50% EtOAc/hexanes); 1H NMR (CDCl3) δ 7.84 (m, 6H), 7.51 (m, 3H), 6.55 (d, 2H, J=8.8), 4.65 (br s, 1H), 4.01 (d, 2H, J=7.8), 3.66 (m, 1H), 3.18 (t, 2H, J=11.2), 2.05 (m, 2H), 1.56 (s, 9H), 1.46 (m, 2H); 13C NMR (CDCl3) δ 170.5, 166.0, 150.1, 133.8, 133.3, 132.9, 131.5, 128.4, 127.9, 127.8, 127.1, 126.8, 124.2, 121.1, 111.9, 79.9, 49.9, 32.6, 28.4; HRMS (FAB) m/z 430.2241 (M)+ (C27H30N2O3 requires 430.2256).
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[CH:10][N:11]([CH3:34])[C:12]=1[C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])=[O:7])[CH2:2][CH2:3][CH3:4].Cl[C:40]1[CH:49]=[CH:48][C:47]([Cl:50])=[C:46]2[C:41]=1[CH:42]=[CH:43][C:44]([S:51]([NH2:54])(=[O:53])=[O:52])=[CH:45]2>>[CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[CH:10][N:11]([CH3:34])[C:12]=1[C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:54][S:51]([C:44]2[CH:43]=[CH:42][C:41]3[C:46](=[C:47]([Cl:50])[CH:48]=[CH:49][CH:40]=3)[CH:45]=2)(=[O:53])=[O:52])=[CH:15][C:14]=1[C:22]([N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1)=[O:23])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1ccc2c(Cl)ccc(Cl)c2c1
Reactant: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)O)cc1C(=O)N1CCc2ccccc2C1
Product: CCCCN(CCCC)C(=O)c1ncn(C)c1-c1ccc(C(=O)NS(=O)(=O)c2ccc3cccc(Cl)c3c2)cc1C(=O)N1CCc2ccccc2C1
Yield: 12.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 265, 4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-5-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoic acid (150 mg, 0.29 mmol) and 8-chloronaphthalene-2-sulfonamide (Intermediate 5, 140 mg, 0.58 mmol) were converted to the title compound (26 mg, 12%). 1H NMR (CD3OD, 1:1 mixture of amide rotamers) δ 8.99 (s, 1H), 8.18-8.09 (m, 3H), 8.05 (dd, J=8.4, 2.0 Hz, 1H), 7.94-7.91 (m, 1H), 7.72 (dd, J=7.2, 1.2 Hz, 1H), 7.69 (s, 0.5H), 7.62-7.55 (m, 1.5H), 7.42 (dd, J=8.0, 4.8 Hz, 1H), 7.21-7.13 (m, 3.5H), 6.93 (d, J=8.0 Hz, 0.5H), 4.78 (br s, 0.5H), 4.62-4.49 (m, 1.5H), 3.90 (br s, 0.5H), 3.60 (br s, 0.5H), 3.50 (s, 3H), 3.49-3.39 (m, 2H), 3.24 (t, J=6.4 Hz, 0.5H), 3.18-3.13 (m, 1.5H), 2.90 (br s, 1.5H), 2.85-2.65 (m, 2.5H), 1.50-1.09 (m, 8H), 0.89-0.79 (m, 6H); MS(ESI+) m/z 742.2 (M+H)+.
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:50])[O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][C:43]=2[CH3:49])[CH:34]=[CH:35][CH:36]=1)#[N:30]>>[C:29]([C:31]1[CH:32]=[C:33]([NH:37][C:38]([O:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([B:25]([OH:27])[OH:26])=[CH:44][C:43]=2[CH3:49])=[O:50])[CH:34]=[CH:35][CH:36]=1)#[N:30]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: Cc1cc(Br)ccc1CCOC(=O)Nc1cccc(C#N)c1
Product: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc(C#N)c1
Yield: 64 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 30C (730 mg, 2.0 mmol) was reacted with 5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 30D (420 mg, 64%) as a brown oil. 1H NMR (400 MHz, MeOD) δ ppm 2.29 (s, 3 H) 2.94 (t, J=7.07 Hz, 2 H) 4.26 (t, J=7.07 Hz, 2 H) 7.11 (d, J=7.33 Hz, 1 H) 7.24 (d, J=7.58 Hz, 1 H) 7.33 (t, J=7.96 Hz, 1 H) 7.36-7.52 (m, 2 H) 7.56 (d, J=7.83 Hz, 1 H) 7.77 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:14]([N:15]=1)=[CH:13][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2.[Cl:16][CH2:17][CH:18]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>COCCOC>[Cl:16][CH2:17][CH2:18][N:10]1[CH2:9][CH2:8][C:7]2[CH:13]=[C:14]3[N:15]=[C:2]([CH3:1])[O:3][C:4]3=[CH:5][C:6]=2[CH2:12][CH2:11]1
Reactant: Cc1nc2cc3c(cc2o1)CCNCC3
Reactant: O=CCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COCCOC
Product: Cc1nc2cc3c(cc2o1)CCN(CCCl)CC3
Yield: 36 %

Procedure:
A mixture 2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (1 mmol), chloroacetaldehyde (2 mmol), NaBH(OAc)3 (2 mmol) in dry DME (10 ml) was stirred at room temperature for 3 h. The mixture was partitioned between aqueous Na2CO3 (0.5 M) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound (36% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-])=[CH:5][C:4]=1[F:10])[CH3:2].ClC1C=C[N:15]=[C:14](C#N)C=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:14]#[N:15])[C:4]=1[F:10])[CH3:2]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: CCc1cc[n+]([O-])cc1F
Product: CCc1ccnc(C#N)c1F

Procedure:
The title compound was prepared from 4-ethyl-3-fluoropyridine-N-oxide according to the procedure for preparing 4-chloro-2-pyridinecarbonitrile described in Example 33.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12]OS(C)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[N:10]([CH3:12])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: COS(C)(=O)=O
Reactant: Clc1nc(Cl)c2[nH]ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.1 %

Procedure:
A mixture of 2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidine (2.67 g, 14.2 mmol), methanesulfonic acid methyl ester (1.26 mL, 14.9 mmol) and cesium carbonate (9.25 g, 28.4 mmol) in anhydrous N,N-dimethylformamide (21 mL) was stirred at RT (room temperature) under N2 for 15 h. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with 1:1 water/brine (3×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 2.50 g (87.1%) of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine as a white solid. MS(ESI) m/z: 202.2/204.1 [M+1]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[N:15]=[CH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Br:24])[CH:18]=3)(=O)=O)=CC=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:24][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([CH2:13][CH2:12][N:27]3[CH2:28][CH2:29][CH2:30][C@H:26]3[CH3:25])[N:15]=[CH:16]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3ccc(Br)cc3cn2)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2ccc(Br)cc2cn1
Temperature: 52.5 °C

Procedure:
The product from Example 52F was dissolved in a solution of (2R)-2-methylpyrrolidine (0.26 g, 3.0 mmol) in acetonitrile (20 mL). The solution was treated with potassium carbonate (0.5 g, 3.6 mmol) and heated at 50-55° C. for 20 hours in a sealed flask. The mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with MTBE (20 mL) and water (20 mL) and the pH was adjusted to 3-3.5 with concentrated HCl. The aqueous layer was separated, extracted with MTBE (10 mL), adjusted to a pH of 8-8.5 with potassium carbonate, and extracted with isopropyl acetate (20 mL). The organic layer was separated and concentrated in vacuo. The residue was dissolved in heptane (20 mL), filtered, and the filtrate concentrated under vacuum to provide the title compound. 1H NMR (CDCl3) δ 1.10 (d, J=6.1 Hz, 3H); 1.35-1.49 (m, 1H); 1.62-1.85 (m, 2H); 1.85-1.98 (m, 1H); 2.23 (q, J=8.8. Hz, 1H); 2.28-2.42 (m, 1H); 2.46-2.57 (m, 1H), 3.04-3.19 (m, 2H); 3.19-3.30 (m, 2H); 7.47 (s, 1H); 7.60 (d, J=8.8 Hz, 1H), 7.64-7.70 (m, 1H), 8.05 (m, 1H); 9.09 (s, 1H); HRMS Calcd. for [C16H19BrN2+H+]: 319.0810. Found: 319.0795.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3=[O:22])[CH2:14][CH2:15]2)[S:33]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=2)(=[O:35])=[O:34])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCCC1N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Product: COc1ccc(S(=O)(=O)N(c2ccc(C(F)(F)F)cc2)C2CCN(C3CCCCC3=O)CC2)cc1

Procedure:
The title compound, MS (ISP): m/e=589.4 (M+H+), was prepared as for example 99, steps (A) to (F). Step (B) was performed using 4-trifluoromethyl-aniline, and yielded (+/−)-trans-2-[4-(4-trifluoromethyl-phenylamino)-piperidin-1-yl]-cyclohexanol, which was oxidized to (+/−)-2-[4-(4-trifluoromethyl-phenylamino)-piperidin-1-yl]-cyclohexanone in step (C). This was then reacted with 4-methoxy-benzensulfonyl chloride in step (D), yielding (+/−)-N-(4-trifluoromethyl-phenyl)-4-methoxy-N-[1-(2-oxo-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide. The final step (F) was performed with bromobenzene.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C(Cl)=O.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH2:20])=[CH:17][CH:16]=[CH:15][CH:14]=2.O.Cl.Cl[CH2:24]Cl>N1C=CC=CC=1.[OH-].[Na+]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[N:20]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=[CH:24]1
Reactant: Nc1cnc2ccccc2c1N
Reactant: ClCCl
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: c1coc(-n2cnc3cnc4ccccc4c32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Furoyl chloride (1.1 g, 0.8 ml, 8.1 mmol) in dry dichloromethane (15 ml) was added dropwise to a solution of to 3,4-diaminoquinoline 8 (1.0 g, 6.0 mmol) in dry pyridine (6.2 ml) under nitrogen. The solution was stirred for 2 hours at room temperature. Water (15 ml) was added to quench the reaction and the solvent was evaporated under reduced pressure to afford an orange solid. This crude solid in 2N NaOH (15 ml) was refluxed for 2 hours. After cooling on ice the pH was adjusted to 7 using concentrated HCl. The solid that precipitated was filtered off and washed with water and ether. Then extracted with ethyl acetate (3 times 15 ml) and washed with water (3 time 15 ml) and dried over MgSO4. The solvent was evaporated and the residue was dried. Eluent for column chromatography was 1-5% methanol in dichloromethane. Yield: 0.62 g (44%). Mp.: 236-238° C. 1H NMR (DMSO-d6): δ 6.74 (s, 1H, Ar); 7.35 (d, 1H, J=3.7 Hz, Ar); 7.69-7.73 (m, 2H, Ar); 7.83 (s, 1H, Ar); 8.09 (s, 1H, Ar); 8.46 (s, 1H, Ar); 9.09 (s, 1H, Ar). 13C NMR (DMSO-d6): δ 111.4, 112.6, 120.7, 121.8, 126.5, 127.2, 129.5, 138.2, 143.6, 144.3, 145.1, 147.2, 155.4.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:15][C:16]1[CH:17]=[CH:18][C:19]([OH:26])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22].O[CH2:28][CH2:29][NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:26][CH2:28][CH2:29][NH:30][C:31]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:37])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COC(=O)c1cc(Br)ccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
DIAD (9.62 g, 47.6 mmol) was added to a mixture of methyl 5-bromo-2-hydroxybenzoate (10 g, 43.3 mmol), 1,1-dimethylethyl (2-hydroxyethyl)carbamate (6.98 g, 43.3 mmol) and triphenylphosphine (12.47 g, 47.6 mmol) in THF (250 ml) and stirred at RT for 2.5 hr. Additional triphenylphosphine (2.5 g) was added followed by DIAD (4 ml) and the mixture left standing overnight. Evaporation and purification by flash chromatography eluting with 25% EtOAc/hexane gave the title compound as a yellow oil (8.92 g). MS (ES): C15H2081BrNO5 requires 375; found 276 [M+H−100]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1N.N([O-])=O.[Na+].S(=O)(=O)(O)N.[BrH:19]>O>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[Br:19]
Reactant: Br
Reactant: Cc1cccc(C)c1N
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cccc(C)c1Br
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To an initial charge of 125 ml of 48% aqueous HBr are added, in portions, 24.24 g [0.2 mol] of 2,6-dimethylaniline. The resulting thick suspension is stirred at 80° C. for 15 minutes. It is then cooled to −10° C., and a solution of 16 g [0.232 mol] of NaNO2 in 70 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 160 mg of sulphamic acid are added. Then the suspension of the diazonium salt, cooled to −10° C., is metered within about 45 minutes into a solution, heated to 60° C., of 31.6 g [0.22 mol] of Cu(I)Br in 130 ml of 62% aqueous HBr. The reaction mixture is then stirred at 80° C. for another 1 hour, allowed to cool to room temperature and admixed with 250 ml of water, the phases are separated and the aqueous phase is extracted three times with 100 ml each time of methylene chloride. The combined organic phases are washed with 50 ml each of water and saturated aqueous NaCl solution, dried and concentrated under reduced pressure. This gives 33.3 g of an oil which, according to GC, contains 75.6% of 2,6-dimethylbromobenzene (68% of theory).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.[NH2:36][C:37]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.C(C1C=C(N=C=S)C=CC=1)#N>>[C:37]([C:7]1[CH:2]=[C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH:4]=[CH:5][CH:6]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: N#Cc1cccc(N=C=S)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4cccc(C#N)c4)cc3)cc2C1=O

Procedure:
The compound of example 69 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 3-cyanophenyl isothiocyanate. The compound of example 69 was used directly without isolation for the preparation of compound of example 70.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24](Br)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24]([O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:16])=[O:17])=[CH:12][CH:11]=1
Reactant: OCc1cccnc1
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(Br)n1
Product: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(OCc2cccnc2)n1

Procedure:
Prepared by the method of Example 20b using pyridine-3-methanol and 5-chloro-N-(3-bromo-5-methyl-2-pyrazinyl)-2-thiophenesulphonamide.