Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][N:9]2[CH:19]=1)=[O:5])C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[S:29]([NH2:32])(=[O:31])=[O:30].[Cl-].C([Al+]CC)C.C(O)(=O)C>ClCCl.CCCCCCC.C(O)(C)C>[Cl:14][C:13]1[C:8]2[N:9]([CH:19]=[C:6]([C:4]([NH:32][S:29]([C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[Cl:20])(=[O:31])=[O:30])=[O:5])[N:7]=2)[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:12]=1
Reactant: CCOC(=O)c1cn2cc(C(F)(F)F)cc(Cl)c2n1
Reactant: COc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1ccc(Cl)c(S(=O)(=O)NC(=O)c2cn3cc(C(F)(F)F)cc(Cl)c3n2)c1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a stirred slurry of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester (see PCT Patent Publication WO 2010/129500 for preparation) (3 g, 10.3 mmol) and 2-chloro-5-methoxybenzenesulfonamide (see PCT Patent Publication WO 2010/129500 for preparation) (2.4 g, 10.8 mmol, 1.05 equiv) in dichloromethane (24 mL) at 17° C. under nitrogen was added diethyl aluminum chloride (1.5 mL, 12.0 mmol, 1.16 equiv) over approximately 1 minute. The addition of diethylaluminum chloride was accompanied by ca. 13° C. temperature rise and gas evolution. After complete addition of diethylaluminum chloride the temperature of the reaction mixture was adjusted to 40° C. and the batch became an off-white slurry. The reaction mixture was held stirring for about 24 h at 40° C. HPLC analysis (after 24 h) indicated 3.6 area % of 8-chloro-6-(trifluoromethyl)imidazo[1,2,a]pyridine-2-carboxylic acid ethyl ester remaining. Iso-propyl alcohol (1.6 mL) and heptane (12 mL) were respectively added to the reaction resulting in formation of a thicker slurry. Aqueous 10% acetic acid (15 mL, 25.6 mmol, 2.5 equiv) was then added resulting in a strong exotherm. The reaction mass was held for about 1.5 h at 20-25° C. and was then filtered and the filter cake was washed with water (12 ml). The solid product was split into two portions, the larger portion was dried in a vacuum oven at 80° C. for 16 hours and the smaller portion was air-dried for 16 hours to give the title compound (2.8 g and 0.95 g respectively) in 86.8% combined yield. The vacuum-dried product conformed with polymorph Form A and the air-dried portion did not. The polymorph Form A was characterized by its powder X-ray diffraction pattern (See Characterization Example 2).
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:21]I>C(Cl)Cl>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[N:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(N=Nc2ccc(O)cc2)cc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
Aqueous KOH (0.3 M, 6 mL) was added to a solution of 14 (0.21 g, 1 mmol) in CH2Cl2 (50 mL). After stirring for 10 min, the precipitate was filtered, washed with cold H2O (10 mL), and dried. The resulting solid was suspended in CH2Cl2 (50 mL) and MeI (150 μL, 2 mmol) was added (see FIG. 25). The mixture was heated for 40 h under reflux and Ar. After cooling to ambient temperature, the mixture was washed with water (20 mL). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography [SiO2: hexanes/CH2Cl2 (1:1)] resulting in 11 (0.10 g, 52%) as an orange solid. mp=151° C.; FABMS: m/z=258 [M+H]+; 1H-NMR (400 MHz, chloroform-d): δ=3.88 (3H, s), 6.99-7.01 (2H, m), 7.93-7.95 (4H, m), 8.30-8.33 (2H, m); 13C-NMR (100 MHz, CDCl3): δ=55.9, 114.7, 123.3, 124.9, 125.8, 147.2, 148.5, 156.2, 163.5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:6]=2[CH:17]=1.[CH3:18][Li].O>O1CCCC1.C(OCC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7]([CH3:18])([OH:16])[C:6]=2[CH:17]=1
Reactant: [Li]C
Reactant: Cc1ccc2ccc3ccccc3c(=O)c2c1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C(C)(O)c1ccccc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the ketone from Step C (22 g) in dry tetrahydrofuran (400 ml) at 0° C. under nitrogen was added a solution of methyl lithium in diethyl ether (100 ml of 1.4M). The solution was stirred for 1 hr at 0° C. then water was cautiously added and solvents evaporated to give an aqueous mixture which was extracted with ether (2×150 ml). The combined extracts were washed with water, dried and evaporated. Crystallisation from ether/hexane gave 3,5-dimethyl-5H-dibenzo[a,d]cyclohepten-5-ol (20.18 g), m.p. 102°-103° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=2)[CH:14]=1.[CH3:34][NH:35][CH3:36].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[C:17]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:35]([CH3:36])[CH3:34])=[CH:27][CH:26]=2)[CH:14]=1
Reactant: CNC
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3)nc(N3CCCCC3)c2)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN(C)C)cc3)nc(N3CCCCC3)c2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-formylphenyl)-6-(piperidin-1-yl)isonicotinamide (0.2 g, 0.45 mmol) in methanol (12 mL), dimethyl amine (2.6 mL, 4.5 mmol, 2M solution in THF) and acetic acid (0.02 g, 0.45 mmol) were added and reaction mass stirred at rt for 90 min. Then reaction mass was cooled to 0° C. and sodium cyanoborohydride (0.056 g, 0.9 mmol) was added. Reaction stirred at 0° C. for 2 h and then stirred at rt for overnight. On completion, solvent was removed under reduced pressure, residue treated with water and extracted with ethyl acetate. Combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel obtaining N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(4-((dimethylamino)methyl)phenyl)-6-(piperidin-1-yl)isonicotinamide as light green solid (0.173 g, 79%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Product: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-indazole-5-carbaldehyde and 1-bromomethyl-4-chloro-2-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([N:17]([CH3:22])[S:18]([CH3:21])(=[O:20])=[O:19])[CH:10]=[C:11]([C:14]([NH:57][C@@H:58]([CH2:72][C:73]3[CH:74]=[C:75]([F:80])[CH:76]=[C:77]([F:79])[CH:78]=3)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCn1ccc2c(N(C)S(C)(=O)=O)cc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 40 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a mixture of 1-Butyl-4-[methyl (methylsulfonyl) amino]-1H-indole-6-carboxylic acid (0.2 g) in methylene chloride (15 mL) was added triethylamine (0.156 g), HOBT (0.105 g), and HATU (0.293 g). The mixture was stirred at 39° C. for 10 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.293 g) was added. The mixture was stirred at 40° C. for 4 h then poured into methylene chloride (50 mL), washed with water followed by brine then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 5% methanol in methylene chloride as eluent to give 0.21 g of the title compound: MS (ESI+) for C34H42F2N4O4S1 m/z 640.8 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3o2)cc(Cl)c2[nH]ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCNCC4)ccc3o2)cc(Cl)c2[nH]ccc12

Procedure:
A solution of tert-butyl 4-[(2-{4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-cyanopyridin-3-yl}-1-benzofuran-5-yl)methyl]piperazine-1-carboxylate (176 mg, 0.29 mmol) in CH2Cl2 (4 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 4 h and concentrated to provide 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[5-(piperazin-1-ylmethyl)-1-benzofuran-2-yl]nicotinonitrile as a yellow solid in quantitative yield (182 mg). HPLC retention time: 6.5 min.(g); MS: 497.3 (M+H); and HRMS: 497.1851.
Reaction SMILES: C(C1C(CC2SC=CC=2)=CC2C(C)(C)CCC(C)(C)C=2C=1)=O.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][C:29]1[C:30](/[CH:43]=[CH:44]/[C:45]2[CH:55]=[CH:54][C:48]([C:49]([O:51]CC)=[O:50])=[CH:47][CH:46]=2)=[CH:31][C:32]2[C:33]([CH3:42])([CH3:41])[CH2:34][CH2:35][C:36]([CH3:40])([CH3:39])[C:37]=2[CH:38]=1>>[CH3:39][C:36]1([CH3:40])[CH2:35][CH2:34][C:33]([CH3:41])([CH3:42])[C:32]2[CH:31]=[C:30](/[CH:43]=[CH:44]/[C:45]3[CH:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[CH:54][CH:55]=3)[C:29]([CH2:28][C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[CH:38][C:37]1=2
Reactant: CCOC(=O)c1ccc(/C=C/c2cc3c(cc2Cc2cccs2)C(C)(C)CCC3(C)C)cc1
Agent: CC1(C)CCC(C)(C)c2cc(Cc3cccs3)c(C=O)cc21
Product: CC1(C)CCC(C)(C)c2cc(Cc3cccs3)c(/C=C/c3ccc(C(=O)O)cc3)cc21
Yield: 63.3 %

Procedure:
Horner-Emmons olefination (following the procedure of Example) of 2-formyl-3-[(thiophene-2-yl)methyl]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (94 mg, 0.3 mmol) followed by ester hydrolysis (following the procedure of Example) of ethyl (E)-4-{2-[3-((thiophene-2-yl)methyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl]vinyl}benzoate (53 mg, 0.11 mmol) provides 4-[(E)-2-(5,5,8,8-tetramethyl-3-thiophen-2ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)vinyl]benzoic acid (30 mg, 63%) as a white crystalline solid 44 (m.p. 229.1-229.6° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:28]3[CH:29]=[C:30]([NH:34][CH:35]4[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]4)[CH:31]=[N:32][CH:33]=3)=[CH:16][N:17](S(C3C=CC(C)=CC=3)(=O)=O)[C:12]2=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:28]3[CH:29]=[C:30]([NH:34][CH:35]4[CH2:40][CH2:39][CH2:38][N:37]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:36]4)[CH:31]=[N:32][CH:33]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC4CCCN(C(=O)OC(C)(C)C)C4)c3)c3nc(-c4c(F)cccc4F)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5F)nc34)c2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
A solution of tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (33 mg, 0.050 mmol) in THF (1 mL) was treated with NaOH 10N (0.050 mL, 0.500 mmol). The reaction was heated to reflux at 80° C. After 4 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-6% MeOH/DCM), affording tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (21 mg, 83%). MS (ESI, pos. ion) m/z: 506.3 (M+1) A solution of tert-butyl 3-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-ylamino)piperidine-1-carboxylate (21 mg, 0.042 mmol) in MeOH (1 mL) was treated with HCl, 5-6N in IPA (0.083 mL, 0.415 mmol). The reaction was heated to 50° After 1 h, the reaction was cooled to 23° C., and the product (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N-(piperidin-3-yl)pyridin-3-amine MS (ESI, pos. ion) m/z: 406.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][O:11][CH3:12])[C:5]([CH3:13])=[CH:4][C:3]=1[OH:14].Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][O:11][CH3:12])[C:5]([CH3:13])=[CH:4][C:3]=1[O:14][C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH:21]=1
Reactant: COCOc1c(C)cc(O)c(Cl)c1C
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1c(C)cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c(Cl)c1C
Yield: 75.5 %

Procedure:
By using 5.65 g of 2-chloro-4-methoxymethoxy-3,5-dimethylphenol, 8.88 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 1.35 g of sodium hydride (55% by weight) and 100 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 9.19 g of the title compound were obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH2:55])([CH2:30][C:31]1[N:32]=[CH:33][N:34]([C:36]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:35]=1)[CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[C:57]1([S:63]([N:66]2[CH2:71][CH:70]3[CH:68]([CH:69]3[N:72]=[C:73]=[S:74])[CH2:67]2)(=[O:65])=[O:64])[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[C:57]1([S:63]([N:66]2[CH2:71][CH:70]3[CH:68]([CH:69]3[N:72]3[C:3](=[O:2])[C:4]([CH2:5][C:6]4[N:7]=[CH:8][N:9]([C:11]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH:10]=4)([CH2:30][C:31]4[N:32]=[CH:33][N:34]([C:36]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:35]=4)[NH:55][C:73]3=[S:74])[CH2:67]2)(=[O:65])=[O:64])[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: COC(=O)C(N)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=S(=O)(c1ccccc1)N1CC2C(C1)C2N=C=S
Product: O=C1N(C2C3CN(S(=O)(=O)c4ccccc4)CC32)C(=S)NC1(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Using the same procedure as described in Example 1B, the reaction mixture of the title compound of 53B (0.68 mmol) and 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo[3.1.0]hexane (6.71 mmol, prepared in 1A) was heated to reflux overnight under an atmosphere of dry N2. It was then poured into 10% K2CO3 aqueous solution and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated to afford the crude product. The crude product was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1) as eluents to afford the title compound of 56B as a yellow solid, 0.548 g (0.558 mmol, 82% yield).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:23][CH2:22][CH2:21]4)[CH2:16][CH2:15]3)=[O:13])[CH2:7][CH2:8][C:9]=2[N:10]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:20]1([N:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[CH2:11][N:6]3[CH2:7][CH2:8][C:9]4[N:10]=[C:2]([C:32]5[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=5)[S:3][C:4]=4[CH2:5]3)[CH2:15][CH2:16]2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=C(CN1CCc2nc(Br)sc2C1)N1CCN(C2CCC2)CC1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2nc3c(s2)CN(CC(=O)N2CCN(C4CCC4)CC2)CC3)c1
Temperature: 110 °C

Procedure:
A mixture of 2-bromo-5-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine (40 mg, 0.1 mmol), 3-methylsulfonyl-phenylboronic acid (40 mg, 0.2 mmol), Na2CO3 (42 mg, 0.4 mmol) and Pd(PPh3)4 (12 mg, 0.01 mmol) in DME (4 mL) and water (1 mL) is degassed with argon and heated at 110° C. in a sealed tube overnight. The mixture is cooled and the layers are separated. The aqueous layer is extracted with EtOAc (4 ml) and the combined extracts are dried and evaporated. The residue is purified by PTLC to give the title compound as a white solid. MS (M+1): 475.0; 1H NMR (δ, CDCl3): 8.44 (t, 1H), 8.15 (td, 1H), 7.94 (td, 1H), 7.62 (t, 1H), 3.86 (s, 2H), 3.65 (q, 4H), 3.46 (d, 2H), 3.09 (s, 2H), 2.97 (s, 3H), 2.68-2.78 (m, 1H), 2.33 (q, 4H), 1.62-2.07 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:9][C:8](=[O:10])[O:7][C:5](=[O:6])[CH2:4]1.[CH3:13][O:14][C:15]([C:17]1([S:21][C:22]2[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=2[Cl:30])[CH2:20][CH2:19][CH2:18]1)=[O:16]>C1C=CC=CC=1>[Cl:30][C:23]1[C:22]([S:21][C:17]2([C:15]([O:14][CH3:13])=[O:16])[CH2:18][CH2:19][CH2:20]2)=[CH:27][C:26]([NH:28][C:8](=[O:10])[CH2:9][CH:3]([C:2]([F:1])([F:12])[F:11])[CH2:4][C:5]([OH:7])=[O:6])=[C:25]([F:29])[CH:24]=1
Reactant: COC(=O)C1(Sc2cc(N)c(F)cc2Cl)CCC1
Reactant: O=C1CC(C(F)(F)F)CC(=O)O1
Solvent: c1ccccc1
Product: COC(=O)C1(Sc2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(F)cc2Cl)CCC1
Yield: 84.7 %

Procedure:
A mixture of 3.6 g of 3-trifluoromethylglutaric anhydride and 5.8 g of 1-(5-amino-2-chloro-4-fluoro-phenylthio)-cyclobutanecarboxylic acid methyl ester in 65 ml of benzene is heated under reflux for 3 hours while stirring. The resulting precipitate is then separated off, washed with diisopropyl ether and dried, yielding 7.9 g of N-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclobutylthio)-phenyl]-3-trifluoromethylglutaric acid monoamide having a melting point of from +165° to +167° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]1[C:12](=[O:36])[N:13]([CH2:22][C:23]([NH:25][CH:26]([CH:33]([CH3:35])[CH3:34])[CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:24])[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:15][C:8]2=1)=[O:2].Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O.C(OCC)(=O)C>CS(C)=O.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]1[C:12](=[O:36])[N:13]([CH2:22][C:23]([NH:25][CH:26]([CH:33]([CH3:34])[CH3:35])[C:27](=[O:32])[C:28]([F:29])([F:30])[F:31])=[O:24])[C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:15][C:8]2=1)=[O:2]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C=O)cccc32)c1=O)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)cc2c([nH]c3c(C=O)cccc32)c1=O)C(=O)C(F)(F)F
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of 2-(8-formyl-1-oxo-3-phenyl-1,2-dihydropyrido[3,4-b]indol-2-yl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide (0.1 g) in dimethylsulfoxide (1 mL) and toluene (1 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.46 g) and dichloroacetic acid (0.I mL). The resulting solution was allowed to stir for 2 hours. The mixture was poured into ethyl acetate, washed (1N hydrochloric acid, H2O), dried, and evaporated. The resulting material was chromatographed, with ether:ethyl acetate (gradient, 1:1, 0:1) as the eluent, to give the title compound (0.1 g) as a white solid; TLC: Rf =0.5, methanol:dichloromethane (5:95); 300 MHz.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:9]([C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Se](=O)=[O:20].C(=O)([O-])O.[Na+].[BH4-].[Na+].[Cl-].[NH4+]>ClC1C=CC=CC=1.CO>[OH:20][CH2:1][C:2]1[S:3][C:4]2[C:9]([C:10](=[O:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=[Se]=O
Reactant: Cc1sc2ccccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: Clc1ccccc1
Product: O=c1c(-c2ccccc2)c(CO)sc2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
The compound (1.0 mmol, 252 mg) obtained in (2) above and selenium dioxide (1.2 mmol, 133 mg) were dissolved in 5 mL of chlorobenzene, and the solution was refluxed under a nitrogen atmosphere for 12 hours. After the disappearance of the starting materials was confirmed by NMR, the temperature of the solution was returned to room temperature, and a saturated aqueous sodium hydrogen carbonate solution was poured thereinto to terminate the reaction. Then, the organic layer extracted with methylene chloride was dried over magnesium sulfate, and the solvents were distilled off under reduced pressure. The residue was passed through a silica gel column, and directly used in the subsequent reaction. The obtained mixture was dissolved in 2 mL of methanol, to which sodium borohydride (1.0 mmol, 38 mg) was added; and under a nitrogen atmosphere, the resulting product was stirred at 0° C. for 2 hours. Then, a saturated aqueous ammonium chloride solution was added thereto to terminate the reaction. Afterward, the organic substances were extracted with ethyl acetate, the obtained organic layer was dried over magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized with hexane/ethyl acetate. Thereby, the title compound (0.38 mmol, 104 mg) was obtained in a two-step yield of 38%.