Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][S:44][CH:43]([C:47]([OH:49])=O)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[NH:56][N:55]=[C:54]2[C:60]([O:62][CH3:63])=[O:61]>CN(C=O)C>[CH3:63][O:62][C:60]([C:54]1[C:53]2[C:57](=[CH:58][CH:59]=[C:51]([NH:50][C:47]([CH:43]3[S:44][CH2:45][CH2:46][N:41]([C:39]([O:38][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:40])[CH2:42]3)=[O:49])[CH:52]=2)[NH:56][N:55]=1)=[O:61]
Reactant: COC(=O)c1n[nH]c2ccc(N)cc12
Reactant: CC(C)(C)OC(=O)N1CCSC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[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: COC(=O)c1n[nH]c2ccc(NC(=O)C3CN(C(=O)OC(C)(C)C)CCS3)cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.9 g, 5 mmol) and diisopropyl ethyl amine (DIEA) (2.7 mL) was added to a suspension of 4-(tert-butoxycarbonyl)thiomorpholine-2-carboxylic acid (1.3 g, 5 mmol) in DMF (10 mL) and was stirred at room temperature for 15 minutes. Methyl 5-amino-1H-indazole-3-carboxylate (0.95 g, 5 mmol)) was added to the reaction and was stirred at room temperature for an additional 30 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×20 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product (2.1 g) was progressed to the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:25]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:25])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc([N+](=O)[O-])ccc3nc21
Yield: 65 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-5-nitroanthranilic acid (3.8 g, 13.77 mmol) and POCl3 (20 ml) is refluxed for 8 hours. The reaction mixture is poured into ice waterl, neutralized with concentrated NH4OH, and the resulting solid is collected by filtration, washed with water and dried to afford 2.5 g (65%) of 1-ethyl-4-chloro-6-nitro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(O)C.Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:25][CH:26]1[CH2:27][CH2:28]1)[C:9]1[CH:14]=[C:13]([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1coc(-c2ccnc(N(CC3CC3)C(=O)OC(C)(C)C)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CC1CC1)c1cc(-c2nc(C(=O)O)co2)ccn1
Yield: 95.7 %

Procedure:
A solution of ethyl 2-(2-((tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (13.88 g) and 2M aqueous sodium hydroxide solution (140 mL) in a mixed solvent of ethanol (140 mL)/THF (140 mL) was stirred at room temperature for 4 hr, and neutralized with 2M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (12.32 g).
Reaction SMILES: ClC1C(OCC2(C(F)(F)F)CCCCC2)=C[C:5](F)=[C:6]([CH:14]=1)C(OC(C)(C)C)=O.[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH:29]1[CH2:38][O:39][C:40]1[C:52](Cl)=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=1)[CH2:35]2>>[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH:29]1[CH2:38][O:39][C:40]1[C:52]([CH:14]3[CH2:6][CH2:5]3)=[CH:51][C:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[C:42]([F:54])[CH:41]=1)[CH2:35]2
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2C3CC4CC(C3)CC2C4)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2C3CC4CC(C3)CC2C4)cc1F

Procedure:
Following the procedure as described in Example 158 step 3, and making variations as required to replace tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 4-(adamantan-2-ylmethoxy)-5-chloro-2-fluorobenzoate, the title compound was obtained as colorless oil (1.99 g, 92%): MS (E+) m/z 401.3 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30]([CH2:32][N:33]([CH3:38])[CH2:34][C:35]([OH:37])=O)=[O:31].[Cl-].[Na+]>CC(N(C)C)=O.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:31])[CH2:32][N:33]([CH3:38])[CH2:34][C:35]1=[O:37]
Reactant: CN(CC(=O)O)CC(=O)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN1CC(=O)N(c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.108 g, 0.34 mmol) and diisopropylethylamine (0.074 g, 0.57 mmol) were added sequentially at ambient temperature to a stirred solution of N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenylcarbamoylmethyl]-N-methylglycine (0.103 g, 0.26 mmol) in dimethylacetamide (1 ml), the mixture was stirred at ambient temperature for 1 hour, then it was diluted with water (10 ml). Sodium chloride (1 g) was added, the mixture was stirred at ambient temperature for 30 minutes, then the resulting solid was collected by filtration, washed with water (1 ml) and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-4-methylpiperazine-2,6-dione (0.071 g) as a beige solid, m.pt. 205–208° C.; 250 MHz 1H-nmr (CDCl3) δ (ppm): 2.4 (s, 3H) (CH3), 3.5 (q, 4H) (2×CH2), 4.25 (s, 2H) (ArCH2—), 7.1 (m, 2H) (2×ArH), 7.25 (m, 1H) (ArH), 7.7–7.85 (m, 3H) (3×ArH), 8.4 (m, 1H) (ArH), 10.35 (s, 1H) (CONH); m/z (M+H)+. 381, 100% purity.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH:12]3[CH2:13][CH2:14][CH:8]2[CH2:9][O:10][CH2:11]3)[S:5][CH:6]=1.C(O)C.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:3]=[C:4]([N:7]3[CH:12]4[CH2:13][CH2:14][CH:8]3[CH2:9][O:10][CH2:11]4)[S:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1csc(N2C3CCC2COC3)n1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(-c2csc(N3C4CCC3COC4)n2)cc1
Temperature: 92.5 °C
Yield: 86.9 %

Procedure:
To a solution of 8-(4-bromothiazol-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Step-1 of o compound 56, 0.29 g, 1.05 mmol) in a mixture of toluene:ethanol (1.5 ml:4.5 ml) were added (4-chlorophenyl) boronic acid (0.18 g, 1.16 mmol) and potassium carbonate (0.29 g, 2.11 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.06 g, 0.05 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with mixture of 10% methanol in dichloromethane (2×10 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.28 g, 88.0%). MS: m/z 307 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH:18]([C:21]1([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH2:23][O:22]1)([CH3:20])[CH3:19]>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:23][C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)([OH:22])[CH:18]([CH3:20])[CH3:19])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(C)C1(c2ccncc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccncc2)C(C)C)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
To a stirred solution of sodium hydride (0.192 g, 50-60%) in dry DMF (5 mL) at 0° C. was added 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (0.3 g). The reaction mixture was stirred at RT for 30 min. To the reaction mixture was added 4-(2-isopropyloxiran-2-yl)pyridine (0.317 g in 2 mL DMF) at RT. After 12 h stirring, the reaction mixture was diluted with ice-water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified by column chromatography (silica gel 100-200 mesh, 5% MeOH:DCM) to obtain pure product (50 mg). 1HNMR (DMSO, Oxalate salt) d (ppm): 8.30 (d, 2H), 7.30 (d, 2H), 7.15 (s, 1H), 7.10 (d, 1H), 6.82 (d, 1H), 4.40 (m, 2H), 4.22 (m, 2H), 3.4 (m, 2H), 3.20 (m, 1H), 2.80 (s, 3H), 2.62 (m, 1H), 2.5 (m, 1H), 2.25 (s, 3H), 1.15 (d, 3H), 0.6 (d, 3H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH:18]4[CH2:19][CH:15]([CH2:16][CH2:17]4)[CH:14]2[CH2:13][N:12]([CH3:20])[CH2:11]3)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH3:21][I:22]>CCOCC>[I-:22].[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]23[CH:18]4[CH2:19][CH:15]([CH2:16][CH2:17]4)[CH:14]2[CH2:13][N+:12]([CH3:21])([CH3:20])[CH2:11]3)=[CH:8][CH:9]=1)=[N+:2]=[N-:3]
Reactant: CI
Reactant: CN1CC2C3CCC(C3)C2(c2ccc(N=[N+]=[N-])cc2)C1
Solvent: CCOCC
Product: C[N+]1(C)CC2C3CCC(C3)C2(c2ccc(N=[N+]=[N-])cc2)C1
Product: [I-]

Procedure:
A mixture of 150 mg of 3a-(4-azidophenyl)octahydro-2-methyl-4,7-methano-1H-isoindole and 0.05 ml of methyl iodide in 4 ml of ether was allowed to stand for 2 weeks to give 200 mg of the desired product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[N:4][C:3]=1[O:14][CH:15]([CH3:17])[CH3:16].[H-].[Na+].[CH2:20]([O:27][C:28]1[C:33]([CH2:34]Cl)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([O:27][C:28]1[C:33]([CH2:34][N:9]2[C:8](=[O:13])[C:7]3[C:2]([CH3:1])=[C:3]([O:14][CH:15]([CH3:17])[CH3:16])[N:4]=[CH:5][C:6]=3[O:12][CH2:11][CH2:10]2)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: Cc1c(OC(C)C)ncc2c1C(=O)NCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CN2CCOc3cnc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94608.2 %

Procedure:
To a solution of 6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131f, 70 mg, 0.30 mmol) in dry DMF (6 mL) was added NaH (36 mg, 0.90 mmol, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 10 minutes. To the mixture was added 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 155 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (20 mL). The solution was washed with brine (5×15 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131 g, 0.14 g, 100%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[BH4-].[Li+].CO.C(Cl)(Cl)Cl>COCCOC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH2:3][OH:2])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:7])([CH3:10])([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Yield: 97 %

Procedure:
This compound was prepared in 97% yield from the ester 4c (9.84 g, 40 mmol) by reduction with lithium borohydride in dry DME analogous to the method described earlier1,2. TLC Rf 0.47 (eluent MeOH/CHCl3, 7/93). 1H NMR (CDCl3) δ 0.83-1.03 (m, 6H, CHCH3, CH2CH3), 1.03-1.40 (m, 2H, CH2CH3, CH2CH3), 1.44 (s, 9H, t-Bu), 2.21-2.61 (m, 1H, CHCH3), 3.32-3.88 (m, 4H, CHCH2OH), 4.52-4.68 (m, 1H, NH), CI MS, m/e 218 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[CH:13]1([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:18][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: OC1CCCC1
Reactant: COc1ccc(C(=O)Cl)nc1Cl
Product: COc1ccc(C(=O)OC2CCCC2)nc1Cl

Procedure:
6-Chloro-5-methoxypyridine-2-carbonyl chloride (5.8 g) is added to dry cyclopentanol (50 mL) and the mixture refluxed for 4 hours. The mixture is concentrated, the residue dissolved in ethyl acetate (400 mL) and the ethyl acetate solution is washed with water (3×250 mL). After drying (MgSO4) the solution is evaporated to dryness to give cyclopentyl 6-chloro-5-methoxypyridine-2-carboxylate (6.3 g) as a buff solid, m.p. 90-92° C. [Elemental analysis: C, 55.9; H, 5.47; Cl, 13.9; N, 5.48%. calculated: C, 56.36; H, 5.52; Cl, 13.8; N, 5.48%.].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)(=[O:3])[CH3:2].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(C(C)C)C(C)C)C>S(Cl)(Cl)=O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([C:15]([F:14])([F:23])[F:24])[CH:17]=2)=[O:10])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Oc1cccc(C(=O)Nc2cccc(C(F)(F)F)c2)c1

Procedure:
Using 3-(acetyloxy)benzoic acid (9.01 g, 50.0 mmol), thionyl chloride (10 mL), 3-(trifluoromethyl)aniline (12.1 g, 75.0 mmol) and N-ethyl-N-isopropylpropane-2-amine (12.9 g, 100 mmol), and in the same manner as in Example A25(i), the title compound (16.2 g, quantitatively) was obtained as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:10]=1[NH2:11].[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[Br:17][CH2:18][C:19]([NH:11][C:10]1[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:9]=1[CH3:8])=[O:20]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(N)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)CBr)c(C)c1

Procedure:
117 g of triethylamine and 140 g of 2,4-dimethylaniline are dissolved in 2 l of methylene chloride, and a solution of 233 g of alpha-bromoacetyl bromide in 400 ml of methylene chloride is added with ice-cooling, at at most 15° C., within 30 min. After a reaction time of 30 min, the precipitate is filtered off with suction, the residue is dissolved in 3 l of methylene chloride and combined with the filtrate and washed twice with 2 l of water and 2 l of sat. sodium chloride solution. The mixture is dried over sodium sulphate, filtered off with suction and concentrated, and the residue is recrystallized from ethanol. This gives 193 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH2:23])[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.Cl.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([C:18]3[N:19]=[C:20]([NH:23][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)[S:21][CH:22]=3)=[C:13]([CH3:24])[CH:12]=2)=[CH:25][CH:26]=1
Reactant: COCCOc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-amine (12-6, 322.3 mg, 0.90 mmol) in CH2Cl2 (10.0 ml) was added triethylamine (0.40 mL, 2.6 mmol) followed by isonicotinoyl chloride hydrochloride (387.2 mg, 2.1 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-(4-{4-(4-(2-methoxyethoxy)phenoxy)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (12, 230 mg) as white solids in 56% yield: 1H NMR (500 MHz, DMSO-d6) δ 13.0 (brs, 1 H), 8.78 (d, J=5.8 Hz, 2 H), 7.98 (d, J=5.8 Hz, 2 H), 7.12 (s, 1 H), 6.96-7.00 (m, 4 H), 6.67 (s, 2 H), 4.01-4.07 (m, 2 H), 3.63-3.64 (m, 2 H), 3.26 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 476.4 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (560 mg) and 1,2-dichloroethane (15 mL) was added morpholine (170 mg) at room temperature, and the reaction mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (590 mg) was added at room temperature, and the mixture was further stirred at room temperature for 15 hr. Morpholine (170 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (590 mg) was added at room temperature, and the mixture was further stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was to washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (400 mg, yield 63%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([C:17]([NH:19][C@H:20]([C:24]([NH:26][C@H:27]([C@H:35]([OH:72])[C@@H:36]([OH:71])[C@@H:37]([NH:45][C:46](=[O:70])[C@H:47]([CH:67]([CH3:69])[CH3:68])[NH:48][C:49]([N:51]([CH2:53][C:54]1[N:55]=[C:56]([NH:59]C(OC(C)(C)C)=O)[S:57][CH:58]=1)[CH3:52])=[O:50])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[CH:21]([CH3:23])[CH3:22])=[O:18])[CH2:3][C:4]1[N:5]=[C:6]([NH:9]C(OC(C)(C)C)=O)[S:7][CH:8]=1.CO>C(Cl)(Cl)Cl>[CH3:52][N:51]([C:49]([NH:48][C@H:47]([C:46]([NH:45][C@H:37]([C@H:36]([OH:71])[C@@H:35]([OH:72])[C@@H:27]([NH:26][C:24](=[O:25])[C@H:20]([CH:21]([CH3:22])[CH3:23])[NH:19][C:17]([N:2]([CH2:3][C:4]1[N:5]=[C:6]([NH2:9])[S:7][CH:8]=1)[CH3:1])=[O:18])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:70])[CH:67]([CH3:69])[CH3:68])=[O:50])[CH2:53][C:54]1[N:55]=[C:56]([NH2:59])[S:57][CH:58]=1
Reactant: CC(C)[C@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(NC(=O)OC(C)(C)C)n1)C(C)C
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)N(C)Cc1csc(N)n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(N)n1)C(C)C

Procedure:
Using the procedure of Example 58B but replacing the resultant compound of Example 58A with the resultant compound of Example 92 provided, after silica gel chromatography using first 5% then 10% methanol in chloroform, 62 mg (43%) of the desired compound (Rf 0.16, 10% methanol in chloroform) as an off-white solid, m.p. 122°-124° C. Mass spectrum: (M+1)+ =837.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[C:8]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:7]2[N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[C:10]3=[CH:9][C:8]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)cc12
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2nc(-c3ccc(F)cc3)c(-c3ccncc3)cc12)c1ccncc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
In a volumetric flask, 3-amino-6-(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (0.20 g, 0.7 mmol, obtained in example 70), isonicotinoyl chloride hydrochloride (0.12 g, 0.7 mmol, obtained in section a) and pyridine (1 mL) were introduced under argon atmosphere. This was stirred at room temperature for 2 days. It was concentrated and the residue dissolved in a mixture of CHCl3 and 1 N HCl. The phases were separated and the aqueous phase was extracted with CHCl3 (×2). The aqueous phase was basified by slow addition of 1 N NaOH. Brine was added and extracted with CHCl3 and EtOAc. The organic phase was dried over Na2SO4 and concentrated to dryness. The crude product obtained was purified by chromatography on silica gel using CHCl3-MeOH mixtures of increasing polarity as eluent, to afford 98 mg of the title compound (yield: 68%).