Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2].I[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][C:20]([NH:23][C:24]([NH:26][CH:27]([CH3:28])[CH3:29])=[O:25])([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCCCCI
Reactant: CCOCc1nc2cnc3cc(O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Product: CCOCc1nc2cnc3cc(OCCCCCCNC(=O)OC(C)(C)C)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Yield: 92.3 %

Procedure:
Following the method described in Part L of Example 2, N-{2-[2-(ethoxymethyl)-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (3.12 g, 7.80 mmol) was treated with tert-butyl 6-iodohexylcarbamate (2.81 g, 8.58 mmol) to afford 4.31 g of tert-butyl 6-{[2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexylcarbamate. The material was used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]([F:27])([F:26])[C:11]([F:25])([F:24])[C:12](=O)[CH2:13][C:14](=O)[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17].[OH-].[NH4+]>P(=O)(O)(O)O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:14]([C:15]([F:20])([F:21])[C:16]([F:17])([F:18])[F:19])=[CH:13][C:12]=2[C:11]([F:25])([F:24])[C:10]([F:27])([F:26])[F:9])[N:3]=1
Reactant: O=C(CC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: Nc1cccc(N)n1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc2c(C(F)(F)C(F)(F)F)cc(C(F)(F)C(F)(F)F)nc2n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-diamino pyridine (5.2 g., 4.76 mmole), 1,1,1,2,2,6,6,7,7,7-decafluoroheptan-3,5-dione (14.5 g., 4.80 mmole) and 85% phosphoric acid (50 ml.) is stirred at 90°-95° C. for 6 hours. When cool, the reaction mixture is poured into ice-water and neutralized with ammonium hydroxide to pH 7. The solid is collected, washed with water, dried, and can be purified by recrystallization from benzene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]4[N:18]=[N:19][NH:20][N:17]=4)[CH:14]=3)[NH:9][N:8]=2)[CH:2]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: N#Cc1ccc2[nH]nc(-c3cccnc3)c2c1
Solvent: Cc1ccccc1
Product: c1cncc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)c1

Procedure:
The title compound was prepared from 3-(3-pyridyl)-1H-indazole-5-carbonitrile (0.068 g, 0.031 mmol), azidotributyl tin (0.116 g, 0.096 mL, 0.32 mmol) in toluene (10 mL). The product was isolated using the procedure described for Example 161 (0.009 g, 0.04 mmol, 12.5% yield): 1H NMR (DMSO-d6) δ 14.0 (br s, 1H), 9.2 (d, 1H), 8.8 (s, 1H), 8.7 (d, 1H), 8.5 (d, 1H), 7.83–7.78 (m, 2H), 7.76–7.64 (m, 1H); ES-MS (m/z) 264 [M+1]+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OOC(C)(C)C)(C)(C)C.[CH:18]([O:20][CH2:21][CH3:22])=[CH2:19]>>[CH2:18]([O:20][CH2:21][CH2:22][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH3:19]
Reactant: O=C1CCCCC1
Reactant: C=COCC
Agent: CC(C)(C)OOC(C)(C)C
Product: CCOCCC1CCCCC1=O
Yield: 95 %

Procedure:
2940 g (30 mol) of cyclohexanone were heated to reflux while stirring and, at this temperature, a solution of 87.6 g (0.6 mol) of di-tert-butyl peroxide in 216 g (3 mol) of ethyl vinyl ether was added over the course of 5 hours (h). The mixture was subsequently refluxed for a further 1 h. After the mixture had cooled, the low boilers (tert-butanol, remaining vinyl ether and peroxide) and the excess cyclohexanone were removed by distillation under reduced pressure (25-40 mbar; diaphragm pump). The residue (about 500 g) was distilled under reduced pressure (0.5 to 2 mbar; oil pump). A total of 350 g of a 95% pure 2-(2-ethoxyethyl)cyclohexanone of boiling point 60°-65° C. (0.5 mbar) was obtained, corresponding to a yield of 69% of theory.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28]>C1COCC1>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrCCCCCCCBr
Reactant: CCOC(=O)CC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)CCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.42 mL) in dry THF (30 mL) under argon at 0° C. was added 2.5M n-butyl lithium (15.5 mL) slowly, keeping the temperature below 10° C. The solution was stirred at 0° C. for 30 minutes before cooling to −78° C. Ethyl propionate (4.01 mL) was added dropwise and the solution stirred at −78° C. for 1 hour. 1,7-dibromoheptane (6.63 mL) was added and stirring continued at −78° C. for 1 hour then the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride (30 mL) was added to the reaction followed by ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL), dried over sodium sulfate and evaporated. Purification was by silica gel chromatography eluting with 1-5% ethyl acetate in petroleum ether (40-60° C.) to give ethyl 9-bromo-2-methylnonanoate, which was used without further purification. This material (0.84 g) was dissolved in dry ether (27 mL) and cooled to 0° C. under argon. Diisobutylaluminium hydride (1M in toluene, 6.7 mL) was added dropwise and the reaction was stirred at 0° C. for 1 h 15 minutes. The reaction was quenched by addition of saturated aqueous potassium sodium tartrate and the resulting mixture was stirred for 15 minutes. Ethyl acetate (60 mL) and water (20 mL) were added and the phases separated. The aqueous layer was extracted with ethyl acetate (3×30 mL) then the combined organics were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 10% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless oil. Yield 0.23 g.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[CH:14]=[CH:13]3)[N:9]=1.[OH-].[Na+]>C1COCC1.CO.O>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:14]=[CH:13]3)[N:9]=1
Reactant: COC(=O)COc1ccc2cc(-c3csc(Cc4c(Cl)cccc4Cl)n3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc2cc(-c3csc(Cc4c(Cl)cccc4Cl)n3)ccc2c1
Yield: 75.5 %

Procedure:
A mixture of methyl ({6-[2-(2,6-dichlorobenzyl)-1,3-thiazol-4-yl]-2-naphthyl}oxy)acetate (205 mg, 0.447 mmol), prepared in the previous step, and 1 N NaOH (671 μL, 0.671 mmol) in 20 mL of THF plus 20 mL of methanol plus 10 mL of water was refluxed under nitrogen for 2.5 h. The reaction was filtered, acidified by the addition of 3 mL of 1 N HCl and then concentrated under reduced pressure to remove the THF and methanol. The solid present was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (150 mg, 74%) as an off-white solid, mp 205-207° C. Elemental Analysis for C22H15Cl2NO3S+0.30H2O Calc'd: C, 58.75; H, 3.50; N, 3.11. Found: C, 59.09; H, 3.58; N, 2.92.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:33]1[CH2:34][CH2:35][CH:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=2)[CH2:31][CH2:32]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C2CCNCC2)c1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: Cc1cccc(C2CCN(C(=O)c3cnc4c(Br)cnn4c3NCc3ccccc3)CC2)c1
Yield: 75.2 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 22, step 3 instead of 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid and 4-(3-methylphenyl)piperidine hydrochloride (0.15 g, 0.69 mmol), the title compound (0.22 g, 77%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([CH:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([N+:25]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>CO.[Zn]>[NH2:25][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[CH2:8][CH:9]([CH:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C(C(=O)OC)C(Cc1ccc(F)cc1[N+](=O)[O-])c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: COC(=O)C(C(=O)OC)C(Cc1ccc(F)cc1N)c1ccccc1
Yield: 89.1 %

Procedure:
To a solution of dimethyl [2-(4-fluoro-2-nitrophenyl)-1-phenylethyl]malonate (8a) (5.0 g) in methanol (20 mL) was added ammonium chloride (1.5 g) and zinc dust (11.0 g). The reaction mixture was then heated to reflux for 1 h. The reaction mixture was filtered through a diatomaceous earth pad, and the organic solvents were removed in vacuo. The resulting yellow oil was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous potassium carbonate solution (2×), the organic layer was dried, filtered, and concentrated in vacuo to afford the title compound as a tan gum (4.1 g, 90%). MS APCI, m/z=346 (M+1). LC/MS: 2.51 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6]O.[ClH:12].C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6][Cl:12]
Reactant: Cl
Reactant: COc1cc(CO)ccc1C
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: COc1cc(CCl)ccc1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methoxy-4-methylbenzylalcohol (41.61 g), conc. hydrochloric acid (125 ml) and toluene (83 ml) was stirred at 90° C. for 1 hour. After cooling, ice-water (125 ml) and diisopropyl ether (80 ml) were added to the mixture, and the organic layer was separated, and the aqueous layer was extracted with diisopropyl ether (160 ml). The combined organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give 3-methoxy-4-methylbenzyl chloride (46.35 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:10](OC(OCC)OCC)C>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cc(Br)cnc1N
Solvent: O=CO
Product: Brc1cnc2[nH]cnc2c1
Temperature: 100 °C
Yield: 61 %

Procedure:
A stirred mixture of 5-bromopyridine-2,3-diamine (5 g, 26.6 mmol), formic acid (2.5 mL), and triethylorthoformate (70 mL) was heated at 100° C. for 2.5 h. The reaction mixture was cooled to rt and the solid precipitate was collected by filtration, washed with Et2O and dried to afford 6-bromo-3H-imidazo[4,5-b]pyridine as a solid (3.22 g, 61%) which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (br s, 1H), 8.50 (s, 1H), 8.44 (d, J=2.1 Hz, 1H), 8.31 (d, J=1.9 Hz, 1H). LCMS (ESI) m/z 198 and 200 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]([CH3:28])C)CCCCC1.[CH2:35]([C@@H:42]1[NH:47][CH2:46][CH2:45][N:44]([C:48]2[CH:56]=[C:55]3[C:51]([C:52]([CH2:61][CH3:62])=[N:53][N:54]3[CH:57]3[CH2:60][CH2:59][CH2:58]3)=[CH:50][CH:49]=2)[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.BrC1C=NC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:35]([C@@H:42]1[N:47]([C:24]2[CH:28]=[N:26][CH:21]=[CH:22][CH:23]=2)[CH2:46][CH2:45][N:44]([C:48]2[CH:56]=[C:55]3[C:51]([C:52]([CH2:61][CH3:62])=[N:53][N:54]3[CH:57]3[CH2:58][CH2:59][CH2:60]3)=[CH:50][CH:49]=2)[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: Brc1cccnc1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(c4cccnc4)[C@@H](Cc4ccccc4)C3)ccc12
Temperature: 100 °C
Yield: 94.9 %

Procedure:
Into a 40 mL septum-cap vial were added sodium tert-butoxide (68 mg, 0.71 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (28 mg, 0.07 mmol), and Pd2(dba)3 (0.03 mmol). The vial was sealed and evacuated/purged 5× with nitrogen. A solution of 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole (185 mg, 0.49 mmol) and 3-bromopyridine (158 mg, 1.02 mmol) in 3 mL of toluene was added, and the reaction mixture was heated at 100° C. for 15 h. The reaction mixture was cooled, filtered, concentrated, and purified by silica gel flash chromatography with a 0-100% EtOAc/Hexanes gradient to afford the title compound as a tan solid (30 mg, 13%). LC/MS (Method B) 3.10 min, [M+1]+ 452.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[N:15]([C:16]([NH2:18])=[O:17])[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C@@H:8]([OH:19])[CH2:7][C:5]=2[CH:6]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>O.ClCCl>[CH3:37][C:36]([O:19][C@@H:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]([C:16]([NH2:18])=[O:17])[C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=2[CH2:7]1)=[O:38]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)N1c2ccccc2C[C@H](O)c2ccccc21
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of eslicarbazepine (18 gm), triethylamine (8.5 gm), dimethylaminopyridine (0.1 gm), acetic anhydride (8.7 gm) and dichloromethane (90 mL) was stirred at about 20-25° C. for about 4 hrs. To the resulting solution water was added and resulting solution was stirred for about 15 minutes. Organic layer was separated and washed with 1 N HCl solution followed by washing with water. The solvent was distilled out completely. Ethyl acetate was added to the resulting residue followed by stirring at about 25-30° C. for about 3 hrs. The resulting solid was filtered, washed and dried to obtain the title compound (Yield: 80%; HPLC purity: 99.8%; Chiral purity: 99.3%; d0.9 50.7 μm, d0.5 17.3 μm, d0.1 6.0 μm).
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Se](=O)=[O:14]>O1CCOCC1.O>[C:4]([C:3]1[C:2]([CH:1]=[O:14])=[N:12][CH:11]=[CH:10][CH:9]=1)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cccnc1C
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1C=O
Temperature: 25 °C
Yield: 50.2 %

Procedure:
To a stirred solution of ethyl 2-methylnicotinate (1.657 g, 10.0 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added selenium dioxide (1.568 g, 14.1 mmol) and the resultant mixture was heated to reflux overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3:1 hexanes/ethyl acetate) and provided the title compound (0.90 g, 50%) as a yellow oil. 1H NMR (CDCl3) δ 1.41 (t, 3H, J=7.5 Hz), 4.45 (q, 2 H; J=7.5 Hz), 7.56 (dd, 1H, J=6.0, 6.0 Hz), 8.11 (dd, 1H, J=6.0, 1.0 Hz), 8.87 (dd, 1H, J=6.0, 1.0 Hz), 10.34 (s, 1H).
Reaction SMILES: C1(N)C=CC=CC=1.CC1SC(C([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][C:26]4[CH:27]=[C:28]([NH:32][C:33]([C:35]5[S:36][C:37]([CH3:40])=[CH:38][N:39]=5)=[O:34])[CH:29]=[CH:30][CH:31]=4)[CH:23]=3)[C:18]([CH:41]=[CH:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[N:17]2)=O)=NC=1.CC1SC(C(O)=O)=NC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CN(C=O)C>[CH:41]([C:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][C:26]3[CH:27]=[C:28]([NH:32][C:33]([C:35]4[S:36][C:37]([CH3:40])=[CH:38][N:39]=4)=[O:34])[CH:29]=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)[NH:16][N:17]=1)=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1cnc(C(=O)Nc2cccc(Oc3ccc4c(C=Cc5ccccc5)nn(C(=O)c5ncc(C)s5)c4c3)c2)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1cnc(C(=O)O)s1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: Cc1cnc(C(=O)Nc2cccc(Oc3ccc4c(C=Cc5ccccc5)n[nH]c4c3)c2)s1

Procedure:
3-3-Styryl-4,5-dihydro-1H-indazol-6-yloxy)-phenylamine was converted to 5-methyl-thiazole-2-carboxylic acid {3-[1-(5-methyl-thiazole-2-carbonyl)-3-styryl-1H-indazol-6-yloxy]-phenyl}amide by treatment with 5-methyl-thiazole-2-carboxylic acid and HATU (o-(2-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) in DMF and analogous work-up, DDQ treatment and isolation to Example 4(a), step (iv) (50% yield): 1H NMR (DMSO-d6) δ 10.85 (s, 1H), 8.45 (d, 1H, J=9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7.54-7.34 (m, 5H), 6.96 (d, 1H, J=8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:27])([F:26])[C@@:6]([C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([Br:25])[N:19]=1)([NH:11][S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH2:7][CH2:8][O:9][CH3:10])C.[BH4-].[Li+]>C1COCC1.C(OCC)(=O)C>[Br:25][C:20]1[N:19]=[C:18]([C@:6]([NH:11][S@:12]([C:14]([CH3:16])([CH3:15])[CH3:17])=[O:13])([CH2:7][CH2:8][O:9][CH3:10])[C:5]([F:27])([F:26])[CH2:4][OH:3])[C:23]([F:24])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(F)(F)[C@](CCOC)(N[S@@](=O)C(C)(C)C)c1nc(Br)ccc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCC[C@@](N[S@@](=O)C(C)(C)C)(c1nc(Br)ccc1F)C(F)(F)CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.4 %

Procedure:
To a solution of (R)-3-(6-bromo-3-fluoro-pyridin-2-yl)-2,2-difluoro-5-methoxy-3-((S)-2-methyl-propane-2-sulfinylamino)-pentanoic acid ethyl ester (2.4 g, 4.90 mmol) in THF (38 ml) was added lithiumborohydride (214 mg, 9.81 mmol) in 2 portions. The slightly exothermic reaction was stirred for 6 hours at room temperature. Crushed ice was added carefully and the reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude yellowish resin (2.05 g) was chromatographed over silica gel (Redisep column 40 g, cyclohexane/ethyl acetate 4:6) to give the title compound as a colourless resin. 1.50 g (68.4% yield).
Reaction SMILES: [BrH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH3:14])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2>C(O)(=O)C.CS(C)=O>[Br:1][C:6]1[C:5]([CH3:14])=[CH:4][C:3]([OH:2])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:13])[NH:11]2
Reactant: Br
Reactant: Cc1cc(O)c2[nH]c(=O)ccc2c1
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cc(O)c2[nH]c(=O)ccc2c1Br
Reaction time: 18 h

Procedure:
A 45% solution of hydrobromic acid in acetic acid (324 μL) is added dropwise to a solution of 8-hydroxy-6-methyl-1H-quinolin-2-one (316 mg) in dimethylsulphoxide (9 mL) at room temperature. The reaction mixture is allowed to stand for 18 hours at room temperature and the solvent removed in vacuo.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH2:10]([N:17]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[C:23]2[C:18]1=[C:19]([F:31])[CH:20]=[CH:21][CH:22]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[CH2:10]([N:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:30])[C:24]=2[C:23]2[C:18]1=[C:19]([F:31])[CH:20]=[CH:21][CH:22]=2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCCc2c1c1cccc(F)c1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Oc1cccc2c1c1cccc(F)c1n2Cc1ccccc1
Temperature: 75 °C
Reaction time: 5.5 h
Yield: 51.8 %

Procedure:
Pyridinium bromide perbromide (2.9945 g, 0.0094 mol) is added to a mixture of 9-benzyl-8-fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (2.1145 g, 0.0072 mol) in THF (22 mL) and DMF (16 mL) and the mixture is heated to 75° C. After stirring for 5.5 h, THF is removed under reduced pressure and the residue is partitioned between ethyl acetate and brine. The combined organic layers are washed with dilute sodium thiosulfate/brine and the aqueous layer is backwashed with ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. The residue is recrystallized from ethyl acetate/heptane and the resulting solids are combined with lithium bromide (1.1338 g, 0.013 mol), lithium carbonate (0.8831 g, 0.012 mol), and DMF (24 mL) and heated to 120° C. After 1.5 h, the mixture is partitioned between ethyl acetate and brine. The combined organic layers are washed with dilute brine and then dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (150 mL) using dichloromethane (100) to give 1.0857 g (52%) of the title compound; mp 155-156° C.; MS (ESI−) for C19H14FNO m/z 290.1 (M−H)−; IR (drift) 3524, 1581, 1498, 1456, 1432, 1343, 1318, 1272, 1239, 1134, 966, 790, 731, 714, 698 cm−1; 1H NMR (CDCl3) δ5.33, 5.69, 6.59, 6.98, 7.14, 7.25, 8.10. Anal. Calcd for C19H14FNO: C, 78.33; H, 4.84; N, 4.81. Found: C, 77.67; H, 4.90; N, 4.71.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][C:20]=3[S:19](=[O:33])(=[O:32])[N:18]=2)[C:7]1=[O:34])=[O:4].[C:40](OC(=O)C)(=[O:42])[CH3:41].C(N(CC)CC)C>ClCCl>[C:40]([NH:1][CH2:2][C:3]([NH:5][C:6]1([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([OH:16])=[C:8]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][C:20]=3[S:19](=[O:32])(=[O:33])[N:18]=2)[C:7]1=[O:34])=[O:4])(=[O:42])[CH3:41]
Reactant: CC(C)CCC1(NC(=O)CN)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)NC1(CCC(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of the product of Example 46 (10 mg, 0.017 mmol) in dichloromethane (0.25 mL) was added acetic anhydride (8 μL, 0.087 mmol) followed by addition of triethylamine (7 μL, 0.052 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was then diluted with dichloromethane (1 mL) and washed with aqueous 1 N HCl (2×0.5 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was dissolved in methanol (0.5 mL) and treated with excess K2CO3 for 30 min. The heterogeneous solution was filtered and the filtrate concentrated in vacuo. The residue was then taken up in ethyl acetate (1 mL), washed with aqueous 1 N HCl (2×1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (10% methanol/dichloromethane) afforded the title compound as a light yellow solid (5 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.61-0.75 (m, 6H), 0.79-0.97 (m, 1H), 1.16-1.35 (m, 2H), 1.56-1.71 (m, 1H), 1.78 (s, 3H), 1.83-1.97 (m, 1H), 2.99 (s, 3H), 3.64-3.88 (m, 2H), 7.26-7.34 (m, 2H), 7.35-7.44 (m, 2H), 7.46 (d, J=2.21 Hz, 1H), 7.91 (t, J=5.52 Hz, 1H), 7.96-8.02 (m, 1H), 8.36 (s, 1H), 9.86 (s, 1H), 15.39 (s, 1H); MS m/z 618.0 (M+H)+.