Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8](C(=O)C2C=CC(F)=CC=2)[CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C1=CNCCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Temperature: 93 °C
Yield: 91.1 %

Procedure:
To a stirred solution of 3-(4-fluorobenzoyl)-8-(3-methoxyphenyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (48 mg, 0.10 mmol) in 2 mL of EtOH was added 0.30 mL of 1M Na2CO3 solution at ambient temperature. The reaction mixture was heated at 93° C. reflux under N2for 3.5 hours and samples monitored by LC-MS. The solution was diluted with DCM (10 mL), washed with brine. The aqueous phase was extracted with DCM (10 mL) twice. The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (33 mg) as a yellow solid; 1H-NMR (CDCl3): δ 10.46 (1H, s), 7.73 (1H, d), 7.47 (1H, d), 7.37 (1H, d), 7.26 (2H, m), 7.12 (1H, m), 7.00 (1H, m), 6.79 (1H, m), 5.25 (1H, s), 4.21(2H, m), 3.80 (3H, s), 3.55 (2H, m), 3.11 (2H, m), 1.26 (3H, t). MS (ESI): 363 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH:7][C:8]([NH:10]C(=O)C2C=CC=CC=2)=[S:9])=[N:5][N:6]=1>[OH-].[Na+]>[CH3:1][C:2]1[NH:3][C:4]([NH:7][C:8]([NH2:10])=[S:9])=[N:5][N:6]=1
Reactant: Cc1nnc(NC(=S)NC(=O)c2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nnc(NC(N)=S)[nH]1

Procedure:
The saponification of N-{[(5-methyl-4H-1,2,4-triazole-3-yl)amino]carbonothioyl}-benzamide in methanolic sodium hydroxide solution, could be performed even at room temperature. The N-(5-methyl-4H-1,2,4-triazole-3-yl)thiourea formed was alkylated with methyl iodide at room temperature and the resulting methyl N-(5-methyl-4H-1,2,4-triazole-3-yl)imidothiocarbamate was liberated by extraction of the organic phase with 1 N NaOH. Finally, the methyl N-(5-methyl-4H-1,2,4-triazole-3-yl)imidothiocarbamate was brought to reaction with 2,6-dimethoxybenzylamine in ethanol at 130° C. in the microwave (100 Watt) and the N-(2,6-dimethoxybenzyl)-N′-(5-methyl-4H-1,2,4-triazole-3-yl)guanidine was isolated following chromatographic purification on preparative HPLC (Merck: Chromolith RP-18E, 100-25; eluent water/acetonitrile/0.1 molar acetic acid).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(#N)C.[OH-:28].[Na+].[OH:30]O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([S:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:24])(=[O:30])=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [OH-]
Reactant: CCCCCCCC(Sc1cccc[n+]1[O-])c1cc(C)ccc1C
Reactant: OO
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CCCCCCCC(c1cc(C)ccc1C)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
To a solution of 34.3 gm (0.1 mol) 2-[1-(2,5-dimethylphenyl) octylthio]pyridine N-oxide and 10.7 gm (0.26 mol) acetonitrile in 400 ml of methanol was added sufficient NaOH solution (6 N to minimize water) to adjust the pH in the operating range of 9.0 to 9.5 (true), approximately 11–12 (meter). 17 gm (0.26 mol) of 50% hydrogen peroxide was added in increments.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[NH:5]1>CS(C)=O>[O:3]=[C:4]1[N:8]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:18])[F:19])[CH:10]=2)[C:7](=[O:21])[C:6]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:5]1[CH2:22][CH2:6][CH2:7][OH:21]
Reactant: N#Cc1ccc(N2C(=O)NC3(CCOCC3)C2=O)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(N2C(=O)N(CCCO)C3(CCOCC3)C2=O)cc1C(F)(F)F
Temperature: 50 °C
Yield: 147.7 %

Procedure:
Using the procedure of Example 4, 109 mg of 50% sodium hydride, 510 mg of the product of Example 2 and 4 ml of dimethylsulfoxide were reacted and rinsing was carried out with 0.5 ml of dimethylsulfoxide. Then, 20 minutes after the release of hydrogen had stopped, 1.004 g of 3-bromopropoxydiphenyl-tert-butyl-silane were added and the solution was heated to about 50° C. Proceeding as in Example 4, the solution was taken up in 30 ml of methanol, 10 ml of 2N hydrochloric acid, 10 ml of chloroform and refluxed. After purification on silica with methylene chloride-acetone: 8-2 as eluant, 441 mg of the expected product (white crystals) melting at 155°-156° C. were obtained.
Reaction SMILES: [Cl-].[NH4+].O.[CH3:4][O:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12]([N+:17]([O-])=O)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[C:30]2[N+:33]([O-])=O)=[N:25]1>[Fe].C(OCC)(=O)C.CCO>[CH3:4][O:5][CH2:6][CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH:32]=[C:31]2[C:26]([CH:27]=[CH:28][CH:29]=[C:30]2[NH2:33])=[N:25]1
Reactant: COCCn1cc2c([N+](=O)[O-])cccc2n1
Reactant: COCCn1ncc2c([N+](=O)[O-])cccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COCCn1cc2c(N)cccc2n1
Product: COCCn1ncc2c(N)cccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Iron powder (170 mg), ammonium chloride (160 mg), and water (3 ml) were added to an EtOH (10 ml) solution containing the mixture of 1-(2-methoxyethyl)-4-nitro-1H-indazole and 2-(2-methoxyethyl)-4-nitro-2H-indazole obtained in the 1st step, followed by stirring at 80° C. for 2 hours. Ethyl acetate was added to the reaction solution, insoluble matter was removed by filtration, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel-alumina column chromatography. 1-(2-methoxyethyl)-1H-indazol-4-amine (49 mg) and 2-(2-methoxyethyl)-2H-indazol-4-amine (40 mg) were thus obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:15][S:16]([NH:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([Cl:26])=[O:25])=[CH:22][CH:21]=1)(=[O:18])=[O:17]>>[ClH:26].[CH2:13]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([NH:19][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:21][CH:22]=1)[CH3:14]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CCNc1ccccc1
Product: CCN(CC)CCN(C(=O)c1ccc(NS(C)(=O)=O)cc1)c1ccccc1
Product: Cl

Procedure:
In a manner similar to Example I react N,N-diethyl-N'-phenyl-1,2-ethanediamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26](=[S:28])[NH2:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:30][C:31](=O)[CH2:32][CH3:33]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C@H:13]1[C:26]1[S:28][CH:30]=[C:31]([CH2:32][CH3:33])[N:27]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](C(N)=S)C1
Reactant: CCC(=O)CCl
Solvent: c1ccccc1
Product: CCc1csc([C@@H]2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2NC(=O)OCc2ccccc2)n1
Temperature: 75 °C
Yield: 36.3 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-carbamothioylcyclohexylcarbamate (0.5 g, 0.0012 mol, see Example 12f, Step 2) in dry benzene (20 ml) under nitrogen was added 1-chloro-butan-2-one (0.42 g, 0.0039 mol) of and the reaction mixture was heated at 75° C. for over night. Benzene was removed under vaccum and the crude product was extracted with ethyl acetate. The organic layer was washed with brine, concentrated, and purified by recrystallization from ether to give 0.2 g (35%) of tert-butyl (1R,3R,4S)-4-((benzyloxycarbonyl)amino)-3-(4-ethylthiazol-2-yl)cyclohexylcarbamate as a white solid obtained. 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 1.44 (s, 9H), 1.62 (m, 2H), 1.81 (m, 3 H), 2.22 (m, 2H), 2.78 (q, 2H), 3.50 (bs, 1H), 3.72 (bs, 1H), 4.12 (bs, 1H), 5.04 (s, 2H), 5.40 (bs, 1H), 5.74 (s, 1H), 7.33 (m, 5H); 13H NMR (400 MHz, CDCl3) 13.45, 24.7, 28.0, 28.24, 28.4, 33.3, 42.3, 47.0, 50.4, 61.0, 66.5, 79.0, 111.6, 127.9, 128.0, 128.4, 136.5, 155.2, 155.8, 158.8, 169.8. MS found: (M+H)+=460.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: COc1cccc(C(O)CN)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(OC)c2)cc1
Yield: 55.7 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methoxyphenyl)ethanol (prepared as described in Preparation 43), 4.0 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 2.75 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.11 g of the title compound were obtained having an Rf=0.21 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[CH2:12][C:13](=[CH2:36])[CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[CH2:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28].O.Cl>O1CCCC1.ClCCl>[CH2:12]=[C:13]1[CH2:36][CH:26]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:17]2[CH:18]=[C:19]([C:20]([O:22][CH3:23])=[O:21])[CH:24]=[CH:25][C:16]=2[O:15][CH2:14]1
Reactant: C=C(CCl)COc1ccc(C(=O)OC)cc1CS(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=C1COc2ccc(C(=O)OC)cc2C(S(=O)(=O)c2ccccc2)C1
Reaction time: 0.08 h
Yield: 59.7 %

Procedure:
1.33 ml of 1.06M lithium bis(trimethylsilyl)amide in tetrahydrofuran are added to 478 mg (1.21 mmol) of methyl 4-{[2-(chloromethyl)-2-propenyl]oxy}-3-[(phenylsulfonyl)methyl]benzoate dissolved in 39 ml of tetrahydrofuran. The solution is stirred for 5 minutes and then water, 1N hydrochloric acid and dichloromethane are added to the reaction medium. After separating, the aqueous phase is extracted three times with dichloromethane. The combined organic phases are washed with brine, dried and then concentrated under vacuum. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 40/60) to provide 259 mg (60%) of methyl 3-methylene-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1-benzoxepin-7-carboxylate in the form of a white solid; 1H NMR (300 MHz, CDCl3): 2.98 (dd, J=13.9 and 7.1 Hz, 1H), 3.21 (dd, J=13.9 and 7.1 Hz, 1H), 3.86 (s, 3H), 4.20 (d, J=13.4 Hz, 1H), 4.45 (t, J=7.35 Hz, 1H), 4.73 (d, J=13.4 Hz, 1H), 4.99 (s, 1H), 5.09 (s, 1H), 6.98 (d, J=8.28 Hz, 1H), 7.43 (m, 2H), 7.62 (m, 3H), 7.76 (d, J=2.07 Hz, 1H), 7.94 (dd, J=8.46 and 2 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC(F)(F)CC1Nc1ncc(C(F)(F)F)cn1)c1ccccc1-n1nccn1
Temperature: 140 °C

Procedure:
To a solution of N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 120 mg, 0.39 mmol) in dry DMSO (1.2 ml) was added 2-chloro-5-(trifluoromethyl)pyrimidine (CAS number 69034-12-4; 70 mg, 0.384 mmol) and DIPEA (183 μl, 1.047 mmol). The reaction mixture was heated in a sealed vial at 140° C. for 17 hours then partitioned between ethyl acetate and water. The organics were washed with water, filtered through a hydrophobic frit and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) then was chirally separated using SFC (Waters prep30/MS system using 20% Isopropanol, Daicel AD 10 mm id×250 mm long columns at 30 ml/min, 40° C. and 100 bar) to afford the title compound as a single enantiomer.
Reaction SMILES: [N:1]1C=CC=C(CNC(C2(CC3C=CC=CC=3)CCNCC2)=O)C=1.Cl.C(OC([N:32]1[CH2:37][CH2:36][C:35]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=2)([C:38]([OH:40])=O)[CH2:34][CH2:33]1)=O)(C)(C)C.[CH2:49]([NH2:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH2:49]([NH:56][C:38]([C:35]1([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=2)[CH2:34][CH2:33][NH:32][CH2:37][CH2:36]1)=[O:40])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[NH3:1]
Reactant: O=C(NCc1cccnc1)C1(Cc2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)cc2)(C(=O)O)CC1
Reactant: NCc1ccccc1
Agent: Cl
Product: N
Product: O=C(NCc1ccccc1)C1(Cc2ccc(Cl)cc2)CCNCC1

Procedure:
In analogy to the procedure described for the synthesis of 4-benzyl-piperidine-4-carboxylic acid (pyridin-3-ylmethyl)-amide; hydrochloride (intermediate 1) the title compound was prepared from 4-(4-chloro-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (commercially available) and benzylamine (commercially available) with subsequent cleavage of the protecting group under acidic conditions. The title compound was purified on silica eluting with a gradient formed from DCM and 2N NH3 and methanol. MS (m/e): 236.1/343.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]\[CH2:24][CH:25]2[O:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:18][CH:17]=1>[C].[Pd].C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2[O:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:20][CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(/C=C\CC2OCCCO2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC2OCCCO2)cc1
Yield: 95.5 %

Procedure:
A mixture of (Z)-2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propenyl]-1,3-dioxane (5.0 g), palladium-carbon (5%, 0.1 g) and ethanol (100 ml) was subjected to catalytic hydrogenation at room temperature under one atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with hexane-ethyl acetate (1:1), 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane (4.8 g, 96%) was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[CH:27][C:28]3[CH2:35][C@H:34]4[C@:36]5([CH2:40][N:39]([CH2:41][C:42]([F:45])([F:44])[F:43])[S:38](=[O:47])(=[O:46])[NH:37]5)[C@H:31]([CH2:32][CH2:33]4)[CH2:30][C:29]=3[CH:48]=2)O1>>[F:7][C:8]1[CH:9]=[C:10]([N:5]2[CH:6]=[C:2]([C:25]3[CH:26]=[CH:27][C:28]4[CH2:35][C@H:34]5[C@:36]6([CH2:40][N:39]([CH2:41][C:42]([F:45])([F:44])[F:43])[S:38](=[O:46])(=[O:47])[NH:37]6)[C@H:31]([CH2:32][CH2:33]5)[CH2:30][C:29]=4[CH:48]=3)[N:3]=[CH:4]2)[CH:11]=[CH:12][CH:13]=1
Reactant: Brc1c[nH]cn1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cn(-c4cccc(F)c4)cn3)cc2C1

Procedure:
Prepared from 4-bromo-1H-imidazole, 3-fluorophenylboronic acid and homochiral boronate from Example 24 Step 1 following the procedures in Example 76 Steps 1 and 2. δ (1H, 360 MHz, CDCl3) 1.33-1.43 (2H, m), 1.69-1.73 (2H, m), 2.45-2.48 (2H, m), 2.68-2.82 (2H, m), 3.20-3.26 (2H, m), 3.44 (2H, s), 3.68 (2H, q, J=8.7 Hz), 4.75 (1H, s), 7.07-7.20 (3H, m), 7.24 (1H, s), 7.45-7.56 (3H, m), 7.61 (1H, s), 7.89 (1H, s). MS (ES+) 521 ([MH]+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:17])[C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([F:15])=[CH:10][C:9]=1[Cl:16])=[O:4].C(=O)([O-])[O-].[Ca+2].[C:23](Cl)(Cl)=[S:24].C(=O)=O>ClCCl.O>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[S:17])[C:8]1[CH:13]=[C:12]([N:14]=[C:23]=[S:24])[C:11]([F:15])=[CH:10][C:9]=1[Cl:16])=[O:4]
Reactant: COC(=O)COC(=S)c1cc(N)c(F)cc1Cl
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Solvent: O
Solvent: ClCCl
Product: COC(=O)COC(=S)c1cc(N=C=S)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.8 g of the resulting 5-amino-2-chloro-4-fluorothiobenzoic acid (methoxycarbonylmethyl) ester in 100 ml of dichloromethane is added dropwise at from 25° to 30° C. to a suspension of 6 g of calcium carbonate, 4 ml of thiophosgene, 20 ml of dichloromethane and 20 ml of water. When the evolution of carbon dioxide has ceased, the batch is stirred for a further 18 hours at room temperature. After filtering and washing with water, the organic phase is separated off, dried over sodium sulfate and then concentrated by evaporation to yield 4.8 g of 2-chloro-4-fluoro-5-isothiocyanatothiobenzoic acid (methoxycarbonylmethyl) ester in the form of an oil which is used without further purification in the next reaction step.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:8]([F:11])([F:10])[F:9])=[CH:5][N:6]=1.C([Li])CCC.CON(C)[C:28](=[O:30])[CH3:29].[Cl-].[NH4+]>C1COCC1.O>[Si:13]([O:12][CH:7]([C:4]1[S:3][C:2]([C:28](=[O:30])[CH3:29])=[N:6][CH:5]=1)[C:8]([F:11])([F:10])[F:9])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC(c1cnc(Br)s1)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ncc(C(O[Si](C)(C)C(C)(C)C)C(F)(F)F)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
In THF (5 mL) was dissolved 2-bromo-5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl)thiazole (515 mg, 1.37 mmol) obtained in Step 2. n-Butyllithium (1.65 mol/L solution in n-hexane, 1.24 mL, 2.05 mmol) was added dropwise at −78° C. and the mixture was stirred at −78° C. for 30 minutes. A solution of N-methoxy-N-methylacetamide (1.38 mL, 13.7 mmol) in THF (1 mL) was added to the reaction mixture and the mixture was stirred at −78° C. for 2 hours. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture. Extraction with ethyl acetate and drying over anhydrous magnesium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-(5-(1-(tert-butyldimethylsilyloxy)-2,2,2-trifluoroethyl) thiazol-2-yl)ethanone (437 mg, 94%).
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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>[C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([C:30]3[CH:31]=[CH:32][C:27]([C:19]4[S:18][C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[N:20]=4)=[CH:28][CH:29]=3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Reactant: OB(O)c1ccc(-c2nc3ccccc3s2)cc1
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: CCO
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccccc2c2cc(-c3ccc(-c4nc5ccccc5s4)cc3)ccc21
Yield: 79.5 %

Procedure:
A mixture of 5.8 g of 9-Acetyl-3-bromocarbazole and 5.7 g of (4-benzo[d]thiazol-2-yl) phenylboronic acid were stirred together in 30 ml of toluene. To this was added 0.03 g of tetrakis(triphenylphosphine)palladium, 4.2 g of potassium carbonate and 10 ml of aqueous ethanol were added and refluxed under nitrogen for 6 h. The reaction was quenched with water and the toluene layer was removed and passed through a celite column. The organic layers were combined and then evaporated in a rotary evaporator under vacuum to yield 6.7 g of 9-acetyl-3-[(4-benzo [d]thiazol-2-yl) phenyl]-9H-carbazole as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4]([O:6]C)=O.[Br:13][C:14]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][N:15]=1.[NH2:22][C:23]1[CH:24]=[CH:25][C:26]2[C:30]([CH:31]=1)=[N:29][N:28]([CH3:32])[CH:27]=2>>[Br:13][C:14]1[CH:19]=[C:18]([CH2:20][NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=2[C:4]([NH:22][C:23]2[CH:24]=[CH:25][C:26]3[C:30]([CH:31]=2)=[N:29][N:28]([CH3:32])[CH:27]=3)=[O:6])[CH:17]=[CH:16][N:15]=1
Reactant: COC(=O)c1c(N)cccc1F
Reactant: Cn1cc2ccc(N)cc2n1
Reactant: O=Cc1ccnc(Br)c1
Product: Cn1cc2ccc(NC(=O)c3c(F)cccc3NCc3ccnc(Br)c3)cc2n1

Procedure:
2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide was prepared from methyl 2-amino-6-fluorobenzoate via reductive amination with 2-bromo-pyridine-4-carbaldehyde, followed by subsequent amidation with 6-amino-2-methyl-indazole in analogy to the procedures detailed in WO2004/013102, particularly Example 6A, supra; 1H-NMR (300 MHz, d6-DMSO) 10.51 (1H, s), 8.31 (1H, d), 8.26-8.28 (2H, m), 7.65 (1H, d), 7.59 (1H, s), 7.40 (1H, d), 7.13-7.25 (2H, m), 6.73 (1H, t), 6.50 (1H, t), 6.29 (1H, d), 4.47 (2H, d), 4.13 (3H, s).