Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:13]=[C:12](Cl)[N:11]=1.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O>[Cl:9][C:10]1[N:11]=[C:12]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:15]=1
Reactant: NCCCCC(=O)O
Reactant: Clc1cc(N2CCOCC2)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(O)CCCCNc1cc(N2CCOCC2)nc(Cl)n1
Temperature: 40 °C
Reaction time: 40 h
Yield: 60.4 %

Procedure:
5-Aminopentanoic acid (140 mg, 1.19 mmol), 4-(2,6-dichloropyrimidin-4-yl)morpholine (prepared as in Method 22; 234 mg, 1.0 mmol) and DIEA (0.530 mL, 3.0 mmol) were dissolved in N,N-dimethylformamide (6 mL). The reaction solution was stirred at 40° C. for 40 hours. The reaction was diluted with EtOAc (100 mL) and washed with 0.5 M HCl (40 mL), water (40 mL), brine (40 mL), dried with Na2SO4, filtered and evaporated to give a solid. The crude product was chromatographed on a silica gel column by eluting with 80% EtOAc in hexane to give 5-(2-chloro-6-morpholinopyrimidin-4-ylamino)pentanoic acid as a white solid (190 mg, 60%). LC/MS (m/z): 315.0 (MH+), Rf 1.79 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[CH2:5][N:6]([CH3:28])[C:7](=[O:27])[C@@H:8]([N:16]([CH2:24][CH:25]=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([CH2:43][C@H:44]([NH2:49])[CH2:45][C:46]([OH:48])=[O:47])=[CH:35]1>>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[CH2:5][N:6]([CH3:28])[C:7](=[O:27])[C@@H:8]([N:16]([CH2:24][CH2:25][NH:49][C@H:44]([CH2:45][C:46]([OH:48])=[O:47])[CH2:43][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:34][CH:35]=1)[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccccc1CN(C)C(=O)[C@H](Cc1ccccc1)N(CC=O)C(=O)OC(C)(C)C
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Agent: Cl
Product: COc1ccccc1CN(C)C(=O)[C@H](Cc1ccccc1)N(CCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C

Procedure:
Prepare by the method of Example 1 using (S)-N-(2-methoxybenzyl)-N-methyl-2-[N'-(t-butoxycarbonyl)-2-oxo-ethylamino]-3-phenyl-propionamide (0.71 g, 1.6 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (0.45 g, 1.76 mmol). Purify by chromatography eluting with 50% ethyl acetate/hexane to give the title compound: TLC Rf =0.56 (silica gel, 50% ethyl acetate/hexane)
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][CH2:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1cccc(CCN2CCC[C@@H](Cl)C2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
Sixty-percent sodium hydride (0.30 g, 7.5 mmols) was washed with petroleum ether, and then suspended in 30 ml of dimethyl sulfoxide. To the suspension were added 990 mg (5.0 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 1.4 g (5.5 mmols) of (R)-(-)-3-chloro-1-(3-methoxyphenethyl)piperidine [[α]D25 =-8.9° (c=1.2, ethanol)] in 5 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 12 hours and at 45° C. for 2.5 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:5. This mixed solvent was then distilled off under reduced pressure. The thus-obtained residue was further subjected to column chromatography, and eluted with a mixed solvent of chloroform and methanol at a ratio of 200:1. This mixed solvent was distilled off under reduced pressure to give 1.64 g of (S)-(-)-5,11-dihydro-5-[1-(3-methoxyphenethyl)-2-pyrrolidinylmethyl]-dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 79%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[C:11]([CH2:13][OH:14])[CH:12]=1.O1CCCC1.[H-].[Na+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Cl>O>[F:24][C:25]([F:34])([F:35])[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][O:14][CH2:13][C:11]1[CH:12]=[C:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:15][CH3:16])=[CH:9][CH:10]=1
Reactant: COc1ccc(CO)cc1-c1ncccn1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COCc2cccc(C(F)(F)F)c2)cc1-c1ncccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a 250 ml single neck round bottom flask equipped with a reflux condensor and an argon inlet was added 3.24 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol and 70 ml of anhydrous tetrahydrofuran. The system was cooled to 0° C. and after cooling 0.45 gm of sodium hydride was added. The system was stirred for an additional 20 minutes and 2.8 ml of 3-trifluoromethylbenzylchloride added. The system was allowed to come to room temperature and was then heated to reflux for 20 hours at this time, water was added to the system and the product extracted with methylene chloride. The methylene chloride was washed with water and then dried over sodium sulfate. The methylene chloride was removed by stripping to give 4.13 gm of the 5-pyrimidyl-4-methoxyphenylcarbinol 3-trifluoromethylbenzylether as an orange oil and listed as Compound No. 7 in Table I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:46])[F:45])[CH:38]=1)=[O:36]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:33][CH2:34][C:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([C:44]([F:47])([F:45])[F:46])[CH:38]=2)=[O:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)c(C(F)(F)F)c2)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.20 equiv; 252.61 mmol; 57.92 g) in THF (400 mL), add NMM (3 equiv; 631.52 mmol; 69.66 mL). Cool to −10° C. with a dry ice-acetone bath. Add isobutyl chloroformate (1.1 equiv; 231.56 mmol; 30.26 mL) dropwise maintaining the temperature below −5° C. After 30 min at from −5 to 10° C., add 2-amino-1-(4-fluoro-3-(trifluoromethyl)-phenyl)-ethanone hydrochloride (54.23 g; 1.00 equiv; 210.51 mmol) suspended in THF (300 mL) and stir the mixture in the bath at −5° C. for 20 min and then 1 h at RT. Partition between water and EA; wash the organic layer with water then saturated NaCl aqueous (brine), dry over anhydrous MgSO4, filter and concentrate in vacuo. Suspend the crude in MTBE and stir for 2 h. Filter the solid and dry in vacuo to give the title compound (64.44 g; 70.79%). 1H NMR (300 MHz, DMSO): 8.37-8.26 (m, 3H), 7.74-7.68 (m, 1H), 4.61 (d, J=5.5 Hz, 2H), 3.91 (d, J=12.9 Hz, 2H), 2.75-2.64 (m, 2H), 2.46-2.37 (m, 1H), 1.69-1.60 (m, 2H), 1.39 (s, 12H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:26][CH3:27])=[CH:11][CH:10]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].Cl.C(N(CC)CC)C.O>CN1CCCC1=O>[CH2:26]([C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:30][N:29]=[N:28][N:2]=3)=[CH:10][CH:11]=2)[C:20]2=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]2[N:18]=1)[CH3:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 6 h

Procedure:
10 g (0.027M) of 3-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine, 5.3 g (0.081M) of sodium azide and 5.6 g (0.041M) of triethylamine hydrochloride were suspended in 70 ml of N-methylpyrrolidone. The temperature of an oil bath was raised to 150° to 160° C. over a period of 20 min while stirring with a stirrer. The temperature was returned to room temperature after 6 hr, and water was added thereto. The mixture was washed with ethyl acetate (50 ml×3). The watery phase was acidified with acetic acid and extracted with ethyl acetate (100 ml×5). The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo. The blackish brown oleaginous substance as the residue was purified by medium pressure column chromatography (SiO2, ACOEt:EtOH=40:1~20:1~10:1). The yield was 11 g. Brown oleaginous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:23]1(=O)[CH:28]=[CH:27][C:26](=[O:29])[CH:25]=[CH:24]1>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:15][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=3[C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12

Procedure:
The material prepared in Example 1A (250 g, 1.19 mole) was combined with zinc chloride (243.5 g, 1.784 mole) and toluene (3.75 L). The reaction mixture was heated to reflux under a nitrogen atmosphere. Benzoquinone (167 g, 1.546 mole) in tetrahydrofuran (500 mL) was added dropwise to the reaction, and upon completion of the addition, the reaction mixture was heated at reflux for 6 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was concentrated in vacuo to a brown solid. The solid was recrystallized from acetonitrile yielding the title compound as a brown solid (125 g, 35%). MS m/z 301 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.C(N)C.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:13]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:8]2[CH:9]=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[N:6]=[CH:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCCc1c[nH]cn1
Agent: CCN
Solvent: CN(C)C=O
Product: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.0 g (15.85 mmol) of 4-(3-hydroxypropyl)-1H-imidazole and 5.5 ml (54.3 mmol) of dry ethylamine in 15.6 ml of dimethylformamide is treated with 4.86 g (17.4 mmol) of triphenylmethyl chloride in 5 ml of dimethylformamide under nitrogen. The mixture obtained is stirred at room temperature for 2 hours and is then poured onto 350 g of crushed ice. The resulting solid is collected by filtration, washed three times with water and purified on a chromatographic column using, as eluent, chloroform and then a chloroform/methanol (1/1) mixture to give 1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole, M.p.: 132°-133° C.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][NH2:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:14](N1C=CN=C1)(N1C=CN=C1)=[S:15]>C(Cl)Cl.N#N>[N:13]([CH2:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[C:14]=[S:15]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Agent: N#N
Solvent: ClCCl
Product: S=C=NCCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 88.9 %

Procedure:
2-adamantan-1-yl-ethylamine (380 mg, 2.12 mmol) was dissolved in CH2Cl2 (10 ml) under a dry atmosphere of N2. To this solution was added 1,1'-thiocarbonyl-diimidazole (420 mg, 2.12 mmol). After stirring at ambient temperature for 12 hours, the solution was partitioned between 0.1 N HCl and CH2Cl2. The CH2Cl2 layer was washed with water, then saturated NaHCO3 solution and finally brine. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated under vacuum to give 417 mg of a yellow solid. The product was chromatographed on silica gel using hexanes to give 125 mg of the titled compound as a white solid: 1H NMR (CDCl3)δ 3.52 (m, 2H), 1.98 (br s, 3H), 1.49-1.76 (m, 17H).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[CH:15]([NH:16][CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.CC1C=CC(S(O[CH2:29][CH2:30][CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:13]12[CH:15]([N:16]([CH3:17])[CH2:29][CH2:30][CH2:31][NH:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=3)[CH:10]([CH2:11][CH2:12]1)[CH2:9][NH:8][CH2:14]2
Reactant: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Reactant: CNC1C2CCC1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCNc1ccc(C#N)cc1)C1C2CCC1CNC2
Temperature: 90 °C
Yield: 65.5 %

Procedure:
A mixture of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine (Preparation B; 4.0 g, 17.4 mmol), 3-(4-cyanoanilino)propyl 4-methyl-benzenesulfonate (Preparation G(ii); 5.74 g, 17.4 mmol), and potassium carbonate (2.40 g, 17.4 mmol) in DMF (85 mL) was heated at 90° C. under nitrogen overnight. The mixture was partitioned with water (200 mL) and diethyl ether (150 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered and then concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 3.40 g (50%) of the sub-title compound as a white solid.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>[Pd]>[N+:9]([CH2:12][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: [Pd]
Product: O=[N+]([O-])CC(O)c1ccccc1
Reaction time: 1 h

Procedure:
A 250 mm-long tube filled with 3600 mg of pellets (72 pellets, each weighing 50 mg were used, the supported palladium being 0.85 mol % with respect to the reactive substrate) was used as a microreactor. A mixture obtained by mixing 2.1 g (20 mmol) of benzaldehyde and 1.2 g (20 mmol) of nitromethane was filled in a gas tight syringe, and the reaction was conducted at a temperature of 60° C. The flow rate was set to 2.2 ml/h and the retention time was set to 1 hour. After analyzing the resulting product by 1H-NMR, it was confirmed that the inversion rate was 18%, and the objective substance of 2-nitro-1-phenyl-ethanol was approximately obtained quantitatively.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].B(Br)(Br)Br.C(Cl)Cl.CCOC(C)=O>C(Cl)Cl>[NH2:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[S:16][C:17]4[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29]
Reactant: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(N)c(C(F)(F)F)c4)cc3)sc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(C(=O)Nc2ccc(-c3nc4ccc(O)cc4s3)cc2)cc1C(F)(F)F
Yield: 21.9 %

Procedure:
Prepared as described in the Demethylation section using 4-amino-3-trifluoromethyl-N-[4-(6-methoxybenzothiazol-2-yl)-phenyl]-benzamide (0.30 g, 0.68 mmol) in dry DCM (10 ml) and BBr3 (1.0 M solution in DCM, 5.42 ml, 5.42 mmol) to give the title compound (0.064 g, 22%) as an orange solid after work-up and flash chromatography (3:1 DCM/EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:9]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[O:19][CH2:18][CH2:17][O:16]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCCO
Reactant: O=C(Cc1ccccc1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2(Cc3ccccc3)OCCO2)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-bromophenyl)-2-phenylethanone (5.0 g, 18 mmol), ethylene glycol (3.0 mL, 54 mmol) and tosic acid (0.04 g, 0.2 mmol) in toluene (30 mL) was heated to reflux with a Dean-Stark trap for 15 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated to give crude 2-benzyl-2-(4-bromophenyl)-1,3-dioxolane as a white solid. To the crude material was added zinc cyanide (2.3 g, 20 mmol), tetrakis(triphenylphosphine)palladium (3.3 g, 2.8 mmol), DMF (20 mL) and dioxane (20 mL) and the resulting suspension was purged with nitrogen for 15 minutes prior to being heated 100° C. for 15 hours. The reaction was cooled to room temperature, poured into ether and filtered. The organic filtrate was washed with water, saturated bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% ethyl acetate/hexane→50% ethyl acetate/hexane) gave the title compound as white solid. MS (M+H+): calculated=265.31, observed=266.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19].[F:20][C:21]([F:30])([F:29])[C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:27][C:24]4[CH:23]=[C:22]([C:21]([F:30])([F:29])[F:20])[S:26][CH:25]=4)=[CH:13][C:12]3=[O:18])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:19]
Reactant: OCc1csc(C(F)(F)F)c1
Reactant: Cc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1nc2ccc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)cc2n1C
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a suspension of 1-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg) in THF (5 ml) were added (5-(trifluoromethyl)thiophen-3-yl)methanol (78 mg), 1,1′-(azodicarbonyl)dipiperidine (128 mg) and tributylphosphine (0.13 ml) at room temperature, and the mixture was stirred at 50° C. overnight. After cooling, the mixture was purified by NH silica gel column chromatography (EtOAc/MeOH). The same reaction was conducted, and the combined products were purified by preparative HPLC (C18, mobile phase: H2O/CH3CN (0.1% TFA included)). The desired fraction was neutralized with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo to give the title compound (129 mg) as a white solid.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[C:16]([O:20][C:21](=[O:41])[NH:22][C@@H:23]1[C:31]2[C:26](=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].N#N>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.COCCOC.O>[C:16]([O:20][C:21](=[O:41])[NH:22][C@@H:23]1[C:31]2[C:26](=[C:27]([C:2]3[S:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([C:12]#[N:13])[CH:14]=4)=[N:4][CH:3]=3)[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2c(B3OC(C)(C)C(C)(C)O3)cccc21
Reactant: N#Cc1cc(-c2ncc(Br)s2)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 80 °C
Yield: 83 %

Procedure:
Prepared using General Procedure 4. A solution of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 (2.0 g, 7.0 mmol), (S)-tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate IND INT-17 (2.5 g, 7.0 mmol), potassium carbonate (2.9 g, 21 mmol) and a 3:1 mixture of DME/H2O (30 mL) was degassed with N2 for 10 min before the addition of Pd(PPh3)4 (0.57 g, 0.005 mmol). The mixture was degassed with N2 for an additional 2 min and the suspension was heated under nitrogen at 80° C. for 12 h. Upon cooling, the reaction mixture was diluted with EA (20 mL) and washed with brine (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (30% EA/hexanes) to produce 3.0 g (83%) of (S)-tert-butyl(4-(2-(3-cyano-4-fluorophenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate as a white solid. LCMS-ESI (m/z) calculated for C24H22FN3O2S: 435.5; found 436.1 [M+H]+, tR=4.14 min. 1H NMR (400 MHz, CDCl3) δ 8.20 (m, 2H), 7.93 (s, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.32 (m, 3H), 5.26 (m, 1H), 4.76 (d, J=8.4 Hz, 1H), 3.09 (m, 2H), 2.65 (ddd, J=12.5, 8.3, 4.6 Hz, 1H), 1.84 (dq, J=12.9, 8.5 Hz, 1H), 1.48 (s, 9H).
Reaction SMILES: [N+](C1C=C(S(CC[O:15][C:16](=[O:51])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[C:27]3[S:35]([CH2:37][C:38]3[C:43]([CH3:44])=[C:42]([O:45][CH2:46][C:47]([F:50])([F:49])[F:48])[CH:41]=[CH:40][N:39]=3)=[O:36])(=[O:25])=[O:24])[CH:18]=2)(=O)=O)C=CC=1)([O-])=O.C([O-])(O)=O.[Na+:56]>C1COCC1.O>[Na+:56].[CH3:44][C:43]1[C:38]([CH2:37][S:35]([C:27]2[N:26]([S:23]([C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=3)[C:16]([O-:51])=[O:15])(=[O:25])=[O:24])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=2)=[O:36])=[N:39][CH:40]=[CH:41][C:42]=1[O:45][CH2:46][C:47]([F:50])([F:48])[F:49]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1cccc(C(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1cccc(C(=O)[O-])c1
Yield: 93.6 %

Procedure:
A solution of 3-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)-pyridin-2-ylmethanesulfinyl]-benzimidazole-1-sulfonyl}-benzoic acid 2-(3-nitro-benzenesulfonyl)ethyl ester (Intermediate 2, 900 mg, 1.17 mmol) and NaHCO3 (118 mg, 1.41 mmol, 1.2 eq.) in THF-H2O (6 mL-3 mL) was heated to 70° C. for 20 min, during which time the heterogeneous mixture became clear. Thereafter all the volatile materials were removed in vacuo, the residual gummy material was dissolved in CH2Cl2, and the mixture was filtered to remove solids. The filtrate was evaporated to dryness in vacuo, and the residual yellow foam was treated with ether-EtOAc (5:1) to precipitate a solid. This solid was collected by filtration to give 630 mg (94%) of 3-{2-[3-methyl-4-(2,2,2-trifluoro-ethoxy)pyridin-2-yl methanesulfinyl]-benzimidazole-1-sulfonyl}benzoic acid sodium salt (sodium salt of Compound 1).