Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH3:16][CH:17]([CH3:30])[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29])(=[O:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:29]([CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:19]([CH2:18][CH:17]([CH3:30])[CH3:16])(=[O:21])=[O:20])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: CC(C)CS(=O)(=O)c1ccccc1CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)CS(=O)(=O)c1ccccc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 57.3 %

Procedure:
2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.0 g), 1-{2-[(2-methylpropyl)sulfonyl]phenyl}methanamine hydrochloride (2.69 g) and potassium carbonate (2.94 g) were stirred in ethanol (30 ml) at 90° C. for 5 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (1.02 g).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[Br:5][C:6]1[N:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[C:25]([Cl:33])[CH:24]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]2)=[N:10][CH:11]=1>CO.N1C=CC=CC=1>[Br:5][C:6]1[N:7]=[CH:8][C:9]([NH:12][C:13](=[O:34])[CH:14]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:25]([Cl:33])[CH:24]=2)[CH2:15][CH:16]2[CH2:21][CH2:20][C:19](=[N:4][O:2][CH3:3])[CH2:18][CH2:17]2)=[N:10][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CON=C1CCC(CC(C(=O)Nc2cnc(Br)cn2)c2ccc(S(C)(=O)=O)c(Cl)c2)CC1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of methoxylamine hydrochloride (16 mg, 0.18 mmol) in methanol (0.5 mL) and pyridine (0.5 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 59, 62 mg, 0.12 mmol). The reaction mixture was heated under reflux for 2 h, cooled to 25° C., and concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 7/3 hexanes/ethyl acetate eluted to 4/6 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-methoxyimino-cyclohexyl)-propionamide (51 mg, 80%) as a white foam: EI-HRMS m/e calcd for C21H24BrClN4O4S (M+H)+ 543.0463. found 543.0464.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH2:25][C:26]#[N:27].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:27][CH2:26][C:25]#[N:24])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCN
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCC#N)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
6-((trans)-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (310 mg, 1 mmol), 2-aminoacetonitrile (112 mg, 2 mmol, 2.0 eq) and acetic acid (180 mg, 3 mmol, 3.0 eq) in DCE (10 mL) was stirred at rt for 10 min. Then NaBH(OAc)3 (636 mg, 3 mmol, 3.0 eq) was added to the mixture and the mixture was stirred at rt for 15 h. Then saturated NaHCO3 was added to the mixture until pH=8. The mixture was extracted with DCM (20 mL×3). The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with DCM/CH3OH (20/1) to give product the title compound as a colorless oil (240 mg, yield: 69%). ESI-MS (M+H+): 351.2. 1H NMR (400 MHz, CDCl3) δ: 7.70 (dd, 2H), 7.68 (s, 1H), 7.41 (dd, 1H), 7.13 (d, 2H), 4.30-4.23 (m, 1H), 4.05 (s, 2H), 3.57 (s, 2H), 2.26 (d, 2H), 1.90 (d, 2H), 1.48-1.42 (m, 2H), 1.20-1.09 (m, 3H), 0.90 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:18].[OH-].[Na+].[OH-].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][N:9]2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(C(=O)O)cn(C)c2c1
Temperature: 0 °C
Reaction time: 1.3 h
Yield: 85.8 %

Procedure:
To a stirring solution of 6-methoxy-1H-indole-3-carboxylic acid 16a (8.0 g, 41.2 mmole) in anhydrous DMF (100 ml) at 0° was added NaH (60% dispersion in oil, 4.12 g, 103 mmole) in a single portion. After stirring at 0° C. for 1.3 hour, iodomethane (7.5 ml, 120 mmole) was added via syringe. The resultant mixture was stirred for 18 hours, gradually warming to room temperature, then poured into 0.2N NaOH (1 L) and extracted with EtOAc (3×250 ml). The combined extracts were washed sequentially with 1N NaOH (50 ml), water (3×50 ml), and brine (50 ml) then dried over Na2SO4 and concentrated, in vacuo. The resulting crude 6-methoxy-1-methyl-1H-indole-3-carboxylic acid Methyl ester was triturated with hexanes and collected by filtration. This material was suspended in aqueous KOH (3.36 g, 60 mmol in 150 ml) and the resulting suspension heated at reflux for 3.5 hours. The mixture was then poured onto 200 g of ice and washed with CH2Cl2 (2×50 ml). The aqueous layer was acidified with 6N HCl to pH 2 resulting in a white precipitate which was collected by filtration, washed with water and air dried to yield 7.25 g (86%) of the title compound which was carried on without any further purification. 1H NMR (DMSO-d 6) δ11.84(1H, broad s), 7.88 (1H, s), 7.84 (1H, d, J=8.7 Hz), 7.02 (1H, d, J=2.2 Hz), 6.82 (1H, dd, J=2.2, 8.7 Hz), 3.81 (3H, s), 3.79 (3H, s). Anal. Calcd. for C11H11NO3.0.2 H2O: C, 63.27; H, 5.50; N, 6.71.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O>[ClH:12].[N:16]1[CH:17]=[CH:18][C:13]([NH:1][C:2]2[C:3]3[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=3[S:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: Nc1csc2ccccc12
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc2c(Nc3ccncc3)csc2c1
Yield: 95.1 %

Procedure:
A solution of 3-aminobenzo[b]thiophene (3g, 20 mmol) and 4-chloropyridine hydrochloride (3.5 g, 23 mmol) in 50 mL of 1-methyl-2-pyrrolidinone was stirred at 80° for three hours, and thereafter cooled, stirred with water, basified with sodium carbonate and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride solution and dried (anhydrous magnesium sulfate), filtered and concentrated to 8 g dark oil. Elution through silica with ethyl acetate via flash column chromatography yielded 5 g of an amber oil. Conversion to the hydrochloride salt in methanol-ether yielded 3 g of a hygroscopic solid. Recrystallization from 50% methanol in ether yielded 1.8 g of rust colored crystals, mp 268°-270° (dec.).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].[O:19]=[S:20]1(=[O:33])[CH2:25][CH2:24][CH:23]([C:26]2[C:27](F)=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:27]2[C:26]([CH:23]3[CH2:24][CH2:25][S:20](=[O:33])(=[O:19])[CH2:21][CH2:22]3)=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O=S1(=O)CCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(c1ccc(Oc2ncccc2C2CCS(=O)(=O)CC2)cc1)c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.485 g, 2.035 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-2-fluoropyridine (0.311 g, 1.356 mmol), and cesium carbonate (1.326 g, 4.07 mmol) in NMP (5 mL) in a sealed tube was heated at 200° C. in 2 h. The reaction mixture was cooled, taken in H2O, filtered the dark brown solid, purified by ISCO (50% EtOAc/Hexanes) to give the expected product as a tan solid. MS (ESI, pos. ion) m/z: 448.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12](I)=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=[C:9]2[CH2:20][O:21][Si](C(C)(C)C)(C)C)=[CH:5][CH:4]=1.[CH:31]([S:34]([N:37]1[C:41]2[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[NH2:49])(=[O:36])=[O:35])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl.O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:31]([S:34]([N:37]1[C:41]2[CH:42]=[C:43]([C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=4)[C:9]([CH2:20][OH:21])=[N:10][C:11]=3[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[NH2:49])(=[O:35])=[O:36])([CH3:33])[CH3:32]
Reactant: COc1ccc(Cn2c(CO[Si](C)(C)C(C)(C)C)nc(-c3ccccc3)c2I)cc1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(B(O)O)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2c(CO)nc(-c3ccccc3)c2-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 36 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-2-tert-butyldimethylsilyloxymethyl-4-(phenyl)-5-iodoimidazole (50 mg, 0.0935 mmol) in dry toluene (0.8 mL) previously bubbled with a stream of nitrogen, add PdCl2(PPh3)2 (4.5 mg, 0.00641 mmol) in one portion. After 5 minutes, add a suspension of 1-isopropylsulfonyl-2-amino-benzimidazole-6-boronic acid (40 mg, 0.141 mmol) in ethanol (0.8 mL) previously bubbled with a stream of nitrogen, followed by sodium carbonate (2M in water, 0.32 mL, 0.640 mmol). Stir the mixture for 2.5 hours at 100° C., cool to room temperature, dilute with 10% HCl (5 mL), extract with EtOAc (15 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, CH2Cl2/MeOH 19:1→5:1), dissolve the material obtained in MeCN (0.5 mL), and treat with HF (48% in H2O, 0.12 mL, 3.31 mmol) at room temperature for 4 hours. Dilute the mixture with EtOAc (15 nm), wash with saturated NaHCO3 (5 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, CH2Cl2/MeCN/MeOH 85:15:5) to provide 18 mg (36% yield). MS (MS+): m/z=532 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31](=O)[CH3:32])=[CH:27][CH:26]=3)=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl.CN.[CH2:37]([N:39](CC)CC)C.[BH4-].[Na+]>C(O)C.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH:17]([S:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:20]3[O:24][C:23]([C:25]4[CH:26]=[CH:27][C:28]([CH:31]([NH:39][CH3:37])[CH3:32])=[CH:29][CH:30]=4)=[N:22][N:21]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)=[CH:13][CH:12]=1)(=[O:16])=[O:15])([CH3:18])[CH3:19]
Reactant: CCN(CC)CC
Reactant: CC(=O)c1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)cc1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNC(C)c1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)cc1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
A mixture of 1-[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]ethanone (130 mg, 0.2805 mmol), methylamine hydrochloride (37.88 mg, 0.5610 mmol), Ti(OiPr)4 (159.4 mg, 165.5 μL, 0.5610 mmol) and triethylamine (56.77 mg, 78.20 μL, 0.5610 mmol) was stirred at room temperature in ethanol (2 mL) under nitrogen overnight. The reaction mixture was treated with sodium borohydride (15.92 mg, 16.85 μL, 0.4208 mmol) and stirred at room temperature over weekend and then was quenched with aqueous ammonia (1 mL conc in 4 mL water). The mixture was extracted with dichloromethane and the organic extracts dried over MgSO4 and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were passed through a bicarbonate cartridge and concentrated in vacuo. The solid was triturated with acetonitrile to give the product as a pale yellow solid (27.0 mg, 22%); 1H NMR (400 MHz, DMSO) d 1.20 (d, 6H), 1.28 (d, 3H), 4.48 (m, 1H), 3.69 (q, 1H), 7.72 (d, 2H), 7.97 (d, 2H), 7.98 (v br s, 2H), 8.12 (d, 2H) and 9.07 (s, 1H) ppm; MS (ES+) 479.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C(OCC)(=O)C.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:8][C:6]1[CH:5]=[CH:4][C:3]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2ccc(Cl)cc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) is added to a solution of 2-fluoro-4-chlorophenylboronic acid (1.25 g, 7.17 mmol) and 4-bromo-1-ethyl-2-nitrobenzene (1.50 g, 6.52 mmol) in 1,2-dimethoxyethane (12 ml) and the mixture is stirred at room temperature for 15 minutes. A solution of sodium carbonate (5.52 g, 52 mmol) in water (26 ml) is added and the mixture is heated to reflux for 17 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and the two phases separated. The organic phase is collected, the aqueous phase is extracted with ethyl acetate and the organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure to give 4′-chloro-4-ethyl-2′-fluoro-3-nitrobiphenyl (1.795 g), used without further purification in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12]1(N=C=NC2CCCCC2)CCCCC1.CO>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromophenylacetic acid (1.0 g, 4.65 mmol), 1,3-dicyclohexylcarbodiimide (1.44 g, 6.98 mmol) and MeOH (149 mg, 4.65 mmol) in dichloromethane (40 ml) was added 4-dimethylaminopyridine (57 mg, 0.465 mmol). The reaction mixture was stirred at RT for 1 hr. The white solid was precipitated out which was removed with filtration. The reaction solution was concentrated to give a crude product which was purified on silica gel column with dichloromethane. The product was collected which contain a little amount of DCU (1.36 g). NMR (CDCl3): □ 7.20-7.46 (4H, m), 3.72 (3H, s), 3.621(2H, s).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH2:25]C(O)=O)[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([C:35]([O:37][CH3:38])=[O:36])#[C:30][C:31]([O:33][CH3:34])=[O:32]>C(OC(=O)C)(=O)C>[CH3:34][O:33][C:31]([C:30]1[C:29]([C:35]([O:37][CH3:38])=[O:36])=[CH:25][N:13]([CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[C:11]=1[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:32]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N(CCc1ccc([N+](=O)[O-])cc1)CC(=O)O
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c(CCNC(=O)OC(C)(C)C)c1C(=O)OC
Temperature: 85 °C

Procedure:
To a mixture of {(3-tert-Butoxycarbonylamino-propionyl)-[2-(4-nitro-phenyl)-ethyl]-amino}-acetic acid (0.253 mmol) in 1 ml acetic anhydride is dimethyl acetylene dicarboxylate (0.278 mmol) added. After stirring at 85° C. for 4½ hours the solvent is evaporated in vacuo. The dark brown oil is chromatographed using ethyl acetate 2:Hexane 3 as a mobile phase to yield 2-(2-tert-Butoxycarbonylamino-ethyl)-1-[2-(4-nitro-phenyl)-ethyl]-1H-pyrrole-3,4-dicarboxylic acid dimethyl ester, 79 mg, as a yellow oil (66%): 1H NMR (CD3OD) 1.50 (s, 9H), 2.84 (t, 2H), 3.14-3.34 (m, 4H), 3.77 (s, 3H), 3.82 (s, 3H), 4.33 (t, 2H), 6.74 (t, 1H), 7.29 (s, 1H), 7.44 (d, 2H), 8.16 (d, 2H) LRMS calcd 475.50, found [M] 475.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:25]3[CH2:28][CH2:27][CH2:26]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+]([O-])=O)=C[CH:34]=1)=[O:31].N1C=CC=CC=1.C1([C@H](O)C)CC1>C(Cl)Cl.ClCCCl>[CH:38]1([C@H:33]([O:32][C:30](=[O:31])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[C:10]4[C:15]([C:16]=3[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:11]=4)=[CH:6][CH:7]=2)[CH3:34])[CH2:37][CH2:36]1
Reactant: CS(=O)(=O)COc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: C[C@@H](O)C1CC1
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCS(C)(=O)=O)cc3n2C2CCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
2-(4-Amino-phenyl)-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indole-3-carbonitrile (100 mg, 0.25 mmol) was combined with p-nitrophenyl chloroformate (120 mg, 0.6 mmol), DCE (1 mL), and pyridine (60 μL, 0.75 mmol) and stirred at room temperature for 1 h. To this mixture was added (R)-1-Cyclopropylethanol (90 μL, 0.92 mmol) and then heated at 80° C. for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with dilute aqueous NaOH solution. The organic layer was dried, concentrated and purified by silica gel chromatography (95:5 CH2Cl2/EtOAc) to provide (R)-[4-(3-cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid 1-cyclopropyl-ethyl ester (105 mg, 83%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27]C)/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH3:23])[C:10]=2[N:9]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[OH:27])/[CH:6]=[CH:7]/[C:8]1[N:16]([CH3:17])[C:15]2[C:14](=[O:18])[N:13]([CH2:19][CH3:20])[C:12](=[O:21])[N:11]([CH2:22][CH3:23])[C:10]=2[N:9]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(OC)c3)n2C)n(CC)c1=O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
Compound 65 (2.00 g, 5.20 mmol) obtained in Example 8 was dissolved in 40 ml of methylene chloride. To the solution was added 26 ml (26 mmol) of boron tribromide (1.0M methylene chloride solution) under ice cooling in argon atmosphere, and the mixture was stirred overnight at room temperature. Methanol was added thereto and the mixture was separated with chloroform-an aqueous solution of sodium bicarbonate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was recrystallized from ethanol to give 643 mg (yield 35%) of Compound 173 as pale yellow grains.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([I:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(I)cc2[nH]1
Product: Clc1nc2ccc(I)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
5-Iodo-1,3-dihydro-2H-1,3-benzimidazol-2-one (7 g) [see Preparation 24] was added to a solution of phosphoryl chloride (135 ml). The reaction mixture was then heated to 120° C. and stirred for 2 hours, after which time the phosphoryl chloride was removed under reduced pressure and the residue diluted with water. The residual aqueous solution was neutralised with aqueous potassium hydrogen carbonate solution and the product extracted with 90:10, by volume, dichloromethane:methanol, dried over magnesium sulphate and the solvent removed under reduced pressure to afford 2-chloro-6-iodo-1H-1,3-benzimidazole (3.68 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH:28]#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl.[OH-].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:28]([C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)#[C:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reactant: C#CCCCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC#Cc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Yield: 452.2 %

Procedure:
To a solution of 5-bromo-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 54b (450 mg, 1.3 mmol) in 10 mL of methylene chloride was added triethylamine (0.6 mL), Pd(PPh3)2Cl2 (25 mg), CuI (a catalytic amount) and 1-octyne (0.37 mL, 0.26 mmol). The reaction mixture was heated at reflux for 40 hours. The mixture was diluted with methylene chloride, and 2 mL of 10% NaOH were added. The organic layer was separated and dried, and the solvent was removed under reduced pressure. The residue was purified by chromatography, eluting with 1 to 2% methanol in methylene chloride to afford the title compound (438 mg). MS (CI/NH3) m/z 373 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ0.91 (m, 3H), 1.32 (m, 2H), 1.41 (s, 9H), 1.44 (m, 2H), 1.61 (m, 2H), 2.30 (m, 2H), 2.41 (m, 2H), 3.88 (m, 2H), 4.11 (m, 1H), 4.30 (m, 1H), 4.50 (m, 1H), 7.23 (m, 1H), 8.23 (br s, 2H).