Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][NH:8][CH:9]=O)=[N:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=CNCc1ncc(Br)s1
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Brc1cn2cncc2s1
Temperature: 90 °C
Yield: 60.3 %

Procedure:
Toluene (1.0 L) was added to 104 g of 5-bromo-2-formylaminomethylthiazole, and the mixture was heated to 90° C. and was stirred. A solution of 65.8 g of phosphorus oxychloride in 100 ml of toluene was added to the reaction mixture, and the mixture was stirred at that temperature for 1.5 hr. After standing to cool, 2 L of a 0.5 N aqueous hydrochloric acid solution was added, and the aqueous layer was separated. The aqueous layer was adjusted to pH 6.2 by the addition of a 5 N aqueous sodium hydroxide solution and was extracted with 1.5 L of ethyl acetate and then with 1.0 L of ethyl acetate. The organic layers were combined, were washed with a 5% aqueous sodium bicarbonate solution and a 20% aqueous sodium chloride solution in that order, and were dried over anhydrous magnesium sulfate. The solvent was removed to bring the volume to about 100 ml, 500 ml of ethyl acetate:hexane=1:4 solution was added thereto, and the mixture was stirred in an ice-water bath for crystallization to give 57.6 g of 2-bromimidazo[5,1-b]thiazole.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[C:7](Cl)[C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C(C)(C)C>[Cu].C(OCC)(=O)C>[C:4]([OH:6])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: [Cu]
Agent: CC(C)(C)C(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A 100-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with 2,6-dichlorobenzoic acid (5.0 g, 26.2 mmol) and copper powder (3.3 g, 78.6 mmol). Pivalic acid (15 mL) was added, and the resulting mixture was heated to 130°-135° C. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (3 hours). Ethyl acetate (50 mL) was added as the reaction mixture was cooled to room temperature. The resulting mixture was filtered, and the solids were washed with ethyl acetate. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting pale tan organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum, affording 2.89 g of benzoic acid as an off-white solid, mp 118°-119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:19]2[N:23](COCC[Si](C)(C)C)[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:21][C:20]=2[I:38])(O)[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:10](/[C:19]2[NH:23][C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:21][C:20]=2[I:38])=[CH:11]\[CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CSc1ccc(C(O)(CC2CCOCC2)c2c(I)nc(-c3ccccn3)n2COCC[Si](C)(C)C)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(/C(=C\C2CCOCC2)c2[nH]c(-c3ccccn3)nc2I)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 84.1 %

Procedure:
To a solution of 1-[3-chloro-4-(methylsulfanyl)phenyl]-1-(4-iodo-2-(pyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanol (0.520 g) in ethanol (10 mL) was added 3M hydrochloric acid (10 mL), and the mixture was stirred at 80° C. for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-60:40, volume ratio) to give the title compound (0.343 g, yield 84%) as a colorless oil. MS: 358 (MH+).
Reaction SMILES: [N:1]1([C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])=[S:7])[CH:5]=[CH:4]N=C1.N[C:23]1[CH:24]=[C:25]([CH:28]=CC=1)[CH2:26][OH:27]>C1COCC1>[OH:27][CH2:26][C:25]1[CH:28]=[C:5]([NH:1][C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][C:12]([O:19][CH3:20])=[C:13]([O:17][CH3:18])[CH:14]=3)[C:9]2=[O:21])=[S:7])[CH:4]=[CH:23][CH:24]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(C(=S)n1ccnc1)C2
Reactant: Nc1cccc(CO)c1
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)C(C(=S)Nc1cccc(CO)c1)C2

Procedure:
2-(Imidazole-1-carbothioyl)-5,6-dimethoxy-indan-1-one, Intermediate B, (1.0 g, 3.3 mmol) was mixed with 3-aminobenzyl alcohol (0.40 g, 3.3 mmol), and 30 mL THF in a flask. 5,6-Dimethoxy-1-oxo-indan-2-carbothioic acid (3-hydroxymethyl-phenyl)-amide was obtained after stirring the reaction mixture for 4 hours at room temperature. HPLC/MS m/z 358 (M+H)+. The intermediate was not isolated, the mixture was mixed with hydrazine (0.13 mL, 4 mmol), and acetic acid (2–3 drops). The reaction was heated at 78° C. for 12 hours. The reaction solution was then diluted with ethyl acetate, washed with water, and dried over Na2SO4. The solvent was removed and the title compound was purified by HPLC with a C-18 reversed phase column and CH3CN—H2O-TFA as gradient solvents. The title compound, [3-(6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-ylamino)-phenyl]-methanol, Compound 36, was obtained as a solid TFA salt. MS m/z 338 (M+H)+; HPLC:100% (uv 214 mu);
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]=[CH:3][CH2:4][C:5]([OH:7])=[O:6].[H-].[Na+].I[CH3:13]>CN(C=O)C>[CH3:13][O:6][C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][C:1]([OH:9])=[O:8]
Reactant: CI
Reactant: O=C(O)C=CCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of glutaconic acid in DMF (0.1 M) at 0° C. was added NaH (1 eq). After 15 min, iodomethane (1.2 eq) was added, and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated ammonium chloride, and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed (silica; 10% MeOH/CHCl3) to afford a colorless viscous oil. EI-MS m/z 143 (M−H)−
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH:13]=[CH:12][CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].[Cl:14]Cl.[OH-].[Na+]>O>[Cl:14][C:8]1[C:9]([OH:10])=[CH:11][CH:12]=[CH:13][C:6]=1[OH:7]
Reactant: ClCl
Reactant: Oc1cccc(O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(O)c1Cl
Temperature: 110 °C
Yield: 42.1 %

Procedure:
Into a 500 mL flask containing 156 mL of 96% (w/w) sulfuric acid are added 52.5 g of resorcinol. Before the resorcinol completely dissolves, another 156 mL of 96% (w/w) sulfuric acid and another 52.5 g of resorcinol are added. The resulting exotherm causes the temperature of the mixture to increase to as much as 90° C. When this the temperature is reached, or when the temperature of the mixture no longer increases, the mixture is heated to 110° C. for two hours. Then, the mixture is cooled to 15° C., after which time 120 g of chlorine are added at such a rate to maintain a temperature of 15° C. The mixture is then poured into a 2 liter flask containing 450 g of ice and 400 mL of water. To the resulting aqueous phase is added aqueous sodium hydroxide (prepared by dissolving 76 g of sodium hydroxide into 150 mL of water) followed by a 24-hour reflux of the mixture. The temperature of the solution is reduced to room temperature, and after extraction by ethyl ether and ether evaporation, the residual mixture, which contains resorcinol and 2-chlororesorcinol, is subjected to flash column chromatography, using CH2Cl2 as eluent. This affords 29 g (21% yield) of the pure 2-chlororesorcinol (M.P. 97° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][N:5]([C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7])[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Reactant: ClCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(CCN1CCOCC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
A solution of N-tert-butoxycarbonyl glycine methyl ester (9.4 mL, 63.6 mmol) in DMF (250 mL) was cooled in an ice bath and treated with NaH (60% dispersion in mineral oil, 2.85 g, 71.2 mmol). After stirring at 0° C. under N2 for 30 min and then at room temperature for 30 min, the mixture was cooled in an ice bath and treated with a solution of 4-(2-chloroethyl)morpholine (10.5 g, 70 mmol) in DMF (50 mL). After stirring at 0° C. for 30 min, the mixture was stirred at room temperature overnight. The mixture was diluted with H2O (600 mL) and then extracted with EtOAc (5×300 mL). The combined organic layers were washed with H2O (4×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (0.79 g, 4%) as a colorless oil: MS (ESI) m/e 303 (M+H)+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([CH3:16])[CH2:5]1)=[N+]=[N-].[CH:17]1([S:20](Cl)(=[O:22])=[O:21])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>CCO.[OH-].[OH-].[Pd+2]>[CH:17]1([S:20]([NH:1][C@@H:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([CH3:16])[CH2:5]2)(=[O:22])=[O:21])[CH2:19][CH2:18]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1C[C@H](NS(=O)(=O)C2CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a slurry of 20 wt % Pd(OH)2 on C (0.605 g, 0.862 mmol) in EtOH (75 mL) was added a solution of (2R,4S)-tert-butyl 4-azido-2-methylpyrrolidine-1-carboxylate (3.9 g, 17 mmol, synthesized as described in Rosen, T.; Chu, D. T. W.; Lico, I. M.; Fernandes, P. B.; Marsh, K.; Shen, L.; Cepa, V. G.; Pernet, A. G. J. Med. Chem. 1988, 31, 1598-1611) in EtOH (25 mL). The reaction mixture was sparged with hydrogen and an atmosphere of hydrogen was maintained via balloon. The reaction mixture was stirred for about 2 h at ambient temperature and then was filtered and concd in vacuo. The residue was dissolved in DCM (100 mL), cooled to about 0° C. and TEA (6.01 mL, 43.1 mmol) was added followed by cyclopropanesulfonyl chloride (2.67 g, 19.0 mmol). The reaction mixture was stirred at ambient temperature for about 15 h, saturated aqueous NaHCO3 (50 mL) was added to the reaction mixture and the organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (80 g) eluting with 20-80% EtOAc in heptane to provide (2R,4S)-tert-butyl 4-(cyclopropanesulfonamido)-2-methylpyrrolidine-1-carboxylate (2.55 g, 48%) as an oil: LC/MS (Table 1, Method a) Rt=1.98 min (ELSD); MS m/z: 305 (M+H)+.
Reaction SMILES: O[C@H:2]([CH3:15])[C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:47][C:48]([CH3:52])([CH3:51])[CH2:49][OH:50]>CC#N>[C:5]1([C@:3]2([OH:4])[O:50][CH2:49][C:48]([CH3:52])([CH3:51])[NH:47][C@H:2]2[CH3:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(N)CO
Reactant: C[C@@H](O)C(=O)c1cccc2ccccc12
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc2ccccc12
Yield: 41.5 %

Procedure:
Compound 4q was synthesized by a procedure similar to that described for (2S,3S)-4a employing (R)-2-hydroxy-1-(naphthalen-1-yl)propan-1-one (10h, 1.15 g, 0.058 mol), Proton sponge (1.5 g, 0.070 mol), triflic anhydride (1.1 mL, 64 mmol), and 2-amino-2-methyl-1-propanol (1.1 g, 0.012 mol) in CH3CN (45 mL). After purification, 1.35 g (86%) of the free base 4q was isolated and converted to the D-tartrate salt, which was recrystallized from H2O-MeOH-Et2O solvent system: mp 115-116+C.; [α]20D −9.5° (c 0.74, CH3OH); 1H NMR (methanol-d4) δ 8.89 (d, 1H, J=8.4 Hz), 7.97-7.89 (m, 3H), 7.54-7.50 (m, 3H), 4.33 (s, 1H), 3.70 (d, 1H, J=12.2 Hz), 3.48 (q, 1H, J=7.0 Hx), 1.77 (s, 3H), 1.41 (s, 3H), 0.96 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 136.5, 132.3, 131.9, 130.5, 130.2, 128.1, 127.4, 127.0, 126.1, 99.0, 75.1, 68.1, 67.3, 53.9, 24.8, 22.9, 15.8, 15.2; LCMS (ESI) m/z 272.3 [(M-tartrate)+, M=C19H24NO5]; Anal. (C19H24NO5.0.75H2O) calcd: C, 63.41; H, 7.14; N, 3.89. found: C, 63.63; H, 7.44; N, 3.70.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([NH:22][CH2:23][C:24]([NH2:26])=[O:25])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[O:29]1CCCC1>C(Cl)(Cl)Cl.CO.[Pd]>[OH:29][NH:26][C:24](=[O:25])[CH2:23][NH:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[CH:14][CH:15]=1)(=[O:20])=[O:21]
Reactant: NC(=O)CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CNS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)NO
Reaction time: 10 h

Procedure:
A room temperature mixture of N-[phenyl-methyl)-oxy]-2-[4-(4-phenyl-piperidin-1-yl)-benzenesulfonyl-amino]-acetamide (0.1115 g, 0.0002325 mol) in methanol-tetrahydrofuran (1:1, 25 mL) was hydrogenated at 50 p.s.i. over 5% palladium on barium sulfate (0.018 g) for approximately 10 hours. Additional catalyst (0.020 g) was added, and the mixture hydrogenated again for approximately 10 hours. The mixture was filtered through celite, and the filtrate was rotary evaporated to give a glaze. The glaze was dissolved in chloroform-methanol, silica gel (1.6 g, 230-400 mesh) was added, and the mixture was rotary evaporated to dryness. The powder was poured onto a column of silica gel (10 g, 230-400 mesh) and eluted with hexanes-ethyl acetate-acetic acid (10:20:1, 16×10 mL and 10:20:2, 16×10 mL). Fractions containing product were rotary evaporated, and the residue triturated with chloroform. The chloroform suspension was filtered, and the filtercake was dried in vacuo; yield 0.0054 g (6.0%), mp=164-166° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].BrC1C=CC(OC)=CC=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@H](C)C2)cc1OC
Agent: COc1ccc(Br)cc1
Product: COc1ccc(N2CCN[C@H](C)C2)cc1

Procedure:
The title compound was prepared following the procedure of Intermediate 25, but starting from 1-bromo-4-methoxybenzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a yellow oil. M+(ESI): 207.2. HPLC (Condition A), Rt: 1.2 min (HPLC purity: 92.2%).
Reaction SMILES: FC1C=CC(N=C=O)=CC=1.CN.NC(N)=O.C(CC(O)=O)#N.N([O-])=O.[Na+].NC1[N:33]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:32](=[O:41])[N:31](C)[C:30](=O)C=1.[H][H].NC1C(=O)N(C)C(=O)N(C2C=CC(F)=CC=2)C=1N>>[CH3:30][NH:31][C:32]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:41]
Reactant: [H][H]
Reactant: Cn1c(=O)cc(N)n(-c2ccc(F)cc2)c1=O
Agent: CN
Agent: Cn1c(=O)c(N)c(N)n(-c2ccc(F)cc2)c1=O
Agent: N#CCC(=O)O
Product: CNC(=O)Nc1ccc(F)cc1

Procedure:
N-Methyl-N'-(4-fluorophenyl)urea was prepared preliminarily from 4-fluorophenyl isocyanate and methylamine by the same procedure as in Reference Example 1. The urea compound as the starting material was reacted with cyanoacetic acid to form a uracil ring. Using sodium nitrite a nitroso group was introduced into the 5-position of the uracil ring in the obtained 6-amino-3-methyl-1-(4-fluorophenyl)uracil and then reduced with hydrogen gas to prepare 5,6-diamino-1-(4-fluorophenyl)-3-methyluracil.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Br:21]Br>C1(C)C=CC=CC=1>[Br:21][CH2:9][C:8](=[O:10])[CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C(c1ccccc1)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(CBr)C(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of 2.1 g. of 1,1-diphenyl-2-propanone in 25 ml. of acetic acid is heated to 60°-70° C. and 0.5 ml. of bromine in 4 ml. of acetic acid is added dropwise. The reaction mixture is held at 60°-70° C. for one hour and then poured into ice. Toluene is added. The toluene layer is separated, washed with water, dried over magnesium sulfate and concentrated, giving 1-bromo-3,3-diphenyl-2-propanone.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:28])[F:27])[C@@H:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:2]1.FC(F)(F)C(O)=O.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>ClCCl>[C:42]([C@@H:40]([C@H:38]([C:37]([OH:46])=[O:45])[OH:39])[OH:41])([OH:44])=[O:43].[O:1]1[CH2:5][CH2:4][C@@H:3]([N:6]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:27])([F:28])[F:29])[C@H:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(Cc2ccccc2C(F)(F)F)[C@@H]2CCOC2)C1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccccc1CN([C@@H]1CCOC1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1,1-dimethylethyl (3R)-3-((3R)-tetrahydrofuran-3-yl{[2-(trifluoromethyl)phenyl]-methyl}amino)pyrrolidine-1-carboxylate (0.12 g, 0.29 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL). After stirring at room temperature for 3 h the solvent was removed in vacuo and the crude product taken up in methanol. This solution was absorbed onto a cationic ion exchange resin (Isolute™ SCX-2) and the basic components recovered from the column by elution with 2N ammonia in methanol. The eluate was evaporated, taken up again in methanol and L-tartaric acid (1 equivalent) added. The solvent was removed in vacuo and the resultant gum triturated with diethyl ether to yield the title compound as a pink microcrystalline solid. 1H NMR (300 MHz, CD3OD) δH: 7.82 (d, 1H), 7.57 (d, 1H), 7.53 (t, 1H), 7.32 (t, 1H), 4.31 (s, 2H), 3.92-3.82 (m, 3H), 3.70-3.47 (m, 5H), 3.37-3.22 (m, 2H), 3.17-3.03 (m, 1H), 2.94 (dd, 1H), 2.12-1.96 (m, 2H), 1.85-1.67 (m, 2H); MS: [M+H]=315.
Reaction SMILES: N#N.C([S:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1)(=O)C>>[SH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1
Reactant: CC(=O)SCc1ccnc(C)c1
Agent: N#N
Product: Cc1cc(CS)ccn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
To 15 mL of ice-cold, N2 -purged 1N NaOH was added all at once 4-(acetylthiomethyl)-2-methylpyridine (1.358 g, 0.0075 mol). After stirring for 15 min at 0° C. the reaction mixture was washed with ether (2×5 mL), neutralized with concentrated HCl and extracted with methylene chloride (3×10 mL). Evaporation of the methylene chloride solution afforded the thiol (0.89 g, 96%) as a pale yellow oil which gradually became pink on standing: 1Hnmr (CDCl3) δ8.43, 7.37 (ABq, J=5 Hz, 2H), 7.43 (s, 1H), 3.63 (d, J=7.5 Hz, CH2), 2.55 (s, CH3), 1.81 (t, J=7.5 Hz, SH).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].[CH3:29][CH:30]1[CH2:34][C:33]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=2[O:31]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[N:8]([C:36]2[CH:37]=[CH:38][C:32]3[O:31][CH:30]([CH3:29])[CH2:34][C:33]=3[CH:35]=2)[C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC1Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CC(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.5 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.63 g, 93%).
Reaction SMILES: CC(C[AlH]CC(C)C)C.CO[C:12](=O)[CH2:13][N:14]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH2:30][CH2:31][CH2:32][NH:33][S:34]([C:37]1[C:38]2[CH:39]=[CH:40][N:41]=[CH:42][C:43]=2[CH:44]=[CH:45][CH:46]=1)(=[O:36])=[O:35]>>[C:18]([O:17][C:15](=[O:16])[N:14]([C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[CH2:13][CH2:12][NH:30][CH2:31][CH2:32][NH:33][S:34]([C:37]1[C:38]2[CH:39]=[CH:40][N:41]=[CH:42][C:43]=2[CH:44]=[CH:45][CH:46]=1)(=[O:36])=[O:35])([CH3:21])([CH3:20])[CH3:19]
Reactant: NCCNS(=O)(=O)c1cccc2cnccc12
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: CC(C)(C)OC(=O)N(CCNCCNS(=O)(=O)c1cccc2cnccc12)c1ccc(Br)cc1
Yield: 71 %

Procedure:
By following similar procedure as described in Example 1, DIBAL-H reduction of [(4-bromo-phenyl)-tert-butoxycarbonyl-amino]-acetic acid methyl ester (aqueous Rochelle's salt work-up) and subsequent reductive amination with isoquinoline-5-sulfonic acid (2-amino-ethyl)-amide gives the free amine product as a solid (71% yield). ESIMS: m/z 549 [(M+H)+, 79Br], 551 [(M+H)+, 81Br].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11](O)=[O:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1.B.S(C)C.CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: O=C(O)C1CCc2cc(Br)ccc2O1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: OCC1CCc2cc(Br)ccc2O1
Reaction time: 4 h
Yield: 86 %

Procedure:
To a stirred mixture of 80 parts of 6-bromo-3,4-dihydro-2H-benzopyran-2-carboxylic acid and 225 parts of tetrahydrofuran were added dropwise 400 parts of a solution of borane, compound with thiobismethane 0.2N in tetrahydrofuran. Upon completion, stirring was continued for 4hours at room temperature. 80 parts of methanol were added dropwise and stirring was continued for 30 minutes at reflux temperature. The solvent was distilled off till half its volume. The remaining solvent was evaporated and the residue was distilled, yielding 63 parts (86%) of 6-bromo-3,4-dihydro-2H-1-benzopyran-2-methanol; bp. 150° C. at 39.9 Pa (intermediate 1).