Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[Br:27]N1C(=O)CCC1=O>CN(C=O)C.O>[C:1]([N:5]1[CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Br:27])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCC3
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 340 mg of 13b in 3 ml of DMF was added in small portions 160 mg of N-bromosuccinimide. After stirring for an additional 15 minutes the reaction mixture was diluted with 3 ml of water and stirred for an additional 15 minutes. The precipitate was filtered and dried, to give 380 mg of 13c, as white crystalline material. Mp: 218-220° C. MS-ESI: [M+1] 495.06, 497.06, 499.08. NMR (CDCl3) δ 1.53 (s, 9, tertC4H9), 1.95 (m, 2, CH2), 2.71 (t, 2, CH2), 2.97 (t, 2, CH2), 3.38 (t, 2, CH2), 4.45 (t, 2, CH2) 6.77, 8.56 (2×s, 2, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]2[CH2:14][CH2:15][CH2:16][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=1>>[ClH:1].[CH:9]1([O:8][C:6]2[N:5]=[C:4]3[CH2:14][CH2:15][CH2:16][C:3]3=[C:2]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][OH:26])=[CH:20][CH:19]=3)[CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1cc(OC2CCCC2)nc2c1CCC2
Reactant: Nc1ccc(CCO)cc1
Product: Cl
Product: OCCc1ccc(Nc2cc(OC3CCCC3)nc3c2CCC3)cc1
Yield: 70.2 %

Procedure:
Following general procedure B1, 4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.045 g, 0.19 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.039 g, 0.28 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.050 g, 70%) as a white solid. MW=374.90. 1H NMR (DMSO-d6, 300 MHz) 13.82 (s, 1H), 9.52 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 6.11 (s, 1H), 5.00-4.89 (m, 1H), 3.63 (t, J=7.0 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.84-2.69 (m, 4H), 2.15 (quin, J=7.5 Hz, 2H), 1.91-1.52 (m, 8H); APCI MS m/z 339 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37])[NH:32][CH2:31][CH2:30]2>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([O:26][CH3:25])=[C:35]([C:36]([F:38])([F:39])[F:37])[CH:34]=3)[CH2:30][CH2:31]2)=[O:17])=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: Cc1ccncc1-c1cc(NC(=O)Oc2ccccc2)ccc1C
Solvent: CN(C)C=O
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1ccc(C)c(-c3cnccc3C)c1)CC2
Temperature: 100 °C
Yield: 46.2 %

Procedure:
Phenyl N-(4-Methyl-3-(4-methylpyrid-3-yl)phenyl)carbamate (D69) (0.5 g 0.0016 mole) in dry dimethylformamide (20 ml) was treated with 5-methoxy-6-trifluoromethylindoline (D11) (0.34 g, 0.0016 mole) under argon and heated to 100° C. for 6 hrs. The mixture was allowed to cool and evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and the solution washed with 10% aqueous sodium hydroxide solution (2×20 ml) and then with saturated aqueous sodium chloride solution (30 ml). The organic phase was then dried (Na4SO4) filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with 1% methanol/dichloromethane. Trituration of the resulting residue with diethyl ether gave the title compound (E28) (0.326 g, 47%) m.p. 138-140° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:17])[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>>[O:28]1[CH2:27][CH:26]1[CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:17])[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C(F)(F)F)cnc1-c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1c(C(F)(F)F)cnc1-c1ccc(OCC2CO2)cc1

Procedure:
25 g of the 2-(4-hydroxyphenyl)-1-methyl-5-(trifluoromethyl)-1H-imidazole obtained according to Example (20c) and 25 g of anhydrous potassium carbonate are suspended in 250 ml of epichlorohydrin and the mixture is heated under reflux for 10 minutes. The mixture is subsequently filtered and excess epichlorohydrin is removed in a rotary evaporator. The residue is dissolved in ether, the solution is stirred with silica gel and active carbon, the solution is filtered and hexane is added until crystallisation begins. After filtration, 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-5-(trifluoromethyl)-1H-imidazole is obtained in the form of a colourless crystallisate having a melting point of 99°-101°.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]\[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(=C\C(C)c1ccc(C)cc1)CO
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([C@H](C)[C@@H]2C[C@@]2(C)CO)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 5.3 g, 6.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −20° C. Chloroiodomethane (2.26 g, 12.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 10 minutes, and then cooled to −20° C. At the same temperature, (E)-2-methyl-4-(4-methylphenyl)pent-2-en-1-ol (0.60 g, 3.2 mmol) was added dropwise over a period of 10 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (2.5 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.24 g, 1.18 mmol, 36% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(4-methylphenyl)ethyl)cyclopropyl]methanol (0.013 g, 0.064 mmol, 2% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].[BH4-].[Na+].CO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)CN
Reactant: O=Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)CNCc1ccc(F)cc1
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (6.0 mL, 55.93 mmol), and isobutylamine (3.72 g, 50.85 mmol) in toluene (30 mL) was heated at reflux using Dean-Stark apparatus of 5 hours. The mixture was stood at ambient temperature for 18 hours then cooled in an ice-bath. Sodium borohydride (2.89 g, 76.28 mmol) was added followed by MeOH (5 mL). After 1 hour at 0° C. the reaction was quenched with 1M HCl, basified with a saturated solution of NaHCO3 and extracted into EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-10% MeOH in DCM) afforded the title compound (6.98 g, 76%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 2H), 7.00 (m, 2H), 3.74 (s, 2H), 2.42 (d, J=6.8 Hz, 2H), 1.76 (m, 1H), 0.91 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[CH:3]1[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17](OCC)=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>CCOCC>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:5]2[O:4][CH:3]([C:2]([Cl:1])([Cl:22])[Cl:23])[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]=2[CH:13]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reaction time: 1 h

Procedure:
A solution of ethyl 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate (2.0 g.) in anhydrous ether (25 ml.) was added at room temperature during 20 minutes to a suspension of lithium aluminium hydride (0.2 g.) in anhydrous ether (25 ml.). The mixture was stirred for 1 hour, then ethyl acetate (5 ml.) was added, followed by water (10 ml.). The mixture was filtered, and the ether layer of the filtrate was separated. The aqueous phase was extracted with ether (3×10 ml.), the combined extracts were dried, and the solvent was evaporated. The residue was crystallised from ethanol to give 6-hydroxymethyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 134°-136° C.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[C:16]([Mg]Cl)#[CH:17].O>O1CCCC1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[C:16]#[CH:17])=[CH:13][CH:14]=1
Reactant: C#C[Mg]Cl
Reactant: CN(C)CCCOc1ccc(C=O)cc1
Solvent: O
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCCCN(C)C)cc1

Procedure:
To a solution of 4-(3-dimethylaminopropoxy)benzaldehyde (0.83 g, 4 mmol) (Aldrich) in dry tetrahydrofuran (30 mL) under argon at room temperature was added ethynylmagnesium chloride (5 mmmol, 10 mL, 0.5M solution in tetrahydrofuran) (Aldrich) dropwise. The resulting solution was stirred for 1.5 h at which time 100 mL water was added, and the THF was removed in vacuo. The product was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give clean 3-[4-(3-dimethylaminopropoxy)-phenyl]-3-hydroxy-1-propyne which was used directly, without further purification. (Yield 831 mg, 89%)
Reaction SMILES: [CH2:1]([C:3]1[C:10]2[N:6]([N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[CH:4]=1)[CH3:2].CO>C(O)(=O)C>[CH2:1]([C:3]1[C:10]2[N:6]([N:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:9]=2)[N:5]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:28][N:29]=[N:30][N:31]=3)=[CH:19][CH:20]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cn(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n2nc(C(C)C)nc12
Solvent: CC(=O)O
Solvent: CO
Product: CCc1cn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n2nc(C(C)C)nc12
Yield: 95.4 %

Procedure:
A mixture consisting of 2.38 g of 7-ethyl-2-isopropyl-5-[[2'-(N-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole, 90 ml of methanol and 10 ml of acetic acid was heated under reflux for 2 hours. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was subjected to silica gel column chromatography. Elution with methanol-chloroform (1:9, v/v) gave 1.43 g of 7-ethyl-2-isopropyl-5-[[2'-(tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo[1,5-b][1,2,4]triazole in the form of colorless amorphous foamy material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc(CN2CC=C(c3ccc(F)cc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
A solution of 3.6 g (0.020 mol) of 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine in 100 ml of tetrahydrofuran was treated with 13.9 ml (0.10 mol) of triethylamine and 7.3 g (0.020 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 3.5 g (58%) of 5-[4-(4-fluoro-phenyl)-3,6-dihydro-2H-pyridin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as brownish crystals; m.p. 265°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([OH:9])[C:7]=1[Cl:8].[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([Cl:8])[C:6]=1[OH:9]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(Cl)c(Cl)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7 mmol) and tin (II) chloride (5.8 g, 26.1 mmol) in ethanol(50 ml) was heated at 80° C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(1.4 mg, 90%). 1H NMR (CD3OD): δ6.71 (d, 1H), 6.45 (d, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH:62]=O)[CH:59]=[CH:58][C:57]=1[F:64].C(O)(=O)C>C(#N)C.ClCCl>[CH3:53][O:54][C:55](=[O:65])[C:56]1[CH:61]=[C:60]([CH2:62][N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH:59]=[CH:58][C:57]=1[F:64]
Reactant: COC(=O)c1cc(C=O)ccc1F
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)c1cc(CN2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)ccc1F
Reaction time: 24 h
Yield: 92.3 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.100 g, 0.181 mmol), 2-fluoro-5-formyl-benzoic acid methyl ester (0.100 g, 0.543 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as a white foam (0.120 g, 92%), 1H NMR (CDCl3, 300 MHz) δ 1.23-1.34 (m, 2H), 1.64-1.72 (m, 2H), 2.10-2.20 (m, 1H), 2.32 (s, 3H), 2.76-2.80 (m, 1H), 2.94-3.02 (m, 1H), 3.89 (s, 3H), 4.14 (s, 3H), 4.23-4.54 (m, 2H), 4.76-5.02 (m, 2H), 5.62-5.70 (m, 1H), 6.90 (s, 1H), 7.10 (m, 1H), 7.35-7.43 (m, 2H), 7.56-7.80 (m, 2H), 7.89-7.92 (m, 1H); ESI MS m/z 719 [C32H28F10N6O2+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][NH:4]1.C(N(CC)CC)C.[C:23](=[S:25])=[S:24].[CH3:26]I>C(O)C>[OH:1][CH2:2][C@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:5][N:4]1[C:23]([S:25][CH3:26])=[S:24]
Reactant: S=C=S
Reactant: CI
Reactant: OC[C@H]1Cc2c([nH]c3ccccc23)CN1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSC(=S)N1Cc2[nH]c3ccccc3c2C[C@@H]1CO

Procedure:
In the same manner as described in Example 2 by using (3R)-3-hydroxymethyl-1,2,3,4-tetrahydro-β-carboline (22.58 g), triethylamine (15.7 ml), CS2 (6.93 ml), methyl iodide (7.16 ml) and 70% ethanol (340 ml), there is prepared the title compound (28.7 g, 88%) as colorless needles, m.p. 106°-108° C. (recrystallized from aqueous ethanol), [α]D20 -158.6° (c=1.0, methanol). NMR (CDCl3, δ): 2.67 (s, 3H, CSSCH3), Mass m/e: 292 (M+), 244 (M+ --CH3SH).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.O=P(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[Cl:15][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=[CH:6][N:5]=1
Reactant: Cc1cccc2nc[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cccc2ncnc(Cl)c12
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 1A (1.44 g, 9.0 mmol) in toluene (24 ml) was added POCl3 (13.5 ml) and DEA (3.6 ml). The mixture was refluxed under N2 for 30 min. After cooling to room temperature, the reaction mixture was concentrated under vacuum. The residue was dissolved in EtOAc, washed with 10% citric acid solution, followed by saturated NaHCO3. The residue was dried with MgSO4, filtered, and concentrated to give 1B (1.37 g, 85%) as a solid. 1H-NMR (400 MHz, CDCl3): 8.96 (s, 1H), 7.94 (d, J=8.52 Hz, 1H), 7.80 (dd, J=7.17 Hz, J=8.52 Hz, 1H), 7.51 (d, J=7.17 Hz, 1H), 3.05 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][C:6]=2[Cl:12].CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:64]([SH:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:64]([S:71][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[N:7][C:6]=2[Cl:12])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1
Reactant: Clc1nccc2cc(Br)cnc12
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1nccc2cc(SCc3ccccc3)cnc12
Temperature: 40 °C
Yield: 51.4 %

Procedure:
To a vial charged with 3-bromo-8-chloro-1,7-naphthyridine (Anichem, North Brunswick, N.J.) (360 mg, 1.479 mmol) was added dioxane (5914 μl), DIEA (516 μl, 2.96 mmol), Xantphos (171 mg, 0.296 mmol), Pd2(dba)3 (135 mg, 0.148 mmol) and benzyl mercaptan (184 μl, 1.552 mmol). The vessel was sealed and heated to 40° C. overnight. The mixture was cooled to RT, filtered through diatomaceous earth and dried under reduced pressure. The crude residue was purified with a 25 g silicycle HP column (25 μm spherical silica) ramping EtOAc in heptane (0 to 100%, 10% DCM throughout) to provide 3-(benzylthio)-8-chloro-1,7-naphthyridine (0.218 g, 0.760 mmol, 51.4% yield) as a light yellow solid. m/z (ESI) 287.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH3:14][C:15]([O-:18])(C)[CH3:16].[K+].[CH:20](O)(C)C>C([O-])(O)=O.[Na+]>[CH:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:18][CH:15]([CH3:16])[CH3:14])=[N:7][CH:6]=1)([CH3:20])[CH3:2]
Reactant: CC(C)O
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Product: CC(C)OC(=O)c1cnc(OC(C)C)c(Cl)c1
Reaction time: 24 h

Procedure:
5,6-Dichloronicotinic acid ethyl ester (5.33 g, 24.2 mmol) is added to a solution of KOtBu (2.72 g, 24.2 mmol) in isopropanol (50 mL). The mixture is heated at 80° C. for 15 h before another portion of KOtBu (272 mg, 2.42 mmol) is added. Stirring is continued at 80° C. for 24 h. The mixture is diluted with sat. aq. NaHCO3 solution, extracted with diethyl ether, and the combined org. extracts are dried (Na2SO4), filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 9:1 to give 5-chloro-6-isopropoxy-nicotinic acid isopropyl ester; LC-MS: tR=1.10 min, [M+1]+=258.05.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[C:25]([Cl:34])[CH:24]=2)=[CH:21][S:20][C:19]1=[N:35][C:36](=[O:52])[CH2:37][C:38]1[C:46]2[C:45](=[O:47])[N:44]([CH3:48])[C:43](=[O:49])[N:42]([CH3:50])[C:41]=2[O:40][C:39]=1[CH3:51])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11])=O)(C)(C)C.[Na].ClC1C=C(C2N=C(NC(=O)CC3C4C(=O)N(C)C(=O)N(C)C=4OC=3C)SC=2)C=CC=1OC(F)(F)F>CC(C)=O>[ClH:34].[NH2:8][C@H:9]([C:14]([O:16][CH2:17][N:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[C:25]([Cl:34])[CH:24]=2)=[CH:21][S:20][C:19]1=[N:35][C:36](=[O:52])[CH2:37][C:38]1[C:46]2[C:45](=[O:47])[N:44]([CH3:48])[C:43](=[O:49])[N:42]([CH3:50])[C:41]=2[O:40][C:39]=1[CH3:51])=[O:15])[C@H:10]([CH2:12][CH3:13])[CH3:11]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCn1c(-c2ccc(OC(F)(F)F)c(Cl)c2)csc1=NC(=O)Cc1c(C)oc2c1c(=O)n(C)c(=O)n2C
Agent: Cc1oc2c(c1CC(=O)Nc1nc(-c3ccc(OC(F)(F)F)c(Cl)c3)cs1)c(=O)n(C)c(=O)n2C
Agent: [Na]
Solvent: CC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)OCn1c(-c2ccc(OC(F)(F)F)c(Cl)c2)csc1=NC(=O)Cc1c(C)oc2c1c(=O)n(C)c(=O)n2C
Product: Cl

Procedure:
Step-1: [4-[3-Chloro-4-(trifluoromethoxy)phenyl]-2-{[(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetyl]imino}-1,3-thiazol-3 (2H)-yl]methyl N-(tert-butoxycarbonyl)-L-isoleucinate: The title compound was prepared by the reaction of sodium salt of N-{4-[3-Chloro-4-(trifluoromethoxy)phenyl]-1,3-thiazol-2-yl}-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide (1.0 g, 0.0018 mol) in dry acetone (40 ml) with intermediate 6 (2.36 g, 0.0063 mol) in dry acetone (10 ml) to obtain 210 mg of product as a pale yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.74 (t, J=7.5 Hz, 3H), 0.89 (d, J=6.9 Hz, 3H), 1.25 (s, 9H), 1.80-1.87 (m, 2H), 2.36 (s, 3H), 3.33 (s, 3H), 3.50-3.57 (m, 5H), 3.73 (s, 2H), 4.26-4.33 (m, 1H), 5.19 (d, J=9.0 Hz, 1H), 6.49 (d, J=12.2 Hz, 1H), 6.64 (d, J=11.7 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 7.71-7.79 (m, 1H), 11.40 (br s, 1H); ESI-MS (m/z): 772.01 (M+H)+.