Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:25])=[N:5][C:6]([NH2:24])=[N:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])#N.S(=O)(=O)(O)[OH:27]>O.[Pd]>[CH:1]([C:3]1[C:4]([NH2:25])=[N:5][C:6]([NH2:24])=[N:7][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH2:13][P:14]([O:20][CH:21]([CH3:23])[CH3:22])([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[O:27]
Reactant: CC(C)OP(=O)(COCCOc1nc(N)nc(N)c1C#N)OC(C)C
Reactant: O=S(=O)(O)O
Agent: [Pd]
Solvent: O
Product: CC(C)OP(=O)(COCCOc1nc(N)nc(N)c1C=O)OC(C)C
Yield: 42 %

Procedure:
5-Cyano-2,4-diamino-6-[2-(diisopropoxyphosphorylmethoxy)ethoxy]pyrimidine (1.5 g, 4 mmol) was hydrogenated in water (36 ml) and sulfuric acid (6 ml) over 5% palladium on charcoal (0.25 g) under stirring for 20 h at room temperature. The mixture was filtered through a pad of Celite and the catalyst was washed with hot water and hot methanol (100 ml each). The filtrate was neutralized with aqueous NaOH and solvents evaporated. The residue was mixed with hot methanol, salts were filtered off and the mixture was taken down. Product was purified by column chromatography on silica gel (elution with 3% MeOH in CHCl3) to give 0.63 g (42%) of 5-formyl-2,4-diamino-6-[2-(diisopropoxyphosphorylmethoxy)ethoxy]pyrimidine.
Reaction SMILES: CCCCC[C@H](O)CC[C@H]1[C@H]([OH:22])C[C@H]2[C@@H]1CC1C(C2)=C(OCC(O)=O)C=CC=1.[NH+]1C=CC=CC=1.C(CCOP([O-])([O-])=O)#N.[CH:44]1([N:50]=[C:51]=[N:52][CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>N1C=CC=CC=1.O>[C:51]([NH:50][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1)([NH:52][CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1)=[O:22]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Agent: N#CCCOP(=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The procedure was adapted after Steroids, 2(6), 567-603 (1963). The methyl ester of treprostinil (2) (60 mg, 0.15 mmoles) was dissolved in 2 ml dry pyridine and a pyridinium solution of the previously prepared pyridinium solution of 2-cyanoethylphosphate 1M (0.3 ml, 0.3 mmoles) (cf. Methods in Enzymology, 1971, 18(c), 54-57) were concentrated to dryness in vacuo at 40° C. Anhydrous pyridine was added and the reaction mixture was again concentrated; the operation was repeated twice in order to remove water completely. Finally the residue was dissolved in 2 ml anhydrous pyridine and 190 mg (0.9 mmoles) dicyclohexylcarbodiimide were added as a solution in 2 ml anhydrous pyridine. The reaction mixture in a closed flask was stirred magnetically for 48 hours at room temperature. 1 ml water was added and after one hour, the mixture was concentrated to a thick paste in vacuo. The reaction mixture was treated overnight at room temperature with 3 ml of a 1/9 water/methanol solution containing 35 mg sodium hydroxide. The white solid (dicyclohexylurea) formed was removed by filtration and it was washed well with water. The aqueous-methanolic solution was concentrated almost to dryness in vacuo, water was added and the solution was extracted with n-butanol (3×2 ml), then with methylene chloride (1×2 ml). The pH of the solution was adjusted to 9.0 by treatment with a sulfonic acid ion exchange resin (H+cycle—Dowex), treatment with Dowex resin for a longer time (˜12 hours) lead to both the cleavage of the TBDMS group and the recovery of the free carboxyl group. The resin was filtered and the solution was concentrated to dryness affording the corresponding bisphosphate 4 (43 mg, yield 52%).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH:9][C@@H:8]([C:12]([OH:14])=[O:13])[CH2:7]1)(=[O:5])=[O:4].C([O-])(O)=O.[Na+].[CH2:20]([O:27][C:28](Cl)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.O1CCOCC1.CCOCC>[CH2:20]([O:27][C:28]([N:9]1[CH2:10][CH2:11][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:7][C@@H:8]1[C:12]([OH:14])=[O:13])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)N1CCN[C@@H](C(=O)O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)[C@@H](C(=O)O)C1
Reaction time: 2 h
Yield: 102.1 %

Procedure:
To a solution of (2R)-4-methanesulfonylpiperazine-2-carboxylic acid hydrochloride (2.10 g) in H2O (20 ml) and dioxane (20 ml) were added NaHCO3 (2.38 g) and a solution of benzyloxycarbonyl chloride (1.76 g) in Et2O (10 ml) at room temperature. After stirring for 2 hours, Et2O and dioxane were evaporated in vacuo. The solution was acidified with 1N HCl and extracted with AcOEt (80 ml). The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give 3.0 g of (2R)-1-benzyloxycarbonyl-4-methanesulfonylpiperazine-2-carboxylic acid as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:6]=[CH:5]2.[C:21]1(Cl)[C:25](Cl)=[S+:24]S[N:22]=1.[Cl-]>C(Cl)Cl.CCOC(C)=O.N1C=CC=CC=1.[Cu]I>[C:21]([C:25]1[S:24][C:3]2[C:4]3[C:9](=[CH:8][C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]=2[N:1]=1)#[N:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(Br)c(N)ccc2c1
Reactant: Clc1ns[s+]c1Cl
Agent: [Cu]I
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(ccc3nc(C#N)sc32)c1
Temperature: 110 °C
Yield: 28.4 %

Procedure:
To a stirred solution of tert-butyl (6-amino-5-bromonaphthalen-2-yl)carbamate (540 mg, 1.6 mmol) in dry DCM, 351 mg of Appel's salt (1.68 mmol) was added. Upon completion, the reaction was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4 and evaporated. The crude material thus obtained was dissolved in 10 mL of pyridine and treated with 529 mg (2.78 mmol) of CuI. The reaction was heated in a 110° C. oil bath for 40 min, and then the solvents were removed under reduced pressure. The resulting solids were taken up in EtOAc and filtered. The filtrate was washed with 1 N HCl, the aqueous layer extracted with 2×EtOAc, and the combined organic layers dried over Na2SO4. The solvents were removed under reduced pressure, and the resulting material subjected to silica gel chromatography eluting with 15→35% EtOAc in heptanes to yield 148 mg of a yellow solid. 1H NMR (CD2Cl2) d 8.21 (d, 1H); 8.12 (d, 1H); 8.03 (d, 1H); 7.96 (d, 1H); 7.64 (dd, 1H); 6.90 (br s, 1H); 1.55 (s, 9H).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C@H:4]([N:8]1[CH2:12][C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]1=[O:21])[C:5]([OH:7])=O.Cl.[OH:24][C@@H:25]([CH2:55]O)[CH2:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:67]=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:24][C:25]([CH3:55])([CH3:67])[CH2:26][N:27]1[CH:31]=[CH:30][C:29]([NH:32][C:5](=[O:7])[C@@H:4]([N:8]2[CH2:12][C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][C:9]2=[O:21])[CH2:3][CH:2]([CH3:1])[CH3:22])=[N:28]1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)O)C1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1OC1=CC(=O)N([C@@H](CC(C)C)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 0 °C
Yield: 35.8 %

Procedure:
To a solution of (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid (prepared as in Example 120, 0.214 g, 0.71 mmol) in N,N-dimethylformamide (4.5 mL) was added 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 0.142 g, 0.91 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.618 g, 1.40 mmol). The mixture was stirred at 0° C. and triethylamine (0.142 g, 1.40 mmol) was added. The mixture was stirred at room temperature for 4 h and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 25 g, 30% to 100% ethyl acetate/hexanes) which afforded (S)-4-methyl-2-(2-oxo-4-o-tolyloxy-2,5-dihydro-pyrrol-1-yl)-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (0.112 g, 36%) as a tan solid: HR-ES-MS m/z calculated for C24H32N4O4 [M+H]+ 441.2497, observed 441.2496, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.89 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.37-1.64 (m, 2H), 1.66-1.85 (m, 1H), 2.19 (s, 3H), 3.89 (br. s., 2H), 4.20 (d, J=18.1 Hz, 1H), 4.59 (d, J=18.1 Hz, 1H), 4.63 (s, 1H), 4.68 (s, 1H), 4.88 (dd, J=10.4, 4.4 Hz, 1H), 6.44 (d, J=2.1 Hz, 1H), 7.11-7.32 (m, 3H), 7.35 (d, J=6.6 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 10.79 (br. s., 1H).
Reaction SMILES: [C:1]1([NH:7][CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl:19][CH2:20][CH2:21][C:22](O)=[O:23]>C1C=CC=CC=1>[C:1]1([N:7]([CH:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:15][CH2:16][CH2:17]2)[C:22](=[O:23])[CH2:21][CH2:20][Cl:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(NC2CCc3ccccc3C2)cc1
Reactant: O=C(O)CCCl
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(CCCl)N(c1ccccc1)C1CCCc2ccccc21

Procedure:
0.1 mol of 2-phenylamino-1,2,3,4-tetrahydronaphthalene, 0.15 mol of the chloride of β-chloropropionic acid and 25 ml of benzene are refluxed during 4.5 hours. The solvent and the reagent excess are then removed. The residue is recrystallized from petroleum ether. M.P. 78°-81°C.
Reaction SMILES: C(OC([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)=O)C.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:12]([N:7]1[CH2:6][CH2:11][NH:10][CH2:9][CH2:8]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-ethoxycarbonylpiperazine (4.6 g, 29.1 mmol) in dry methylene chloride (200 mL), was added benzoyl chloride (3.55 ml, 29.1 mmol) and triethylamine (2 ml) sequentially. After stirring for 8 hours at room temperature, a saturated NaHCO3 solution was added and the aqueous phase was extracted with ethyl acetate (3×200 ml). The organic layers were combined, dried over MgSO4 and concentrated to give a crude mixture, which included the desired product XXXIX. The crude was then used for the further reaction without purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:32])([C:28]([CH3:31])([CH3:30])[CH3:29])[O:3][CH2:4][C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C:11]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH2:13]2)[CH2:7][C@H:6]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[K+].[K+].[CH:39](I)([CH3:41])[CH3:40].CC(OC)(C)C>CN(C=O)C.O>[CH3:32][Si:2]([CH3:1])([C:28]([CH3:29])([CH3:31])[CH3:30])[O:3][CH2:4][C@@H:5]1[C@@H:14]2[C@@H:8]([O:9][CH2:10][C:11]([CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:39]([CH3:41])[CH3:40])=[O:19])=[CH:12][CH2:13]2)[CH2:7][C@H:6]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1
Reactant: CC(C)I
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1[C@H]2CC=C(CCCC(=O)O)CO[C@H]2C[C@H]1OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCCC1=CC[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@@H]2OC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
Under the argon atmosphere, the compound (15.4 mmol) produced in Example 7 was dissolved in DMF; potassium carbonate (5.31 g, 38.5 mmol) and isopropyl iodide (2.31 mL, 23.1 mmol) were added, followed by stirring at 60° C. for 3 hours. After cooling, MTBE and water were added, and extraction; washing with a saturated saline; drying with anhydrous sodium sulfate; and concentration were carried out. Purification by silica gel column chromatography (hexane:ethyl acetate=90:10→50:50) was carried out to obtain a titled compound (7.25 g) having the following physical property values.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:15])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.C(OCC)C>[CH2:35]([O:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:15])[C:4]=1[CH2:1][CH:2]=[CH2:3])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=CCc1c(O)nc2ccccc2c1O
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1c(O)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 3-(prop-2-en-1-yl)quinoline-2,4-diol (4.0 g), triphenylphosphine (6.78 g) and benzyl alcohol (2.27 ml) in THF (240 ml) at 0° C. was added dropwise a THF (12 mL) solution of diisopropylazodicarboxylate (5.02 ml). Upon completion of addition, the mixture was allowed to stir at room temperature for 60 minutes. The reaction mixture was concentrated in vacuo to give a thick oil. Oil dissolved in DCM (20 mL) and solids started to precipitate. The solids were filtered and washed with DCM (10 mL). This provided 2.0 g of the desired product. Purification of the mother liquors using flash chromatography (ISCO, 1-8% acetone/DCM) gave an oil that was a mixture of products. This oil was dissolved in 15 mL of diethyl ether and seeded with the desired product. The mixture was stirred overnight and crystallization occurred. The solids were filtered and washed with ether to provide the desired product (1.06 g) as a white solid for a total of 3.06 g of product. LRMS (ES+) M/Z (M+H)+ 292.1.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1cccnc1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 45.3 %

Procedure:
Nicotinoyl chloride hydrochloride (122 mg, 0.685 mmol, commercially available product) and triethylamine (250 μl, 1.79 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (152 mg, 0.622 mmol), obtained as described in Referential Example 1-2. The resulting mixture was warmed to room temperature and stirred for 16.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15 g, hexane/ethyl acetate=1.5/1-1/1). Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl)phenyl]nicotinamide (GIF-0343) (98.4 mg, 45.3%) was yielded as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccnc1-c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 54.9 %

Procedure:
To a solution of 2-(4-chlorophenyl)-1H-imidazole (9f) (20 mmol) in anhydrous THF (200 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.2 g, 30 mmol) and stirred for 30 min. Benzenesulfonyl chloride (2.82 mL, 22 mmol) was added and the reaction mixture was stirred overnight. After dilution by 100 mL of saturated NaHCO3 solution (aqueous), the reaction mixture was extracted by ethyl acetate (500 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 2:1) to give a pale solid. Yield: 54.9%. 1H NMR (500 MHz, CDCl3) δ 7.65 (d, J=2.0 Hz, 1H), 7.58 (t, J=7.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.38 (t, J=8.0 Hz, 2H), 7.34-7.36 (m, 4H), 7.12 (d, J=1.5 Hz, 1H). MS (ESI): calculated for C15H11ClN2O2S, 318.0. found 341.0 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[NH:7][CH2:6][CH2:5][O:4]1.[CH2:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11].[C:17](=[S:19])=[S:18]>>[Cl:1][C:2]([Cl:9])([Cl:8])[CH:3]1[N:7]([C:17]([S-:19])=[S:18])[CH2:6][CH2:5][O:4]1.[CH2:10]([NH+:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH3:11]
Reactant: CCN(CC)CC
Reactant: ClC(Cl)(Cl)C1NCCO1
Reactant: S=C=S
Product: CC[NH+](CC)CC
Product: S=C([S-])N1CCOC1C(Cl)(Cl)Cl
Reaction time: 18 h

Procedure:
A mixture of 114 g (0.60 mole) 2-trichloromethyloxazolidine, 121.2g. (1.2 moles) triethylamine and 68.4 g. (0.9 mole) carbon disulfide was heated at 50° for seven hours and then was left standing for 18 hours at room temperature. The yellow solids were filtered, stirred with anhydrous ethyl ether, and filtered again to obtain 195.5 g (88.7% conversion) of the desired product, m.p. 107°-110°C.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].[F:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13].F[C:15]1[C:16]([N+:21]([O-])=O)=[N:17][CH:18]=[CH:19][CH:20]=1>>[F:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:21]=[C:3]1[CH2:1][OH:2]
Reactant: NCCCCF
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: O=C(O)C(F)(F)F
Product: OCc1nc2ncccc2n1CCCCF

Procedure:
Intermediate 42-5 was prepared in the same manner as intermediate 11-5 using the TFA salt of 4-fluorobutan-1-amine and 3-fluoro-2-nitropyridine as starting materials.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>CN(C)C=O.O>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:5]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:3]=[C:2]([O:39][C:36]3[CH:37]=[CH:38][C:33]([I:32])=[CH:34][CH:35]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccc(I)cc3)n2)cc1Cl
Temperature: 80 °C
Yield: 90.1 %

Procedure:
A mixture of compound 133 (2.0 g, 5.22 mmol), potassium carbonate (3.6 g, 26.10 mmol) in dimethylformamide (10 mL) was added 4-iodophenol (1.38 g, 6.26 mmol). It was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound as white solid (2.66 g, 90%). mp 80-82° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4 (pH 7.0); solvent B=CH3CN], Gradient elution program: T/% B=0/60, 10/60, 25/80, 40/80, 45/60, 50/60; 268 nm, Rt 38.47 min, 97.83% purity; MS (CI): m/z 566 (M+H, 100).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:7]1[C:11]([CH:12]=O)=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[C:3]([C:7]1[C:11]([CH2:12][NH:2][CH3:1])=[CH:10][N:9]([CH2:14][C:15]([NH:17][C:18]2[S:22][C:21]3[CH2:23][CH2:24][CH2:25][CH2:26][C:20]=3[C:19]=2[C:27]([NH:29][CH3:30])=[O:28])=[O:16])[N:8]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: CN
Reactant: CNC(=O)c1c(NC(=O)Cn2cc(C=O)c(C(C)(C)C)n2)sc2c1CCCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NC)CCCC3)nc1C(C)(C)C
Reaction time: 17 h
Yield: 31.9 %

Procedure:
Methylamine (45.0 mg, 50 μl, 1.449 mmol) was added to a solution of 2-(2-(3-tert-butyl-4-formyl-1H-pyrazol-1-yl)acetamido)-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (100 mg, 0.248 mmol) and acetic acid (100 μl, 1.74 mmol) in DMF (1 mL). Sodium triacetoxyborohydride (527 mg, 2.484 mmol) was added and the reaction stirred for 17 h. The reaction was quenched with water (500 μl) and purified by preparative reverse phase HPLC. The clean fractions were passed down an SCX cartridge and eluted with 2M NH3 in MeOH. Volatiles were blown down under a nitrogen atmosphere to yield the title product (33 mg, 0.079 mmol, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[O:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:23])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH:18]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:19][C:38]([CH:37]4[CH2:35][CH2:36]4)=[O:34])=[CH:20][CH:21]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Br[Mg]c1ccccc1
Reactant: N#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Reactant: C1CCOC1
Product: O=C(NC(c1ccccc1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1)C1CC1
Temperature: 25 °C

Procedure:
In a solution of 0.80 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzonitrile in 10 mL of tetrahydrofuran under nitrogen atmosphere, 1.0 mL of 32% tetrahydrofuran solution of phenyl magnesium bromide was added dropwise with stirring at room temperature, after the completion of the addition dropwise, it was continued to stir at room temperature further for 3.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 10 mL of methanol, 0.075 g of sodium boron hydride was added, and stirred at room temperature for 2 hours. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (10 mL×2), and the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 mL of chloroform, and under cooling with ice and with stirring, 0.20 g of triethyl amine and 0.21 g of cyclopropanecarbonyl=chloride were added dropwise, after the completion of the addition dropwise, it was continued to stir at room temperature further for 1 hour. After the completion of the reaction, the reaction mixture was washed with water (10 mL×1), and the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous magnesium sulfate in that order, and the solvent was distilled off under reduced pressure. The residue was purified with medium pressure preparative liquid chromatography (medium pressure collection apparatus: YFLC-Wprep manufactured by Yamazen Corporation) that was eluted with ethyl acetate-hexane (gradient of 1:9 to 1:2) to obtain 0.16 g of the aimed products as colorless resinous substance.