Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11].[C:14]1([C:20]2[S:24][C:23]([S:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]3[C:34]([NH:36][O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[O:35])(=[O:27])=[O:26])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:14]1([C:20]2[S:24][C:23]([S:25]([N:28]3[CH2:33][CH2:32][N:31]([S:10]([CH2:9][CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)(=[O:12])=[O:11])[CH2:30][C@@H:29]3[C:34]([NH:36][O:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][O:39]3)=[O:35])(=[O:26])=[O:27])=[CH:22][CH:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=S(=O)(Cl)CCc1ccccn1
Reactant: O=C(NOC1CCCCO1)[C@H]1CNCCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)[C@H]1CN(S(=O)(=O)CCc2ccccn2)CCN1S(=O)(=O)c1ccc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
2-(2-Pyridyl)ethanesulfonyl chloride hydrochloride (214 mg) was added to a solution of (2R)-1-(5-phenylthiophene-2-sulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide (200 mg) and triethylamine (188 mg) in CHCl3 (3 ml) with cooling on an ice bath. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by SiO2 column chromatography eluted with MeOH in CHCl3 (1%) to give 184 mg of (2R)-1-(5-phenylthiophene-2-sulfonyl)-4-[2-(2-pyridyl)ethanesulfonyl]-N-(2-tetrahydropyranyloxy)-2-piperazinecarboxamide as an amorphous powder.
Reaction SMILES: O1CCCC1.[C:6]([CH2:9][CH2:10][C:11](=[N:22][NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)(=[O:8])[NH2:7].C([BH3-])#N.[Na+].Cl>CO>[C:6]([CH2:9][CH2:10][CH:11]([NH:22][NH:23][C:24]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=1)=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)(=[O:8])[NH2:7]
Reactant: NC(=O)CCC(=NNC(=O)Nc1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)CCC(NNC(=O)Nc1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
In a mixed solvent of 15 ml of tetrahydrofuran and 15 ml of methanol was dissoved 0.46 g (1.0 mmole) of 2-[3-carbamoyl-1-(3-trifluoromethylphenyl)propylidene]-N-(4-trifluoromethoxyphenyl)hydrazinecarboxamide, after which to the resulting solution were added 0.46 g (7.7 mmoles) of sodium cyanoborohydride and then 5 drops of a saturated methanolic solution of hydrochloric acid, and the reaction was carried out for 36 hours.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].[C:16](=O)(O)[O-:17].[Na+].C(Cl)(Cl)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:15])[CH:6]([N:7]=[C:16]=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3]
Reactant: O=C([O-])O
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)N=C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To an ice-cold suspension of L-phenylalanine ethyl ester hydrochloride (25.0 g, 109 mmol) in methylene chloride (800 mL) a saturated solution of sodium bicarbonate (800 mL) was added and the mixture was vigorously stirred at 0° C. for 30 minutes. Stirring was stopped to allow the separation of the two layers and a solution of phosgene in toluene (20%, 100 mL, 190 mmol) was added directly into the organic layer. Stirring was resumed while keeping the mixture at 0° C. for one hour and at room temperature for one additional hour. The organic layer was separated, and washed sequentially with water and a saturated solution of sodium chloride, dried with sodium sulphate, filtered and evaporated to yield a colorless oil that slowly solidifies (22.7 g, 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[O:14]1C=CC=[CH:16][CH:15]1OCCBr.O>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:16][CH2:15][OH:14]
Reactant: COc1ccc(O)cc1OC
Reactant: BrCCOC1C=CC=CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(OCCO)cc1OC
Reaction time: 0.33 h

Procedure:
A mixture of 3,4-dimethoxyphenol (155 mg, 1.0 mmol) and 60% sodium hydride (50 mg, 1.25 mmol) in DMA (6 ml) was stirred for 20 min under an atmosphere of nitrogen. 2-(2-Pyranyloxy)ethylbromide (220 mg, 1.0 mmol) was added dropwise. The reaction mixture was stirred for 6 hours at room temperature and then the mixture was poured into water (100 ml). The mixture was extracted with ethyl acetate (2×30 ml) and the combined organic extracts were dried (MgSO4). The organic phase was concentrated and the residue was dissolved in 2-propanol (30 ml) and 4 N HCl (20 ml) was added. The mixture was heated at reflux temperature for 30 min and then stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The organic solution was dried (MgSO4) and the solvent was evaporated. The oily residue was purified on silica gel (50 g) eluting with a mixture of heptane and ethyl acetate (3:2). This afforded 100 mg (50%) of 2-(3,4-dimethoxyphenoxy)ethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:27])=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1.[ClH:29].[N:30]1([CH2:35][CH2:36][CH2:37][C:38](O)=[O:39])[CH2:34][CH2:33][CH2:32][CH2:31]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:29].[CH3:28][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:27][C:38](=[O:39])[CH2:37][CH2:36][CH2:35][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:12][C:13]([CH:15]([CH3:26])[CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:14][C:4]=2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Reactant: O=C(O)CCCN1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CC(CCCc1ccc(F)cc1)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.55 g. (9.37 mmoles) of 4,4-dimethyl-9-hydroxy-7-(4-p-fluorophenyl-1-methylbutyl)-1,2,3,4-tetrahydrocyclopenta [c] [1]benzopyran are combined with 1.82 g. (9.37 mmoles) of γ-pyrrolidinobutyric acid hydrochloride and 2.06 g. (10.0 mmoles) of dicyclohexylcarbodiimide in 150 ml. of methylene chloride and stirred at room temperature for 21/2 hours. The insoluble by-product of dicyclohexylurea is removed by filtration and the filtrate is evaporated to give a residue which crystallized upon standing. The material is triturated with ether and filtered. Recrystallization from benzene-ether gives the product as colorless crystals.
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:40])[C:5]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH2:31][CH:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[CH2:38]Cl)[O:29][N:28]=4)[N:26]=3)[CH2:18][CH2:17]2)=[O:15])[N:6]=1.O.ClCCl.[CH3:45][O:46][CH2:47][CH2:48][OH:49]>>[F:3][CH:4]([F:40])[C:5]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[S:23][CH:24]=[C:25]([C:27]4[CH2:31][CH:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[CH2:38][O:49][CH2:48][CH2:47][O:46][CH3:45])[O:29][N:28]=4)[N:26]=3)[CH2:18][CH2:17]2)=[O:15])[N:6]=1
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4CCl)C3)cs2)CC1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCCOCc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methoxyethanol (1.5 ml) was admixed at room temperature with sodium hydride (60%, 17 mg) and then stirred at room temperature for 2 hours. To this mixture was added dropwise a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-[4-(4-{5-[2-(chloromethyl)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]ethanone (0.20 g) in 2-methoxyethanol (1.5 g), and the mixture was then stirred at room temperature for 16 hours. Subsequently, the reaction mixture was admixed with water and dichloromethane. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(5-{2[(2-methoxyethoxy)methyl]phenyl}-4,5-dihydro-1,2-oxazol-3-yl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (0.11 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:33]([NH:36][CH2:37][CH2:38][CH3:39])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH2:33]([N:36]([CH2:37][CH2:38][CH3:39])[C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[CH2:34][CH3:35]
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CCCNCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(Cl)ccn1
Yield: 67.3 %

Procedure:
Stir a solution of 4-chloro-2-pyridine carboxylic acid (1.0 g, 6.3 mmol), 1-hydroxybenzotriazole (850 mg, 6.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.21 g, 6.3 mmol), dipropyl amine (862 μL, 6.3 mmol), and triethylamine (1.75 mL, 12.6 mmol) in dichloromethane (63 mL) at room temperature over the weekend. Wash the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 10:90 to 20:80 ethyl acetate:hexanes)to give the title compound (1.02 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](C=O)=[CH:4][C:3]=1[OH:11].[OH-:12].[Na+].OO.Cl>>[Br:1][C:2]1([OH:12])[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][CH:3]1[OH:11]
Reactant: [OH-]
Reactant: O=Cc1cc(O)c(Br)cc1Cl
Agent: Cl
Agent: OO
Agent: [Na+]
Product: OC1C=CC(Cl)=CC1(O)Br
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 25.0 grams (0.106 mole) of 2-bromo-4-chloro-5-formylphenol in 106 mL (0.106 mole) of aqueous 1N sodium hydroxide was warmed to about 50° C., and 150 mL (0.133 mole) of aqueous 3% hydrogen peroxide was added dropwise. Upon completion of addition, the reaction mixture was allowed to cool to ambient temperature as it stirred for about 18 hours. After this time, the reaction mixture was made acidic with aqueous 6N hydrochloric acid. The mixture was then filtered to collect a solid. The solid was washed with water and dried under vacuum, yielding 21.2 grams of 2-bromo-4-chlorocatechol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH2:22]O)=[C:12]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[N:13]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:35])(=O)=O>ClCCl>[Cl:35][CH2:22][C:11]1[O:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:13][C:12]=1[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: COc1ccc(-c2nc(COC3CCCCO3)c(CO)o2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(COC3CCCCO3)c(CCl)o2)cc1
Temperature: 25 °C

Procedure:
2.0 g [2-(4-Methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazol-5-yl]-methanol were dissolved in 30 ml dichloromethane and cooled in an ice bath. 0.88 ml triethylamine were added, followed by the addition of 0.49 ml methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. The reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 2.5 g of 5-chloromethyl-2-(4-methoxy-phenyl)-4-(tetrahydro-pyran-2-yloxymethyl)-oxazole as an oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=S)=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH3:28]>>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][C:9]2[C:10]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[NH:28])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)cc1
Product: COc1ccc(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (1.05 g, 0.00488 mol), N-[3-(4-methoxybenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.5 g, 0.0041 mol)and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 0.96 g (61.5%) m.p. 165°-166 ° C.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[CH:11]=2)[N:4]=1.[CH2:27]([O:34][CH2:35][CH:36]1[CH:40]([CH2:41][N:42]2[CH:46]=[C:45](Br)[CH:44]=[N:43]2)[O:39][C:38](=[O:48])[NH:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH2:27]([O:34][CH2:35][CH:36]1[CH:40]([CH2:41][N:42]2[CH:46]=[C:45]([C:14]3[CH:13]=[C:12]([CH3:25])[CH:11]=[C:10]([NH:9][C:5]4[N:4]=[C:3]([CH:2]([F:1])[F:26])[CH:8]=[CH:7][N:6]=4)[CH:15]=3)[CH:44]=[N:43]2)[O:39][C:38](=[O:48])[NH:37]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C1NC(COCc2ccccc2)C(Cn2cc(Br)cn2)O1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COCc3ccccc3)c2)c1
Temperature: 110 °C

Procedure:
A mixture of 4-(difluoromethyl)-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine (111 mg, 0.307 mmol), 4-[(benzyloxy)methyl]-5-[(4-bromo-1H-pyrazol-1-yl)methyl]-1,3-oxazolidin-2-one (109 mg, 0.298 mmol), potassium phosphate tribasic (239 mg, 1.13 mmol), and Pd(dbpf)Cl2 (4 mg, 0.006 mmol) in dioxane (2 mL) was stirred and heated to 110° C. in a microwave reactor for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by prep-TLC (ethyl acetate/petroleum ether) to give 4-[(benzyloxy)methyl]-5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one. MS ESI calc'd. for C27H27F2N6O3 [M+H]+ 521. found 521. 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J=4.8 Hz, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.77 (s, 1H), 7.40 (s, 1H), 7.38-7.26 (m, 5H), 7.15 (s, 1H), 7.05 (d, J=4.8 Hz, 1H), 6.56 (t, J=54.4 Hz, 1H), 4.88-4.76 (m, 1H), 4.54 (s, 2H), 4.48-4.46 (m, 2H), 3.94-3.92 (m, 1H), 3.48-3.46 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1.[N:34]1([CH2:40][CH2:41][CH2:42]Cl)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:31]=[CH:30][CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC
Reactant: ClCCCN1CCCCC1
Product: COc1cc(-c2nc3ccc(OCCCN4CCCCC4)cc3n2Cc2ccccc2C(F)(F)F)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 104 with 3-(piperidin-1-yl)propyl chloride essentially as previously described mp 138° C., IR, NMR, MS. 584
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:8]([O:22][CH2:23][C:24](OCC)=[O:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([CH:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COC(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCCO)c2cccc(Cl)c2F)C1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)-methyl)piperidine-1-carboxylate (4.368 g, 10.2 mmol) in MeOH (85 mL) was added NaBH4 (3.18 g, 81.5 mmol) in portions such that the temperature remained below 40° C. After addition, the mixture was stirred at rt for 2˜3 h. TLC showed the starting material had disappeared. The solvent was removed in vacuo and the residue was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give (R)-tert-butyl 3-((3-chloro-2-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (3.5 g, 89%). 1H NMR (400 MHz, CDCl3): 1.18 (m, 1H), 1.38-1.46 (s, 9H), 1.65 (m, 1H), 1.85 (m, 2H), 2.66 (m, 1H), 3.25 (m, 1H), 3.38 (m, 2H), 3.69 (m, 3H), 3.93 (m, 1H), 4.52 (m, 6H); MS (E/Z): 388 (M+1)
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@@H:6]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH2:5][N:4]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])#[N:2].N[CH2:27][CH2:28][SH:29]>O1CCCC1>[CH3:12][S:9]([O:8][C@H:6]1[CH2:5][N:4]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[O:14])[C@H:3]([C:1]2[S:29][CH2:28][CH2:27][N:2]=2)[CH2:7]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C#N)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: NCCS
Solvent: C1CCOC1
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C2=NCCS2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 24 h
Yield: 41.3 %

Procedure:
To a solution of (2S,4R)-2-cyano-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2 g) in tetrahydrofuran (40 ml) was added 2-aminoethanethiol (630 mg) at ambient temperature. After stirring for 24 hours at the same temperature, the mixture was evaporated. The residue was extracted with dichloromethane, washed with water and brine successively, and dried over magnesium sulfate. The organic layer was evaporated, and then the obtained oil was subjected to a column chromatography on silica gel and eluted with a mixture of dichloromethane and acetone (4:1,V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-thiazolin-2-yl)pyrrolidine (0.96 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:5]1([C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCCCCBr
Reactant: COc1ccc(N)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2CCCC2)c(OC)c1
Temperature: 150 °C
Yield: 62.8 %

Procedure:
Ex-38A: Method A: A mixture of 2,4-dimethoxyaniline (1.0 g, 6.53 mmol), 1,4-dibromobutane (1.41 g, 6.53 mmol) and potassium carbonate (3.61 g, 26.1 mmol) in N,N-dimethylformamide (70 mL) was heated at 150° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was taken up in a mixture of water and ethyl acetate. After the mixture was partitioned, the aqueous solution was extracted with ethyl acetate. The combined solution of ethyl acetate was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography. Elution with ethyl acetate and hexane (1:2, v/v) gave 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (0.85 g, 63%). 1H-NMR (300 MHz, CDCl3) δ 6.76 (d, J=8.9 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 6.41 (dd, J=2.7, 8.9 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.18–3.14 (m, 4H), 1.95–1.90 (m, 4H). Method B: Sodium tert-butoxide was charged to a mixture of 1-bromo-2,4-dimethoxybenzene (3.03 g, 14.0 mmol), pyrrolidine (1.75 mL, 20.9 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.26 g, 0.28 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.35 g, 0.56 mmol) in degassed toluene (60 mL). The reaction mixture was heated at 100° C. under N2 for 17 h. After cooling to room temperature, the reaction mixture was diluted with water (60 mL) and partitioned. The aqueous solution was further extracted with ethyl acetate. The combined ethyl acetate and toluene was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography with ethyl acetate and hexane (1:2, v/v) to give 1-pyrrolidin-1-yl-2,4-dimethoxybenzene as a brown oil (1.82 g, 63%).
Reaction SMILES: [H-].[Na+].COP([CH2:9][C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])(OC)=O.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([C:33]2[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=2[CH3:41])=[CH:31][C:30]([C:42]([OH:45])([CH3:44])[CH3:43])=[N:29]1>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]1[C:32]([C:33]2[CH:40]=[CH:39][C:36](/[CH:37]=[CH:9]/[C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([O:15][CH3:16])=[O:14])=[CH:35][C:34]=2[CH3:41])=[CH:31][C:30]([C:42]([OH:45])([CH3:43])[CH3:44])=[N:29]1
Reactant: COC(=O)c1cccc(CP(=O)(OC)OC)c1
Reactant: Cc1cc(C=O)ccc1-c1cc(C(C)(C)O)nn1-c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(/C=C/c2ccc(-c3cc(C(C)(C)O)nn3-c3c(Cl)cccc3Cl)c(C)c2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
To a suspension of NaH (52 mg of a 60% dispersion in mineral oil) in THF (7.5 mL) cooled to 0° C. in an ice bath was added methyl 3-((dimethoxyphosphoryl)methyl)benzoate as a solution in THF (1 mL) followed by a THF (1 mL) rinse of the phosphonate vial and syringe to insure complete transfer. The ice bath was removed and the reaction was allowed to warm to ambient temperature. After 90 minutes at ambient temperature, 4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylbenzaldehyde (0.49 mmol impure from previous step) was added via cannula to the reaction mixture followed by a THF (1 mL) rinse of the flask and cannula after 1 hour-45 minutes at ambient temperature the reaction was quenched by addition of saturated aqueous NH4Cl and EtOAc. The layers were separated and the aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford a yellow syrup. The crude product was purified by flash column chromatography eluting with a gradient from 0% to 40% MeCN/CH2Cl2 to afford (E)-methyl 3-(4-(1-(2,6-dichlorophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-methylstyryl)benzoate (180 mg, 70% yield) of slightly impure product. This material was carried on to the ester hydrolysis without further purification. MS(ES): 521 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[C:19]([F:20])=[C:18]([F:21])[CH:17]=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:25][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3ccc(F)c(F)c3o2)c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2ccc(F)c(F)c2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-6,7-difluorobenzoxazole (235 mg, 0.8 mmol) and propylamine (328 μL, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.