Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:21](=[N:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(N=Cc2ccccc2)c2c(c1)ncn2-c1ccccc1

Procedure:
To a solution of 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (0.50 g, 1.81 mmol) in anhydrous toluene (10 ml) was added benzaldehyde, p-toluenesulphonic acid (10 mg) and molecular sieves. The resultant mixture was stirred at reflux for 1.5 hours. The molecular sieves were removed by filtration and the filtrate was concentrated under reduced pressure. The concentrate was partitioned between aqueous sodium carbonate (2M) and ethyl acetate. The organic phase was dried and concentrated, and the concentrate was eluted through silica gel with a mixture of ethyl acetate and ligroin (1:1 v/v). Removal of solvent from the eluate left the desired product as a yellow solid (0.37 g, 56%) m/z, 366.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([CH:5]=[C:6]([Cl:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C@@H:3]1[C:15](O)=[O:16].S(Cl)([Cl:21])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4]([CH:5]=[C:6]([Cl:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[C@@H:3]1[C:15]([Cl:21])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)C(F)(F)F)[C@@H]1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)C(F)(F)F)[C@@H]1C(=O)Cl
Temperature: 80 °C

Procedure:
21.5 g (0.07 mol) of (±)-cis/trans-2,2-dimethyl-3-(2-chloro-3,3,4,4,4-pentafluoro-1-butenyl)-cyclopropane-1-carboxylic acid were dissolved in 150 ml of carbon tetrachloride, and 50 ml of thionyl chloride were added. The mixture was then warmed to 80° C. for 1 hour, while stirring. After distilling off the excess thionyl chloride and the solvent, the residue was distilled under a high vacuum. 21 g of (±)-cis/trans-2,2-dimethyl-3-(2-chloro-3,3,4,4,4-pentafluoro-1-butenyl)-cyclopropane-1-carboxylic acid chloride of boiling point 50°-54° C./0.3 mbar were obtained. ##STR10##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[NH2:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[F:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[F:20])[O:21][C:8]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Nc1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.4 %

Procedure:
To a solution of 3-cyano-4-fluoronitrobenzene (9.36 g, 56.3 mmol) and 3-amino-4-fluorophenol (7.16 g, 56.3 mmol) in N,N-dimethylformamide (150 ml) was added potassium carbonate (11.7 g, 84.5 mmol), and the mixture was stirred at room temperature for 4 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. 5% Aqueous sodium hydrogen carbonate solution (300 mL) was added to the residue, and the mixture was extracted with ethyl acetate (270 mL)/tetrahydrofuran (30 mL). The aqueous layer was extracted with ethyl acetate (270 mL)/tetrahydrofuran (30 mL), and the combined organic layer was washed with saturated brine (300 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by basic silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (15.6 g, quantitative) as a beige powder.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:11])\[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9].[H][H]>C1C=CC=CC=1>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][C@@H:4]([CH2:3][CH2:2][OH:1])[CH3:11])[CH3:10]
Reactant: [H][H]
Reactant: CC(C)=CCC/C(C)=C\CO
Solvent: c1ccccc1
Product: CC(C)=CCC[C@H](C)CCO
Yield: 93.4 %

Procedure:
In a 100 ml stainless steel-made autoclave whose atmosphere had been displaced with nitrogen were charged 1.54 g (10 mmole) of nerol, 0.0837 g (0.1 mmole) of Rh(COD)((+)-cBINAP)Cl obtained in Example 4, and 10 ml of benzene, and hydrogenation reaction was carried out at room temperature and at a hydrogen pressure of 30 kg/cm2 for 17 hours. There was obtained 1.46 g of (S)-(-)-citronellol at a conversion of 99% and a selectivity of 99%. From the results of optical rotation [α]25D =-3.65° (c=10.1, chloroform), the optical yield was found to be 70%ee.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[O:19][N:18]=[C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])[CH:16]=3)=[N:12][C:11]=2[CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:5]1([CH2:4][O:6][C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[O:19][N:18]=[C:17]([O:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH3:23])[CH:16]=4)=[N:12][C:11]=3[CH:32]=2)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1cc(-c2nc3cc(O)ccc3o2)on1)NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](COc1cc(-c2nc3cc(OCC4CC4)ccc3o2)on1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
(Bromomethyl)cyclopropane (0.388 mL) was added to a mixture of tert-butyl [(1S)-2-{[5-(5-hydroxy-1,3-benzoxazol-2-yl)isoxazol-3-yl]oxy}-1-methylethyl]carbamate (500 mg), potassium carbonate (552 mg) and DMF (13 mL), and the mixture was stirred at 60° C. for 5 hr. The solvent was evaporated under reduced pressure, water was added thereto, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with hexane-ethyl acetate to give the title compound (510 mg).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:20].C[O:22][B:23](OC)[O:24]C.Cl>O1CCCC1>[CH3:13][C:12]1[C:7]([B:23]([OH:24])[OH:22])=[C:8]([CH3:20])[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1
Reactant: COB(OC)OC
Reactant: Cc1cc(-c2ccccc2)cc(C)c1Br
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
tert-Butyllithium (1.7 M solution in hexanes, 36.2 ml, 62.6 mmol) is added dropwise to a solution of 4-bromo-3,5-dimethylbiphenyl (7.27 g; 28 mmol) in dry tetrahydrofuran (150 ml) at −78° C. and stirred under an atmosphere of nitrogen for 30 minutes. Trimethylborate (9.54 ml; 84 mmol) is added and the resulting mixture is stirred at −78° C. for 30 min and then allowed to warm to room temperature. The reaction mixture is acidified with aqueous hydrochloric acid and extracted with ether (2×150 ml). The organic layers are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give a yellow solid. The crude product is triturated with iso-hexane and filtered to give 3,5-dimethylbiphen-4-ylboronic acid (5.89 g) as a white powder.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([CH3:28])=[CH2:27])[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CO>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([CH:26]([CH3:27])[CH3:28])[CH:23]=[CH:22][C:21]=3[C:29]3[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[C:32]([F:38])=[CH:31][C:30]=3[O:39][CH3:40])[C@H:14]2[CH3:41])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Solvent: CO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(C)C)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(4′-fluoro-4-isopropenyl-5′-isopropyl-2′-methoxybiphenyl-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (15 mg, 0.025 mmol) in methanol (1 mL) was subject to H2 (balloon atmosphere) at 20° C. overnight. The crude mixture was filtered through a syringe filter. The filtrate was evaporated in vacuo and purified by preparative TLC plates developed by 20% EtOAc in hexanes to give the titled compound. LC-MS: 612 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 1:1 mixture of rotamers δ 7.84 (s, 1 H), 7.64-7.68 (m, 2 H), 7.30 (s, 0.5), 7.20-7.27 (m, 1.5 H), 7.13-7.17 (m, 1 H), 7.02 (d, J=8.5 Hz, 0.5H), 6.99 (d, J=8.0 Hz, 0.5 H), 6.65 (d, J=6.0 Hz, 0.5 H), 6.63 (d, J=6.0 Hz, 0.5 H), 5.52 (d, J=8.0 Hz, 0.5H), 5.25 (d, J=8.0 Hz, 1 H), 4.87 (d, J=15.5 Hz, 0.5 H), 4.82 (d, J=15.5 Hz, 0.5H), 4.03 (d, J=15.0 Hz, 0.5 H), 3.81 (d, J=15.0 Hz, 0.5 H), 3.69-3.77 (m, 4 H), 3.14-3.24 (m, 1 H), 2.92-3.02 (m, 1 H), 1.14-1.33 (m, 12 H), 0.48 (d, J=6.5 Hz, 1.5 H), 0.30 (d, J=7.0 Hz, 1.5 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25]Cl)[C:3]=1[F:28].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:27])[CH2:25][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:3]=1[F:28]
Reactant: C1CCNCC1
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCl)c(F)c3o2)cc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CN4CCCCC4)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
515 mg (1.25 mmol) of Compound 159 obtained in EXAMPLE 159 was dissolved in 10 mL of dimethylformamide, 0.62 mL (6.2 mmol) of piperidine and 0.22 mL (1.25 mmol) of diisopropylethylamine were added, and the mixture was stirred at 50° C. for 2 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetonitrile=4:1) and recrystallized from ethyl acetate, to give 441 mg of Compound 164 (yield: 77%).
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[S:12])/[N:7]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:36]>CO.O1CCOCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[S:12])[C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])/[N:7]([CH2:22][C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3].[ClH:36]
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 112C (160 mg, 0.306 mmol) in methyl alcohol (2 mL) added hydrogen chloride (4 M) in dioxane (1 mL) and stirred at rt for 2 hr. The reaction concentrated to give the title compound as HCl salt. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.27 (m, 1H) 1.34-1.38 (m, 1H) 1.40 (s, 9H) 1.61 (m, 2H) 1.81 (m, 2H) 2.53-2.63 (m, 1H) 3.02 (m, 1H) 3.13 (m, 1H) 3.81 (s, 3H) 4.03-4.09 (m, 1H) 4.33 (m, 1H) 6.85 (d, J=8.73 Hz, 1H) 6.93 (s, 1H) 7.21-7.24 (m, 1H) 7.53 (d, J=2.78 Hz, 1H); MS (DCI/NH3) m/z 438 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:20](OCC)(=[O:25])[CH2:21][C:22]([CH3:24])=O.Cl>CO>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]2[N:19]=[C:22]([CH3:24])[CH:21]=[C:20]([OH:25])[N:16]2[N:15]=1)(=[O:13])=[O:12]
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Solvent: CO
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Reaction time: 18 h

Procedure:
A solution of 32.2 g (0.10 mol) of N-(2,6-dichloro-3-methylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide and 14 ml (0.11 mol) of ethyl acetoacetate in 500 ml of methanol containing 1 ml of 12N hydrochloric acid was heated to reflux with stirring for about 18 hours. The solid present was collected by filtration and the filtrate was heated to reflux for another day. The mixture obtained was cooled in an ice bath and the solid present was collected by filtration. The filtrate was concentrated to about 200 ml by evaporation of methanol and heated to reflux overnight. The mixture obtained was filtered to collect the solid present. The filtrate was concentrated to about 150 ml, treated with about 2 ml of ethyl acetoacetate, and heated at reflux for about 3 days. The solids present were collected by filtration and dried to obtain 6.4 g, 10.0 g, 8.2 g and 11.1 g crops of the title compound for a total of 35.7 g (92 percent of theory). The first obtained crop melted at 346°-7° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Product: CCOC(=O)n1c(C(=O)c2cc(F)cc(F)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′,5′-difluoroacetophenone (prepared according to the method of S. Kajigaeshi et al., Bull.Chem.Soc.Jpn., 1987, 60, 1159-1160).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH2:5][CH:4]([CH2:7]O)[CH2:3]1.C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:11][CH2:7][CH:4]1[CH2:5][O:6][C:2]([CH3:9])([CH3:1])[CH2:3]1
Reactant: CC1(C)CC(CO)CO1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)CC(CBr)CO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
To a solution of (5,5-dimethyltetrahydrofuran-3-yl)methanol (2.00 g) in dichloromethane (30 ml) were added carbon tetrabromide (6.10 g) and triphenylphosphine (4.80 g) at room temperature. The reaction mixture was stirred at room temperature for 20 hr, and extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.40 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[N:10]([CH2:19][C:20]3[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=3)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]([CH:46]2[CH2:48][CH2:47]2)[C:38]1=[O:49].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:46]1([N:39]2[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[N:37]([CH2:36][CH2:35][CH2:34][N:15]3[CH2:14][CH2:13][C:12]4([N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH2:9][N:10]([CH2:19][C:20]5[CH:21]=[C:22]([CH:30]=[CH:31][CH:32]=5)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[C:11]4=[O:18])[CH2:17][CH2:16]3)[C:38]2=[O:49])[CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCNCC3)C2=O)c1
Reactant: O=c1n(CCCCl)c2ccccc2n1C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCn4c(=O)n(C5CC5)c5ccccc54)CC3)C2=O)c1
Temperature: 81 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A mixture of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (163.5 mg, 0.372 mmol, 1 equiv), 1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (93 mg, 0.372 mmol, 1 equiv), sodium iodide (22.3 mg, 0.15 mmol, 0.4 equiv) and potassium carbonate (102.8 mg, 0.74 mmol, 2 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 10 g cartridge, Rf=0.5, gradient—1%-10% methanol in dichloromethane) to afford the title compound (166 mg, 68%); MS for C38H44FN5O4 m/z 654.24 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C@@H:9]([CH3:15])[C:10](OCC)=[O:11])=[CH:6][CH:5]=1>C(O)C>[Br:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C@@H:9]([CH3:15])[CH2:10][OH:11])=[CH:6][CH:5]=1
Reactant: CCOC(=O)[C@H](C)Oc1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@@H](CO)Oc1ccc(Br)cc1
Reaction time: 10 h

Procedure:
Sodium borohydride (1.15 g) was added to a solution of (2S)-2-(4-bromophenoxy)propionic acid, ethyl ester (7.5 g, Example 4a)) in ethanol (20 ml) at 5° C. The resulting solution was allowed to attain room temperature and was stirred for 10 hours before being concentrated under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (50 ml). The mixture was extracted into ethyl acetate and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was used directly in the next step without further purification (6.32 g).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH:30]([CH2:35][N:36]([CH3:38])[CH3:37])[CH2:29][CH2:28]3)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.N1C=CC=CC=1>[CH3:38][N:36]([CH2:35][CH:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH2:23][C:22]3[CH:21]=[CH:20][C:19]([NH:18][S:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=4)(=[O:16])=[O:15])=[CH:40][CH:39]=3)[CH:26]=2)[CH2:31]1)[CH3:37]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CC1CCc2cc(OCc3ccc(N)cc3)ccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Reaction time: 0.25 h
Yield: 56 %

Procedure:
THF solution (1 ml) of 4-methoxybenzenesulfonyl chloride (270 mg) was added dropwise to pyridine solution (6 ml) of 6-[(4-aminobenzyl)oxy]-2-[(N,N-dimethylamino)methyl]tetralin (300 mg) under ice-cooling, which was stirred for 15 minutes. After stirring at room temperature for further 15 minutes, 10% aqueous potassium carbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: ethyl acetate), and recrystallized (ethyl acetate-IPE) to give the titled compound (260 mg).
Reaction SMILES: C[O-].[Na+].[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2F)[CH2:7]1.O.[C:27](OCC)(=[O:29])C>CO>[Cl:4][CH2:5][C:6]1([CH3:25])[O:10][N:9]=[C:8]([S:11][CH2:12][C:13]2[C:14]([C:21]([F:24])([F:23])[F:22])=[N:15][N:16]([CH2:19][CH3:20])[C:17]=2[O:29][CH3:27])[CH2:7]1
Reactant: CCOC(C)=O
Reactant: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCn1nc(C(F)(F)F)c(CSC2=NOC(C)(CCl)C2)c1OC
Yield: 59.1 %

Procedure:
4.3 g (22.5 mmoles) of sodium methoxide (in the form of a 28% methanol solution) was added, at room temperature, into a solution of 5.4 g (15.0 mmoles) of 5-chloromethyl-3-(1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-methyl-2-isoxazoline dissolved in 30 ml of methanol. The mixture was heated for refluxing for 8 hours, to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 3.3 g (yield: 59.1%) of 5-chloromethyl-3-(1-ethyl-5-methoxy-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5-meth-yl-2-isoxazoline.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:10][C:11]1[C:16]([NH:17]C(=O)C)=[CH:15][C:14](C2C=CC=CC=2C([O-])=O)=[C:13]([N+:30]([O-:32])=[O:31])[CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl>C(O)C.O>[CH2:3]([O:10][C:11]1[C:16]([NH2:17])=[CH:15][C:14]([OH:1])=[C:13]([N+:30]([O-:32])=[O:31])[CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCOc1cc([N+](=O)[O-])c(-c2ccccc2C(=O)[O-])cc1NC(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCOc1cc([N+](=O)[O-])c(O)cc1N
Reaction time: 8 h
Yield: 81.3 %

Procedure:
Sodium hydroxide (2.15 g, 53.7mmol) was carefully added to a stirred solution of 50b (890 mg, 2.15 mmol) in 80 ml ethanol and 20 ml water. The reaction mixture was stirred overnight and was then acidified with concentrated HCl. Extracted three times with dichloromethane, and the combined organic layers were washed with brine and dried over MgSO4. The crude product was adsorbed onto silica gel and purified via flash chromatography with gradual elutions from 85/10/5 to 75/20/5 (Hex/EtOAc/dichloromethane). Evaporation of solvent yielded 469 mg (81%) of an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[S:8](=[O:16])(=[O:15])[C:7]=2[CH:17]=1.[BH4-].[Na+].Cl>CS(C)=O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:10][CH:9]([S:11](=[O:13])(=[O:14])[NH2:12])[S:8](=[O:15])(=[O:16])[C:7]=2[CH:17]=1
Reactant: COc1ccc2c(c1)S(=O)(=O)C(S(N)(=O)=O)=C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1ccc2c(c1)S(=O)(=O)C(S(N)(=O)=O)C2
Reaction time: 0.5 h

Procedure:
The product from Step A (200 mg) was dissolved in 1.5 ml of DMSO and was added rapidly dropwise to a solution of 200 mg of NaBH4 in 5 ml of 95% ethanol. After 30 minutes, the mixture was poured into dilute HCl and extracted with ethyl acetate. The extract was washed with water, and brine and dried (Na2SO4) and evaporated to dryness. The residue was pure by TLC and the structure was not contraindicated by 'H-NMR. Mass spectrum shows m/e=277. Calc'd for C9H11NO5S2 : C, 38.98; N, 5.05; H, 4.00%. Found: C, 39.34; N, 5.15; H, 3.95%.