Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:46][C@H:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])[CH2:48][C:49]([OH:51])=[O:50]>CN(C=O)C>[CH3:23][C:2]([CH3:22])([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:9]=[C:8]([C:18]([NH:46][C@H:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[CH2:48][C:49]([OH:51])=[O:50])=[O:20])[CH:7]=1
Reactant: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1F
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
324 mg (0.675 mmol) of 5-(3,3-dimethyl-2-oxo-butoxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid were dissolved in 5 ml of DMF and 0.675 mmol of TOTU and 1.35 mmol of EDIA were added. The mixture was stirred for 5 min at room temperature, then 0.675 mmol of (S)-3-amino-3-(2-methyl-phenyl)-propionic acid were added and the mixture was stirred overnight at room temperature. After evaporation of the solvent, the residue was subjected to preparative HPLC to give the title compound in a yield of 67%.
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.[F:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:21][S:22][C:23]1[CH:24]=[C:25]([O:33]COC)[C:26](=[O:32])[N:27](COC)[CH:28]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:21][S:22][C:23]1[CH:24]=[C:25]([OH:33])[C:26](=[O:32])[NH:27][CH:28]=1
Reactant: COCOc1cc(SCc2ccc(F)c(F)c2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: O=c1[nH]cc(SCc2ccc(F)c(F)c2)cc1O

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 5-[(3,4-difluorobenzyl)sulfanyl]-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 25).
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.[C:19]1([CH3:27])[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[OH:26][CH:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:27])=[CH:20][CH:21]=1)[C:2]#[C:1][C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Reactant: Cc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C#CC2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 1) (15.0 g, 82.3 mmol) in tetrahydrofuran (165 mL), 2.77 M n-butyllithium (solution in n-hexane, 62.4 mL, 172.9 mmol) was added dropwise at −72° C. for 25 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. Thereafter, p-tolualdehyde (10.2 mL, 86.4 mmol) was added dropwise at −72° C. for 5 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. The reaction solution was allowed to warm to room temperature and poured into saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (17.7 g, 58.5 mmol, 71%) as an amorphous product.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC(C2C=COC=2)=CC=1.Br[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1.[Br:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1>CCO>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: OB(O)Oc1ccc(Br)cc1
Agent: c1ccc(-c2ccc(-c3ccoc3)cc2)cc1
Solvent: CCO
Product: N#Cc1ccc(-c2ccc(Br)cc2)cc1
Yield: 67.3 %

Procedure:
As described in Example 1(a) for the preparation of 3-biphenyl-4-yl-furan, 4-bromobenzonitrile (9.42 g, 51.8 mmol) and 4-bromophenylboric acid (5.20 g, 25.9 mmol) were coupled in EtOH to afford 4.50 g (67%) of 4′-bromo-biphenyl-4-carbonitrile as a grey powder, mp 147-8° C. (lit 153-5° C.; McNamara, J.; Gleason, W. B. J. Org. Chem. 1976, 41, 1071). The material had an NMR spectrum that matched literature (see Amatore, C.; Juland, A.; Negri, S. J. Organomet. Chem. 1990, 390, 389-398) and was typically used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH:13]([NH:17][C:18](=[O:20])[CH3:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.O>CS(C)=O.ClCCl>[C:18]([NH:17][CH:13]1[C:14](=[O:16])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)(=[O:20])[CH3:19]
Reactant: CC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)NC1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Pyidin-sulphur trioxide in 6.5 mL DMSO was added to 1.34 g benzyl-3-acetamido-4-hydroxypyrrolidine-1-carboxylate and 2.5 mL DIPEA in 8 mL dichlormethane at 0° C. The reaction was stirred 1 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and sodium chloride solution and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate) to give 1.1 g of the desired product. (M+H)+: 277
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25]Cl)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[C:28]1([CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:21]([O:23][CH2:24][CH2:25][NH:37][CH2:36][CH2:35][CH:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCNCCC(c2ccccc2)c2ccccc2)C1c1cccc([N+](=O)[O-])c1
Reaction time: 1.75 h
Yield: 40.5 %

Procedure:
A solution comprising 5.92 g of methyl 2-chloroethyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate and 9.50 g of 3,3-diphenylpropylamine in 20 ml of xylene was refluxed under stirring for 105 minutes. The mixture was then cooled. By dilution with diethyl ether a semisolid compound was obtained, and it was separated from the liquid by decantation. The residue was treated with diethyl ether at 0°-4° C. and the supernatant was decanted. This procedure was repeated until a solid was obtained, and this was collected by filtration. Mother liquors and washings from the decantation were collected and evaporated to dryness under vacuum. The residue was chromatographed on a silica gel column (270 g) using a mixture of chloroform and acetone as eluent. Pure fractions were combined and the solvent was evaporated off. The residue was dissolved in diethyl ether and hydrogen chloride in diethyl ether was added. The solid (3.92 g) was crystallized from ethyl acetate or isopropyl acetate and recrystallized from ethyl acetate to give 3.46 g of the title compound, m.p. 128°-132° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:31]#[C:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:8]\[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:30])[C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>N1C2C(=CC=CC=2)C=CC=1.CO>[C:1]1(/[C:7](/[CH:31]=[CH:32]\[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:8]/[C:9]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:30])[C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(C(=O)N2CCN(C(=O)/C=C(/C#Cc3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Reactant: [H][H]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: COc1cc(C(=O)N2CCN(C(=O)/C=C(\C=C/c3ccccc3)c3ccccc3)CC2)cc(OC)c1OC
Reaction time: 15 h
Yield: 61 %

Procedure:
0.025 g of 10% w/w palladium-on-barium sulfate and two drops of quinoline were added to 5 ml of a methanol solution containing 0.250 g of 1-[(E)-3,5-diphenylpent-2-en-4-ynoyl]-4-(3,4,5-trimethoxybenzoyl)piperazine (prepared as described in Example 58). Hydrogen gas was introduced into the reaction mixture at room temperature and at atmospheric pressure. The reaction mixture was then shaken for 15 hours, after which the catalyst was filtered off and the solvent was removed by distillation under reduced pressure. The residue was subjected to moderate pressure liquid chromatography using a Lobar B column. 0.153 g of the title compound was obtained as a powder from those fractions eluted with mixtures of methylene chloride and ethyl acetate ranging from 3:2 to 1:3 by volume.
Reaction SMILES: CC(C)=O.C(Br)CCCCCC.C(=O)([O-])[O-].[K+].[K+].C([O:22][C@@H:23]1[C@@H:36]([O:37]C(=O)C)[C@H:35]([O:41]C(=O)C)[CH2:34][O:33][C@H:24]1[S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=O)C>C(O)(=O)C>[S:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C@@H:24]1[O:33][CH2:34][C@@H:35]([OH:41])[C@H:36]([OH:37])[C@H:23]1[OH:22]
Reactant: CCCCCCCS[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCCCCCCBr
Product: CCCCCCCS[C@@H]1OC[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To 20 ml. of a 50% aqueous acetone solution were added 2.92 g. of 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside (17) and 1.79 g. of n-heptyl bromide. To the solution was further added 1.38 g. of potassium carbonate and then a boiling under reflux was carried out for one hour. After completion of the reaction, the solution was neutralized with acetic acid, extracted with chloroform washed with water, and dried. The used solvent was distilled away to obtain 2.55 g. of colorless oily n-heptyl 2,3,4-tri-O-acetyl-1-thio-β-D-xylopyranoside (18). The yield was 65.3%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH2:9]([N:11]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[O:18])[NH:12]1)[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH2:9]([N:11]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=[O:18])[N:12]1[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1)[CH3:10]
Reactant: CCN1NC(=O)CC1(C)C
Reactant: Fc1ccc(I)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCN1N(c2ccc(I)cn2)C(=O)CC1(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
(200 mg, 0.90 mmol) 2-Fluoro-5-iodopyridine was dissolved in toluene (1 ml) and 1-ethyl-5,5-dimethyl-pyrazolidin-3-one [CAS 26485-97-2] (128 mg, 0.90 mmol, 1.0 equiv.) and cesium carbonate (440 mg, 1.35 mmol, 1.5 equiv.) were added under nitrogen. The mixture was stirred for 4 hours at 100° C. The crude product was purified by flash chromatography by directly loading the toluene mixture onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 50:50. The desired 1-ethyl-2-(5-iodo-pyridin-2-yl)-5,5-dimethyl-pyrazolidin-3-one (88 mg, 28% yield) was obtained as a yellow oil, MS: m/e=346.3 (M+H+).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH3:17]I.Cl>C(O)C>[CH3:17][S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(S)cc(C(F)(F)F)c1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 10 g. (0.045 mole) of 3-mercapto-5-trifluoromethylbenzoic acid, and 100 ml. of 1N sodium hydroxide in 100 ml. of ethanol is added 3.8 ml. (0.06 mole) of methyl iodide. After the reaction has stirred at room temperature for one hour, it is acidified with 12N hydrochloric acid, and the precipitate of the final product is filtered and dried,8.6 g., m.p. 135°-140° C. A sample is sublimed at 175° C. and 0.03 mm pressure, m.p. 151°-152.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:12]([C:14](=[O:29])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:28])[C:20]=2[CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[N:13]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[C:12]([C:14](=[O:29])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:28])[C:20]=2[CH:21]2[CH2:22][CH2:23][CH:24]([OH:27])[CH2:25][CH2:26]2)[N:13]=1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
tert-Butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(4-oxocyclohexyl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (68 mg, 0.13 mmol) was dissolved in methanol (3 mL) and sodium borohydride (16 mg, 0.39 mmol) was added. The mixture was stirred at RT for 30 min then quenched with sat. NaHCO3 and extracted with ethyl acetate three times. Combined organic layers were dried over sodium sulfate, filtered and concentrated to give the crude tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-hydroxycyclohexyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (58 mg, 85%).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17]C)=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[K+]>CO.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=2)[CH2:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCCc2ccc(C(=O)OC)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCN1CCCc2ccc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.6 %

Procedure:
To a stirred solution of methyl 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylate (156 mg, 0.63 mmol) in methanol (1.3 mL) was added potassium hydroxide (6.3 mL of a 1 M solution in water, 6.3 mmol). The reaction mixture was stirred at room temperature for 48 h and concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 1 N hydrochloric acid and extracted with chloroform (4×100 mL). The combined organic extracts were dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) afforded 1-butyl-1,2,3,4-tetrahydroquinoline-7-carboxylic acid (139 mg): ESI MS m/z 234 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]([O:44][CH3:45])[O:42][CH3:43])=[CH:37][N:36]=2)[OH:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27]([CH:28]([O:30][CH2:31][CH3:32])[CH3:29])[N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]([C:33]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]([O:42][CH3:43])[O:44][CH3:45])=[CH:37][N:36]=2)=[O:34])=[C:7]([Cl:46])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(O)c2ccc(C(OC)OC)cn2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C(=O)c2ccc(C(OC)OC)cn2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(C)OCC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
500 mg (0.77 mmole) of the compound obtained in step 1 was dissolved in 8 ml of methylene chloride and to the resulting solution was added 73 mg (7.74 mmole) of manganese dioxide. The mixture was stirred for 5 hours at room temperature and the resultant was removed from the solvent and purified with silica gel column chromatography to obtain 346 mg of the title compound (yield 70%).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[Mo:10](=O)(=O)=O.[Na].C1(S(O)(=O)=O)C=CC=CC=1>O>[Mo:10].[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3]
Reactant: O=[Mo](=O)=O
Agent: Nc1nc(N)nc(N)n1
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na]
Solvent: O
Product: [Mo]
Temperature: 105 °C
Reaction time: 2 h

Procedure:
Melaminium octamolybdate having a 2/1 molybdenum/melamine molar ratio was prepared by adding 5.00 grams of melamine, 11.42 grams of molybdenum trioxide, 28.57 grams of the sodium salt of benzenesulfonic acid and 300 milliliters of water to a 500 milliliter round-bottom flask equipped with a water-cooled condenser and refluxing the mixture at about 105° C. with continual stirring for 2 hours. The mixture then was cooled to room temperature and was filtered. A white crystalline product was recovered and was washed with water and vacuum dried at 100° C. for 11/2 hours. Infrared and x-ray diffraction analyses identified the recovered crystalline product to be melaminium octamolybdate. 15.83 grams of the product were recovered, representing a yield of 94.39 percent of the theoretical yield.
Reaction SMILES: [OH:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>>[OH:1][C:2]1[C:8]([F:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:19]([NH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[Br:11])=[O:20]
Reactant: Nc1ccc(F)c(F)c1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccccc1Br)Nc1ccc(F)c(F)c1O

Procedure:
The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol) and 2-bromo phenyl isocyanate(0.4 g) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z 343(M+H)+
Reaction SMILES: [CH2:1]=O.Cl.[NH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[SH:15]>O.C(OCC)C.C(N(CC)CC)C>[F:14][C:11]([F:12])([F:13])[C:9]1[CH:8]=[CH:7][C:6]2[S:15][CH2:1][NH:4][C:5]=2[CH:10]=1
Reactant: Nc1cc(C(F)(F)F)ccc1S
Reactant: C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)NCS2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
37% formalin (0.22 mL) was diluted with water (6 mL), and diethylether (6 mL), triethylamine (0.37 mL) and 2-amino-4-trifluoromethylbenzenethiol hydrochloride (611 mg) were added to the solution, and then the mixture was stirred at room temperature for 30 minutes. The organic layer was separated and the aqueous layer was extracted with diethylether. The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (b).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:28])=[C:4]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.ClCCl.[C:32]1(=[O:46])[N:36]([CH2:37][C:38](Cl)=[O:39])[C:35](=[O:41])[C:34]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:33]12>O>[Si:11]([O:10][CH2:9][C:4]1[C:5]([Cl:8])=[CH:6][CH:7]=[C:2]([NH:1][C:38](=[O:39])[CH2:37][N:36]2[C:35](=[O:41])[C:34]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:33]3[C:32]2=[O:46])[C:3]=1[Cl:28])([C:24]([CH3:25])([CH3:27])[CH3:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(N)c1Cl)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To a mixture of 3-amino-1-(tert-butyldiphenylsilyloxy-methyl)-2,6-dichlorobenzene (348 mg) triethylamine (0.15 ml) and dichloromethane (3.5 ml) was added phthalimidoacetyl chloride (186 mg) under ice-cooling, and the mixture was stirred for 1.5 hours at ambient temperature. Water was added thereto, and the resulting precipitates were collected by vacuum filtration and washed with diisopropyl ether to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-(phthalimidoacetylamino)benzene (460 mg) as crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][C:12]([Cl:22])([Cl:21])[CH2:13][O:14][S:15]([N:18]=[C:19]=[O:20])(=[O:17])=[O:16].CCCCCC>ClCCl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:19]([NH:18][S:15]([O:14][CH2:13][C:12]([Cl:22])([Cl:21])[Cl:11])(=[O:16])=[O:17])=[O:20])[N:7]=1
Reactant: O=C=NS(=O)(=O)OCC(Cl)(Cl)Cl
Reactant: COc1nc(C)nc(N)n1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
14.0 g (0.1 mole) of 2-amino-4-methoxy-6-methyl-1,3,5-triazine were suspended in 250 ml of dichloromethane, and a solution of 25.5 g (0.1 mole) of 2,2,2-trichloro-eth-1-oxysulfonyl isocyanate in 100 ml of dichloromethane was added dropwise at 0° to 5° C. The reaction mixture was further stirred for 18 hours at room temperature and cooled to 0° C., and n-hexane was added. The precipitated reaction product was filtered off under suction and recrystallized from absolute ethanol. 35.3 g (89.4% of theory) of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-N'-(2,2,2-trichloro-eth-1-oxy-sulfonyl)-urea of melting point 128° C. were obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]([OH:8])=[O:7])[CH2:3][OH:4].O1CCOC[CH2:10]1.[ClH:15]>CO>[ClH:15].[NH2:1][C@@H:2]([CH2:3][OH:4])[CH2:5][C:6]([O:8][CH3:10])=[O:7]
Reactant: N[C@@H](CO)CC(=O)O
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)C[C@@H](N)CO
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of L-β-homoserine (1.00 g) in methanol (8.4 mL), a 4 mol/L hydrogen chloride-1,4-dioxane solution (8.4 mL) was added and thereafter the mixture was stirred at 60° C. for 3 hours. The reaction mixture was concentrated under reduced pressure to give the titled compound as a pale yellow oil (1.42 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([N:41]3[CH2:46][CH2:45][CH:44]([C:47]([F:50])([F:49])[F:48])[CH2:43][CH2:42]3)=[O:40])=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[CH2:16][CH2:15]2)[C:10]1=[O:31].C1COCC1.O.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:41]3[CH2:46][CH2:45][CH:44]([C:47]([F:50])([F:48])[F:49])[CH2:43][CH2:42]3)=[O:40])=[CH:37][CH:38]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1)N1CCC(C(F)(F)F)CC1
Reaction time: 2 h
Yield: 76 %

Procedure:
Treat a mixture of (R)-3-[3,5-dichloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one (0.34 g), THF (6 mL) and water (6 mL) with TFA (2 mL) at room temperature for 1 hour and at 50° C. for 2 hours. Cool the reaction, dilute with ethyl acetate, and wash with sodium bicarbonate (sat.). Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 100% ethyl acetate and 10% methanol in methylene chloride to afford 0.205 g (76%) of the titled product. MS (m/z): 598 (M+).