Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13](CC)[C:14](=[O:16])[O-])(=[O:12])=[O:11].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1>ClC1C=CC=CC=1>[F:19][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([NH:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([CH3:29])[N:22]=1)=[O:16])(=[O:11])=[O:12]
Reactant: COc1nc(C)nc(N)n1
Reactant: CCN(C(=O)[O-])S(=O)(=O)c1ccccc1OC(F)F
Solvent: Clc1ccccc1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2OC(F)F)n1

Procedure:
A solution of 1.48 g of N-(2-difluoromethoxy-phenylsulfonyl)-ethylcarbamate and 0.62 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 20 ml of chlorobenzene is refluxed. After concentration of the yellow solution by evaporation, and chromatographical purification of the residue, there is obtained a colourless oil which crystallises from an acetone/diethyl ether mixture by the addition of hexane. The yield is 0.45 g (23.1% of theory) of N-(2-difluoromethoxyphenyl-sulfonyl)-N'-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-urea, m.p. 140°-141° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH2:8][C:7]2([CH3:15])[CH3:14])(=[O:3])[CH3:2].[BH4-].[Na+].[Cl-].[Na+]>CO>[CH3:15][C:7]1([CH3:14])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)[O:10][CH2:9][CH2:8]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc2c(c1)C(C)(C)CCO2
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 6.0 g of 6-acetyl-4,4-dimethylchroman in 50 ml of methanol was added, all in one portion, with stirring, 3.78 g of sodium borohydride at ca. 0° C. Stirring was continued at ca. 0° C. for 1.5 hours, and then the reaction mixture was poured into 500 ml of saturated sodium chloride solution. The resulting mixture was extracted with diethyl ether, and the combined ether extracts were dried (MgSO4) and evaporated in vacuo to give 6.0 g of the title compound as an oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][N:28]([CH3:32])[C:29](Cl)=[O:30]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:29](=[O:30])[N:28]([CH3:32])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (24 mg, 24%), MS (ISP) m/z=400.4 [(M+H)+], mp 260° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and dimethylcarbamic chloride.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17](Cl)(=O)=O)=[CH:16][C:10]=2[N:9]=1)=[O:6].[CH3:21][CH2:22][CH2:23]Br>[Fe]>[CH3:3][O:4][C:5]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([S:17][CH2:21][CH2:22][CH3:23])=[CH:16][C:10]=2[N:9]=1)=[O:6]
Reactant: COC(=O)Nc1nc2cc(S(=O)(=O)Cl)ccc2[nH]1
Reactant: CCCBr
Agent: [Fe]
Agent: Cl
Product: CCCSc1ccc2[nH]c(NC(=O)OC)nc2c1
Reaction time: 1 h

Procedure:
Into 100 ml. of a 10% aqueous hydrochloric acid solution 1.5 g. of Sn powder are added at 0 to 10° C., followed by the addition of 10.8 g. (0.033 moles) of 2-[(methoxycarbonyl)amino]-1H-benzimidazol-5-sulfonic acid chloride hydrochloride. The reaction mixture is stirred at the same temperature for one hour. Thereafter 10 g. of Fe powder are added and it is stirred at 25° to 30° C. for 6 hours. The metals are dissolved and 2-[(methoxycarbonyl)amino]-1H-benzimidazole-5-thiol precipitates. The precipitate is filtered off, dissolved in a 10% aqueous potassium hydroxide solution and is subsequently reacted with 6 ml. of n-propyl bromide at 40° to 45° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:13]Br.C([O-])(O)=O.[Na+]>C(OCC)C.O>[Br:13][CH:3]1[C:2](=[O:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a 0° C. solution of ethyl 4-oxocyclohexanecarboxylate (6.0 g, 35.3 mmol) in diethyl ether (200 mL) was added dropwise a solution of bromine (5.3 g, 33.3 mmol) in diethyl ether (20 mL). The resulting mixture was stirred at room temperature for 40 min, then was cooled in an ice/water bath, diluted with water, and neutralized with aqueous NaHCO3 solution. The organic layer was separated and washed with water then brine, then was dried over MgSO4 and concentrated to an oil, which was used in next reaction without purification.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](O)=[O:29])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:32]=[C:33]([C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1)[NH2:34]>>[N:36]1[CH:37]=[CH:38][N:39]=[CH:40][C:35]=1[C:33]1[N:34]=[C:28]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:29][N:32]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1cnccn1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(OC(F)(F)F)cc3)CC(c3nc(-c4cnccn4)no3)C2)CC1

Procedure:
100 mg (0.24 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 108A) and 49 mg (0.35 mmol) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 2. Yield: 69 mg (56% of theory).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[O:8])[CH2:3]1>C(O)C.[Pd]>[NH2:15][C:11]1[CH:10]=[C:9]([C:7]([N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)C1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(C(=O)N2CCC(O)C2)c1
Yield: 100 %

Procedure:
A mixture of 2.36 g of (3-hydroxypyrrolidin-1-yl)-(3-nitrophenyl)methanone in 40 ml of ethanol and in the presence of 300 mg of palladium on carbon at 10% was stirred under hydrogen atmospheric pressure for 2 days. The reaction medium was filtered through celite and washed with 50 ml of ethanol. The solvent was concentrated to 30 ml. This solution of (3-aminophenyl)-(3-hydroxypyrrolidin-1-yl)methanone was used in the next step. Supposed yield=100%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1.[CH:14]([NH:16][NH2:17])=O>C(O)CCC>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:14]=[N:16][N:17]=2)[N:4]=1
Reactant: NNC=O
Reactant: Clc1ccc(-c2ccccn2)nn1
Solvent: CCCCO
Product: c1ccc(-c2ccc3nncn3n2)nc1

Procedure:
A mixture of 1.0 g. of 3-chloro-6-(2-pyridyl)pyridazine and 0.6 g. of formic acid hydrazide in 50 ml. of n-butyl alcohol is heated at the reflux temperature for 18 hours. The volatiles are removed in vacuo and the residue is partitioned between dilute aqueous sodium hydroxide and methylene chloride. The organic layer is dried over sodium sulfate and filtered. The filtrate is evaporated and the residue is crystallized from methylene chloride-hexane to afford 1.0 g. of the desired product as off-white to yellow crystals, m.p. 191°-192° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[CH2:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C:30]#[CH:31].C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:31]#[C:30][CH2:29][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:18]=[C:19]([O:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH:20]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(Br)cc(OCC3CC3)c2)cc1C
Reactant: C#CCN1CCOCC1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCC3CC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopropylmethoxybenzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (200 mg; 0.43 mmol) and 4-prop-2-ynyl-morpholine (161 mg; 1.3 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 173 mg; 79%. HPLC-MS: m/z: 510.1 (M)+; Rt: 1.9 min.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][NH:33][CH2:34][CH2:35][OH:36]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:33]([CH2:34][CH2:35][OH:36])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)=[O:25])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Reactant: OCCNCc1ccccn1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccn2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with 2-[(pyridin-2-ylmethyl)-amino]-ethanol
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.ClCCl.O[C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([C:24]([O:26]C)=[O:25])([CH2:17]3)[CH2:15]1)[CH2:21]2.[OH-].[Na+]>O.O1CCCC1.CO>[F:7][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][C:16]([C:24]([OH:26])=[O:25])([CH2:17]3)[CH2:15]1)[CH2:21]2
Reactant: COC(=O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C12CC3CC(CC(F)(C3)C1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Under a N2 atmosphere was added 26.17 ml (0.20 ml) of diethylaminosulfur trifluoride (DAST) to 24 ml. of dry dichloromethane which was cooled to -78° C. To this solution was added drop-wise a dichloromethane solution (10 ml) of methyl 3-hydroxyadamantane-1-carboxylate (42.0 g, 0.20 mol). The suspension was allowed to warm to ambient temperature and stirred for 1 hour. To the resultant solution was added water (500 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford 41.6 g (98%) of crude product, mp <34° C, which slowly crystallized. 1H NMR (CDCl3) 1.70-1.80 (m-6H), 2.20-2.35(m-3H), 2.50-2.60 (m-6H), 7.00-7.70 (m-5H) 13C NMR (CDCl3) 30.84 (10.11), 34.79 (0.91), 37.56, 41.81 (17.73), 43.70 (20.15), 44.86 (10.16), 51.86, 92.13 (184.14). Under a N2 atmosphere was added to crude ester (41.6 g, 0.196 mol), 100 ml of methanol, 75 ml of tetrahydrofuran (THF), 50 ml of water followed by 16.0 g (0.40 mol) of NaOH pellets. The solution was allowed to stir overnight. The organic solvents were removed under reduced pressure, water (200 ml) was added and the solution was acidified to a pH of 1.0 with 6N HCl. The resultant solids were filtered, washed with water and air dried to afford 37.0 g (95%) of 3-fluoroadamantane-1-carboxylic acid (mp 154-156° C). An analytical sample of the title compound was obtained following an EtOAc/hexane recrystallization. Crystals from the recrystallization were suitable for X-ray analysis. Anal. Calc'd for C11H15O2F: C, 66.65; H, 7.63; F, 9.58; Found: C, 66.44; H, 7.72; F, 9.22.
Reaction SMILES: C(OC1C=CC(CCNC2C=CC=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=CC=1)C1C=CC=CC=1.C([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][N:52]([CH2:71][CH3:72])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[CH:59]2[CH2:68][CH2:67][C:66]3[C:61](=[CH:62][CH:63]=[C:64]([O:69][CH3:70])[CH:65]=3)[CH2:60]2)=[CH:46][CH:45]=1)C1C=CC=CC=1>>[CH2:71]([N:52]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH:59]1[CH2:68][CH2:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([O:69][CH3:70])[CH:65]=2)[CH2:60]1)[CH2:51][CH2:50][C:47]1[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=1)[CH3:72]
Reactant: CCN(CCc1ccc(OCc2ccccc2)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: COc1ccc2c(c1)CCC(c1ccccc1NCCc1ccc(OCc3ccccc3)cc1)C2
Product: CCN(CCc1ccc(O)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Yield: 104.8 %

Procedure:
Synthesized from [2-(4-benzyloxyphenyl)ethyl][2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Example 36, [2-(4-benzyloxyphenyl)ethyl]ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (976 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (835 mg).
Reaction SMILES: [F:1][C:2]([O:10][C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])([C:6]([F:9])([F:8])[F:7])[C:3]([OH:5])=[O:4].[Cl-].[C:22]1([S+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C(C)=O)C(C)C>ClCCl>[F:1][C:2]([O:10][C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:14])([F:15])[F:16])([C:6]([F:9])([F:8])[F:7])[C:3]([O-:5])=[O:4].[C:35]1([S+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC(=O)CC(C)C
Product: O=C([O-])C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Yield: 35.4 %

Procedure:
To 6.6 g (0.02 mol) of 2,3,3,3-tetrafluoro-2-(1,1,2,2,3,3,3-heptafluoropropoxy)propionic acid were added an amount (0.03 mol) of triphenylsulfonium chloride aqueous solution, 60 g of methyl isobutyl ketone, and 25 g of dichloromethane. An organic layer was taken out, and washed with 50 g of water three times. After the solvent was distilled off in vacuum, the residue was added to diisopropyl ether for crystallization. On filtration and drying, 4.2 g of white crystals was obtained (yield 35%). The compound thus obtained was analyzed by spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:16]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cc(OC)ccc1C(=O)O

Procedure:
The reaction of methyl 2-hydroxy-4-methoxy-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-Allyloxy-4-methoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.18 (s, —CO2H); 7.70 (m, 1 arom. H); 6.58 (m, 2 arom. H); 6.01 (m, —CH═CH2); 5.51, 5.24 (2 d-like, CH═CH2); 4.62 (d-like, CH2—CH═CH2); 3.81 (s, OCH3). 13C-NMR (100 MHz, d6-DMSO): 166.45 (C═O); 163.45; 159.40; 133.25; 133.22; 116.91; 112.98; 105.37; 100.01; 68.63; 55.45.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([N:21]5[CH2:25][CH2:24][CH:23](C(O)=O)[CH2:22]5)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.O[N:31]1[C:35]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.N>CN(C=O)C.C(OC)(C)(C)C>[CH3:35][NH:31][C@@H:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)[CH2:22]1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN[C@@H]1CCN(c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-[1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl]pyrrolidine-3-carboxylic acid (143 mg, 0.328 mmol) and 1-hydroxybenzotriazole hydrate (93 mg, 0.69 mmol) in DMF (4.0 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (132 mg, 0.690 mmol) followed by N-methyl morpholine (159 μL, 1.31 mmol). The resulting solution was stirred for 4 hours at room temperature then ammonia (7 N in methanol, 234 μL, 1.64 mmol) was added and the reaction was stirred overnight. To the reaction was added more 1-hydroxybenzotriazole hydrate, N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and N-methyl morpholine and the solution was stirred for 1 hour at room temperature then ammonia (0.5 N in dioxane) was added. After 6 hours, the solution was diluted with methyl tert-butyl ether (100 mL) and the organic solution was washed with saturated sodium bicarbonate (2×20 mL) and brine (20 mL). The combined aqueous layers were combined and lyophilized. The resulting solids were slurried in 1:1 methanol:chloroform, filtered and the filtrate was concentrated. The crude product was purified by flash chromatography using a Horizon purification system on a 40S column eluting with chloroform/7 N methanolic ammonia (0.1-6%) to afford the title compound as the racemic mixture (86 mg, 70%). The mixture was separated by SCF chromatography to afford pure the enantiomers in 100% ee (peak 1, 37%; peak 2, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH3:31])[C:4]=1[C:5]([NH:7][C:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][C:12](=[O:14])[CH2:11][N:10]([CH3:15])[CH2:9]1)=[O:6].[BH4-].[Na+]>CO>[OH:14][CH:12]1[CH2:11][N:10]([CH3:15])[CH2:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[C:22]([S:30][CH3:31])=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:3]=2[O:2][CH3:1])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CC(=O)CN(C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CC(O)CN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.5 %

Procedure:
To a solution of 23 mg (0.0508 mmol) rac-2-methoxy-N-(1-methyl-5-oxo-3-phenyl-piperidin-3-yl)-6-methylsulfanyl-4-trifluoromethyl-benzamide in 0.46 ml methanol was added 3.9 mg (0.102 mmol) sodium borohydride. The mixture was stirred at room temperature for 30 minutes, quenched with 1.0 ml HCl 1N and stirred for 15 minutes. Water was added and the mixture was basified with a 2M sodium carbonate solution. The mixture was extracted 3 times with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: heptane/ethyl acetate 0 to 100%) to provide 4.5 mg (20%) of the title compound as a white solid. MS (m/e): 455.2 (MH+).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].ClOC(C)(C)C.ClNC1C(=CC=CC=1)C([O-])=O.[S:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.C(N(CC)CC)C>[NH2:4][C:3]1[C:5]([CH:30]2[CH2:31][CH2:32][CH2:33][S:29]2)=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: C1CCSC1
Reactant: COC(=O)c1ccccc1N
Agent: CC(C)(C)OCl
Agent: O=C([O-])c1ccccc1NCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(C2CCCS2)c1N
Reaction time: 2 h

Procedure:
A solution of methyl anthranilate (75.5 g; 0.5 mole) in CH2Cl2 (1.0 l) is cooled to -70° and a solution of tert-butyl hypochlorite (54 g; 0.5 mole) in CH2Cl2 (150 ml) is added slowly keeping the temperature at -70°. The resultant N-chloroanthranilate solution is stirred for 1.0 hr and then tetrahydrothiophene (110 ml) is added at such a rate as to maintain the exotherm to less than 10°. The dark solution is stirred at -70° for 2.0 hr, triethylamine (125 ml) is added dropwise, and the solution is stirred for 24 hrs. The solvents are removed and the residue is diluted with CH2Cl2, washed with (1 N) NaOH solution, water and dried. Removal of solvents gives an oil. Unreacted methyl anthranilate is removed under reduced pressure (b.p. 95°-100°/0.35 mm) at bath temperature at 150°. The residue is dissolved in CH 2 Cl2 and partially chromatographed through silica gel. The solid residue is recrystallized from methanol. Yield 27.0 g; mp 75°-9°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(Br)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 90 °C
Yield: 63.3 %

Procedure:
A mixture of (R)-6-bromo-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 5.13 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.38 g, 7.69 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.84 g, 1.03 mmol) and K2CO3 (1.42 g, 10.25 mmol) in dioxane (21 mL) and water (7 mL) was heated at 90° C. overnight. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give 4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.6 g, 61%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 8.64 (brs, 1H), 7.36-7.20 (m, 3H), 7.19-7.05 (m, 2H), 6.99 (s, 1H), 6.81 (s, 1H), 5.49 (brs, 1H), 4.79 (q, J=6.4 Hz, 1H), 4.72-4.57 (m, 2H), 3.88 (brs, 2H), 3.35 (m, 2H), 2.06 (brs, 2H), 1.60-1.57 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[Cl:13][S:14](O)(=[O:16])=[O:15]>>[Cl:13][S:14]([C:10]1[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: CCOc1ccccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 0 °C
Yield: 81.1 %

Procedure:
In a 250 ml three-neck flack, 2-ethoxy benzoic acid (50 g, 0.30 mol) was added dropwise to an ice-cooled mixtures of sulfoxide dichloride (22 ml, 0.30 mol) and chlorosulfonic acid (82.6 ml, 1.24 mol) under stirring. At the same time, the temperature of the reacting mixture was kept below 25° C. The resulting mixture was stirred at room temperature for 18 hours and then poured into ice water with stirring, and white deposit appeared. The reaction mixture was stirred for another 1 hour, filtered, washed with water, and dried in vacuum, which gave 64.4 g of crude product as white solid (II) (yield 81%). m.p. 108-110° C. The crude product was used directly in the next step without further purification.