Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)[CH3:2].COC(OC)OC.[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:36][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)=[N:7][CH:6]=1)[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCOC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1
Reaction time: 3.5 h
Yield: 110.1 %

Procedure:
Combine 6-(4-Formyl-phenoxy)-nicotinic acid ethyl ester (0.62 g, 2.29 mmol), MeOH (12 mL), Trimethylorthoformate (8 mL), and Phenethylamine (0.26 mL, 2.06 mmol). After the reaction stirs at room temperature under a Nitrogen atmosphere for 3.5 hours, add NaBH4 (251.0 mg, 2.75 mmol). After the reaction stirs at room temperature for 12 hours, concentrate under reduced pressure and add the mixture to a 5 g SCX column. Wash the column with MeOH and elute with 1N NH3 MeOH to afford 854.0 mg (99% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 2.8 (2H, t), 2.8-3.0 (4H, m), 3.8 (2H, s), 3.9 (3H, s), 6.9 (1H, d), 7.1-7.4 (9H, m), 8.3 (1H, d), 8.8 (1H, s); MS m/z 377 (M+1).
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:10])[O:5]C(C)(C)C.[OH:31][CH:32]1[O:48][C@H:47]([CH2:49][OH:50])[C@@H:37]([O:38][CH2:39][C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)[C@H:35]([OH:36])[C@@H:33]1[OH:34].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4](=[O:5])[OH:10].[OH:31][CH:32]1[O:48][C@H:47]([CH2:49][OH:50])[C@@H:37]([O:38][CH2:39][C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)[C@H:35]([OH:36])[C@@H:33]1[OH:34]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)C(O)O[C@@H]2CO)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of Fmoc-Asp(O-tBu)-Man(4-MBzl) (3.5 g) and 50% TFA in methylene chloride (50 mL) was stirred at room temperature for 45 min. The solvent was evaporated and the product was precipitated by the addition of ether. The solid was collected and air dried to yield a white solid (2.23 g, 70%). mp 155°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([OH:27])=O)=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:60][NH:61][CH2:62][CH:63]([OH:66])[CH2:64][OH:65]>CN(C)C=O.O>[OH:66][CH:63]([CH2:64][OH:65])[CH2:62][N:61]([CH3:60])[C:25]([C:22]1[N:14]2[C:13]([CH2:12][N:11]([C:9]([C:7]3[CH:6]=[CH:5][C:4]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])=[C:3]([O:2][CH3:1])[CH:8]=3)=[O:10])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15]2)=[CH:24][CH:23]=1)=[O:27]
Reactant: CNCC(O)CO
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a stirred solution of the 10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.300 g, 0.65 mmol)) in N,N-dimethylformamide (15 mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.150 g, 0.78 mmol) and 1-hydroxybenzotriazole (0.110 g, 0.78 mmol). After the solution became homogeneous 3-methylamino-1,2-propanediol (0.082 g, 0.78 mmol) was added, and the solution was stirred at room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated to dryness. The residue was subjected to silica chromatography eluting with 10% methanol in chloroform. The pure fractions were concentrated and the residue azeotroped and triturated several times with hexane to provide the title product (0.118 g) as a white solid, m.p. 119-123° C.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][CH:17]([F:38])[O:18][C:19]1[CH:20]=[N:21][C:22]([C:28]2[NH:29][C:30](=[O:37])[C:31]([CH:34]([CH3:36])[CH3:35])([CH3:33])[N:32]=2)=[C:23]([CH:27]=1)[C:24](O)=[O:25]>C(Cl)Cl>[F:16][CH:17]([F:38])[O:18][C:19]1[CH:27]=[C:23]2[C:24](=[O:25])[N:29]3[C:30](=[O:37])[C:31]([CH:34]([CH3:36])[CH3:35])([CH3:33])[N:32]=[C:28]3[C:22]2=[N:21][CH:20]=1
Reactant: CC(C)C1(C)N=C(c2ncc(OC(F)F)cc2C(=O)O)NC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)C1(C)N=C2c3ncc(OC(F)F)cc3C(=O)N2C1=O
Reaction time: 8 h

Procedure:
Dicyclohexylcarbodiimide (1.07 g, 5 mmol) in 20 mL CH2Cl2 is added to a stirred solution containing 1.54 g (4.7 mmol) 5-(difluoromethoxy)-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinic acid in 30 mL CH2Cl2 under nitrogen at room temperature. The mixture is stirred overnight, filtered and concentrated to give the product, 7-(difluoromethoxy)-2-isopropyl-2-methyl-5H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-3(2H), 5-dione.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:5]([OH:7])=O.ClCl.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH2:43][CH:44]1[C:55](=[O:56])[N:46]2[C:47]([C:52]([OH:54])=[O:53])=[C:48]([CH3:51])[CH2:49][S:50][C@H:45]12.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C>ClCCl.CO>[CH3:1][O:2][N:3]=[C:4]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[C:11]([Cl:18])[CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:5]([NH:43][CH:44]1[C:55](=[O:56])[N:46]2[C:47]([C:52]([OH:54])=[O:53])=[C:48]([CH3:51])[CH2:49][S:50][C@H:45]12)=[O:7]
Reactant: CON=C(C(=O)O)c1ccc2cccc(Cl)c2c1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: ClCl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C)CS[C@H]12)c1ccc2cccc(Cl)c2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Four hundred twenty milligrams of α-methoxyimino-α-(8-chloro-2-naphthyl)acetic acid were converted to the acid chloride by reaction with excess chlorine and 500 mg of triphenyl phosphite in 20 ml of dichloromethane. The reaction mixture was added in one portion to a stirred solution of 350 mg of 7-amino-3-methyl-3-cephem-4-carboxylic acid in 5 ml of dichloromethane containing 2 ml of bis(trimethylsilyl)trifluoroacetamide. The reaction mixture was stirred at 25° C. for six hours and then diluted by addition of 20 ml of methanol. The solvent was removed by evaporation under reduced pressure to provide 7-[α-methoxyimino-α-(8-chloro-2-naphthyl)acetamido]-3-methyl-3-cephem-4-carboxylic acid. The product thus formed is dissolved in formic acid containing zinc metal dust to give, following isolation and purification, 7-(8-chloro-2-naphthyl)glycylamido-3-methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:27](=[O:29])C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[Na+].BrBr>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:24])([CH3:26])[CH3:25])=[CH:11][C:10]=1[C:27]([OH:29])=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CC(=O)c1cc(C(C)(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 78.8 %

Procedure:
1-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-ethanone [prepared as per WO 2004/072051] (2.02 g, 5.2 mmol) was dissolved in 1,4-dioxane (30 ml), a solution of sodium hydroxide (2.08 g, 52.0 mmol) in water (30 ml) was added and the mixture was stirred and treated dropwise with bromine (0.8 ml, 15.6 mmol). The resulting mixture was stirred at room temperature for 16 hours. The 1,4-dioxane was removed in vacuo and the mixture acidified to pH 2 or below by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate, the organic layer was separated, the solvent removed in vacuo and the residue subjected to column chromatography on silica. Elution with 30% ethyl acetate in petroleum ether afforded 2,4-bis-benzyloxy-5-tert-butyl-benzoic acid (1.6 g, 79%) as a pale yellow oil. 1H NMR (DMSO-d6) 12.18 (1H, br s), 7.69 (1H, s), 7.52 (4H, t), 7.45-7.33 (6H, m), 6.93 (1H, s), 5.24 (2H, s), 5.23 (2H, s), 1.32 (9H, s). MS: [M+H]+ 391.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CN1CCCC1=O.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>C(#N)C>[C:22]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(OCCCO)c1ccc(O)cc1
Solvent: CC#N
Solvent: CN1CCCC1=O
Product: C=C(C)C(=O)OCCCOC(=O)c1ccc(O)cc1
Temperature: 0 °C

Procedure:
To a solution of 23 g of 4-hydroxybenzoic acid (3-hydroxypropyl)ester in 100 ml of acetonitrile was added 20 ml of N-methylpyrrolidone with stirring, followed by 16 g of methacryloyl chloride. After the mixture was reacted with stirring at 35° C. for 8 hours, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate/n-hexane to give 4-hydroxybenzoic acid (3-methacryloyloxypropyl)ester (Ph-1).
Reaction SMILES: [CH:1]1[C:6](Cl)=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]=[CH2:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C(#N)C>[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]=[CH:22][C:6]1[CH:1]=[CH:2][C:3]2[O:11][C:9](=[O:10])[NH:8][C:4]=2[CH:5]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC=Cc1ccc2oc(=O)[nH]c2c1
Temperature: -78 °C
Reaction time: 60 h

Procedure:
A mixture of chlorzoxazone, 3-(t-butoxycarbonylamino)-1-propene, palladium diacetate, tritolylphosphine, and acetonitrile is cooled to −78° C., degassed, and sealed in a reaction tube. The mixture is kept at 50° C. with stirring for 60 hours, then cooled and opened and the acetonitrile removed under vacuum. The residue is dissolved in ethyl acetate and washed successively with 5% aqueous NaHCO3 and brine. After drying over Mg2SO4, the mixture is filtered and evaporated. Silica gel chromatography gives 5-(3-(t-butoxycarbonylamino)-1-propenyl)-2-benzoxazolone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=1.[Br:25]N1C(=O)CCC1=O>Cl.C(O)=O>[Br:25][C:18]1[C:13]2[NH:12][C:11](=[O:22])[C:10]([CH3:24])([CH3:23])[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:14]=2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=1
Reactant: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: O=CO
Product: CC1(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])cc(Br)c2NC1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
30 g (0.092 mol) of 5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 600 ml of concentrated hydrochloric acid and 600 ml of formic acid, treated with 49.5 g of N-bromosuccinimide and stirred at room temperature for 48 hours. Subsequently, an additional 33 g of N-bromosuccinimide are added thereto and the mixture is stirred at room temperature for 4 days. The solution is evaporated and the residue is poured into ice and aqueous ammonia. After extracting the aqueous solution three times with methylene chloride, the organic phase is dried and evaporated. The residue is chromatographed on 2 kg of silica gel with methylene chloride and methylene chloride/ethyl acetate (20:1) as the elution agent. There is obtained 9-bromo-5-(o-fluorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 164° (ether/n-hexane).
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:24]1([S:30]([NH:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]2[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
224.5 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 207 mg of benzenesulfonyl chloride and 303 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 98 mg. MS (ES+): m/e=464.1 (M+H)+; 408.1.
Reaction SMILES: CN1C2C(C(F)(F)F)=CC(NC3C=NC=CC=3)=CC=2C2CNCCC12.C(OC([N:33]1[CH2:51][CH2:50][C@@H:36]2[N:37]([C:47](O)=O)[C:38]3[C:39]([C:45]#[N:46])=[CH:40][C:41]([NH2:44])=[CH:42][C:43]=3[C@@H:35]2[CH2:34]1)=O)(C)(C)C.Br[C:53]1[C:54]([C:59]#[N:60])=[N:55][CH:56]=[CH:57][CH:58]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[C:59]([C:54]1[C:53]([NH:44][C:41]2[CH:42]=[C:43]3[C:38](=[C:39]([C:45]#[N:46])[CH:40]=2)[N:37]([CH3:47])[C@H:36]2[CH2:50][CH2:51][NH:33][CH2:34][C@@H:35]32)=[CH:58][CH:57]=[CH:56][N:55]=1)#[N:60]
Reactant: N#Cc1ncccc1Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc(C#N)c1N2C(=O)O
Agent: CN1c2c(cc(Nc3cccnc3)cc2C(F)(F)F)C2CNCCC21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CN1c2c(C#N)cc(Nc3cccnc3C#N)cc2[C@@H]2CNCC[C@@H]21

Procedure:
The title compound was prepared by following the general method for (5-methyl-6-trifluoromethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indol-8-yl)-pyridin-3-yl-amine (Method B) as a yellow solid (35 mg, 35%) from (4aS,9bR)-8-amino-6-cyano-3,4,4a,9b-tetrahydro-1H-pyrido[4,3-b]indole-2,5-dicarboxylic acid tert-butyl ester (Example 162, 100 mg, 0.31 mmol), 3-bromo-pyridine-2-carbonitrile (56 mg, 0.31 mmol) and Cs2CO3 (199 mg, 0.6 mmol). MS (ESI): 331 (base, M+H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[O:7]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CI>CN(C)C=O>[CH3:1][N:23]([S:20]([C:17]1[CH:18]=[CH:19][C:14]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH:24]([CH2:25][OH:26])[CH2:27][OH:28]
Reactant: O=S(=O)(NC(CO)CO)c1ccc(Oc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C(CO)CO)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
After potassium carbonate (45.39 g, 328.4 mmol) was added to a solution of N-(4-phenoxybenzenesulfonyl)serinol (10.62 g, 32.84 mmol), the product of (1) above, in N,N-dimethylformamide (250 ml), methyl iodide (5.12 g, 36.12 mmol) was added dropwise to the mixture. After stirring it at room temperature for 2 hours, the same amount of methyl iodide was further added to this mixture and stirred for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure, ice-water was added to the resulting residue and this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound (8.32 g, yield 75%) as a white powder.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[F:8][C:9]1[C:17]2[NH:16][C:15]([CH3:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[F:19][C:20]([F:41])([F:40])[S:21]([O:24][C:25]1[CH:39]=[CH:38][C:28]([O:29][C:30]2[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=2)=[CH:27][CH:26]=1)(=[O:23])=[O:22]>O>[F:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[CH:26][C:25]([O:24][S:21]([C:20]([F:41])([F:19])[F:40])(=[O:23])=[O:22])=[CH:39][CH:38]=4)=[CH:37][CH:36]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc2cccc(F)c2[nH]1
Reactant: O=S(=O)(Oc1ccc(Oc2ccc(CBr)cc2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2c(F)cccc2n1Cc1ccc(Oc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (10 ml) and sodium hydride (60% oil suspension; 29 mg), 4-fluoro-2-methylbenzimidazole (110 mg) was added while stirring, and stirring was continued at room temperature for 1 hour. To the reaction mixture, a solution of 4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl bromide (300 mg) in anhydrous N,N-dimethylformaide (3 ml) was dropwise added, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene extract was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to eliminate toluene The residue was purified by silica gel column chromatography to give 4-fluoro-2-methyl-1-[4-(4-trifluoromethylsulfonyloxyphenoxy)benzyl]benzimidazole (164 mg) as a colorless liquid nD26 1.5615.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][C:11](=O)[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([CH2:22][CH2:21][CH2:20][CH2:19][NH2:23])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)CC(C)(C)N1OC1CCCCC1
Reactant: CCCCN
Product: CC1(C)CC(CCCCN)CC(C)(C)N1OC1CCCCC1

Procedure:
The product is prepared analogously to the method described in Example II-1, by reaction of 126.7 g (0.5 moles) of 1-cyclohexyloxy-2,2,6,6-tetramethyl-4-oxopiperidine and 38.4 g (0.52 moles) of n-butylamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH:35][CH:36]2[CH2:38][CH2:37]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:41](Cl)=[O:42].C(N(CC)CC)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:36]2[CH2:37][CH2:38]2)[C:41]([N:40]([CH3:39])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:42])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)ccc1OC
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)N(C)c2ccccc2)C2CC2)C(C)C)ccc1OC
Temperature: 60 °C

Procedure:
A mixture of (3R*,4R*)-3-cyclopropylaminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (216 mg, 0.41 mmol), N-methyl-N-phenyl carbamoylchloride (274 mg, 1.62 mmol), triethylamine (0.45 mL, 3.24 mmol) and DMAP (1 mg, 0.008 mmol) in THF (15 mL) is heated at 60° C. for 4 h. After cooling to RT 1N HCl is added and the mixture is extracted with ethyl acetate, the combined organic extracts are dried (Na2SO4), filtered and the solvent is evaporated. Purification by flash chromatography on silica gel (eluent gradient: CH2Cl2 100% CH2Cl2/MeOH 9:1) affords the title compound. MS (LC-MS): 667.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 6.02 min.
Reaction SMILES: C1(C2C=C(C3ON=C(C4C=CC=C5C=4CC[C@H]5NCCO)N=3)SC=2C(F)(F)F)C=CC=CC=1.[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([CH:69]=[CH:70][C:71]=1[O:72][CH2:73][CH3:74])[CH2:40][C:41]1[O:45][N:44]=[C:43]([C:46]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:47]=2[CH2:48][CH2:49][C@@H:50]3[N:55]([CH2:63][C:64]([N:66]([CH3:68])[CH3:67])=[O:65])C(=O)OC(C)(C)C)[N:42]=1)[CH3:35]>>[CH2:34]([O:36][C:37]1[CH:38]=[C:39]([CH:69]=[CH:70][C:71]=1[O:72][CH2:73][CH3:74])[CH2:40][C:41]1[O:45][N:44]=[C:43]([C:46]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:47]=2[CH2:48][CH2:49][C@@H:50]3[NH:55][CH2:63][C:64]([N:66]([CH3:67])[CH3:68])=[O:65])[N:42]=1)[CH3:35]
Reactant: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@@H]4N(CC(=O)N(C)C)C(=O)OC(C)(C)C)no2)cc1OCC
Agent: OCCN[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Product: CCOc1ccc(Cc2nc(-c3cccc4c3CC[C@@H]4NCC(=O)N(C)C)no2)cc1OCC

Procedure:
(S)-2-((4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-N,N-dimethylacetamide 66 was prepared analogously to compound 67 from (S)-tert-butyl (4-(5-(3,4-diethoxybenzyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-(dimethylamino)-2-oxoethyl)carbamate INT-64.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]([NH:23][C:24]3[C:33]([CH3:34])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=3[CH3:35])=[O:22])[C:18]([CH3:36])=[CH:17][CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]([NH:23][C:24]3[C:25]([CH3:35])=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][C:33]=3[CH3:34])=[O:22])[C:18]([CH3:36])=[CH:17][CH:16]=2)[CH2:11]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(CO)C3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
To a solution of methyl 4-[[6-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-1-yl]-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (1.1 g, 2.15 mmol) in THF (7 ml) is added Bu4NF 1.0 M in THF (5.00 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 6 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 0-50% ethyl acetate in hexanes to afford the title compound as an off-white solid (0.36 g, 42%). Mass spectrum (m/z): 398.2 (M+1).