Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH:7][C@@H:8]([CH3:16])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2.[CH:21]1[C:33]2[CH:32]([CH2:34][O:35][C:36]([NH:38][C@@H:39]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=3)[C:40](O)=[O:41])=[O:37])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>>[S:1]1[CH:5]=[C:4]([CH2:6][N:7]([C@@H:8]([CH3:16])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])[C:40](=[O:41])[C@@H:39]([NH:38][C:36](=[O:37])[O:35][CH2:34][CH:32]2[C:33]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[C:31]2=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:46][CH:45]=2)[C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]1=2
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1csc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 65 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)—N-(benzo[b]thiophen-3-ylmethyl)-1,1-diethoxypropan-2-amine (Compound IX-6) 1.45 g (4.941 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 2.50 g (5.44 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=7:3) to obtain the title compound 2.36 g (59%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][Mn:7](C(O)C)([CH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)(=[C:12]=[O:13])(=[C:10]=[O:11])=[C:8]=[O:9].[CH2:22](N(CC)CC)[CH3:23]>ClCCl>[CH3:6][Mn:7]([CH:2]([C:1](=[O:4])[CH:22]=[CH2:23])[CH3:3])([CH:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1)(=[C:10]=[O:11])(=[C:12]=[O:13])=[C:8]=[O:9]
Reactant: CC(O)[Mn](C)(=C=O)(=C=O)(=C=O)C1C=CC=C1
Reactant: CCN(CC)CC
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)C(C)[Mn](C)(=C=O)(=C=O)(=C=O)C1C=CC=C1
Reaction time: 96 h
Yield: 108.1 %

Procedure:
Acryloyl chloride (9 grams), methyl(α-hydroxyethyl)-cyclopentadienyltricarbonylmanganese (13.1 grams), and triethylamine (10.1 grams) were dissolved in 200 ml dichloromethane under a nitrogen atmosphere. A 0.1 gram sample of N,N-dimethylaminopyridine (DMAP) was added as a catalyst. For 4 days the solution was stirred and protected from light while and a white precipitate slowly formed. The reaction mixture was extracted twice with dilute HCl and the dichloromethane phase was dried with magnesium sulfate. The magnesium sulfate was removed by filtration and the dichloromethane solution was filtered through silica gel to remove a colored impurity. The solution was then rotary evaporated to a yellowish oil that was vacuum dried to give 16.2g (97%) of methyl(α-acryloylethyl)cyclopentadienyl-tricarbonylmanganese as a mixture of 1,2 and 1,3 isomers.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([CH:13]([OH:20])[CH:14]([N+:17]([O-])=O)[CH2:15][CH3:16])[CH:10]=[CH:9][N:8]=1>[Pd].C1COCC1.CO>[NH2:17][CH:14]([CH2:15][CH3:16])[CH:13]([C:11]1[CH:10]=[CH:9][N:8]=[C:7]([O:6][CH3:5])[CH:12]=1)[OH:20]
Reactant: CCC(C(O)c1ccnc(OC)c1)[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(N)C(O)c1ccnc(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonium formate (2.5 g, 40 mmol) and palladium on charcoal (10%, 390 mg) is added to a solution of 1-(2-methoxypyridin-4-yl)-2-nitrobutan-1-ol (1.7 g, 7.5 mmol) in 38 ml THF and 38 ml methanol. The reaction mixture is stirred overnight at room temperature, filtered through a path of cellites and concentrated. Yield 620 mg of a racemic mixture of two diastereomers, 42%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:28]4[CH:39]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(-c5ccccc5)cccc4n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3cn4c(-c5ccccc5)cccc4n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (551 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (469 mg, yield: 90%). This was recrystallized from ethanol-hexane. Melting point: 160–161° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][C@H:21]([CH3:23])[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:19][C@H:18]1[CH3:32])=[O:16].O1CCCC1.CO.O.[OH-].[Li+]>Cl.O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:20]2[C@@H:21]([CH3:23])[CH2:22][N:17]([C:15](=[O:16])[CH2:14][CH2:13][C:7]3[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=3[O:5][CH2:4][C:3]([OH:33])=[O:2])[C@H:18]([CH3:32])[CH2:19]2)=[CH:30][CH:29]=1
Reactant: COC(=O)COc1cc(C)ccc1CCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(CCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of (2-{3-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-3-oxo-propyl}-5-methyl-phenoxy)-acetic acid methyl ester (0.18 g, 0.40 mmol) in 2:2:1 tetrahydrofuran:methanol:water (5 mL) was added lithium hydroxide hydrate (0.026 g, 0.62 mmol) and the reaction was stirred at ambient temperature for 2 hours. The reaction was diluted with 0.2 M hydrochloric acid, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by trituration in methylene chloride/diethyl ether to give the title compound (0.16 g).
Reaction SMILES: [Br:1]Br.[C:3]([N:7]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[NH:10][C:9](=[O:19])[CH2:8]1)([CH3:6])([CH3:5])[CH3:4].C([O-])(=O)C.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Br:1][C:16]1[CH:17]=[CH:18][C:11]2[NH:10][C:9](=[O:19])[CH2:8][N:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: CC(C)(C)N1CC(=O)Nc2ccccc2C1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)N1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 25 °C
Reaction time: 29 h
Yield: 64.3 %

Procedure:
Bromine (1.72 g, 10.8 mmol) is added to a mixture of 4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.3 mmol) and sodium acetate (0.39 g, 4.8 mmol) in acetic acid. The reaction mixture is stirred at room temperature for 29 hours, concentrated in vacuo, diluted with ethyl acetate, washed sequentially with 0.1N sodium hydroxide solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. Chromatography of the residue using silica gel and 20% to 25% ethyl acetate in hexanes solutions gives the title product as a white solid (0.86 g, mp 205°-208° C.).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][C:9]=1[CH2:10][CH2:11][OH:12])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[S:6][C:5]3[C:3](=[O:2])[O:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1OCCc2cc(-c3ccc(Cl)cc3)sc21
Temperature: 80 °C
Yield: 42.9 %

Procedure:
Dissolve 5-(4-chloro-phenyl)-3-(2-hydroxy-ethyl)-thiophene-2-carboxylic acid methyl ester (3.4 g, 11.46 mmol) in toluene (60 mL) and add p-toluenesulfonic acid monohydrate (0.3 g, 1.58 mmol) and heat to 80° C. for one hour. Cool the mixture to room temperature and dilute with ethyl acetate (50 mL). Wash the solution with 1 N NaOH and extract the aqueous portion twice with ethyl acetate. Combine the organic fractions, dry over Na2SO4, filter, and concentrate. Triturate the solid with ether and then filter and dry under vacuum to give 1.3 g (43%) of the title compound. LC-MS/ES m/z (35Cl) 265.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][N:18]=[C:19]([CH3:21])[CH3:20])=[O:5].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:22])[CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][CH:19]([CH3:20])[CH3:21])=[O:5]
Reactant: CC(C)=NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cc(C)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(NC(=O)c2c(Cl)cccc2Cl)c2nccc(NNC(C)C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.2 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-6-methyl-4-(2-isopropylidenehydrazino)quinoline (159 mg) in methanol (5 ml) was added sodium cyanoborohydride (25 mg) and acetic acid (50 mg), and the mixture was stirred at ambient temperature for 24 hours. The mixture was concentrated to dryness and the residue was triturated with water (5 ml) and filtered. The solid was treated with hot water (5 ml), allowed to cool to ambient temperature, filtered and washed with water to give 8-(2,6-dichlorobenzoylamino)-6-methyl-4-(2-isopropylhydrazino)quinoline (117 mg) as pale yellow powder.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[O-]
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 95 %

Procedure:
Potassium t-butoxide (1.05 g, 9.37 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2, 5-thiadiazolidin-3-one 1,1-dioxide (2.4 g, 8.95 mmol) in 25 ml of THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added methyl iodide (6.35 g, 44.73 mmol) and the resulting mixture was allowed to stir at 0° C. for 0.5 hour and at room temperature for 4 hours. The resulting mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 2.4 g (95%) of 2-phenylmethyl-4-propyl-5-methyl-1,2,5-thiadiazol-idin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =propyl; R3 =CH3) as an oil.
Reaction SMILES: CN([Si:9]([CH3:12])([CH3:11])[CH3:10])C(=O)C(F)(F)F.[C:13]([NH:21][CH:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([OH:33])=[O:32])=[C:26]([CH3:30])[CH2:27][S:28](=[O:29])[C@H:23]12)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.NS(O)(=O)=O.[Br:41]N1C(=O)CCC1=O>ClCCl>[C:13]([NH:21][CH:22]1[C:34](=[O:35])[N:24]2[C:25]([C:31]([O:33][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:32])=[C:26]([CH2:30][Br:41])[CH2:27][S:28](=[O:29])[C@H:23]12)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
324 mg (1.63 mmoles) of N-methyl-N-trimethylsilyltrifluoroacetamide were added to a suspension of 409 mg (1.22 mmoles) of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 25 ml of dichloromethane and after stirring at room temperature for 10 minutes, a clear, slightly yellow solution was obtained. This was diluted to 40 ml with dicloromethane and 50 mg of amidosulfonic acid (0.51 mmole) were added. This solution was cooled in an ice-bath and was brominated in one hour with 301 mg (1.70 mmoles) of N-bromosuccinimide to obtain a yield of 59% of trimethylsilyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[N:19][CH:20]=1.O[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][C:31]([O:33][CH3:34])=[O:32].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][O:22][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:18]=[N:19][CH:20]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccccc1OCc1cncc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 15 h
Yield: 61 %

Procedure:
To a mixture of [5-(5-methyl-2-phenyl-4-oxazolyl)methoxy-3-pyridyl]methanol (1.50 g), methyl 2-(2-hydroxyphenyl)acetate (0.76 g), triphenylphosphine (1.44 g) and tetrahydrofuran (50 mL) was dropwise added a solution (40%, 2.39 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give crude crystals from a fraction eluted with ethyl acetate-hexane (1:1, v/v) which crude crystals were further subjected to silica gel column chromatography to give crystals (1.24 g, 61%) of methyl 2-[2-[[5-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-3-pyridyl]methoxy]phenyl]acetate from a fraction eluted with tetrahydrofuran-hexane (3:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 77-78° C.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([O:33]C)=[O:32])=[CH:23]2.O[CH2:39][CH2:40][CH2:41][NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=1[NH:42][CH2:41][CH2:40][CH2:39][O:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][CH2:36][CH3:37])[C:31]([OH:33])=[O:32])=[CH:23]2
Reactant: OCCCNc1ccccn1
Reactant: CCCC(Cc1cc2cc(O)ccc2[nH]1)C(=O)OC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.12 g, 0.48 mmol) was added to the solution of methyl 2-[(5-hydroxyindolyl)methyl]pentanoate (0.03 g, 0.12 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.026 g, 0.17 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.09 g, 0.46 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%-50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.016 g, 36%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (m, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 7.02 (d, J=3.3 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.53 (m, 1H), 6.40 (m, 2H), 4.32 (br s, 1H), 4.42 (m, 1H), 4.25 (m, 3H), 3.52 (m, 5H), 2.91 (m, 1H), 2.20 (m, 2H), 1.72 (m, 2H), 1.43 (m, 3H), 0.95 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27](CCl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:32]N(C=O)C>>[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[C:13]([CH3:32])[C:7]=3[N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCCCc1nc2ccccc2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCc1nc2c(C)cccc2n1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.42 h
Yield: 96 %

Procedure:
A suspension of 1.50 g (8.62 mmol) of 2-butylbenzimidazole (described in European Patent Application #400,835, May 12, 1990) and NaH (272 mg, 1.05 eq) in DMF (20 mL) was stirred 25 minutes. Next, 4-benzyloxybenzyl chloride (2.10 g, 1.05 eq) was added to the reaction mixture. After stirring overnight, the reaction mixture was concentrated in vacuo and the residue was chromatographed on a medium pressure liquid chromatograph eluted with 30% ethyl acetate/hexane to yield 3.08 g (96%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CCc1cc(Br)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a mixture of 26 g of 4-bromo-2-ethyl-6-methylphenol, 24.8 g of benzyl bromide and 200 ml of N,N-dimethylformamide was added 21.7 g of potassium carbonate, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was poured into ice water, and extracted twice with 500 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 35.6 g of 4-bromo-2-ethyl-6-methyl-1-benzyloxybenzene (97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1
Reactant: Oc1cccc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(Cl)c2)cc1
Yield: 95 %

Procedure:
3-Chlorophenol (0.52 g, 4 mmol), 4-fluorobenzaldehyde (0.50 g, 4 mmol), and potassium carbonate (0.56 g, 4 mmol) were stirred in DMF (5 mL) at 80° C. for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over Na2SO4, filtered and evaporated to give the title compound in 95% yield. 1H NMR (CDCl3, 300 MHz) δ 6.95-7.40 (m, 9H), 7.85-8.31 (m, 4H), 9.94 (s, 1H). MS m/e 233 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:28][C:11]3=[N:12][C:13]([N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])=[C:14]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH:15]=[C:10]3[C:9]=2[C:29](=[O:32])[NH:30][CH3:31])=[CH:4][CH:3]=1.C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[NH4+]>CN(C=O)C>[NH2:34][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][C:14]1[CH:15]=[C:10]2[C:9]([C:29]([NH:30][CH3:31])=[O:32])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[O:28][C:11]2=[N:12][C:13]=1[N:22]([CH3:27])[S:23]([CH3:26])(=[O:24])=[O:25]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCC(=O)O)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(CCCC(N)=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido) furo[2,3-b]pyridin-5-yl)butanoic acid (2.0 mg) in DMF (0.25 ml) is added HATU (3.3 mg). Stirred at rt for 10 min. Ammonium hydroxide (28% in water, 0.018 ml) is added and the mixture is stirred at rt for 30 min and purified by preparative HPLC to afford the title compound (M+H)+=463.1; Retention time=1.10 min, Method A. 1H NMR (400 MHz, DMSO) δ ppm 8.54 (br s, 1H), 8.09 (m, 1H), 8.06-7.97 (m, 2H), 7.53-7.47 (m, 2H), 7.27 (br s, 1H), 6.76 (br s, 1H), 3.21 (s, 3H), 3.19 (s, 3H), 2.86 (s, 3H), 2.84-2.77 (m, 2H), 2.13-2.08 (m, 2H), 1.91-1.81 (m, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[OH:14].[CH3:15][C:16](OC(C)=O)=[O:17]>N1C=CC=CC=1>[OH:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:14][C:16](=[O:17])[CH3:15])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2ncnc(O)c2cc1O
Solvent: c1ccncc1
Product: COc1cc2ncnc(O)c2cc1OC(C)=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 7-Methoxy-quinazoline-4,6-diol (6.2 g, 32.3 mmol), Ac2O (100 mL) and pyridine (10 mL) was heat to 100° C., and stirred for 3 hours. The reaction was then cooled to room temperature and poured to ice water (300 mL). The product was isolated by filtration, washed with water (200 mL) and dried to give 7.61 g (32.4 mmol, 100%) of desired product.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C@H:10]1[C@H:15]([F:16])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[F:16][C@@H:15]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[NH:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: [H][H]
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1F)OCC
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1F)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.3 %

Procedure:
A mixture of trans-benzyl 3-(diethoxyphosphorylamino)-4-fluoropiperidine-1-carboxylate (0.54 g, 1.4 mmol) and 10% Pd/C (0.074 g, 0.070 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 6 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-fluoropiperidin-3-ylphosphoramidate (0.35 g, 99%) as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[O:6][C:7]3[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@H:16](C(=O)C5C=CC=CC=5)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.[OH-:34].[Na+]>CO>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]2[O:6][C:7]3[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][C@H:16]([OH:34])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: O=C(c1ccccc1)[C@@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 8-chloro-11-[(6S,8R)-8-benzoyl-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-oxazepine in methanol (5 mL) was added 1% aqueous sodium hydroxide. The reaction was stirred for 1 hour and the solvent removed under reduced pressure. The residue was dissolved in methylene chloride and washed with water, dried (MgSO4) and evaporated to dryness to give 3.5 mg (31%) of 8-chloro-11-[(6S,8R)-8-hydroxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenz[b,f]-1,4-oxazepine as an off-white solid; mp 90°-92° C.; Rf(50% acetone/hexanes): 0.20; HRMS (FAB): MH+ of C20H20 N3O2Cl, calculated 370.1322, found 370.1327.