Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:27])[C@@H:19]([CH2:28][CH2:29][OH:30])[O:18][C@H:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:16]=2[CH:38]=1>ClCCl.O.C(N(CC)CC)C>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:27])[C@@H:19]([CH2:28][CH:29]=[O:30])[O:18][C@H:17]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[C:16]=2[CH:38]=1
Reactant: CC(C)(C)CN1C(=O)[C@@H](CCO)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)CN1C(=O)[C@@H](CC=O)O[C@H](c2ccccc2Cl)c2cc(Cl)ccc21
Reaction time: 0.08 h
Yield: 64.2 %

Procedure:
To 25 ml of dichloromethane solution containing 0.70 ml of oxalyl chloride was added 5 ml of dichloromethane solution containing 0.71 ml of dimethylsulfoxide at -78° C., followed by stirring for 5 minutes. To the solution was slowly added 10 ml of dichloromethane solution containing 1.69 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-ethanol obtained in Example 160, followed by stirring for 15 minutes at -78° C. To the reaction mixture was added 2.79 ml of triethylamine and the mixture was further stirred for one hour at 0° C. and for 1.5 hours at room temperature. After the addition of 100 ml of water, extraction was performed with 100 ml of dichloromethane. The dichloromethane layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure. The residue was purified by column chromatography using silica gel (eluent, hexane:ethyl acetate=1:1) to give 1.08 g of trans-7-chloro-5-(2-chlorophenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetaldehyde as light-yellow crystals, m.p. 173° to 176° C.
Reaction SMILES: [C:1]1([CH2:11][C:12](O)=[O:13])([CH2:7][C:8](O)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O.C(OCC)C>[OH:9][CH2:8][CH2:7][C:1]1([CH2:11][CH2:12][OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: OCCC1(CCO)CCCCC1
Yield: 93.6 %

Procedure:
To a solution of 1,1,-cyclohexanediacetic acid (6.0 g) in tetrahydrofuran (90 mL) was added lithium aluminum hydride (2.28 g) under ice cooling. The solution was stirred under reflux for 4 hours, and then, cooled on ice, to which diethyl ether (200 mL), water (2.3 mL) and a 15% aqueous sodium hydroxide solution (2.3 mL) were added. After stirring the solution at room temperature for 30 minutes, water (6.9 mL) was added and the solution was stirred at room temperature for additional 30 minutes. Anhydrous magnesium sulfate was added to the solution, and it was filtered under reduced pressure. The filtrate was concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, ethyl acetate) to give the title compound (4.83 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16]Cl>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccc(C=O)cc1

Procedure:
A stirred solution of 61.0 g (0.50 mole) of 4-hydroxybenzaldehyde in 400 ml of dimethylformamide (nitrogen atmosphere) is gradually treated with 24.0 g of 50% NaH. The temperature is kept below 35° using an ice water bath. When the addition is completed, the thick mixture is heated to 70° several minutes, then cooled to 35° before the addition of 417 ml of 1.8N (0.75 mole) of 3-dimethylaminopropyl chloride in toluene.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Fluoro-3-nitro-aniline (54.2 g, 0.347 mol) was added in portions to acetic anhydride (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. The brown solid was collected and dried in vacuo to give the title compound. Yield: 67.5 g (98%). 1H NMR (400 MHz, CHLOROFORM-D) δ 2.04 (s, 3 H), 7.51 (dd, J=11.23, 9.08 Hz, 1 H), 7.80 (ddd, J=9.08, 4.00, 2.93 Hz, 1 H), 8.47 (dd, J=7.03, 2.73 Hz, 1 H), 10.38 (s, 1 H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([OH:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4].Cl[C:18]1[C:19]2[C:26]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:3]([O:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([O:15][C:18]1[C:19]2[C:26]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[O:24][C:20]=2[N:21]=[CH:22][N:23]=1)[CH3:14])([CH3:4])([CH3:6])[CH3:5]
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Reactant: C[C@@H](O)CCCCC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@H](C)CCCCC(=O)OC(C)(C)C)c23)cc1

Procedure:
Add 87 mg (2.16 mmol) sodium hydride (60% dispersion in mineral oil) to a solution of 350 mg (1.73 mmol) (6R)-6-hydroxyheptanoic acid tert.-butyl ester in 5 ml THF, with ice cooling. After stirring for ten minutes with ice cooling, add a solution of 644 mg (1.82 mmol) 4-chloro-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 5 ml THF and 32 mg (0.09 mmol) tetra-n-butylammonium iodide. Stir the reaction mixture for 48 h at RT. After adding water and ethyl acetate, wash the separated organic phase with 1 N hydrochloric acid and concentrate by vacuum evaporation. Take up the residue in acetonitrile/DMSO and purify by preparative RP-HPLC (gradient: water/acetonitrile). 425 mg (47% of theor.) of the desired product is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([O:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:25]([O:27][CH2:28][CH:29]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26].Cl>O1CCOCC1.O>[CH:40]1[C:41]2[CH:29]([CH2:28][O:27][C:25]([N:13]3[CH2:12][C:11]4([CH2:10][CH2:9][N:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)[CH2:18][CH2:17]4)[O:16][CH2:15][CH2:14]3)=[O:26])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:36]=2[CH:37]=[CH:38][CH:39]=1
Reactant: c1ccc(CN2CCC3(CC2)CNCCO3)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCOC2(CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
To a solution of compound 402 (2.81 g, 11.4 mmol) in 1,4-dioxane (53 mL) was added 10% sodium bicarbonate in water (21.5 mL) followed by 9-fluorenylmethyl chloroformate (2.96 g, 11.4 mmol). The resulting mixture was stirred at room temperature for four hours, and then neutralized with 3N HCl. The solution was concentrated to a solid and then purified by flash chromatography (0-10% methanol in DCM with 1% NH4OH) to give compound 403 as a white solid (1.2 g, 22.5%). LCMS-ESI (POS), M/Z, M+1: Found 469.1, Calculated 469.2.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:32])([F:31])[C:16]1[CH:30]=[CH:29][C:19]([O:20][C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]3[CH:29]=[CH:30][C:16]([C:15]([F:14])([F:31])[F:32])=[CH:17][CH:18]=3)=[CH:28][CH:27]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Oc2ccc(CBr)cc2)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)n1ncc(SCc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)c(Cl)c1=O
Yield: 85.5 %

Procedure:
In 30 ml of N,N-dimethylformamide were dissolved 2.2 g (0.01 mol) of 2-tert.-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 3.5 g (0.0105 mol) of 4-(4'-trifluoromethylphenoxy) benzyl bromide, and thereto was added 2.1 g (0.02 mol) of anhydrous sodium carbonate to effect reaction at 85° to 90° C. for 4 hours. After the reaction, the reaction liquid was allowed to cool, poured into water and then extracted with benzene. The benzene layer was washed with 5% aqueous solution of sodium hydroxide and then with water, dried over anhydrous sodium sulfate and then freed of benzene by distillation under reduced pressure. The oily residue was incorporated with n-hexane and the precipitated crystals were filtered off to obtain white crystals (yield: 85.5%).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.O[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:4]1[CH2:5][CH2:6][CH:2]([O:1][C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: OC1CCOC1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OC2CCOC2)cc1
Reaction time: 2 h
Yield: 88 %

Procedure:
In 30 ml of tetrahydrofuran were dissolved 3 g of 3-hydroxytetrahydrofuran, 6.5 g of methyl 2-(4-hydroxyphenyl)-2-oxoacetate and 9 g of triphenylphosphine. The thus prepared solution was mixed with 6.5 g of diethyl azodicarboxylate, and the mixture was stirred for 2 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using dichloromethane as an eluant, thereby obtaining 7.5 g of methyl 2-[4-[(tetrahydro-3-furanyl)oxy]phenyl]-2-oxoacetate in an oily form.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23]([C:25]1([NH2:34])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])[CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1([NH:34][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1CCCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (500 mg, 2.84 mmol) in DCM (10 mL) is added oxalyl chloride (0.50 mL, 5.68 mmol) dropwise. The resulting solution is stirred at RT for 2 h. After the removal of DCM and excess oxalyl chloride, the residue, 2-amino-indan-2-carboxylic acid ethyl ester (583 mg, 2.84 mmol) and DIPEA (1.88 mL, 11.3 mmol) are dissolved in DCM (20 mL). The resulting solution is stirred overnight. The reaction solution is diluted with DCM (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give the pure product (37) as white solid (610 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C>>[Cl:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34][C:35]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:36]
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)c1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Agent: CCN=C=NCCCN(C)C
Product: NC(=O)c1ccc2[nH]nc(-c3cccc(NC(=O)Cc4ccc(F)cc4Cl)c3)c2c1
Yield: 16 %

Procedure:
Following Example 290, the reaction of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxamide (200 mg, 0.56 mmol) with 2-chloro-4-fluorophenylacetic acid (0.13 g, 0.71 mmol) and EDCI (0.17 g, 0.89 mmol) furnished 38 mg (14% yield) of the title compound. 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.6 (s, 1H), 8.1 (br s, 1H), 7.9 (dd, 1H), 7.75 (m, 2H), 7.65 (d, 1H), 7.52-7.4 (m, 3H), 7.35 (s, 1H), 7.2 (m, 1H), 3.9 (s, 2H); ES-MS (m/z) 423 [M]+.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CCCNC(=N)N[N+]([O-])=O.S1C=CC=C1CN.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:52][C:53](=[N:76][N+:77]([O-:79])=[O:78])[NH:54][CH2:55][CH2:56][CH2:57][C@H:58]([C:67]([NH:69][CH2:70][C:71]1[S:72][CH:73]=[CH:74][CH:75]=1)=[O:68])[NH:59]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>>[NH2:52][C:53](=[N:76][N+:77]([O-:79])=[O:78])[NH:54][CH2:55][CH2:56][CH2:57][C@H:58]([C:67]([NH:69][CH2:70][C:71]1[S:72][CH:73]=[CH:74][CH:75]=1)=[O:68])[NH2:59]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(N)=N[N+](=O)[O-])C(=O)NCc1cccs1
Agent: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: NC(=N[N+](=O)[O-])NCCC[C@@H](N)C(=O)NCc1cccs1

Procedure:
First of all Boc-Arg(NO2)-OH was reacted with thiophene-2-methanamine and TBTU as in Example 8a). The resulting (R)-N5 -[amino(nitroimino)methyl]-N2 -[(tert.-butyloxy)carbonyl]-N-[(2-thienyl)methyl]-ornithinamide was then reacted, without purification, with trifluoroacetic acid as in Example 23b). The crude product obtained in a quantitative yield was further processed without purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.N1[C:25]2[C:16](=[CH:17][CH:18]=[C:19]3[C:24]=2N=CC=C3)C=CC=1.C(=CC(/C=C/C1C=CC=CC=1)=O)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].IC1C=CC=CC=1>C1(C)C(C)=CC=CC=1.ClCCl.[Cl-].[NH4+]>[C:16]1([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=3)[CH:3]=[CH:2]2)[CH:25]=[CH:24][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccc2cc[nH]c2c1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: O=C(C=Cc1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Cc1ccccc1C
Solvent: Ic1ccccc1
Product: O=Cc1ccc2ccn(-c3ccccc3)c2c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
Combine in a sealed tube 1H-indole-6-carbaldehyde 0.9 g, 6.2 mmol), copper(I) trifluoromethanesulfate-complex (0.2 g, 0.3 mmol), phenanthroline (1.3 g, 6.2 mmol), transdibenzylidenacetone (0.1 g, 0.3 mmol), cesium carbonate (2.6 g, 7.9 mmol) and iodobenzene (1.6 ml, 14.3 mmol) in xylene (40 ml). Heat at about 110° C. After 24 hours, cool to room temperature, dilute with dichloromethane and saturated ammonium chloride. Separate the layer and Extract the aqueous layer with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrated to give a residue. Chromatograph the residue eluting with 8:2 hexane:EtOAc to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([F:12])([F:11])[C:9](=[O:13])[NH:8][C:5]2=[N:6][CH:7]=1.[C:14]([O:18][C:19](=[O:26])[NH:20][C@H:21]1[CH2:24][C@@H:23](O)[CH2:22]1)([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(=O)(O)[O-].[Na+]>[C:14]([O:18][C:19](=[O:26])[NH:20][C@H:21]1[CH2:22][C@H:23]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[C:10]([F:12])([F:11])[C:9]2=[O:13])[CH2:24]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=C1Nc2ncc(Br)cc2C1(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(F)(F)c3cc(Br)cnc32)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
5-Bromo-3,3-difluoro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (1.19 g, 4.78 mmol), tert-butyl(cis-3-hydroxycyclobutyl)carbamate (0.895 g, 4.78 mmol), and triphenylphosphine (1.88 g, 7.17 mmol) were mixed in THF (18 mL) under an argon atmosphere. The mixture was cooled to 0° C. before diisopropyl azodicarboxylate (1.409 mL, 7.17 mmol) was added dropwise via syringe. The reaction mixture was warmed to room temperature and stirred for 19 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified via silica gel column chromatography eluting with EtOAc in hexanes to yield the title compound (0.477 g, 1.141 mmol, 23.9% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[O:28]1[CH2:33][CH2:32][CH:31]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:30][CH2:29]1
Reactant: O=C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(C4CCOCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and tetrahydro-4H-pyran-4-one (0.06 g) dissolved in 1,2-dichloroethane (7 ml) was added under ice cooling sodium triacetoxyborohydride (0.13 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-(tetrahydropyran-4-yl)piperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 56) (0.13 g) as colorless prisms.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C.Cl>ClCCl>[CH3:11][O:12][C:13]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]=[O:22])[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@H](C=O)CC1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a solution of dimethylsulfoxide (9.53 g, 122 mmol) in dry dichloromethane (400 ml) was slowly added oxalyl chloride (7.74 g, 61.0 mmol) at −78° C. The cooling bath was removed and the reaction mixture was stirred at −50° C. for 5 min. A solution of trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (8.75 g, 50.8 mmol) in dichloromethane (108 ml) was added at −65° C. Stirring for 30 minutes was followed by addition of triethylamine (25.7 g, 254 mmol). The cooling bath was removed 15 minutes after completed addition. The reaction mixture was quenched with 1 M aqueous hydrochloric acid solution (152 ml, 152 mmol) at −10° C. The layer were separated. The organic layer was washed with two 250 ml-portions of water and one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as yellow oil (9.3 g, quantitative), which was used in the next step without further purification.
Reaction SMILES: C(O)=O.C(N(CC)CC)C.ClCCl.[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH2:18][C:19]2=[O:24]>O>[Br:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][CH2:18][C@@H:19]2[OH:24]
Reactant: O=C1CCc2c(Br)cccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O[C@H]1CCc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To a mixture of formic acid (1.20 mL, 31.5 mmol) and triethylamine (3.76 mL, 27.0 mmol), a dichloromethane (6.0 mL) solution of 4-bromoindan-1-one (1.90 g, 9.00 mmol) was added, and chloro[(1S,2S)—N-(p-toluenesulfonyl)-1,2-diphenyl ethanediamine](mesitylene)ruthenium(II) (168 mg, 0.270 mmol) was added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. Water was added to the reaction solution, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, then dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=95:5 to 65:35 (v/v)), whereby the objective title compound was obtained as a white solid (1.90 g, yield: 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([NH:13][OH:14])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N:19]=[C:20]=[O:21])(C)C.CO>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([N:13]([OH:14])[C:20]([NH2:19])=[O:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ON[C@H]1CC[C@@H](c2cccc(F)c2)C1
Reactant: C[Si](C)(C)N=C=O
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)N(O)[C@H]1CC[C@@H](c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
To a stirred solution of the compound prepared in Step 6, above (2.4 g, 12 mmol), in THF (10 ml) was added trimethylsilylisocyanate (85%, 2.4 ml, 18 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. Methanol (10 ml) was added and 10 minutes later the solvent was removed under reduced pressure to afford a white solid. Recrystallization from IPE/hexane afforded the title compound (1.6 g, 57% yield) as a colorless solid, m.p. 104.2-105.7° C.