Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.CCCCCC.C(OCC)(=O)C>CS(C)=O>[CH3:8][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: Cc1ccccc1O
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccccc1Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of o-cresol (5.4 g, 50.7 mmol) in DMSO (10 mL) was added dropwise to a stirred mixture of 60% oil dispersion sodium hydride (2.02 g, 50.5 mmol) in DMSO (20 mL). After stirring for 1 hour at ambient temperature, a solution of p-fluorobenzaldehyde (5.36 mL, 50 mmol) in DMSO (10 mL) was added dropwise. After the addition was complete, the reaction mixture was gradually heated to 140-160° C. and maintained at that temperature for 1 hour. The reaction mixture was poured into ice-water and extracted with ether. The combined organic extracts were washed successively with ice-cold dilute aqueous sodium hydroxide solution, dilute aqueous hydrochloric acid solution, water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to give a brown liquid. Chromatography on silica gel eluting with 95:5 hexane-ethyl acetate afforded 6.1 g (51%).of the title compound. 1H NMR (CDCl3, 300MHz) δ 2.19 (s, 3H), 6.98 (m, 3H), 7.2 (m, 3H), 7.82 (m, 2H), 9.9 (s, 1H). MS (DCl/NH3) m/e 213 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(O)[CH2:10][CH3:11])=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH3:11])=[CH:18][CH:17]=1
Reactant: CCC(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Yield: 97.4 %

Procedure:
Into a reactor were introduced 2.86 g (10.5 mmol) of the 1,1-bis(4-methoxyphenyl)propanol, 40 mL of toluene, and 28 mg of p-toluenesulfonic acid monohydrate under a nitrogen atmosphere. Azeotropic dehydration was conducted for 2 hours with toluene refluxing. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, subsequently dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 2.60 g (97%) of the target compound as light-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1COCC1.[Br:17][C:18]([CH3:23])([CH3:22])[C:19](Br)=[O:20]>CCN(CC)CC>[Br:17][C:18]([CH3:23])([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11])=[O:20]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)Nc1cc([N+](=O)[O-])ccc1O
Reaction time: 0.75 h

Procedure:
2-Amino-4-nitro-phenol (3.08 g, Aldrich) was stirred with THF (30 ml, Aldrich) in an ice bath. 2-Bromo-2-methyl-propionyl bromide (2.47 ml, Aldrich) and Et3N (2.0 g, Aldrich) was slowly added via syringe. The mixture was stirred for 45 min then poured into ice. The aqueous phase was extracted by EtOAc (50 mL×4). The organic layer was dried and concentrated. The desired product was crystallized from EtOAc. (Chem. Pharm. Bull 1996, 44(1) 103–114).
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:19].Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[S:28]1[C:24]2[CH:23]=[C:22]([CH2:21][NH:1][C:2]3[C:12]4[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=4[CH:5]=[CH:4][C:3]=3[Cl:19])[CH:30]=[CH:29][C:25]=2[N:26]=[CH:27]1
Reactant: Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: BrCc1ccc2ncsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc4ncsc4c3)c2CC1)C(F)(F)F
Temperature: 150 °C

Procedure:
Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.1 g, 0.35 mmol), 6-bromomethyl-benzothiazole (80 mg, 0.35 mmol), and potassium carbonate (47.0 mg, 0.35 mmol) in anhydrous DMF (1 mL) in a sealed tube. Heat at 150° C. for 3 h to obtain 6-[(benzothiazol-6-yl-methyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1([C:15]([NH:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:19]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:1][C:2]3([C:15]([NH:17][CH3:18])=[O:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]3)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CNC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CNC(=O)C1(NCc2ccc3c(c2)OCCO3)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5 mL of a dichloromethane solution containing 0.30 g of tert-butyl 4-amino-4-((methylamino)carbonyl)piperidine-1-carboxylate, 0.16 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 57 μL of acetic acid were added, the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 0.32 g of sodium triacetoxyborohydride and stirred at the same temperature for 30 minutes. Thereto were added chloroform and an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to obtain 0.31 g of a pale yellow oily substance, tert-butyl 4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)-4-((methylamino)carbonyl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH:9]([N-]C(C)C)(C)C.[Li+].[C:17](=O)([O:26]CC1C=CC=CC=1)[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[CH2:19]([O:18][C:17]([CH:4]1[CH2:3][C:2]([CH3:8])([CH3:1])[N:6]([CH3:9])[C:5]1=[O:7])=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)[N-]C(C)C
Reactant: CC1(C)CCC(=O)N1
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1C(=O)C(C(=O)OCc2ccccc2)CC1(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
In a flame-dried 50 ml three necked flask under argon atmosphere were dissolved 1.27 g (10.0 mmol) of 5,5-dimethylpyrrolidin-2-one in 10 ml of dry THF. After cooling to −75° C., a 2 M solution of lithium diisopropylamide in THF (10.5 ml, 10.5 mmol) was added dropwise maintaining the temperature below −73° C. The solution was stirred for 1 h at −75° C. Then a solution of dibenzyl carbonate (2.72 g, 11.0 mmol) in 5 ml of THF was added dropwise at −75° C., allowed to warm up to r.t. and stirred for 1 h. The reaction was quenched by addition of 5 ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue was loaded onto a 50 g prepacked flash chromatography column. After elution with a 10% to 70% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 1.07 g (41%) of the title compound as a light yellow oil, MS: m/e=262.2 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(C(c3ccccc3)c3ccccc3)C2)nc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a stirred solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (330 mg) in dimethylformamide (6 mL) was added potassium carbonate (158 mg) and 1,1′-(bromomethylene)dibenzene (225 mg), and the mixture was stirred at 60° C. for 2 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (hexane:ethyl acetate=4:1 then chloroform:methanol 20:1) to give ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-(diphenylmethyl)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate (210 mg) as an oil.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].C1COCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 65 °C

Procedure:
A mixture of tert-butyl 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (0.56 g, 1.6 mmol), ammonium acetate (1.0 g, 20 mmol) and 1.0 M sodium cyanoborohydride in THF (4.0 mL, 4.0 mmol) in methanol (4 mL)/acetonitrile (4 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane. The organic extracts were dried over MgSO4 and concentrated to give the crude product, which was used in the next step without further purifications. LCMS calculated for C18H27ClN2O3Na (M+Na)+: m/z=377.2. found: 377.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3C=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=1.B([C:30]1[CH:41]=[CH:40][C:33]([CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[NH2:36])=[CH:32][CH:31]=1)(O)O.C(#[N:44])C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:36][C@@H:35]([CH2:34][C:33]1[CH:40]=[CH:41][C:30]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:21]=[CH:22][N:23]=[CH:24][N:44]=4)=[CH:16][CH:15]=3)[C:10]([F:12])([F:13])[F:11])[N:5]=[C:4]([NH2:26])[N:3]=2)=[CH:31][CH:32]=1)[C:37]([OH:39])=[O:38]
Reactant: CC#N
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3ccncc3)cc2)C(F)(F)F)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(OC(c2ccc(-c3ccncn3)cc2)C(F)(F)F)cc(-c2ccc(C[C@H](N)C(=O)O)cc2)n1
Temperature: 150 °C

Procedure:
In a microwave vial, 4-chloro-6-[2,2,2-trifluoro-1-(4-pyridin-4-yl-phenyl)-ethoxy]-pyrimidin-2-ylamine (30 mg, 0.080 mmol), 4-borono-L-phenylalanine (21 mg, 0.098 mmol) and 1 ml of actonitrile, and 0.7 ml of water were mixed together. Then, 0.3 ml of 1N aqueous sodium carbonate was added to mixture, followed by 5 mole percent of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, and then was purified by Prep-LC to give 6.7 mg of (S)-2-Amino-3-(4-{2-amino-6-[2,2,2-trifluro-1-(4-pyrimidin-4-yl-phenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (400 MHz, CD3OD) δ (ppm) 8.82 (s, 2H), 8.26 (s, 2H), 8.02 (d, J=8 Hz, 2H), 7.97(d, J=8.4 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 7.45 (d, J=8 Hz 2H), 6.89(q, J=6.8 Hz, 1H), 6.81(d, J=2 Hz,1H), 4.29(t, J=1.6 Hz, 1H), 3.39(m, 1H), 3.19(m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[C:20]([N:25]=[C:26]=[O:27])(=[O:24])[C:21]([CH3:23])=[CH2:22]>ClCCCl>[C:20]([NH:25][C:26](=[O:27])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: C=C(C)C(=O)N=C=O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: C=C(C)C(=O)NC(=O)Oc1ccc(C(=O)c2ccccc2)cc1
Yield: 100.2 %

Procedure:
Into a three-necked flask purged with nitrogen gas, p-hydroxybenzophenone (1.98 g; 10 mmol) was charged, and chloroform (10 ml) was added thereto. To the resultant solution, a solution of methacryloyl isocyanate (1.11 g; 10 mmol) in 1,2-dichloroethane (5 ml) was dropwise added in 5 minutes under nitrogen stream while stirring. Chloroform and 1,2-dichloroethane were removed by evaporation under reduced pressure to give p-benzoylphenyl N-methacryloylcarbamate (3.1 g), which was recrystallized from a mixture of benzene and chloroform to give white granules. M.P., 96°-97° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl quinoxaline-6-carboxylate (500 mg, 2.66 mmol) in 10 mL of THF was added sodium hydroxide (5N, 2.5 mL, 12.5 mmol) followed by methanol (2.5 mL). The reaction was stirred at room temperature overnight and then concentrated in vacuo to remove THF/MeOH. The resulting aqueous mixture was acidified with 1N HCl until the pH was slightly acidic (pH=5). The resulting solution was extracted with EtOAc (3×), and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting white solid was used without further purification. LC-MS: 3.50 min. (M+H)=175.16.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:16]2[CH2:17][CH2:18][C:5]3([O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[N:9]4[CH:1]=[CH:2][CH:3]=[C:4]34)[CH2:14][CH2:15]2)=[O:25])=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)c(C(F)(F)F)c1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (100 mg, 0.361 mmol), 4-fluoro-3-(trifluoromethyl)benzoic acid (75.2 mg, 0.361 mmol), and triethylamine (110 mg, 151 μL, 1.08 mmol) were combined in DMF (3 mL) and HATU (137 mg, 0.361 mmol) was added. The reaction was stirred at room temperature for 1 h and was concentrated. The residue was purified by column chromatography (silica gel: 0-50% ethyl acetate in hexanes) to give (4-fluoro-3-(trifluoromethyl)phenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone (113 mg, 73%). ESI-MS m/z calc. 430.1. found 431.1 (M+1)+; Retention time: 2.24 minutes (4 min run).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:19])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([NH:1][CH2:2][C@H:3]([OH:19])[CH2:4][O:5][C:6]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NCC(O)COc1cccc2[nH]c3ccccc3c12
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c5ccccc5c34)CC2)cc1

Procedure:
The title compound was prepared from 1-amino-3-(9H-carbazol-4-yloxy)-propan-2-ol and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 166-179° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.79 (t, 3H), 1.15-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.64 (t, 2H), 2.60-3.00 (m, 5H), 3.60-4.20 (m, 5H), 6.69 (d, 1H), 6.80-7.60 (m, 7H), 7.90 (s, 1H), 8.20 (d, 2H), 11.35 (s, 1H); MS (ES) m/z: 551.1 (MH+); HRMS Calcd. for C30H39N4O4S (MH+): 551.2692. Found: 551.2664.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C(OCC)(=O)C>O1CCCC1.C([Li])CCC>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][O:2]2)[OH:24])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: c1ccc2c(c1)COC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OC(C1CCN(Cc2ccccc2)CC1)C1OCc2ccccc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
After dissolving 591 mg of 1,3-dihydroisobenzofuran in 10 ml of tetrahydrofuran, 3.9 ml of n-butyllithium (1.5 M, n-hexane solution) was added thereto at −70° C. under a nitrogen atmosphere, the mixture was stirred for 1 hour, and then a solution of 1 g of 1-benzylpiperidine-4-carboxaldehyde in tetrahydrofuran (5 ml) was added dropwise and the mixture was stirred for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Purification was performed by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 597 mg of (1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:9][O:8][B:7]([OH:10])[C:6]=2[CH:11]=1.CN1CCOCC1.[O:19]=[C:20]([CH3:40])[CH2:21][CH2:22][C:23]1[CH:28]=[C:27]([NH:29][C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH:26]=[CH:25][C:24]=1[S:36](Cl)(=[O:38])=[O:37]>CC#N>[F:34][C:31]([F:32])([F:33])[C:30]([NH:29][C:27]1[CH:26]=[CH:25][C:24]([S:36](=[O:37])(=[O:38])[NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:9][O:8][B:7]([OH:10])[C:6]=3[CH:11]=2)=[C:23]([CH2:22][CH2:21][C:20](=[O:19])[CH3:40])[CH:28]=1)=[O:35]
Reactant: CC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1S(=O)(=O)Nc1ccc2c(c1)B(O)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
To a solution of 6-amino-3H-benzo[c][1,2]oxaborol-1-ol (0.37 g, 2 mmol) and NMM (0.76 g, 7 mmol) in CH3CN (50 mL) was added a solution of 2-(3-oxobutyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (0.9 g, 2 mmol) in CH3CN (30 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hrs, then the reaction mixture was concentrated in vacuo, the residue was diluted with water and extracted with EtOAc, the organics was dried over Na2SO4, concentrated to give the crude product, the crude was purified by pre-HPLC (column: Luna 300×50.0 mm, 10 um; liquid phase: [A-H2O+0.05% TFA; B-MeCN] B %: 24%-51%, 23 min) to give 2,2,2-trifluoro-N-(4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)-3-(3-oxobutyl)phenyl)acetamide (0.5 g, yield 42%) as yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:28])[CH3:27])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:27][C:10]1([CH3:28])[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:16]=2)[CH2:11]1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cccc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (380.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (330.0 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=367.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[N:13][OH:14].[O-]CCCC.[K+]>C1COCC1.O.C(OCC)(=O)C>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]2[O:14][N:13]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:3]=2[CH:4]=1
Reactant: ON=C(Nc1ccncc1)c1cc(C(F)(F)F)ccc1F
Agent: CCCC[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccc2onc(Nc3ccncc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Synanti 2-fluoro-5-trifluoromethylphenyl-4-pyridinylamino methanone oxime (10.7 g, 35.8 mmol) was dissolved in THF (400 mL) and potassium butoxide (4.4 g, 1.1 eq) was added in one portion. The reaction was stirred for 6 hours at room temperature under nitrogen. The reaction was diluted with water and ethyl acetate. The organic layer was collected and washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. Trituration with ethyl acetate provided the title compound (7.0 g, 70%). The title compound is recrystallized from methanol, mp >280° C.