Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C([Si](C)(C)[O:7][CH:8]1[CH2:15][CH2:14][CH2:13][CH:12]([NH2:16])[CH2:11][CH2:10][CH2:9]1)(C)(C)C>CC(O)C>[NH2:16][CH:12]1[CH2:13][CH2:14][CH2:15][CH:8]([OH:7])[CH2:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCCC(N)CCC1
Agent: Cl
Solvent: CC(C)O
Product: NC1CCCC(O)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 138.6 %

Procedure:
35 mL of 2N aqueous hydrochloric acid were added to a solution of 3.5 g (13.6 mmol) of 5-(tert-butyl-dimethyl-silanyloxy)-cyclooctylamine (59) in 35 mL 2-propanol and the resulting solution was stirred at room temperature overnight. The isopropanol was removed under reduced pressure and the resulting aqueous solution washed with t-butylmethylether. 2.7 g of crude 5-amino-cyclooctanol (60) was obtained by freeze-drying the aqueous layer as a diastereomeric mixture as hydrochloride which was used without further purification. Rt=0.18 min (Method C). Detected mass: 144.2 (M+H+).
Reaction SMILES: Cl[C:2]([F:32])([F:31])[C:3]1[N:8](N)[CH:7]([C:10]([F:13])([F:12])[F:11])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5](CC2C=CC=CC=2)[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([N:35](CC)CC)C.Cl>C(O)C.[Pd]>[F:31][CH:2]([F:32])[C:3]1[N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([NH2:35])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C1=C(C(F)(F)Cl)N(N)C(C(F)(F)F)C(C(=O)OCC)=C1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reaction time: 18 h

Procedure:
A mixture of 340 g (0.722 mol) of product from Example 99, 87.67 g (0.866 mol) of triethylamine and 10.00 g of 5% Pd/C (50% water coated) in 700 ml of ethanol was hydrogenated at 50° C. under 446 kPa of H2 pressure for 18 hours. Then 150 ml of 18% HCl (0.722 mol) was added, and the mixture was hydrogenated at 50° C. under 446 kPa of H2 pressure for 2 hours. The reaction mixture was filtered through celite, and concentrated in vacuo to remove the ethanol. The resie was taken up in H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concenrated in vacuo to 161.7 g (65%) of a brown oil, 90% pure by GC analysis. Then 5.0 g were purified by HPLC in 5% ethyl acetate/cyclohexane affording 3.9 g of product as a yellow solid; mp 29°-30° C.
Reaction SMILES: Br.[NH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].C1COCC1.C([O-])(O)=O.[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>O>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]([NH:2][C:23](=[O:24])[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:4])=[CH:6][CH:7]=1
Reactant: CC(N)c1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.00 g (22.9 mmol) 4-(1-amino-ethyl)-phenol hydrobromide are added to 10 mL THF and 10 mL H2O before 13.5 g (160 mmol) NaHCO3 are added. Then 3.60 mL (25.2 mmol) benzyl chloroformate are added dropwise and the reaction mixture is stirred at r.t. for 3 h. Afterwards the reaction mixture is quenched by the addition of water and is set to a gentle acidic pH value using citric acid (10% in water). Then the product is extracted with EtOAc, the combined organic layers are dried over MgSO4, filtered and the solvent is removed in vacuo. The crude product is purified by flash chromatography (silica gel, PE/EtOAc).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C.O.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To a mixture of 6-nitro-3,4-dihydroquinolin-2(1H)-one (0.5 g, 2.6 mmol) and Cs2CO3 (1.70 g, 5.2 mmol) in DMF (5 mL) was added ethyl 2-bromoacetate (0.317 mL, 2.86 mmol). After stirring at 65° C. for 3 h, the mixture was diluted with H2O and EtOAc, organic layer was separated, and the aqueous layer was further extracted with EtOAc, organic layers were combined, dried over Na2SO4, and was concentrated in vacuo to provide ethyl 2-(6-nitro-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate, which was used directly for next step.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([OH:19])=O)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([CH2:15][CH2:16][C:17]([N:22]([O:23][CH3:24])[CH3:21])=[O:19])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CNOC
Reactant: O=C(O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
A suspension of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid (3.00 g, 11.53 mmol), N,O-dimethylhydroxyamine hydrochloride (2.25 g, 23.06 mmol), triethylamine (4.0 mL, 28.83 mmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (3.32 g, 17.30 mmol) and 1-hydroxybenzotriazole (2.34 g, 17.30 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water, aqueous sodium hydroxide solution, hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (2.75 g, yield 79%) as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]12.C(N(CC)C1C=CC=CC=1)C.[Cl:36][CH2:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47](O)=[O:48])[N:45]=1)=[O:39]>C(Cl)Cl>[Cl:36][CH2:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:50][O:51][CH3:52])[C:47]([NH:1][CH:2]2[C:23](=[O:24])[N:4]3[C:5]([C:12]([O:14][CH2:15][O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:20])[CH3:21])=[O:13])=[C:6]([CH2:9][O:10][CH3:11])[CH2:7][S:8][C@H:3]23)=[O:48])[N:45]=1)=[O:39]
Reactant: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1csc(NC(=O)CCl)n1
Solvent: ClCCl
Solvent: CCN(CC)c1ccccc1
Product: COCC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Temperature: -5 °C

Procedure:
Meanwhile, 121 mg of pivaloyloxymethyl 7-amino-3-methoxymethyl-3-cephem-4-carboxylate and 141 mg of N,N-diethylaniline were dissolved in 5 ml of methylene chloride and stirred at -5° C. The resulting mixture was added dropwise to the mixture containing 2-(2-chloroacetamidothiazol-4-yl]-2-methoxyiminoacetic acid prepared as described above. The reaction mixture was stirred for 15 minutes and then concentrated by evaporation under reduced pressure. To the residue were added 20 ml of ethyl acetate and 5 ml of water, and the ethyl acetate layer was separated, washed, in turn, with 5 ml of a saturated aqueous solution of sodium bicarbonate, 5 ml of a 5% w/v aqueous solution of hydrogen chloride and 5 ml of a saturated aqueous solution of sodium chloride, and finally dried over anhydrous magnesium sulphate. The drying agent was filtered off and the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel eluted with a 2:1 by volume mixture of ethyl acetate and hexane, to afford 55 mg of pivaloyloxymethyl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22]#[N:23])([CH2:18][CH:19]1[CH2:21][CH2:20]1)[CH3:17])([CH3:12])([CH3:11])[CH3:10]>CCO.O>[C:9]([O:13][C:14](=[O:24])[NH:15][C:16]([C:22](=[NH:23])[NH:7][OH:8])([CH3:17])[CH2:18][CH:19]1[CH2:20][CH2:21]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C#N)(CC1CC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(CC1CC1)C(=N)NO
Temperature: 80 °C
Yield: 65.5 %

Procedure:
Sodium bi carbonate (0.204 g, 2.9 mmol) was dissolved in EtOH (10 mL) and water (10 mL). Hydroxylamine hydrochloride (0.204 g, 2.9 mmol) was added at 25° C. A solution of (cyano-cyclopropylmethyl-methyl-methyl)-carbamic acid tert-butyl ester (3) (0.7 g, 2.67 mmol) in ethanol (5 mL) was added thereto and the resulting reaction mixture was heated at 80° C. for 12 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (30 mL) and then filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography (Combi-Flash, 40 g, 5:95 ethyl acetate/n-hexane) to give the title compound (0.45 g, 65%) as white solid; LC-MS (ELSD peak area, ESI) 100%, 258.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](OC(=O)CBr)=[O:4].ClC1C=CC(CN[C:17]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([C:28]=2[OH:29])=[CH:26][C:25]([CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:24][C:23]=3[NH:37][CH3:38])=[O:18])=CC=1.[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>C1COCC1.C(N(CC)CC)C.CO>[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:47][C:17]([C:19]2[C:28](=[O:29])[C:27]3[C:22]4[N:21]([CH:20]=2)[CH2:2][C:3](=[O:4])[N:37]([CH3:38])[C:23]=4[CH:24]=[C:25]([CH2:30][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:26]=3)=[O:18])=[CH:44][CH:43]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CNc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Reactant: O=C(CBr)OC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(CN4CCOCC4)cc1c32
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of bromoacetic anhydride (1.03 g, 4 mmol) in THF (3.0 mL) is added over 30 min to a stirred solution of N-(4-chlorobenzyl)-4-hydroxy-8-(methylamino)-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (308 mg of a 1:1 mixture of compound 9 and 4-chlorobenzylamine), triethylamine (500 mg, 5 mmol) in THF (7.0 mL). After 5 h, methanol (20 mL) and triethylamine (300 mg) are added, and the solution is stirred at room temperature overnight. The solution is evaporated, dissolved in chloroform/methanol, and is applied in chloroform to a silica gel column which is eluted with chloroform and then with 5-10% methanol/chloroform to give the title compound (98 mg) which is precipitated from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.[CH:20]1([S:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:29]3[CH2:30][CH2:31][N:26]([S:23]([CH:20]4[CH2:22][CH2:21]4)(=[O:25])=[O:24])[CH2:27][CH2:28]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=S(=O)(C1CC1)N1CCNCC1
Agent: Cl
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde was treated with 1-cyclopropanesulfonyl-piperazine hydrochloride using General Procedure C (reductive amination) to yield 2-chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])[CH2:6][S:7][C:8]1[CH:9]=[CH:10][C:11]2[O:20][CH2:19][C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:12]=2[CH:28]=1>C(O)C>[CH3:27][N:24]1[CH2:25][CH2:26][C:21](=[C:13]2[C:12]3[CH:28]=[C:8]([S:7][CH2:6][C:5]([OH:29])=[O:4])[CH:9]=[CH:10][C:11]=3[O:20][CH2:19][C:18]3[CH:17]=[CH:16][S:15][C:14]2=3)[CH2:22][CH2:23]1
Reactant: COC(=O)CSc1ccc2c(c1)C(C1CCN(C)CC1)c1sccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(=C2c3cc(SCC(=O)O)ccc3OCc3ccsc32)CC1
Yield: 50.1 %

Procedure:
An aqueous sodium hydroxide (1.4 g, 680 mmol) solution was added to an ethanol (40 mL) solution of the compound obtained in Example 24 (2.9 g, 6.7 mmol), and the mixture was refluxed while heating for 2 hours. After allowing the mixture to cool in the air, the solvents were distilled off under a reduced pressure, water was added to the residue, and the mixture was neutralized with hydrochloric acid. The precipitated crystals were separated by filtration and dried, to give 1.3 g (50%) of the captioned compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[N:12]=[N:13][C:14]([N:17](C)[CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)=[CH:15][CH:16]=1)[C:6]#[N:7].Cl.N1C=CC=CC=1>CO.CS(C)=O>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[N:12]=[N:13][C:14]([NH:17][CH:18]2[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]2)=[CH:15][CH:16]=1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CO
Product: CC1(C)CC(Nc2ccc(-c3ccc(C#N)cc3O)nn2)CC(C)(C)N1
Temperature: 150 °C

Procedure:
To a microwave vial was added 3-methoxy-4-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)benzonitrile (Example 5-1, Step 1, 100 mg, 0.264 mmol) and pyridine hydrochloride (610 mg, 5.27 mmol), and the mixture was heated at 150° C. for 90 minutes in the microwave. The reaction mixture is dissolved in MeOH/DMSO, and purified by preparative HPLC (Waters Sunfire 30 mm ID×50 mm, 0.1% TFA, 15-40% ACN/H2O) to provide the title compound as a minor product (3 mg, 0.008 mmol). LCMS Rt=0.47 min (Method Q); MS (M+1)=352.2. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.81 (d, J=9.54 Hz, 1H), 7.65 (d, J=8.03 Hz, 1H), 7.34 (d, J=1.51 Hz, 1H), 7.18 (dd, J=1.76, 8.28 Hz, 1H), 6.87 (d, J=9.54 Hz, 1H), 4.83 (br. s., 1H), 4.40 (d, J=7.53 Hz, 1H), 2.11 (dd, J=3.64, 12.67 Hz, 2H), 1.59 (td, J=7.72, 15.18 Hz, 1H), 1.33-1.43 (m, 7H), 1.25 (br. s., 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][CH2:4][C:3]2[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=2[F:1])[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: COc1ccc(F)c(C=O)c1
Product: COc1ccc(F)c(CNC2CC2)c1

Procedure:
Synthesized according to typical procedure J from 2-fluoro-5-methoxybenzaldehyde and cyclopropylamine.
Reaction SMILES: [F:1][C:2]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[C:10]2[C:5](=[C:6]([O:20]C)[CH:7]=[CH:8][CH:9]=2)[N:4]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[F:29][C:2]([F:1])([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1)[C:3]1[N:12]=[C:11]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[C:10]2[C:5](=[C:6]([OH:20])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1cccc2c(Nc3cc(C)[nH]n3)nc(C(F)(F)c3ccc(F)cn3)nc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(O)cccc23)n[nH]1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 2.1 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-methoxy-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine from Example 43 step B (150 mg, 0.375 mmol) in DCM (10 mL) at −78° C. under argon was added boron tribromide (1M in DCM, 3.75 mL, 3.75 mmol). The mixture was stirred at −78° C. for 20 min, and then allowed to warm slowly to rt. Additional boron tribromide (1M in DCM, 4 mL, 4 mmol) was added and the mixture was stirred at rt for 6 days. MeOH was added slowly and then the mixture was concentrated under reduced pressure to afford a mixture of brominated products. The mixture was partially purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O). To the recovered product were added a 1:1 mixture of THF/MeOH (8 mL) and palladium hydroxide (20% on carbon, 50 mg) and the mixture was heated under an atmosphere of hydrogen at 50° C. for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure, and then purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazolin-8-ol (3 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.16 (s, 3H) 5.91 (s, 1H) 7.25 (d, J=7.54 Hz, 1H) 7.45 (t, J=8.10 Hz, 1H) 7.89-8.19 (m, 3H) 8.66 (s, 1H) 9.80 (br s, 1H) 10.52 (br s, 1H) 12.16 (br s, 1H). LC-MS (ESI) m/z 387 (M+H)+.
Reaction SMILES: Cl[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[CH:6]2.[NH:24]1[CH:28]=[N:27][CH:26]=[N:25]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[N:24]1([CH:2]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH:7]=[CH:6]3)[CH:28]=[N:27][CH:26]=[N:25]1
Reactant: c1nc[nH]n1
Reactant: O=c1ccc2cc(C(Cl)c3cccc(C(F)(F)F)c3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1ccc2cc(C(c3cccc(C(F)(F)F)c3)n3cncn3)ccc2[nH]1
Yield: 26.9 %

Procedure:
A mixture of intermediate 30 (0.846 g), 1,2,4-triazole (0.346 g) and potassium carbonate (0.7 g) in CH3CN (30 ml) was stirred and refluxed for 2 hours. The solvent was evaporated and the residue was taken up in water and extracted with CH2Cl2. The organic layer was dried MgSO4, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 98/2/0.1) and the solvent of the desired fraction was evaporated, yielding 0.25 g (27%) of (±)-6-[1H-1,2,4-triazol-1-yl[3-(trifluoromethyl)phenyl]methyl]-2(1H)-quinolinone (compound 3).
Reaction SMILES: CI.[F:3][CH:4]([F:13])[O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.[C:14]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:3][CH:4]([F:13])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:14])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(OC(F)F)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cccc(OC(F)F)c1
Yield: 2114.7 %

Procedure:
2.67 g of methyl iodide was stirred on ice in a suspension of 2.00 g of 3-difluoromethoxy phenol and 2.60 g of K2CO3 in DMF (10 ml) at room temperature for two hours. Water was added to the solution and the resulting mixture was extracted with Et2O; the organic layer was washed with saturated brine and then dried over MgSO4; the drying agent was separated by filtration, and the solvent was evaporated under reduced pressure obtained 46.0 g of the title compound (crude form).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]([OH:11])[CH3:10]
Reactant: CC(=O)c1cc(Br)ccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(Br)ccc1N
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 1-(2-amino-5-bromo-phenyl)-ethanone (2.4 g, 11.2 mmol) in anhydrous methanol (50 mL) was added sodium borohydride (1 g, 26 mmol) at rt under nitrogen. The mixture was stirred for 1 h, poured onto ice water, and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated to yield the title compound as an off-white solid (2.1 g, 86%): mp 95-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[N:4][C:3]=1[NH2:12].[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=[N:4][C:3]=1[NH:12][CH:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:23][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Nc1nnc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2nnc(C(F)(F)F)cc2Cl)CC1
Temperature: 85 °C
Yield: 35.7 %

Procedure:
To a stirred solution of D7 (1.6 g, 8.1 mmol) in dimethylformamide (50 ml) at 0° C., under nitrogen, was added NaH (60% in oil; 390 mg, 8.1 mmol) portionwise. The reaction mixture was stirred for 1 h, before 4-(toluene-4-sulfonyloxy)-piperidine-1-carboxylic acid tert-butyl ester (2.9 g, 8.1 mmol), dissolved in dimethylformamide (10 ml), was added dropwise. The reaction mixture was then heated between 80-90° C. for 6 hours. After cooling to room temperature, the solvents were evaporated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and the solvents were evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 3% methanol in dichloromethane) to give D8 (1.1 g, 37%). C15H20ClF3N4O2 requires 380; Found 381 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:35][CH2:36][O:37][CH2:38][CH2:39]Br>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]([C:15]2[NH:16][CH:17]=[C:18]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:32]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)=[C:27]([Cl:33])[CH:26]=4)=[CH:23][NH:22][N:21]=3)[CH:19]=2)=[O:14])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCc1ccc(-c2c[nH]nc2-c2c[nH]c(C(=O)NC(CO)c3ccc(F)c(Cl)c3)c2)cc1Cl
Reactant: BrCCOCCBr
Solvent: CN(C)C=O
Product: O=C(NC(CO)c1ccc(F)c(Cl)c1)c1cc(-c2n[nH]cc2-c2ccc(CN3CCOCC3)c(Cl)c2)c[nH]1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a solution of benzyl amine 11 (0.05 mmol) in DMF (3 mL) was added TEA (0.15 mmol) and 2-bromoethyl ether (0.05 mmol). The resulting solution was stirred for 18 h at 70° C. The solvent was removed under vacuum and the crude products purified by preparatory HPLC to afford II-6 as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([O:12]C)[CH:8]=[CH:7][CH:6]=2)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2c(OC)cccc2n1Cc1ccccc1
Agent: BrB(Br)Br
Product: CCc1cc2c(O)cccc2n1Cc1ccccc1
Yield: 53.7 %

Procedure:
By the method used in Part B, 3.1 g (11.7 mmol) of 2-ethyl-4-methoxy-1-(phenylmethyl)-1H-indole was O-demethylated by treating it with 48.6 mL of 1M BBr3/CH2C12 to give a material that was chromatographed on silica gel (eluted with 20% EtOAc/hexane) to give 1.58 g (54% yield) of 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole, mp, 86-90° C.