Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[CH2:9][NH:8][C:7]1[CH:11]=[CH:12][CH:13]=[N:14][C:6]=1[CH2:5]2.[C:15]1([C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:21]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:22]=[CH:23][C:24]([C:25]([N:8]2[CH2:9][C:10]3[N:4]([CH:3]=[CH:2][CH:1]=3)[CH2:5][C:6]3[N:14]=[CH:13][CH:12]=[CH:11][C:7]2=3)=[O:26])=[CH:28][CH:29]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1cnc2c(c1)NCc1cccn1C2
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2cccn2Cc2ncccc21

Procedure:
A stirred mixture of 9,10-dihydro-4H-3a, 5, 9-triaza-benzo[f]azulene of Step D (0.54 mmol), 4-phenylbenzoylchloride (1.08 mmol) and triethylamine (1.08 mmol) in toluene was refluxed under nitrogen for 72 hours. The reaction was cooled and the solvent removed in vacuo. Chromatography of the residue over silica gel Merck-60 with a solvent gradient from 5 to 20% ethyl acetate in hexane provided the title compound as a tan solid.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(N2C=CN=C2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][N:25]=1.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:44]([C:45]2[NH:46][CH:47]=[CH:48][N:49]=2)=[CH:43][N:42]=[C:41]([NH:50][CH2:51][CH2:52][NH:53]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:40]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:44]([C:45]2[NH:49][CH:48]=[CH:47][N:46]=2)=[CH:43][N:42]=[C:41]([NH:50][CH2:51][CH2:52][NH:53][C:24]2[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][N:25]=2)[N:40]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Agent: NCCc1ncc(-n2ccnc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2nc(NCCNc3cc(Cl)ncn3)ncc2-c2ncc[nH]2)c(Cl)c1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]{2-[(6-chloropyrimidin-4-yl)-amino]ethyl}amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-1-ylpyrimidin-2-ylethylamine and 4,6-dichloropyrimidine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[C:5]([NH2:21])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].C(N(C(C)C)CC)(C)C.Cl[C:36](OCC)=[O:37]>O1CCCC1>[Br:1][C:2]1[C:3]([C:22]([F:23])([F:25])[F:24])=[CH:4][C:5]2[NH:21][C:36](=[O:37])[N:8]([CH:9]3[CH2:10][CH2:11][N:12]([CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:13][CH2:14]3)[C:6]=2[CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 150 °C

Procedure:
A stirred solution of 5-bromo-N-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-4-(trifluoromethyl)-1,2-benzenediamine (D55) (0.34 mmol) in tetrahydrofuran (8 ml) at room temperature under argon was treated with diisopropylethylamine (0.12 ml, 0.68 mmol) followed by ethyl chloroformate (40 mg, 0.38 mmol) and then heated under reflux for 2 hrs. The mixture was concentrated under vacuum and the residue dissolved in dimethylformamide, treated with more diisopropylethylamine (0.12 ml) and heated at 150° C. for 0.75 hr. The solution was then concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried and concentrated under vacuum. The residue was triturated with diethyl ether to afford 6-bromo-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one as a beige solid. This was converted to its HCl salt as a beige solid (55 mg, 33%). MH+=448, 450.
Reaction SMILES: C[O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3c(OC)cccc3s2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COc1ccc(-c2nc3c(O)cccc3s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.2 %

Procedure:
The 4-methoxy-2-(4-methoxyphenyl)benzothiazole (9.0 g) obtained in (2) was dissolved in 15 ml of dichloromethane, and a solution of 8.7 g of boron tribromide in 15 ml of dichloromethane was added dropwise to the solution. The mixture was stirred at room temperature for 2 hours, and then poured into 200 ml of ice water, followed by extraction with chloroform three times. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (eluted with chloroform) to give 4.2 g of 4-hydroxy-2-(4-methoxyphenyl)benzothiazole.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[C:1]([NH:8][C@H:9]([C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N1CCOCC1
Yield: 95 %

Procedure:
In substantially the same manner as in Example 5, morpholine (280 μl) was condensed with Boc-L-homophenylalanine (900 mg, manufactured by Bachem Fein Chemikalien AG, Switzerland) to give N-(BOC-L-homophenylalanyl)morpholine (1.06 g) as a white powder (yield 95%). After Boc group elimination with 4N HCl/ethyl acetate, the product was condensed with (2S,3S)-ethyl hydrogen trans-epoxysuccinate (338 mg) as obtained in Reference Example 8 to yield the title compound (compound 65; 630 mg) as a white powder (yield 77%).
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:28][Si](CC)(CC)CC)([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([N:3]([CH2:4][CH:5]([OH:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][C:16]([C:19]([OH:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCN(CC(O)c1ccccc1)c1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CC(O)c1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.8 %

Procedure:
A solution of 300 mg (0.58 mmol) of 2-{ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amino}-1-phenyl-ethanol in 7.5 mL of THF was treated with 1.5 mL of a 1M TBAF-solution in THF and stirred at RT for 1 hour. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 9:1 yielded 153 mg (65%) of 2-{4-[ethyl-(2-hydroxy-2-phenyl-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, white solid, MS: 408 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C@@:15]12[CH2:22][C:21](=[CH2:23])[CH2:20][C@@H:19]1[C:18](=[O:24])[N:17]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[CH2:16]2)=[O:14])(C)(C)C>ClCCl>[CH2:23]=[C:21]1[CH2:22][C@:15]2([C:13]([OH:14])=[O:12])[C@@H:19]([C:18](=[O:24])[N:17]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[CH2:16]2)[CH2:20]1
Reactant: C=C1C[C@@H]2C(=O)N([C@H](C)c3ccccc3)C[C@]2(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C1C[C@@H]2C(=O)N([C@H](C)c3ccccc3)C[C@]2(C(=O)O)C1
Yield: 87 %

Procedure:
Trifluoroacetic acid (26.0 ml) was added to a solution of [(1S,5S)-7-methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-aza-bicyclo[3.3.0]octan-1-yl]carboxylic acid tert-butyl ester (2.47 g, 8.66 mmol) in dichloromethane (26.0 ml) with stirring under ice-cooling, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, and trifluoroacetic acid was azeotropically distilled with toluene (×3). A 1 mol/l sodium hydroxide solution (15.0 ml) was added to the resulting residue under ice-cooling, and the mixture was washed with diethyl ether (60 ml×2). The aqueous layer was made acidic with 6 mol/l hydrochloric acid (4 ml) under ice-cooling, followed by extraction with ethyl acetate (100 ml×2). The organic layers were combined, washed with water (100 mL) and brine (100 ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 2.15 g of the title compound as white crystals.
Reaction SMILES: Cl.C([O:6][C:7]([N:9]1[CH2:14][CH:13]([CH3:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)=O)(C)(C)C.[CH:25](N(CC)C(C)C)(C)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C.CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:7]([N:9]1[CH2:14][CH:13]([CH3:15])[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11](=[O:24])[CH2:10]1)(=[O:6])[CH3:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C(C)C1
Reaction time: 1 h

Procedure:
A steady stream of anhydrous HCl gas was bubbled through a cold (0° C.) solution of 4-[(tert-butoxy)carbonyl]-1-(4-fluorobenzyl)-6-methylpiperazin-2-one (0.62 g, 1.9 mmol) in ethyl acetate (20 mL) for 5 minutes. The resultant mixture was capped and stirred at the same temperature for 1 h. The product mixture was concentrated under vacuum. The residue was treated with a mixture of N,N-diisopropylethylamine (1.00 mL, 5.8 mmol), DMAP (5 mg), and acetic anhydride (0.22 mL, 2.3 mmol) in methylene chloride (10 mL). The resultant mixture was concentrated and the residue was subjected to column chromatography on silica gel eluting with a mixture of 10% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the title piperazinone.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O.O>CN(C)C=O.C(OCC)(=O)C>[O:11]=[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]1[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23]1
Reactant: O=c1ccc2cccnc2[nH]1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3cccnc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 57.5 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To a solution of 0.15 g of 1,8-naphthyridin-2(1H)-one in 2 mL of N,N-dimethylformamide, 45 mg of 60% sodium hydride was added, and the mixture was stirred at 50 to 65° C. for 1 hour. Thereto was added a solution of 0.44 g of 1-tert-butyl 4-ethyl 4-(3-((methylsulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate in 1.2 mL of N,N-dimethylformamide, and the reaction mixture was stirred at 80 to 90° C. for 1 hour 30 minutes and cooled to room temperature, and water and ethyl acetate were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=3:2 to obtain 0.29 g of 1-tert-butyl 4-ethyl 4-(3-(2-oxo-1,8-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate as a colorless oily substance.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C1CCCCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16]([C:2]2[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:15]=1
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2C#N)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinonitrile (3 g, 14.56 mmol) was dissolved in toluene (70 mL) and ethanol (14 mL). m-tolylboronic acid (2.969 g, 21.814 mmol), aqueous sodium carbonate solution (2 M, 14 mL) and Pd(PPh3)4 (1.684 g, 1.456 mmol) were added. The mixture was flushed with nitrogen and stirred under microwave conditions (7 bar) at 100° C. for 2 h. The concentrated reaction mixture was cooled, diluted with ethyl acetate (200 mL), passed through celite (cyclohexane/ethyl acetate 9:1, 2×1 L) and concentrated in vacuo to afford 2-m-tolyl-6-(trifluoromethyl)nicotinonitrile (1.87 g, 49%).
Reaction SMILES: [Na].C([CH:4]1[CH2:9][CH2:8][C:7](=[N:10]O)[CH2:6][CH2:5]1)C.O.[CH2:13](O)[CH3:14]>>[CH2:13]([NH:10][CH:7]1[CH2:6][CH2:5][CH2:4][CH2:9][CH2:8]1)[CH3:14]
Reactant: CCC1CCC(=NO)CC1
Reactant: CCO
Agent: [Na]
Solvent: O
Product: CCNC1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium (45 g, 1.96 mol) was slowly added to a solution of 4-ethylcyclohexanone oxime (33 g, 0.23 mol) (prepared according to lift. R. O. Hutchins et al. J. Org. Chem. 60 (1995) 7396-7405)) in 99.9% ethanol (500 mL) while keeping the temperature below 65° C. The reaction mixture was heated at reflux temperature for 1½ h and then stirred at room temperature for further 16 h. A mixture of water (500 mL) and ethanol (100 mL) was added and the mixture was extracted with diethyl ether (3×250 mL). The combined organic phases was washed with brine (150 mL), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was dissolved in ethanol (100 mL), pH was adjusted to approx. 3 with 4 N hydrochloric acid (60 mL) and the solution was evaporated to dryness in vacuo to give crude ethylcyclohexylamine. The product was purified by recrystallization from ethanol/acetonitrile (4:1) to give 4-trans-ethylcyclohexylamine, hydrochloride as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[NH2:9])=[CH:4][C:3]=1[F:16].CCN(C(C)C)C(C)C.[OH:26][CH2:27][C@@H:28]([NH:30][C:31]1[N:40]=[CH:39][C:38]2[C:33](=[CH:34][C:35]([C:41](O)=[O:42])=[CH:36][CH:37]=2)[N:32]=1)[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[NH:9][C:41]([C:35]2[CH:34]=[C:33]3[C:38]([CH:39]=[N:40][C:31]([NH:30][C@@H:28]([CH3:29])[CH2:27][OH:26])=[N:32]3)=[CH:37][CH:36]=2)=[O:42])=[CH:4][C:3]=1[F:16]
Reactant: Cn1cc(C(N)c2ccc(Cl)c(F)c2)cn1
Reactant: C[C@@H](CO)Nc1ncc2ccc(C(=O)O)cc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](CO)Nc1ncc2ccc(C(=O)NC(c3ccc(Cl)c(F)c3)c3cnn(C)c3)cc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
To a stirred solution of the hydrochloride salt of 40c (140 mg, 0.506 mmol), and DIPEA (88.1 μL, 0.506 mmol) and DMF (5 mL) under nitrogen was added 70 (125 mg, 0.506 mmol) and HBTU (211 mg, 0.556 mmol) and the reaction was stirred at RT for 18 h. The reaction was poured into water and extracted with EtOAc. The combined extracts were dried (MgSO4) and evaporated and the crude material was purified by reverse phase chromatography (SP4) eluting with a MeCN/H2O gradient (10 to 95% MeCN) to afford 83.5 mg (35.2%) of N-((4-chloro-3-fluorophenyl)(1-methyl-1H-pyrazol-4-yl)methyl)-2-((S)-1-hydroxypropan-2-ylamino)quinazoline-7-carboxamide (I-1).
Reaction SMILES: [F:1][C@@H:2]1[C@@H:8]([CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[O:7][C@H:4]([O:5][CH3:6])[C@@H:3]1[OH:20].[CH3:21]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:1][C@@H:2]1[C@@H:8]([CH2:9][O:10][C:11]([C:13]2[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[O:7][C@H:4]([O:5][CH3:6])[C@:3]1([CH3:21])[OH:20]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CO[C@H]1O[C@H](COC(=O)c2ccccc2C)[C@@H](F)[C@H]1O
Solvent: ClCCl
Product: CO[C@H]1O[C@H](COC(=O)c2ccccc2C)[C@@H](F)[C@@]1(C)O
Temperature: -40 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
The product from Step A (1.0 g, 3.5 mmol) and Dess-Martin periodinane (2.5 g) in dichloromethane (20 mL) were stirred overnight at room temperature and was then concentrated under reduced pressure. The residue was triturated with diethyl ether (50 mL) and filtered. The filtrate was washed with a solution of Na2S2O3.5H2O (12.5 g) in saturated aqueous sodium bicarbonate (100 mL), dried (MgSO4), filtered and evaporated. The residue was dissolved in anhydrous THF (50 mL). TiCl4 (3 mL) and methyl magnesium bromide in ethyl ether (3 M, 10 mL) were added at −78° C. and the mixture was stirred at −50 to −30° C. for 2 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (100 mL) and filtered through Celite. The filtrate was extracted with toluene (100 mL) and evaporated. The residue was chromatographed on silica gel (EtOAc/hexane: 15/85) to afford the title compound as an oil (150 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]#[N:16])[C@H:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]2[NH:26][N:25]=[N:24][N:16]=2)[C@H:10]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC[C@@H]1CC[C@@H](OCc2ccccc2)[C@@H]1c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc([C@@H]2[C@H](Cc3nnn[nH]3)CC[C@H]2OCc2ccccc2)cc1
Temperature: 125 °C
Yield: 64.2 %

Procedure:
To a solution of 342 mg of product from Step D in 7 mL of DMF was added 215 mg of sodium azide and 176 mg of ammonium chloride. The reaction was heated at 125° C. for 4 days and then cooled and diluted with water and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography with 5% methanol in methylene chloride to obtain 250 mg of title compound as a oil. T.l.c. (5% methanol in methylene chloride) Rf =0.2. Mass spec (NH3 /CI): 353(M+1).
Reaction SMILES: N1C2C(=CC(C(O)=O)=CC=2)C=C1.[H-].[Na+].IC.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([O:29]C)=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.[OH-].[Na+]>CN(C=O)C.C1COCC1.CO.O>[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([OH:29])=[O:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1
Reactant: COC(=O)c1ccc2c(ccn2C)c1
Agent: O=C(O)c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2cc(C(=O)O)ccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
Under nitrogen atmosphere, a solution of indole-5-carboxylic acid (1.05 g) in DMF (40 mL) was cooled to 0° C., and thereto was added NaH (544 mg, 60%), and the mixture was stirred at the same temperature for 10 minutes, and stirred at room temperature for 30 minutes. The mixture was cooled to 0° C., and thereto was added iodomethane (3.68 g), and the mixture was stirred at room temperature for 48 hours. Water was added to the mixture, and the mixture was extracted three times with ethyl acetate-toluene, and dried over MgSO4. The solvent was evaporated under reduced pressure to give a crude methyl 1-methylindole-5-carboxylate. To a solution of the crude methyl 1-methylindole-5-carboxylate in THF (50 mL)-MeOH (50 mL) was added a 6N NaOH solution (5.4 mL), and the mixture was stirred at room temperature for 144 hours. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate, and thereto was added a 6N aqueous hydrochloric acid solution to adjust the pH value thereof to pH=5-6. The mixture was extracted twice with ethyl acetate, and dried over MgSO4. The solvent was evaporated under reduced pressure to give 1-methyl-1H-indol-5-carboxylic acid (1.08 g, 96%).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:28]1([CH:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>CN(C=O)C>[C:37]1([CH:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:35][NH:36][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and solid O-benzotriazol-1-yl-N,N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 2,2-diphenylethylamine (0.38 g, 1.9 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.71 g (84%) of the pure titled compound as a white solid; mp 194-195° C. APCI-MS m/z 436.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:11]([NH:15][C:16](=[O:19])[CH2:17]Cl)([CH3:14])[CH2:12][OH:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.CC([O-])(C)C.[K+].O>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C@@:11]2([CH3:14])[NH:15][C:16](=[O:19])[CH2:17][O:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: C[C@@](CO)(NC(=O)CCl)c1cc(Br)cc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(=O)N1
Temperature: 100 °C

Procedure:
N—[(R)-1-(3-Bromo-5-nitro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (4.45 g, 10.76 mmol) and KOtBu (2.414 g, 21.52 g) were suspended in 55 ml tert-butanol under N2 and heated 100° C. for 30 min. After completion water was added to the reaction and tert-butanol was removed under reduced pressure. The product was extracted with ethyl acetate from the remaining aqueous phase. The organic phases were washed with water and brine, combined and dried over Na2SO4. Volatiles were removed under reduced pressure. The crude product was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as tan solid. 1H-NMR (360 MHz, DMSO-d6): 8.88 (1H, NH), 8.35 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 4.16 (m, 1H), 4.06 (s, 2H), 3.74 (m, 1H), 1.50 (s, 3H); MS: 316 [(M+H)+].