Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:4][CH:3]1[CH2:5][CH2:6][C:7]([CH:9]=[CH2:10])=[CH2:8].CC(C)=CCCC(C=C)=C.Cl>>[CH3:11][C:2]([OH:4])([CH2:3][CH2:5][CH2:6][C:7]([CH:9]=[CH2:10])=[CH2:8])[CH3:1]
Reactant: C=CC(=C)CCC1OC1(C)C
Agent: C=CC(=C)CCC=C(C)C
Agent: Cl
Product: C=CC(=C)CCCC(C)(C)O
Temperature: 0 °C

Procedure:
76 g. of epoxymyrcene, prepared according to the method described in paragraph a) by epoxidation of myrcene, were added dropwise between -5° and 0°, with good stirring. Then the mixture was stirred with 200 ml. ice-water and neutralised with diluted HCl. Following the same isolation procedure described in paragraph b) 1. the sec.-myrcenol was obtained with a comparable yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]=[C:8]2[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COc1cccc2c1CCCC2=O
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC=C2N1CCOCC1
Temperature: 3 °C
Reaction time: 8 h

Procedure:
Titanium tetrachloride (15.2 g) in dry toluene (105 ml) is added slowly to a stirred solution of 5-methoxy-1-tetralone (49 g), and morpholine (160 g) in dry toluene (1 l) cooled in an ice bath to a temperature of 3° C. under a nitrogen atmosphere. The reaction mixture is allowed to warm to RT and stirred at RT under N2 overnight. The reaction mixture is filtered, the filtered solid washed with dry toluene and dry THF and the combined filtrates evaporated in vacuo to a yellow solid (63.5 g), M.P. 80°-90° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[O:6]=[C:7]1[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[S:12][C:11]=2[C:10](=[O:20])[CH:9]=[CH:8]1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:8]1[C:7](=[O:6])[C:15]2[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[S:12][C:11]=2[C:10](=[O:20])[CH:9]=1
Reactant: COCCN
Reactant: COC(=O)c1cc2c(s1)C(=O)C=CC2=O
Solvent: C1CCOC1
Product: COCCNC1=CC(=O)c2sc(C(=O)OC)cc2C1=O
Temperature: 25 °C
Reaction time: 27 h

Procedure:
2-Methoxyethylamine (1.6 ml) was added to a solution of methyl 4,7-dihydro-4,7-dioxobenzo[b]thiophene-2-carboxylate (2.4 g) in tetrahydrofuran (100 ml) and the mixture was stirred at room temperature for 27 hours. After evaporation of the solvent, the residue was purified by silica gel column chromatography (elution with chloroform) to give methyl 4,7-dihydro-5-(2-methoxyethyl)amino-4,7-dioxobenzo[b]thiophene-2-carboxylate (1.5 g) as a yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C.CCCCCC>C1COCC1.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1n[nH]c2ccccc12
Temperature: 0 °C
Yield: 68 %

Procedure:
Indazole-3-carboxylic acid (5.00 g, 30.8 mmol) was dissolved in THF (200 ml) and methanol (15 ml). To the resulting solution was added (trimethylsilyl)diazomethane (a 2.0M n-hexane solution, 20 ml, 40.1 mmol) under stirring at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was crystallized by the addition of n-hexane, and the crystals thus obtained were collected by filtration and dried under reduced pressure to give methyl indazole-3-carboxylate (3.71 g, 68%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:17][C:18]([F:42])([F:41])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]>>[F:17][C:18]([F:41])([F:42])[CH2:19][NH:20][C:21]([C:23]1([CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:13][CH2:14][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:10][CH2:11]2)[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:22]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(3-trifluoromethyl-phenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:37])[CH3:36].C1COCC1>>[CH2:35]([NH:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:34])=[C:20]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:24])=[O:25])[CH:21]=2)[CH:5]=[CH:4][N:3]=1)[CH3:36]
Reactant: CCN
Reactant: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Solvent: C1CCOC1
Product: CCNc1nccc(-c2sc(C(C)C)nc2-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)n1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.150 g, 0.286 mmol) and ethyl amine 2.0 M in THF (2 mL, 4.00 mmol), the title compound was obtained as an off-white solid (74 mg, 49% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.65-7.80 (m, 1H), 7.44 (dd, J=7.5, 1.8 Hz, 1H), 7.36-7.42 (m, 1H), 7.21-7.33 (m, 4H), 6.17 (br. s., 1H), 3.16-3.31 (m, 3H), 1.36 (d, J=6.9 Hz, 6H), 1.10 (t, J=7.1 Hz, 3H). MS (ESI): 534.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([Cl:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([Cl:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)CNc1cc(F)c(Cl)cc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(Cl)cc1[N+](=O)[O-]
Yield: 56.9 %

Procedure:
1.16-1.47 (3H, m), 4.04 (2H, d, J=5.3 Hz) 4.16-4.45 (2H, m), 6.47 (1H, d, J=11.1 Hz), 8.25-8.67 (2H, m). 2) By using 0.66 g of N-(4-chloro-5-fluoro-2-nitrophenyl)glycine ethyl ester, 162 mg of imidazole and 4 ml of pyridine, 0.44 g (57%) of N-[4-chloro-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [CH3:1][C:2]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:7])([N+:8]([O-:10])=[O:9])[CH3:1])(=[O:21])=[O:20]
Reactant: CC(C)(CCCO)[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCCOS(C)(=O)=O)[N+](=O)[O-]
Reaction time: 1 h
Yield: 93.8 %

Procedure:
4-Methyl-4-nitropentanol (4.3 g, 29.2 mmol) was dissolved in methylene chloride (100 ml) and triethylamine (6.1 ml, 43.8 mmol) was added, which was followed by ice-cooling. Methanesulfonyl chloride (2.94 ml, 38.0 mmol) was added and the mixture was stirred for 1 h under ice-cooling. The mixture was washed with water (50 ml), 0.5 mol/L hydrochloric acid (50 ml), 5% aqueous sodium hydrogencarbonate solution (50 ml) and saturated brine (50 ml). Methylene chloride was evaporated by concentration under reduced pressure and the residue was subjected to crystallization with ethyl acetate (4 ml) and n-hexane (20 ml). After filtration, the residue was dried under reduced pressure at 40° C. to give the objective compound (6.17 g, yield 93.8%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C[O:14][C:15](=O)[C:16]1[C:21]([I:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]2[C:16](=[C:21]([I:22])[CH:20]=1)[C:15](=[O:14])[N:8]([CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=1)[CH2:24]2
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.6 %

Procedure:
A mixture of 4-trifluoromethyl-benzyl amine (0.142 mL, 1.0 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.270 g, 0.73 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-trifluoromethyl-benzyl)-2,3-dihydro-isoindol-1-one (0.110 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.18 (s, 2H), 4.84 (s, 2H), 7.10 (d, 1H), 7.42 (d, 2H), 7.60 (m, 2H), 7.66 (d, 1H). GC-MS: m/z 435 (M)+, 416 (M−19)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][C:15]=2[CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[C:15]([CH3:39])[CH:16]=1)=[O:22]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To N-[6-(1-tert-butyloxycarbonylpiperidin-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (7.0 g) were added dichloromethane (128 ml) and trifluoroacetic acid (26 ml), stirred at room temperature for 2 hours, and then to the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling. The precipitated solid was washed with n-hexane and water, the obtained solid was dissolved in chloroform, water was added thereto, extracted with chloroform and ethyl acetate, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The precipitated solid was washed with ethyl acetate to give the titled compound (5.39 g) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.C([O:38][C:39](=[O:45])[CH:40](C)[CH2:41][N+]#N)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+]>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH:40]([CH3:41])[C:39]([OH:45])=[O:38])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[CH:34][N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CCOC(=O)C(C)C[N+]#N
Agent: [Rh+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(=O)O)CC2)c2ncnn12
Reaction time: 1 h

Procedure:
To a mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (4 g), rhodium(I) acetate (0.028 g) and toluene (70 mL) was added dropwise a solution (10 mL) of 3-ethoxy-2-methyl-3-oxopropane-1-diazonium (5.5 mL) in toluene at 80° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was purified by silica gel column chromatography. The obtained residue was dissolved in tetrahydrofuran (20 mL) and methanol (20 mL), and 1N aqueous sodium hydroxide solution (20 mL) was added. The reaction mixture was stirred for 1 hr, 1N aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (4.1 g, 89%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:6]1)=[O:4].[OH-].[Na+].O>CO>[C:33]([O:32][C:30]([N:7]1[CH2:8][CH2:9][C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[Cl:29])=[CH:13][CH:12]=2)[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)O)cc2)c(Cl)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a sol. of compound (rac.)-(3R*,4S*)-4-{4-[2-(2,6-Dichloro-4-methylphenoxy)ethoxy]phenyl}-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.15 g, 0.27 mmol) in MeOH (1 mL) was added aq. 1M NaOH (1 mL). The mixture was stirred at 70° C. for 2 h. Water was added, and the mixture was extracted with EtOAc. The org. phase was washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude residue was purified on a pad of silica gel to yield the title compound (93 mg, 65%). LC-MS: tR=1.12 min, ES+=524.24.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:16]([C:26]([N:28]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@@H:29]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:32][C@H:31]([C:42](OC)=[O:43])[CH2:30]2)=[O:27])[N:15]=[N:14]1>C(O)C.C(=O)([O-])O.[Na+]>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[C:17]([CH2:18][O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:16]([C:26]([N:28]([CH2:46][CH:47]([CH3:49])[CH3:48])[C@H:29]2[CH2:30][C@@H:31]([CH2:42][OH:43])[CH2:32][N:33]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:34]2)=[O:27])[N:15]=[N:14]1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nnn(-c3ccccc3F)c2COc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1COc1ccccc1)[C@H]1C[C@@H](CO)CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Calcium(II) chloride (200 mg) was dissolved in ethanol (5 ml), sodium tetrahydroborate (140 mg) was added under ice-cooling and the mixture was stirred at 0° C. for 30 min. A solution (8 ml) of 1-tert-butyl 3-methyl(3R,5S)-5-[{[1-(2-fluorophenyl)-5-(phenoxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (760 mg) in ethanol was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (5:95-75:25) was concentrated under reduced pressure to give the object product (447 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[O:26]1[C:30]([C:31](O)=O)=[CH:29][N:28]=[CH:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:31]([C:30]5[O:26][CH:27]=[N:28][CH:29]=5)[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1N
Reactant: O=C(O)c1cnco1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-c2cnco2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (100 mg), oxazole-5-carboxylic acid (33.3 mg), HATU (118 mg), N,N-diisopropylethylamine (0.154 ml) and DMF (2 ml) was stirred at room temperature for 2 h. The mixture was poured into saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was dissolved in AcOH (2 ml), and the mixture was stirred at 80° C. for 2 h. The mixture was concentrate in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc). The resulting solid was washed with EtOAc/hexane to give the title compound (40.7 mg) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[NH:5][C:4](=[O:18])[CH:3]=1.[H-].[Na+].[Li+].[Br-].I[CH3:24]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:8][C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[C:6](=[O:17])[N:5]([CH3:24])[C:4](=[O:18])[CH:3]=1
Reactant: CI
Reactant: N#Cc1ccccc1Cn1c(Cl)cc(=O)[nH]c1=O
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cn1c(=O)cc(Cl)n(Cc2ccccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
To a cold (0° C.) solution of benzylated 6-chlorouracil 2 (10 g, 38 mmol) in DMF-TH-F (1:1, 300 mL) under nitrogen, was added NaH (60%, 1.6 g, 39.9 mmol) in portions, followed by adding LiBr (2 g). The mixture was stirred at RT for 20 min. After adding iodomethane (5.4 mL, 76 mmol), the flask was sealed and stirred at this temperature for 10 min, RT for 2 h, and 35° C. overnight, and then concentrated in vacuo. The residue was dissolved in CHCl3 and washed with water and brine, dried (Na2SO4), and filtered then concentrated in vacuo. The crude product was crystallized from THF-Hexanes to give 7.6 g (72%) of the title compound 3. 1H NMR (400 MHz, DMSO): δ 7.87 (d, 1H, J=7.6 Hz), 7.70 (t, 1H, J=7.6 Hz), 7.51 (t, 1H, J=7.6 Hz), 7.40 (d, 1H, J=8 Hz), 6.21 (s, 1H), 5.38 (s, 2H), 3.28 (s, 3H). MS (ES) [m+H] calc'd for C13H11ClN3O2, 276.1; found 276.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[C:5]=1[NH2:12].[CH2:14](N(CC)CC)[CH3:15].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)(=O)C>C1(C)C=CC=CC=1.Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]2[O:11][C:14]([CH3:15])=[N:12][C:5]=12)=[O:13]
Reactant: CCN(CC)CC
Reactant: COC(=O)c1ccc(Br)c(O)c1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Br)c2oc(C)nc12
Temperature: 25 °C

Procedure:
To a solution of 2-amino-4-bromo-3-hydroxy-benzoic acid methyl ester (2.46 g) in toluene (250 ml) was added sequentially triethylamine (1.53 ml), pyridinium p-toluenesulfonate (“PPTS”) (0.75 g) and acetyl chloride (0.78 ml). The reaction mixture was heated at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with aqueous hydrochloric acid (1M) (100 ml) and ethyl acetate (200 ml). The phases were separated and the organic extract was washed with aqueous hydrochloric acid (1M) (150 ml) and brine (150 ml) and then dried over sodium sulfate. The solids were removed by filtration and the filtrate was concentrated to give 7-bromo-2 methyl-benzo[d]oxazole-4-carboxylic acid methyl ester (2.94 g). 1H-NMR (400 MHz, CDCl3): 7.87 (d, 1H), 7.52 (d, 1H), 4.04 (s, 3H), 2.77 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:23])=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.O>ClCCl>[CH2:1]([N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[NH:23][C:32]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(NCc2ccccc2)cccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2c(OCc3ccccc3)cccc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 263.1 %

Procedure:
To a solution of N*1*-Benzyl-3-benzyloxy-benzene-1,2-diamine (4.60 g, 15.11 mmol) in 100 mL dichloromethane at 0° C. was added triethylamine (4.201 mL, 30.22 mmol) followed by portionwise addition of triphosgene (1.57 g, 5.29 mmol). The resulting solution was stirred for 2 hours at 0° C. The reaction mixture was allowed to warm to room temperature and was then added to 200 mL water. The organic phase was separated, washed with 100 mL 10% aqueous HCl, 100 mL saturated aqueous sodium bicarbonate, and 100 mL brine, dried over sodium sulfate, and concentrated in vacuo to give 4.60 g (13.92 mmol, 92%) of 1-benzyl-4-benzyloxy-1,3-dihydro-benzoimidazol-2-one as a tan solid. MS: 331 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][N:26]3[CH3:32])=[N:23][N:24]=2)[CH:21]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:32][N:26]1[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: CN1CC(C)(C)C[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CN1CC(C)(C)C[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of Intermediate A (552 mg, 3.89 mmol) in DMF (25 mL) was added NaH (60% in oil, 338 mg, 8.46 mmol) and the mixture stirred at RT for 20 min, before Intermediate 87c (700 mg, 2.82 mmol) was added. This mixture was stirred at 60° C. for 1 h. The cooled reaction mixture was applied to an SCX-2 cartridge (70 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% (2M NH3 in MeOH) in DCM gave the title compound (820 mg, 74%). LCMS (Method 4): Rt 1.53 min, m/z 392 [MH+].