Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([O:14][CH3:15])=[CH:7][C:5]=1[NH2:6])(=[O:3])[CH3:2].[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1.C1(C2NC3C(C(=O)C=2)=CC(OC)=C(OC)C=3)CC1>C(N(CC)CC)C>[CH:16]1([C:19]([NH:6][C:5]2[CH:7]=[C:8]([O:14][CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[CH:10][C:4]=2[C:1](=[O:3])[CH3:2])=[O:20])[CH2:18][CH2:17]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc(C(C)=O)c(N)cc1OC
Agent: COc1cc2[nH]c(C3CC3)cc(=O)c2cc1OC
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)=O)c(NC(=O)C2CC2)cc1OC

Procedure:
2-Acetyl-4-ethoxy-5-methoxyaniline (490 mg), triethylamine (1.0 ml) and cyclopropylcarbonyl chloride (0.25 ml) were reacted in the same manner as in the preparation of compound 95 to give N-cyclopropylcarbonyl-2-acetyl-4-ethoxy-5-methoxyaniline (420 mg). This compound (380 mg) and potassium t-butoxide (770 mg) were reacted in the same manner as in the preparation of compound 95 to obtain 2-cyclopropyl-6-ethoxy-7-methoxy-4(1H)-quinolone (compound 119, 80 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[O:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[C:7]=1[CH2:6][CH2:5]2.[Cl-].[Li+].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:21]([C:18]1[CH:17]=[CH:16][C:15]([C:8]2[C:7]3[CH2:6][CH2:5][C:4]4[C:12]([C:11]=3[O:10][N:9]=2)=[CH:13][CH:14]=[C:2]([CH:26]=[CH2:27])[CH:3]=4)=[CH:20][CH:19]=1)[CH2:22][CH3:23]
Reactant: CCCc1ccc(-c2noc3c2CCc2cc(Br)ccc2-3)cc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1c(-c3ccc(CCC)cc3)noc1-2
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To 7-bromo-3-(4-propylphenyl)-4,5-dihydronaphtho[2,1-d]isoxazole (Preparation 20C, 0.32 g, 0.869 mmol) in dioxane (3 mL) were added sequentially lithium chloride (0.111 g, 2.61 mmol) and tributyl(vinyl)stannane (0.251 mL, 0.869 mmol). The reaction mixture was purged with nitrogen gas for 3 min. Tetrakis(triphenylphosphine) palladium(0) (0.100 g, 0.087 mmol) was added and the resulting yellow solution was purged with nitrogen gas for 2 min., and heated at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography using hexane/ethyl acetate. Fractions corresponding to the desired product were collected and concentrated to yield 3-(4-propylphenyl)-7-vinyl-4,5-dihydronaphtho[2,1-d]isoxazole (0.205 g, 0.650 mmol, 74.8% yield) as a pale yellow solid. LCMS M+1=316.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH2:11].[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:31])[F:32])=[CH:23][CH:24]=1)=[O:30]
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: Cc1ccccc1
Product: O=C(NCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 12 h
Yield: 46.5 %

Procedure:
A solution of 0.20 g of 3,5-dichloro-4-(2-aminoethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene and 0.14 g of 4-trifluoromethoxyphenyl isocyanate dissolved in 10 ml of toluene was heated under reflux, while stirring, for 12 hours, and the reaction mixture was then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.15 g of 3,5-dichloro-4-(2-(N'-(4-trifluoromethoxyphenyl)ureido)ethoxy)-1-(3,3-dichloro-2-propenyloxy)benzene (46% yield), m.p., 125.4° C.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](I)[CH2:18][CH3:19].O>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:17][CH2:18][CH3:19])[C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1
Reactant: CCCI
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(Cl)cc(=O)n(C)c1=O

Procedure:
6-chloro-3-methyl uracil (10 g) and potassium carbonate (10.34 g) in DMF (70 ml) under nitrogen was treated with n-propyl iodide (25.4 g) and heated at reflux for 8 h. The reaction 30 was cooled and then poured into water (700 ml) and extracted with ethyl acetate. The combined organics were dried and evaporated in vacuo to afford the subtitle compound an orange oil, 17.52 g. δ 1HCDCl3 0.98 (3H, t), 1.74 (2H, sextet), 3.33 (3H, s), 4.02 (2H, t), 8.02 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)=[CH:7][CH2:6]1)=[O:4].COC(C1CCC(=O)CC1)=O.C(C1CCNCC1)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1COCC1.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCCCCC1CCN(C2=CCC(C(=O)OC)CC2)CC1
Agent: [Pd]
Agent: CCCCCC1CCNCC1
Agent: COC(=O)C1CCC(=O)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCC1CCN([C@H]2CC[C@H](C(=O)OC)CC2)CC1

Procedure:
A solution of 5 g of 1-(4-methoxycarbonylcyclohexen-1-yl)-4-pentylpiperidine (b.p. 171°/0.4 mm Hg, obtainable from methyl cyclohexanone-4-carboxylate and 4-pentylpiperidine in toluene in the presence of p-toluenesulfonic acid) in 50 ml of THF is hydrogenated under 2 bar of H2 using 0.5 g of 10% Pd-C; the catalyst is filtered off; and the filtrate is evaporated to dryness to give 1-(trans-4-methoxycarbonylcyclohexyl)4-pentylpiperidine, m.p. 5°, b.p. 177°/0.27 mbar.
Reaction SMILES: ClC1C=CC2[C:6]3[N:7](C=C(I)N=3)CCOC=2N=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[N:23]([CH:29]=[C:30]([C:32]4[N:36]([CH:37]([CH3:39])[CH3:38])[N:35]=[CH:34][N:33]=4)[N:31]=3)[CH2:24][CH2:25][O:26][C:27]=2[N:28]=1.[Cl-].C[NH3+].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:37]([N:36]1[C:32]([C:30]2[N:31]=[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([NH:7][CH3:6])=[N:28][C:27]=4[O:26][CH2:25][CH2:24][N:23]3[CH:29]=2)=[N:33][CH:34]=[N:35]1)([CH3:39])[CH3:38]
Reactant: Clc1ccc2c(n1)OCCn1cc(I)nc1-2
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Cl)nc1OCC2
Agent: C[NH3+]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNc1ccc2c(n1)OCCn1cc(-c3ncnn3C(C)C)nc1-2

Procedure:
Following the procedures of Examples herein, including Examples 20-22, 9-chloro-2-iodo-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine was converted to 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine. A mixture of 110 mg (0.33 mmol) of 9-chloro-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepine, 87 mg (1.3 mmol) of methylammonium chloride and 0.23 ml (1.3 mmol) of N,N-diisopropylethylamine in 3.0 ml of N-methylpyrrolidinone was microwaved for 90 min at 170° C. NMP was removed under high vacuum, the residue was basified with 1 M Na2CO3 and partitioned between ethyl acetate and water. The organic extracts were washed with 5% aqueous citric acid, water, brine, dried over MgSO4 and concentrated. The residue was purified by RP HPLC (acetonitrile gradient) to give 367. Yield 12 mg. M/z 326.3, calc. 325.17. 1H NMR (400 MHz, DMSO) δ 8.37 (d, J=8.6, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 6.96 (s, 1H), 6.34 (d, J=8.6, 1H), 5.88 (dt, J=13.0, 6.5, 1H), 4.46 (d, J=9.2, 4H), 2.78 (d, J=2.9, 3H), 1.46 (d, J=6.6, 6H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:17])=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:5])[CH3:2].C(N(CC)CC)C.F[B-](F)(F)F.C([C:32](=[N:38]OC(N(C)C)=[N+](C)C)[C:33](OCC)=[O:34])#N.C(CN)O>CN(C)C=O>[OH:34][CH2:33][CH2:32][NH:38][C:10]([C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH:7]=[C:6]([CH3:17])[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:12]
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)O
Agent: F[B-](F)(F)F
Solvent: NCCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=Cc1ccccc1C(=O)NCCO

Procedure:
Ethyl 3-[2-(2-hydroxyethylcarbamoyl)phenyl]-2-methylacrylate is prepared as described in Example 30, starting with 1.17 g (5.0 mmol) of 2-(2-ethoxycarbonylpropen-1-yl)benzoic acid in 10 cm3 of dimethylformamide, a solution of 0.69 cm3 (5.0 mmol) of triethylamine and 1.64 g (5.0 mmol) of O-[(cyano(ethoxycarbonyl)methylene)amino]1,1,3,3-tetramethyluronium tetrafluoroborate (“TOTU”) in 6 cm3 of dimethylformamide, and a second solution consisting of 306 mg (5.0 mmol) of ethanolamine and 0.69 cm3 (5.0 mmol) of triethylamine in 10 cm3 of dimethylformamide. 1.14 g of ethyl 3-[2-(2hydroxyethylcarbamoyl)phenyl]-2-methacrylate are thus obtained in the form of a yellowish oil, which can be reacted in the following step without further purification.
Reaction SMILES: Cl[C:2]1(Cl)[CH:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])[CH2:4][C:3]1=[O:14]>CO.[Cl-].[NH4+].[Cu].[Zn]>[Si:7]([O:6][CH:5]1[CH2:2][C:3](=[O:14])[CH2:4]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)C1(Cl)Cl
Agent: [Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.3 %

Procedure:
To a solution of 2,2-dichloro-3-tert-butyldimethylsilyloxy-cyclobutanone (see, for example, Journal of Organic Chemistry, 44, 2560 (1979)) (3.20 g, 11.9 mmol) in saturated ammonium chloride methanol (70 mL) was added zinc-copper couple (3.89 g, 59.5 mmol) under nitrogen, and the mixture was stirred at room temperature for 24 hours. The mixture was evaporated, and then thereto was added water and the mixture was extracted with ethyl acetate, washed with saturated ammonium chloride water, and then dried over magnesium sulfate, and filtered. The filtrate was evaporated and purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the titled compound (914 mg, 38%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:5][C:4]([CH3:16])=[N:3]1.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]([N:31]2[CH2:32][CH2:33][N:28]([C:26]3[S:25][N:24]=[C:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:27]=3)[CH2:29][CH2:30]2)=[O:15])=[CH:5][C:4]([CH3:16])=[N:3]1
Reactant: Cc1cc(NC(=O)OCC(Cl)(Cl)Cl)n(C)n1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)n(C)n1
Temperature: 70 °C
Reaction time: 15 h
Yield: 46.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl (1,3-dimethyl-1H-pyrazol-5-yl)carbamate (256 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 146 mg (46.9%) of the desired product as a solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:31])(=[O:30])[C:13]=2[CH:32]=1)=[O:8].N1C=CC=CC=1>ClCCl>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:33])[C:12]2[O:18][C:17]3[C:19]([Cl:29])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:26]([C:1](=[O:3])[CH3:2])[CH2:27][CH2:28]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:31])[C:13]=2[CH:32]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)=O)CC3)cc(Cl)c1O2
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
Acetyl chloride (0.15 mL, 2.06 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cycloheptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in dichloromethane (15 mL) and stirred at 20° C., for 10 min. To this, pyridine (0.33 mL, 4.12 mmol) was added and the mixture was stirred further for 18 h. The solvent was removed from the mixture and water (15 mL) was added. The pH of the reaction mixture was adjusted to 3 using aqueous hydrochloric acid (10%). The solid obtained was filtered and the crude obtained was purified by column chromatography (silica gel, 2% methanol in chloroform) to obtain the title compound. Yield: 0.3 g, (91%); 1H NMR (DMSO-d6, 300 MHz): δ 2.02 (s, 3H, CH3), 2.63 (s, 3H, CH3), 3.15 (s, 2H, CH2), 3.17 (s, 2H, CH2), 3.55 (s, 4H, 2CH2), 3.85, (s, 3H, OCH3), 5.16 (s, 2H, CH2), 7.09 (d, 1H, Ar), 7.15 (d, 1H, Ar), 8.08 (t, 1H, Ar), 8.15 (t, 1H, Ar); MS: m/e (ES+) 479 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH2:22][OH:23])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26]N(C=O)C.[H-].[Na+].CI>O>[CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]4[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]4[CH2:22][O:23][CH3:26])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C=O
Reactant: Cc1nc(CN2CCOC[C@@H]2CO)c2cc(C3CCCCC3)sc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC[C@H]1COCCN1Cc1nc(C)nc2sc(C3CCCCC3)cc12
Reaction time: 0.08 h

Procedure:
To a mixture of {(3S)-4-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]morpholin-3-yl}methanol (132 mg) and DMF was added NaH (60% oil, 15 mg) under ice-cooling, followed by stirring at the same temperature for 5 minutes, and then CH3I (17 μL) was added thereto, followed by stirring at the same temperature for 30 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, then dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-4-{[(3S)-3-(methoxymethyl)morpholin-4-yl]methyl}-2-methylthieno[2,3-d]pyrimidine (102 mg).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: OCCCCOc1ccc(O)cc1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCCCOc1ccc(Oc2ccccc2OC(F)(F)F)cc1
Temperature: 90 °C

Procedure:
A mixture of 3.13 g of 4-(4-hydroxyphenoxy) butan-1-ol, 4.97 g of 4-(trifluoromethoxy)bromobenzene, and 4.75 g of K2CO3 are placed in a flask and flushed with N2 gas. To this are added 17 ml of pyridine and, after heating to 90° C.., 3.42 g of CuO. The reaction mixture is heated at reflux for 2 days, and then cooled and poured into an ice/3N HCl mixture. This mixture is extracted twice with ether; and after separating, the combined ether extracts are washed with saturated NaHCO3, followed by brine, and then dried over MgSO4. Filtration and evaporation yields an oily residue which is purified by flash chromatography on silica gel, using 2:1 hexane/EtOAc as eluant. After evaporation, 4-[4-(4-(trifluoromethoxyphenoxy)phenoxy]butan-1-ol is obtained as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:9](=[O:28])[N:10]1[C:18]2[C:13](=[CH:14][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([NH2:44])[N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:32]([O:31][C:30](=[O:36])[NH:29][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([NH2:44])[N:39]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)=[O:28])([CH3:34])([CH3:35])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Nc1nccc(Cl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2cc(-c3ccnc(N)n3)ccc21
Yield: 80.8 %

Procedure:
To a solution of tert-butyl {(1S)-1-benzyl-2-oxo-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}carbamate (672 mg) and 4-chloro-2-pyrimidinamine (265 mg) in 1,4-dioxane (10 mL) were added 2M sodium carbonate aqueous solution (2.0 mL) and tetrakis(triphenylphosphine) palladium (16 mg) and the mixture was refluxed for 3 hours under nitrogen. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford tert-butyl{(1S)-2-[5-(2-aminopyrimidine-4-yl)-2,3-dihydro-1H-indol-1-yl ]-1-benzyl-2-oxoethyl}carbamate (507 mg) as a powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][NH:16]3)=[N:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.Br[CH2:30][C:31]([O:33]C(C)(C)C)=[O:32].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][N:16]3[CH2:30][C:31]([OH:33])=[O:32])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2cccc3c2CCN3)nc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Oc2cccc3c2CCN3CC(=O)O)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.3 %

Procedure:
6-(2,3-Dihydro-1H-indol-4-yloxy)nicotinic acid ethyl ester (1.13 g, 3.97 mmol) was dissolved in DMF (5 mL). To the solution were added triethylamine (0.665 mL, 4.77 mmol) and tert-butyl bromoacetate (0.704 g, 4.77 mmol), and the resulting solution was stirred for 16 hours at room temperature, followed by stirring for 4 hours at 50° C. Water (100 mL) was added and the resulting solution was extracted with ethyl acetate (100 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated to give a pale brown oil (1.58 g). This oil was dissolved in trifluoroacetic acid (10 mL) and the solution was stirred for 1 hour at room temperature. The solution was concentrated, and the pH of the solution was adjusted to 5 using saturated sodium bicarbonate solution. The resulting solution was extracted with a mixture of ethyl acetate (50 mL)-THF (25 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was recrystallized from a mixed solution of ethyl acetate and n-hexane to yield 0.220 g of the title compound as a pale brown powder.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Br[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([N+:30]([O-:32])=[O:31])[CH:24]=1.O1CCOCC1.CCN(C(C)C)C(C)C>O>[NH2:27][C:26]1[CH:28]=[CH:29][C:23]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][C:13]=3[CH:15]=2)=[CH:24][C:25]=1[N+:30]([O-:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Temperature: 95 °C
Yield: 72.4 %

Procedure:
(4-{[(1,1-dimethylethyl)oxycarbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (2.22 g, 7.57 mmol) and 4-bromo-2-nitroaniline (1.56 g, 7.20 mmol) were taken into dioxane (20 mL), water (4 mL) and DIPEA (5.4 mL, 31 mmol) followed by addition of dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (322 mg, 0.39 mmol) and the mixture was heated to 95° C. for 2 h. The mixture was cooled to room temperature and partitioned with ethyl acetate and 10% aqueous citric acid. The biphasic mixture was filtered through a celite pad and the organic filtrate was washed once with 0.5M aqueous hydrochloric acid, brine then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to give 1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.01 g, 69% yield) as a yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[OH:22][C@H:23]1[CH2:27][CH2:26][NH:25][CH2:24]1.C(N(CC)CC)C.O>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([N:25]2[CH2:26][CH2:27][C@H:23]([OH:22])[CH2:24]2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: O[C@H]1CCNC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N4CC[C@H](O)C4)nc(Cl)nc32)cc1
Yield: 87.6 %

Procedure:
A solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.584 mmol), (S)-3-hydroxypyrrolidine (58 mg, 0.667 mmol) and triethylamine (0.160 mL, 1.15 mmol) in dioxane (5 mL) was stirred at 70° C. for 20 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (S)-1-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-ol (201 mg). MS 393.3 and 395.3 (M+H, Cl pattern).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5](OCC)=[O:6].C(O)(=O)C.[CH3:17][NH:18][NH2:19].[OH-].[Na+].Cl>O.C1(C)C=CC=CC=1>[OH:6][C:5]1[N:18]([CH3:17])[N:19]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: CNN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)(F)F)cc1O
Temperature: 10 °C
Yield: 86.5 %

Procedure:
92.1 g (0.5 mole) of ethyl 4,4,4-trifluoroacetoacetate was dissolved in 60.1 g (1.0 mole) of acetic acid. The solution was cooled to 10° C. or lower with stirring. Thereto was dropwise added, in 1 hour, 65.8 g (0.5 mole) of a 35% aqueous methylhydrazine solution. After the dropwise addition, the mixture was stirred at room temperature for 1 hour and successively at 80° C. for 5 hours to give rise to a reaction. After the reaction, the mixture was cooled to room temperature. Thereto were added 150 ml of toluene, 600 ml of water and 48 g (1.2 moles) of sodium hydroxide. After phase separation, 154 g (1.5 moles) of 35% hydrochloric acid was added to the aqueous layer. The resulting crystals were collected by filtration, washed with 50 ml of water twice, and dried in a hot-air drier, to obtain 71.8 g (yield: 86.5%) of a title compound as light yellow crystals.