Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:36][C@H:33]1[CH2:32][CH2:25][CH2:35][O:34]1
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 78-82° C.; 1H NMR (300 MHz, DMSO-d6) δ7.32-7.09 (m, 1H), 7.05-6.92 (m, 1H), 6.44 (s, 1H), 6.35 (s, 1H), 4.96 (dd, J=9.1, 1.1 Hz, 1H), 4.85 (d, J=9.1 Hz, 1H), 4.51 (t, J=8.7 Hz, 1H), 4.31-4.16 (m, 1H), 4.00-3.59 (m, 1H), 2.98 (t, J=8.6 Hz, 1H), 2.12-1.80 (m, 1H), 1.76-1.61 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ178.0 (2), 162.1 (2), 162.0, 144.7, 131.1 (2), 129.8 (2), 128.7 (2), 123.9, 119.4 (2), 118.4 (2), 117.5 (2), 108.1 (2), 92.9, 77.5, 76.9 (2), 72.3, 68.2 (2), 58.1 (2), 44.9 (2), 29.1 (2), 29.0 (2), 25.6 (2); MS (ES+) m/z 397.9 (M+1), 399.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]2.[C:14]12([C:24]3[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[C:14]12([C:24]3[CH:25]=[C:26]([C:2]4[CH:3]=[C:4]5[C:9](=[CH:10][CH:11]=4)[CH:8]=[C:7]([CH:12]=[O:13])[CH:6]=[CH:5]5)[CH:27]=[CH:28][C:29]=3[O:30][CH3:31])[CH2:15][CH:16]3[CH2:17][CH:18]([CH2:19][CH:20]([CH2:22]3)[CH2:21]1)[CH2:23]2
Reactant: COc1ccc(B(O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=Cc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3cc(C=O)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 6-bromo-2-naphthaldehyde (1.17 g, 4.98 mmol, see Example 3c), 3-(1-adamantyl)-4-methoxyphenyl boronic acid (1.57 g, 5.48 mmol, prepared in a manner similar to that described in Example 3b.) and potassium carbonate (1.55 g, 11.20 mmol) in 75 mL of toluene and water (4 mL) was degassed with argon for 30 minutes . Tetrakis(triphenyl phosphine)palladium(0) (0.575 g, 0.50 mmol) was added and the mixture heated at reflux for 18 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:CH2Cl2, 3:2 to 1:1) to give 1.6 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthaldehyde (82%) as a solid. 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.17(m, 9H), 3.90 (s, 3H), 6.99 (d, J=8.1 Hz, 1H), 7.52–7.60 (m, 2H), 7.82 (d, J=8.4 Hz, 1H), 7.95–8.02 (m, 4H), 8.32 (s, 1H), 10.13 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19]>CN(C=O)C>[CH2:17]([N:2]1[N:3]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:5]=[N:1]1)[CH2:18][CH3:19].[CH2:17]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[N:3]=[N:2]1)[CH2:18][CH3:19]
Reactant: COC(=O)c1c[nH]nn1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1cc(C(=O)OC)nn1
Product: CCCn1ncc(C(=O)OC)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
methyl 1,2,3-triazole-4-carboxylate (17.6 g) was dissolved in DMF (210 ml), potassium carbonate (11.5 g) and iodopropane (14.9 ml) were added to the mixture, and the mixture was stirred for 16 hours at room temperature. After filtration, the solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give methyl 2-propyl-1,2,3-triazole-4-carboxylate (10.3 g), methyl 1-propyl-1,2,3-triazole-5-carbonate (3.2 g) and methyl 1-propyl-1,2,3-triazole-4-carboxylate (2.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>C(OCC)C.C(N(CC)CC)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[O:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)=[CH:15][CH:14]=1
Reactant: Oc1cccc2cc[nH]c12
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Oc2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 7-hydroxyindole (0.7 g.) in ethyl ether (25 ml) and triethylamine (1 ml) is added 0.8 g. 4-methoxyphenyl isocyanate (Aldrich 23860-0). The reaction is stirred for 3 days at room temperature. The solvent is removed in vacuo and the remaining oil is purified by HPLC on silica gel.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:20]([CH3:22])=[CH2:21]>COC(OC)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@@H:12]([CH2:15][CH2:16][OH:17])[CH2:13][O:14][C:20]1([CH3:22])[CH3:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@H](CO)CCO)OCc1ccccc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC1(C)OC[C@H](CCO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 95.6 %

Procedure:
A solution of (S)—N-(benzyloxycarbonyl)-2-aminobutane-1,4-diol (8.00 g, 33.4 mmol) and toluene-4-sulfonic acid monohydrate (318 mg, 1.67 mmol) in 2,2-dimethoxypropane (320 mL) was stirred at room temperature, then after 2 h 2-methoxypropene (7.71 g, 107 mmol) was added, then after 72 h the reaction mixture was partitioned between EtOAc and sat. aq. sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was taken up in DCM (200 mL), then after addition of SiO2 (80 g) and water (4.8 mL) the slurry was stirred for 64 h at room temperature. After dilution with DCM and addition of anhydrous magnesium sulfate, insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated and chromatographed (SiO2; heptane/EtOAc 1:1) to afford the title compound (8.92 g, 96%). Light yellow oil, MS (ISP)=280.1 (M+H)+.
Reaction SMILES: C([Sn](Cl)(Cl)CCCC)CCC.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[C:21]3[N:22]([N:29]=[C:30]([NH2:32])[N:31]=3)[CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19].[CH3:33][C:34]1[N:39]=[CH:38][N:37]=[C:36]([N:40]2[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]2)[CH:35]=1.C1([SiH3])C=CC=CC=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[C:21]3[N:22]([N:29]=[C:30]([NH:32][CH:43]4[CH2:44][CH2:45][N:40]([C:36]5[CH:35]=[C:34]([CH3:33])[N:39]=[CH:38][N:37]=5)[CH2:41][CH2:42]4)[N:31]=3)[CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Nc1nc2c(-c3ccc(F)c(Cl)c3)cc(C3CC3)cn2n1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(F)c(Cl)c5)cc(C5CC5)cn4n3)CC2)ncn1
Temperature: 100 °C

Procedure:
To a solution of dibutyl tin chloride (10 mg, 0.03 mmol) and 8-(3-chloro-4-fluoro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 48a-e, 100 mg, 0.33 mmol) in dry THF (1.5 mL) were added 1-(6-methyl-pyrimidin-4-yl)-piperidin-4-one (example 93b, 63 mg, 0.33 mmol) and phenyl silane (0.016 mL, 0.4 mmol) under an argon atmosphere and heated to 100° C. in the microwave for 40 minutes. The reaction mixture was cooled to room temperature, the solvent was evaporated and the residue was purified by prep-HPLC (acetonitrile/H2O). The title compound was obtained as a white solid (20 mg, 13%). MS ESI (m/z): 477.8 [(M+H)+].
Reaction SMILES: ClC(OCC(C)C)=O.C[N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[NH2:16][C:17]1[N:26]=[C:25]([C:27]([OH:29])=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.OC1CCNC1>CN(C=O)C>[NH2:16][C:17]1[N:26]=[C:25]([C:27]([N:10]2[CH2:15][CH2:14][CH:12]([OH:13])[CH2:11]2)=[O:29])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: Nc1nc(C(=O)O)c2ccccc2n1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: OC1CCNC1
Solvent: CN(C)C=O
Product: Nc1nc(C(=O)N2CCC(O)C2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
68.76 μl of isobutyl chloroformate and 63.93 μl of 4-methylmorpholine are added to a solution of 100 mg of 2-amino-4-carboxyquinazoline in 2 ml of DMF. The mixture is stirred at room temperature for 30 minutes, 50.66 mg of 3-hydroxypyrrolidine are added, and the mixture is stirred for a further 30 minutes. Conventional work-up gives 55.7 mg of “A17”; Rt 0.797; M+H+ 259.28.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].Cl>O.O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[C:8]2[O:27][CH:28]([F:30])[F:29]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(F)cc1

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-fluorobenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.060 g), methanol (1.5 mL), tetrahydrofuran (1.5 mL), water (1.0 mL) and lithium hydroxide (0.01 g) was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse-phase HPLC using a gradient of acetonitrile in water gave title compound as a yellow solid, 0.022 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:19])([CH3:18])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1([C:11]([CH3:18])([CH3:19])[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:10][CH2:9][N:8]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCNC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(CC(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
To a stirred mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-3-carboxylic acid ethyl ester (444 mg, 1.54 mmol), triethylamine (214 μl, 1.54 mmol) and cesium carbonate (251 mg, 0.77 mmol) in acetonitrile (5 ml) was added tert-butyl bromoacetate (351 μl, 2.38 mmol) slowly. The mixture was stirred for 1 hour, filtered and concentrated. The residue was diluted with ethyl acetate, washed with water and dried over MgSO4. Solvent was removed under reduced pressure to give a crude product that was purified by column chromatography on silica gel. Elution with a solution of ethyl acetate in hexanes (1:4) provided 580 mg (94%) of the title compound.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].[OH2:25].Cl.[CH3:27][CH2:28][OH:29]>>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:6]1[N:5]=[C:27]([C:28]([OH:25])=[O:29])[CH:9]=[CH:8][CH:7]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: CCO
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Reactant: O
Agent: Cl
Product: O=C(O)c1cccc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67 %

Procedure:
Compound 1B (71 mg, 0.15 mmol) was dissolved in 2 mL of EtOH. Two milliliters of water were then added followed by 2 mL of concentrated HCl. The reaction was stirred at room temperature for 72 hours until LCMS indicated complete conversion. Nitrogen gas was bubbled through the mixture to remove HCl and EtOH; a white solid precipitated. It was collected by filtration, rinsed with water and a small amount of Et2O and dried under vacuum to provide the product as a white solid (42 mg, 67%): 1HNMR (ppm, DMSO) 2.98 (t, J=6.15 Hz, 2H), 3.92 (t, J=6.06 Hz, 2H), 4.95 (s, 2H), 7.02 (d, J=8.5 Hz, 1H), 7.27 (d, J=7.3 Hz, 7.31-7.49 (m, 4H), 758 (d, J=7.5 Hz, 1H), 7.66-7.71 (m, 1H), 7.77 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.9 Hz); LCMS m/z 431.0 (M+1).
Reaction SMILES: [I:1][CH3:2].[NH2:3][C:4]1[N:5]=[C:6]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[N:8][C:9]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>C1COCC1>[I-:1].[NH2:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][N+:13]([CH3:2])=[CH:12][CH:11]=2)=[N:8][C:7]([C:16]2[CH:17]=[CH:18][C:19](=[O:25])[N:20]([CH:22]([CH3:24])[CH3:23])[N:21]=2)=[C:6]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:5]=1
Reactant: CI
Reactant: CC(C)n1nc(-c2nc(-c3ccncc3)c(N)nc2-c2ccccc2)ccc1=O
Solvent: C1CCOC1
Product: CC(C)n1nc(-c2nc(-c3cc[n+](C)cc3)c(N)nc2-c2ccccc2)ccc1=O
Product: [I-]
Temperature: 30 °C
Reaction time: 18 h

Procedure:
In a sealed tube, iodomethane (0.6 ml) was added to a solution of 6-[5-amino-3-phenyl-6-(4-pyridyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (120 mg) in THF (3 ml) and the mixture was stirred at 25-35° C. for 18 hours. A precipitate was collected by filtration to give 4-[3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinyl]-1-methylpyridinium iodide (152 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C@H:6]([NH:26]C(=O)OC(C)(C)C)[C@H:7]([OH:25])[CH2:8][NH:9][C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.FC(F)(F)C(O)=O.[ClH:45]>C(Cl)Cl.CCOCC>[ClH:45].[ClH:45].[NH2:26][C@@H:6]([CH2:5][C:4]1[CH:34]=[C:35]([F:37])[CH:36]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:25])[CH2:8][NH:9][C:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[CH:17]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)c1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)OC(C)(C)C)CCCCC2)c1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CCCCC2)c1
Reaction time: 1 h

Procedure:
To 1.98 g (3.8 mmol) of compound 5 in 15 mL of CH2Cl2 is added 6.5 mL of trifluoroacetic acid. The mixture is stirred under a nitrogen atmosphere for 1 h and then concentrated. The resulting residue is taken up in ethyl acetate and washed twice with 10% Na2CO3 and once with 1 N NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.6 g (quant.) of a pale yellow oil (free base of 6), which is generally carried on in the next step without characterization. The yellow oil may be dissolved in ether and treated with ethereal HCl to precipitate (dihydrochloride 6 as a white solid after trituration with ether: 1H NMR (CDCl3+CD3OD drop) δ 7.55 (s, 1 H), 7.45-7.15 (m, 3 H), 6.85 (m, 2 H), 6.75 (m, 1 H), 4.4 (d, J=9.5 Hz, 1 H), 3.82 (m, 1 H), 2.97 (m, 2 H), 2.81 (dd, J=8, 14 Hz, 1 H), 2.65 (m, 2 H), 2.5 (obscured by water) 2.26 (m, 1 H), 2.13 (m, 2 H), 1.79 (m, 2 H), 1.59 (m, 1 H), 1.45-1.25 (m, 3 H), 1.28 (d, J=7 Hz, 6 H); MS (CI) m/z 417.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([O:22][C:23]([NH:25][C:26]1([CH2:29]O)[CH2:28][CH2:27]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:29][C:26]3([NH:25][C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:24])[CH2:27][CH2:28]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ccnc2cc1O
Reactant: O=C(NC1(CO)CC1)OCc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ccnc2cc1OCC1(NC(=O)OCc2ccccc2)CC1
Reaction time: 20 h
Yield: 46.2 %

Procedure:
20 ml of DCM were added with 4-chloro-7-hydroxy-6-methoxyquinoline (300 mg, 1.43 mmol; from China Gateway), 1-benzyloxycarbonylamino-1-hydroxymethylcyclopropane (412 mg, 1.87 mmol, 1.3 eq; from China Gateway) and triphenylphosphine (490 mg, 1.87 mmol, 1.3 eq). The resulting solution was dropwise added with a solution of DEAD (378 mg, 1.87 mmol, 1.3 eq) in 3 ml of DCM, keeping the temperature at 0° C. for 2 hours. The mixture was then left at 10° C. for 20 hours, then filtered to recover the unreacted 4-chloro-7-hydroxy-6-methoxyquinoline. The filtrate was evaporated under vacuum and the resulting residue was added with 20 ml of 95% EtOH and left under stirring for 30 min. The solid was collected by filtration, washed with 5 ml of 95% EtOH and dried under vacuum to give 1-[(4-chloro-6-methoxyquinolin-7-yloxy)methyl]-N-benzyloxycarbonyl-1-aminocyclopropane (273 mg; yield: 46%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[CH3:10][Si](C=[N+]=[N-])(C)C>CO.C(OCC)C>[OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([O:6][CH3:10])=[O:5]
Reactant: CC(CO)(CO)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)(CO)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a suspension of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (10.06 g, 75 mmol) in MeOH was dropped 2.0 M solution of (trimethylsilyl)diazomethane in diethyl ether and stirred at room temperature overnight. After solvent was concentrated under reduced pressure, the reaction was quenched with saturated NaHCO3 solution and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure to afford methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate as an oil (3.79 g, 34%). 1H NMR (300 MHz, CDCl3) δ 3.81 (d, 2H), 3.67 (s, 3H), 3.60 (d, 2H), 2.89 (br, 2H), 0.96 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([C:31]4[CH:30]=[N:29][N:28]([CH2:27][C:26]([OH:43])([CH3:42])[CH3:25])[CH:32]=4)[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cnn(CC(C)(C)O)c3)ccc1-2

Procedure:
Following Example 267, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxyethyl)-isopropylamide and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted to give 401. MS: (ESI+)=471.2
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[C:8]=1[F:16])[CH2:3][C:4]([O-])=O.CC(OC(C)=O)=O.[CH:24]([O:31]CC)([O:28][CH2:29][CH3:30])OCC.[NH2:34][C:35]1([CH:39]([CH3:42])[CH2:40][OH:41])[CH2:38][CH2:37][CH2:36]1>C1(C)C=CC=CC=1>[OH:41][CH2:40][CH:39]([C:35]1([NH:34][CH:4]=[C:3]([C:2](=[O:1])[C:7]2[CH:12]=[C:11]([F:13])[C:10]([F:14])=[C:9]([F:15])[C:8]=2[F:16])[C:24]([O:28][CH2:29][CH3:30])=[O:31])[CH2:38][CH2:37][CH2:36]1)[CH3:42]
Reactant: CC(CO)C1(N)CCC1
Reactant: O=C([O-])CC(=O)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1(C(C)CO)CCC1)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (6.13 g, 23.2 mmol), Ac2O (13.2 mL, 0.140 mol) and triethyl orthoformate (7.80 mL, 46.8 mmol) was stirred at 120° C. for 3 hours. The mixture was concentrated in vacuo and dried under high vacuum. To the mixture of the residue in anhydrous toluene (100 mL) was slowly added 2-(1-aminocyclobutyl)propanol (3.00 g, 23.2 mmol) in anhydrous toluene (40 mL) at 0° C. The mixture was stirred at room temperature for 2 hours and the solvent was removed by evaporation. Flash chromatography (AcOEt:Hexane=1:1) of the residue gave the title compound as a colorless solid (6.23 g, 67%). 1H-NMR (400 MHz, CDCl3) δ 0.95 (0.6H, t, J=7.3 Hz), 0.97 (3H, d, J=7.3 Hz), 1.09 (2.4H, t, J=7.3 Hz), 1.54 (1H, t, J=4.9 Hz), 1.85-2.15 (3H, m), 2.19-2.50 (4H, m), 3.62-3.75 (2H, m), 4.02 (0.2H, q, J=7.3 Hz), 4.07 (0.8H, q, J=7.3 Hz), 6.97-7.13 (1H, m), 8.24 (0.8H, d, J=15.3 Hz), 8.25 (0.2H, d, J=15.3 Hz), 10.03 (0.2H, d, J=14.1 Hz), 11.40 (0.8H, d, J=14.1 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:31]([NH:35][CH3:36])[CH:32]([CH3:34])[CH3:33]>>[CH2:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][N:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1
Reactant: CNCC(C)C
Product: CC(C)CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cn3)ccc2o1

Procedure:
The product from Example 44E and isobutyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ8.70 (m, 1H), 8.23 (d, J=1.8 Hz, 1H), 7.98 (m, 3H), 7.59 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 3.0-3.8 (m, 14H), 2.98 (s, 3H), 2.2 (m, 1H), 1.09 (d, J=6.6 Hz, 6H); MS (DCI) m/z 422 (M+H)+;