Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[CH:6][C:5]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[I-].[K+]>CN(C)C=O.CCOC(C)=O>[CH2:20]([N:7]1[CH:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([N+:1]([O-:3])=[O:2])=[N:8]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cn[nH]c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of C1 (2.86 g, 15.4 mmol) in N,N-dimethylformamide (60 mL) was added anhydrous potassium carbonate (12.8 g, 92.6 mmol), benzyl bromide (2.20 mL, 18.5 mmol) and a catalytic amount of potassium iodide. The reaction was heated at 60° C. for 18 hours, then diluted with EtOAc and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Purification using silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) provided C2 as an oil. Yield: 1.35 g, 4.90 mmol, 32%. An NOE experiment revealed a strong interaction between the pyrazole CH and aromatic protons on the phenyl group, supporting the indicated regiochemistry for C2. LCMS m/z 276.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.32 (t, J=7.1 Hz, 3H), 4.31 (q, J=7.1 Hz, 2H), 5.33 (s, 2H), 7.30-7.35 (m, 2H), 7.40-7.45 (m, 3H), 7.78 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C(F)(F)F
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (120 mg, 0.31 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (98.5 mg, 0.62 mM) was added and the resultant mixture stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate/THF) to afford 95 mg (67%) of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.7 (d, 1H, J=8 Hz), 7.5-7.2 (m, 6H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.45 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.7 (s, 2H), 4.9 (s, 2H), and 3.9 (s, 3H). IR (CHCl3, cm−1) 1763 and 1674. MS (ES) m/e 457.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32](O)=[O:33]>>[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:31]=1[C:32]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:4]([C:3]([OH:2])=[O:28])[NH:5][C:6]([C:8]2([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:22][CH:23]=1)=[O:33]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccccc2)CCCC1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1ccc(C[C@H](NC(=O)C2(Cc3ccccc3)CCCC2)C(=O)O)cc1
Yield: 69 %

Procedure:
4-Amino-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester (35.3 mg, 0.093 mmol) and 2-methyl-5-nitrobenzoic acid 20 mg, 0.11 mmol) were reacted as described in example 34 to give 4-[[(2-methyl-5-nitrophenyl)carbonyl]amino]-N-[[1-(phenylmethyl)cyclopentyl]carbonyl]-L-phenylalanine (34 mg, 69%), HR—FAB—MS: obs. mass 530.2298. Calcd. mass 530.2291 (M+H).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]#[N:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[SH2:28]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19](=[S:28])[NH2:20])=[C:13]([C:15]([F:17])([F:18])[F:16])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C#N)s1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=S)s1
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-5-cyano-4-trifluoromethylthiazole [sic] (4.6 g, 14.97 mmol) was dissolved in pyridine (20 ml), triethylamine (24 ml) was added, and the solution was saturated with hydrogen sulfide. After two days at room temperature, the solvent was removed on a rotary evaporator. The crude product was taken up in ethyl acetate and washed in succession with 20% strength sodium hydrogen sulfate solution and water. After drying (MgSO4), the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography. Yield: 2.5 g (7.32 mmol, 49%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc(Oc2ccccc2)cc1)c1nccnc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a mixture of (3-chloropyrazin-2-yl)-(4-phenoxyphenyl)-methanol (12.0 g, 38.4 mmol), phthalimide (11.30 g, 76.8 mmol) and triphenylphosphine (20.10 g, 76.8 mmol) in THF (150 mL) in a flame-dried flask was added diisopropylazodicarboxylate (15.2 mL, 76.8 mmol) drop wise under nitrogen atmosphere. The reaction mixture was stirred at 60° C. for 16 h. TLC (EtOAc/Hexanes, 1:1) showed no starting material left. Solvent was then evaporated to give a crude residue which was purified through column on silica gel using EtOAc/Hexanes (1:1). Yield: 10.5 g (61%); 1H NMR (CDCl3, 300 MHz) δ 6.91 (s, 1H), 7.01-7.22 (m, 5H), 7.39-7.43 (m, 4H), 7.78-7.82 (m, 2H), 7.89-7.94 (m, 2H), 8.40 (d, J=2.4 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([Cl:21])=[C:19]([CH2:22][N:23]3[C:27](=[O:28])[CH2:26][CH2:25][C:24]3=[O:29])[N:18]=[C:17]3[S:30][C:31]4[CH2:32][NH:33][CH2:34][CH2:35][C:36]=4[C:16]=23)=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:21][C:20]1[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[C:16]2[C:36]3[CH2:35][CH2:34][NH:33][CH2:32][C:31]=3[S:30][C:17]2=[N:18][C:19]=1[CH2:22][N:23]1[C:24](=[O:29])[CH2:25][CH2:26][C:27]1=[O:28]
Reactant: O=C1CCC(=O)N1Cc1nc2sc3c(c2c(-c2ccc(OCc4ccccc4)cc2)c1Cl)CCNC3
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1CCC(=O)N1Cc1nc2sc3c(c2c(-c2ccc(O)cc2)c1Cl)CCNC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of the compound obtained in Example 14 (600 mg) in methylene chloride (20 ml) was added titanium tetrachloride (1.1 g) while cooling with ice. After stirring for 2 hours at room temperature followed by addition of water (10 ml), the stirring was continued for further 15 minutes. After discontinuing the stirring, the aqueous layer was isolated, and neutralized with saturated aqueous sodium bicarbonate, and then extracted with ethyl acetate-tetrahydrofurane (3:1, v/v). The extracted organic layer was washed with water, dried (MgSO4) and then the solvent was distilled off to obtain the title compound (305 mg, 62%). The product was recrystallized from dimethylformamide-water. A colorless prism crystal. M.p. 286 to 287° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[CH3:34][Mg]Br.[Cl-].[NH4+]>C1COCC1.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH:14]([OH:15])[CH3:34])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Nc2ncc(C(C)O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (641.5 mg, 1.440 mmol) was suspended in THF (14 mL) and the reaction was cooled in an ice bath under nitrogen. Then, methylmagnesium bromide (3.0 M solution in diethyl ether, 1.65 mL, 4.95 mmol) was added via syringe, and the reaction was allowed to warm up to room temperature. After 1 h and 45 min, the reaction was cooled in an ice bath and the reaction was treated with saturated ammonium chloride, dropwise at first as gas evolution was observed. Then, the reaction was warmed to room temperature and diluted with water (15 mL). The layers were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH. The organic layer and the organic extracts were combined, concentrated, and dried under high vacuum to give 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethanol (725 mg). 1H NMR (CDCl3, 400 MHz) δ 12.52 (s, 1H), 9.81 (s, 1H), 8.43 (s, 1H), 8.36-8.19 (m, 3H), 6.83-6.77 (m, 1H), 5.88 (d, J=9.00 Hz, 1H), 5.01 (d, J=5.87 Hz, 1H), 4.21 (d, J=10.95 Hz, 1H), 3.89-3.81 (m, 1H), 2.91 (s, 3H), 2.21-1.65 (m, 6H), 1.63-1.61 (m, 3H). m/z (ESI, pos. ion) 462 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Cl)[CH:13]=[CH2:14].[NH4+].[Cl-]>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:14][CH:13]=[CH2:12]
Reactant: C=CC[Mg]Cl
Reactant: COCC(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)(COC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methoxy-1-phenyl-ethanone (5.00 g) dissolved in tetrahydrofuran (50 mL) was added to 2 M allylmagnesium chloride in tetrahydrofuran (21 mL) at room temperature. The solution was stirred at room temperature for 3 h and then 10% aqueous NH4Cl solution (50 mL) was added. The resulting mixture was extracted with tert-butyl methyl ether (3×50 mL) and the combined extracts were washed with water (50 mL) and brine (50 mL). The solvent was evaporated to afford the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1.[CH3:27][S:28]([CH2:31][CH2:32][CH2:33]O)(=[O:30])=[O:29]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:33][CH2:32][CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: CS(=O)(=O)CCCO
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCS(C)(=O)=O)cc1OC

Procedure:
The title compound was prepared using the method of example 89 step (vii), using the product of example 89 step (vi) (150 mg) and 3-(methylsulfonyl)propan-1-ol (116 mg), to give the title compound as a gum, 6.3 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]([OH:29])([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: Brc1cccc2cc[nH]c12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc3cc[nH]c23)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
To a solution of 7-bromoindole (400 mg, 2.04 mmol) in THF (20 mL) under an argon atmosphere and cooled to −78° C. was added n-butyllithium (3.1 mL, 2.0M, 6.1 mmol) dropwise. The reaction was stirred at −78° C. for 15 minutes then warmed to 5° C. and maintained for 30 minutes. The reaction was cooled back to −78° C. and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (813 mg, 4.08 mmol) was added dropwise in THF (5 mL). The reaction was allowed to come to room temperature and stirred for 1 h. The reaction was quenched with water (15 mL) and extracted with EtOAc (3×20 mL). The combined acetate layers were washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and chromatographed on silica eluting with 20% acetone in hexanes to afford 4-hydroxy-4-(1H-indol-7-yl)-piperidine-1-carboxylic acid tert-butyl ester as a white foam (520 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH:22]=O)[CH:7]=1)[CH3:2].[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH2:22][NH:34][C@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@H:26]2[OH:35])[CH:7]=1)[CH3:2]
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 2, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-4-methoxy-phenyl]acetic acid ethyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.Br[CH2:14][CH2:15][CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Si:18]([O:17][CH2:16][CH2:15][CH2:14][N:10]1[N:11]=[N:12][C:8]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([I:1])[CH:7]=2)=[N:9]1)([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:20])[CH3:19]
Reactant: Ic1cncc(-c2nn[nH]n2)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cncc(I)c2)n1
Temperature: 80 °C

Procedure:
The reaction mixture of 3-iodo-5-(2H-tetrazol-5-yl)pyridine (273 mg, 1 mmol, 1 eq), (3-bromopropoxy)-tert-butyldimethylsilane (0.31 mL, 1.3 eq), potassium carbonate (207 mg, 1.5 eq) in anhydrous DMF (4 mL) under nitrogen atmosphere was stirred and heated at 80° C. for 5 hours. The mixture was then diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, aqueous ammonium chloride, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated under reduced pressure, and the resulting brown oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:50 to 1:4) giving 3-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)-5-iodopyridine as a soft white solid in the amount of 395 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)(=[O:19])[CH3:18].Cl>CN(C)C=O>[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6])(=[O:19])[CH3:18]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1cc(O)cc(C=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.5 %

Procedure:
3,5-Dihydroxybenzaldehyde (0.96 g) and potassium carbonate (1.44 g) were suspended in N,N-dimethylformamide (5 mL). To the mixture was added 4-bromobutyl acetate (1.49 g) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/5) to give the title compound (0.57 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH3:15])[C@H:10]([CH2:16][N:17]([C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:23]=2)[CH:18]([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37]1([CH2:43][C:44](Cl)=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH3:15])[C:44](=[O:45])[CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:10]([CH2:16][N:17]([C:21](=[O:36])[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][O:34][CH3:35])[CH:23]=2)[CH:18]([CH3:19])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC)C(C)C)cc1OCCCOC
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C)C(=O)Cc2ccccc2)C(C)C)cc1OCCCOC

Procedure:
From (3R,4R)-3-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-methylaminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.7 g, 1.38 mmol), phenylacetyl chloride (0.22 mL, 1.66 mmol) and triethylamine (0.21 mL, 2.1 mmol) in CH2Cl2 (40 mL) and purification by flash chromatography on silica gel (c-hexane/AcOEt 1:1 to 0:1) to give the title compound as colorless oil. TLC, Rf (AcOEt)=0.30. MS (LC-MS): 624.0 [M+H]+; tR (Waters Symmetry C18 column, 20-100% CH3CN/H2O/5 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 4.41 min.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].[CH2:18](I)C.O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH3:18])=[CH:6][C:5]=1[CH3:17]
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 104.5 %

Procedure:
A mixture of powdered potassium hydroxide (3.35 g, 59.67 mmol) in DMSO (40 mL) was stirred at 0° C. for 10 min. 7-bromo-4,4,6-trimethyl-3,4- dihydro-1H-quinoline-2-one (Example 1e) (8.0 g, 29.83 mmol) was added cautiously, followed immediately by the addition of ethyl iodide (12 mL, 149.17 mmol). The reaction mixture was kept at 0° C. for 30 min then slowly warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (MgSO4), filtered and evaporated to give 8.8 g of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one and used without further purification in the Suzuki coupling (step a): 1H NMR (300 MHz; CDCl3): 1.24 (t, J=7.2 Hz, 1 H), 1.25 (s, 6 H), 2.37 (s, 3 H), 2.45 (s, 2 H), 3.98 (q, 2 H), 7.13 (s, 1 H), 7.18 (s, 1 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]>CCOCC>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([Cl:3])=[O:18])[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)N1CCC(CCC(=O)O)CC1
Solvent: CCOCC
Product: CC(=O)N1CCC(CCC(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To thionyl chloride (300 mL) was added 3-(1-acetyl-4-piperidinyl)propionic acid (88.2 g, 0.443 mol) in small portions under ice cooling. The mixture was stirred at room temperature for 10 minutes, and then thionyl chloride was distilled off at 25° C. under reduced pressure. Diethyl ether was added to the residue and then evaporated in vacuo to give a yellow solid. Again, diethyl ether was added, and the solid was crushed with a spatula, and ether was evaporated in vacuo to give 3-(1-acetyl-4-piperidinyl)propionic acid chloride as crude light yellow powder. This light yellow powder and 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one (64.0 g, 0.369 mol) were suspended into 1,2-dichloroethane (200 mL), into which aluminum chloride (162 g, 1.21 mol) was added in small portions at room temperature. The mixture was stirred at room temperature for 12 hours, then added to ice-water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried on anhydrous magnesium sulfate, and evaporated in vacuo to give a light yellow oily material. The oily material was purified by silica gel column chromatography (eluted with ethyl acetate/methanol=9:1) and crystallized from ethanol-diethyl ether to give 123.5 g of 8-[3-[(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one as colorless crystals having mp. 157-159° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=O)=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:6]=2)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:44]([O:51][NH2:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(CC)CC)C>ClCCl>[CH2:44]([O:51][NH:52][C:11]([C:10]1[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:6][C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:8]([F:14])[CH:9]=1)=[O:13])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CN1CCN(c2nc(NC3CC3)c(C(=O)O)cc2F)CC1
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(c2nc(NC3CC3)c(C(=O)NOCc3ccccc3)cc2F)CC1
Yield: 59.8 %

Procedure:
Following the procedure of Example I-2, the reaction of 2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxylic acid (Example H-2, 200 mg, 0.67 mmol) and HOBT (99.5 mg, 0.74 mmol) with EDCI (154.6 mg, 0.81 mmol) in dichloromethane (10 mL) followed by adding O-benzylhydroxylamine hydrochloride (0.81 mmol) and triethylamine (0.113 mL, 0.81 mmol) gave a crude oil. Purification of the oil by flash chromatography on a silica gel column with 5% of MeOH in dichloromethane provided 160 mg of the title compound as an oil.