Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:17][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: OCc1ccc(Cl)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCc2ccc(Cl)c(Cl)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.2 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (448 mg, 2.68 mmol), 3,4-dichlorobenzyl alcohol (665 mg, 3.76 mmol), and triphenylphosphine (980 mg, 3.74 mmol) were dissolved in tetrahydrofuran (8 mL), and a diethyl azodicarboxylate toluene solution (2.2 M, 1.71 mL, 3.76 mmol) was slowly added dropwise thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane/dichloromethane (6/1 (v/v)), whereby the objective title compound was obtained as a yellow solid (351 mg, yield: 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:9].[C:18]([CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24])(O)=[O:19].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH2:6][CH2:7][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH3:9])[C:18](=[O:19])[CH2:21][N:22]1[CH:30]=[C:28]([CH3:29])[C:26](=[O:27])[NH:25][C:23]1=[O:24]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: COC(=O)CNCCN(C)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a suspension of N-[(N-Boc)(N-methyl)-2-aminoethyl]-glycine methyl ester (0.9 g, 0.0037 mol) and DHBT-OH (0.65 g, 0.004 mol) in CH2Cl2 10 ml was added N-1-carboxymethylthymine (0.74 g, 0.04 mol) dissolved in DMF (6 ml). The solution was cooled in an ice bath and DCC (0.905, 0.049 mol) was added. The reaction mixture was stirred for 1 hour and the ice bath was removed. The reaction mixture was left for 16 hours at room temperature. The reaction mixture was filtered and washed twice with 1N KHSO4 (15 ml) and three times with NaHCO3 (15 ml), brine (10 ml) and water (10 ml) and dried with Na2SO4. The product was purified by column chromatography on silica gel with CH2Cl2/MeOH 95:5 eluent. The yield of the title compound was 55%.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:39][O:40][CH2:41][CH2:42][S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:49]2[CH:50]=[CH:51][C:46]([S:43]([CH2:42][CH2:41][O:40][CH3:39])(=[O:44])=[O:45])=[CH:47][CH:48]=2)=[CH:21][CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 55.3 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 122, 550 mg, 0.99 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (603 mg, 2.47 mmol) and dichlorobis(triphenylphosphine)palladium (II) (70 mg, 0.01 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 1.24 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-5-fluoro-2-[1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (320 mg, 55%) as a white solid: LC/MS m/e calcd for C29H29FN2O6S2 [M+H]+ 585.69, observed 585.1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:15])[C@@H:10]([C:12]([OH:14])=[O:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.O1CCCC1>[C:22]([NH:11][C@H:10]([C:12]([OH:14])=[O:13])[C@@H:9]([CH3:15])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
A mixture containing 10 mmoles of O-benzyl-threonine, 10 mmoles of Na2CO3 in water and tetrahydrofuran (THF) is stirred at room temperature. Benzoyl chloride (10 mmoles), dissolved in anhydrous THF, is added gradually with continued stirring at room temperature. The reaction mixture is stirred until the reaction is completed as judged by thin layer chromatography (TLC). The solvent is removed by a rotary evaporator at 30° C. An excess of water is added and the reaction mixture extracted several times with ethyl acetate. The aqueous phase is adjusted to pH 2 with 1N HCl. The precipitate is recovered by filtration and washed with dilute HCl and then with cold water. The precipitate is dried over P2O5 in a vacuum desiccator. The precipitate is homogeneous as judged by TLC. In this reaction sequence, the racemate is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=O)(=[O:5])=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1>O1CCCC1>[CH3:31][N:32]([CH3:44])[CH2:33][CH2:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:11](=[O:13])[C:10]2[CH:14]=[C:6]([S:3]([N:2]([CH3:1])[CH3:17])(=[O:4])=[O:5])[CH:7]=[CH:8][C:9]=2[O:15][CH3:16])=[CH:38][CH:37]=1
Reactant: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)O
Reactant: CN(C)CCOc1ccc(CN)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N(C)C)cc1C(=O)NCc1ccc(OCCN(C)C)cc1
Yield: 91.4 %

Procedure:
To a cooled suspension of 3.20 g of 5-dimethylaminosulfonyl-2-methoxybenzoic acid in 10 ml of tetrahydrofuran were successively added dropwise 1.25 g of triethylamine and 1.34 g of ethyl chloroformate with stirring. The mixture was stirred at the same temperature for 30 minutes and then a solution of 2.00 g of 4-[2-(dimethylamino)ethoxy]benzylamine in 10 ml of tetrahydrofuran was added dropwise with stirring. The mixture was stirred at room temperature for 2 hours and the solvent was evaporated. Hydrochloric acid (10%) was added to the residue and the aqueous solution was washed with ethyl acetate. The aqueous layer was made alkaline with potassium carbonate and was extracted with ethyl acetate. The extract was dried and evaporated. The residue was washed with isopropyl ether to give 4.10 g of colorless crystals, which were recrystallized from a mixture of ethyl acetate and ether to give colorless needles, m.p. 99.5°-100.5° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]=[O:19])[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][Mg]Br.C(OCC)C.[NH4+].[Cl-]>O1CCCC1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([CH:18]([OH:19])[CH3:27])[NH:15][C:12]2=[CH:13][N:14]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxaldehyde (Example 139) (2.89 g, 8.46 mmol) in tetrahydrofuran (42 mL) was added 3.0 M methylmagnesium bromide in diethyl ether (7.05 mL, 21.2 mmol). The reaction mixture was stirred overnight (16 h) under a nitrogen atmosphere at room temperature. The reaction mixture was poured into a stirring saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic extracts were dried over Na2SO4. After filtration and concentration, a small amount of the desired product was obtained by trituration with CH2Cl2. Additional material was obtained by purification using Biotage chromatography on silica (eluting with Hex/EtOAc 90:10 to 0:100) to provide 1-[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl]ethanol (1.74 g, 57%) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ1.53 (3H, d, J=6.6 Hz), 4.69 (4H, s), 4.90-4.99 (1H, m), 6.08 (1H, s), 6.58 (1H, s), 7.17-7.29 (10H, m), 8.26 (1H, s); ESI MS m/z 358 [C23H23N3O+H]+; HPLC (Method A) 98.5% (AUC), tR=18.2 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@:8]([CH:28]=[CH2:29])([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C@@H:12]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C1COCC1>[Pd].CO>[CH2:28]([C@@:8]12[CH2:7][CH2:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:18]=3[C@H:17]1[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@H:9]2[CH2:10][CH2:11][C@@H:12]1[O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH3:29]
Reactant: C=C[C@@]12CCc3cc(OC)ccc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@@]12CCc3cc(OC)ccc3[C@H]1CC[C@]1(C)[C@@H](OC3CCCCO3)CC[C@H]12

Procedure:
0.50 g of 13a was dissolved in 25 ml of solvent mixture that consists of THF and methanol (v/v=7/3) and stirred with 0.30 g of palladium (10% on magnesium carbonate) for 3.75 hours at room temperature under hydrogen atmosphere. Then, the reaction solution was filtered on Celite, the filtrate was evaporated to the dry state in a rotary evaporator and the bright foam that was obtained was used without additional purification in the next stage.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:13]2[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:8]=2[C@H:7]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][C@H:6]2[NH:5]1.I[CH3:29]>C1COCC1>[CH3:29][N:5]1[C@@H:6]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@@H:7]2[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[C:13]=2[C:4]1=[O:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3C(=O)N[C@@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)c2c(cccc2C(F)(F)F)[C@H]2CN(C(=O)OC(C)(C)C)C[C@H]21
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a suspension of NaH (17 mg of 60% in mineral oil, hexane-washed, 0.42 mmol) in 2 mL of THF at ambient temperature was added (±)-cis-tert-butyl 5-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]isoquinoline-2(9bH)-carboxylate from Example 1, Part H (75 mg, 0.21 mmol) as a solution in 2 mL of THF. The reaction was stirred for 20 min, at which time gas evolution had ceased and the reaction mixture was homogeneous. Then there was added iodomethane (0.039 mL, 0.63 mmol) and the reaction was allowed to stir at ambient temperature for 1 h. The reaction was quenched with water, diluted with EtOAc and washed with 1N HCl, sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (230-400 mesh silica gel, elution with 2:1 hexane/EtOAc) to afford 30 mg (39%) of the title compound. LRMS (ESI): 315.22 (M+H—C4H8)+.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[Cl:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27](B3OC(C)(C)C(C)(C)O3)[O:28][C:24]=2[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:22]1[CH:39]=[CH:38][C:25]2[CH:26]=[C:27]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)[O:28][C:24]=2[CH:23]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2cc3ccc(Cl)cc3o2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3cc4ccc(Cl)cc4o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in 1,4-dioxane (1 mL) was added 2-(6-chloro-1-benzofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, crude), and K3PO4 (140 mg, 0.66 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) under nitrogen atmosphere. After stirring 1 h at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 2% ethyl acetate in petroleum ether to afford methyl 2-(6-chloro-1-benzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (60 mg, 43%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>N1C=CC=CC=1>[CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Product: Cc1c(NS(C)(=O)=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-3-nitroaniline (10.0 g, 65.7 mmoles, purchased from Aldrich) in pyridine (70 mL) was treated with methanesulfonyl chloride (5.09 mL, 65.7 mmoles) at 0° C. The reaction mixture was allowed warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the crude products were diluted with diethyl ether (700 mL). The mixture was washed with 1N HCl (250 mL), water (250 mL) and brine (250 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13](N)=[O:14].Cl.[OH-:17].[Na+]>>[O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[CH2:12][C:13]([OH:14])=[O:17]
Reactant: [OH-]
Reactant: NC(=O)CC1Nc2ccccc2NC1=O
Agent: Cl
Agent: [Na+]
Product: O=C(O)CC1Nc2ccccc2NC1=O

Procedure:
2-(3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)-acetamide (22 g, 0.11 mol) was dissolved in 10% NaOH (600 mL) and was heated under reflux for 3 hours. The mixture was cooled down via an ice-bath and was acidified with pre-cooled 10% HCl to pH˜6. The solvent was concentrated and the resulting precipitate was isolated via filtration to give a gray solid as the title product: 1H NMR (DMSO-d6) δ=12.35 (bs, 1H), 10.25 (bs, 1H), 6.74-6.68 (m, 3H), 6.61-6.58 (m, 1H), 5.91 (bs, 1H), 4.08-4.04 (m, 1H), 2.69 (dd, 1H, J=5.1, 16.2 Hz), 2.51 (dd, 1H, J=6.9, 16.2 Hz)
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH:6]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>CO>[CH:6]1([CH:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NCC1CCCCC1
Reactant: ClCC1CO1
Solvent: CO
Product: OC(CCl)CNC(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.7 Grams of epichlorohydrin and 10.2 g of cyclohexylmethylamine are dissolved in 50 ml of methanol. The mixture is stirred for 8 hours at room temperature. Methanol is removed by evaporation under reduced pressure. The resulting crude oily substance is purified by a silica gel column chromatography (chloroform:methanol=8:1) to obtain 8.2 g of N-(dicyclohexylmethyl)-N-(3-chloro-2-hydroxypropyl)amine.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:14]1([OH:21])[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[OH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:21][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture (0.06 moles) of 2-chloromethylquinoline hydrochloride, (0.06 moles) of 1,3-benzenediol and 18 g of potassium carbonate in 50 ml of dimethylformamide is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 2-(3-hydroxyphenoxy)methylquinoline having an m.p. of 151°-53° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].C(N(CC)CC)C>C(#N)C>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:15]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.2 %

Procedure:
under an N2 atmosphere, 4-aminobenzoic acid (2.50 g, 18.2 mmol) was dissolved in acetonitrile (100 ml) and treated with 2-chlorobenzoyl chloride (2.43 ml, 19.1 mmol). Triethylamine (2.66 ml, 19.1 mmol) was added and the reaction was allowed to stir at room temperature for four hours. The reaction was concentrated in vacuo, and the resulting solid was partitioned between Et2O and 0.5N NaOH. The layers were separated and the organic layer was discarded. The aqueous layer was acidified to pH 2 with HCl and the aqueous layer was extracted with ethyl acetate. The organic layer was dried Na2SO4, filtered and concentrated in vacuo. The resulting solid was triturated with Et2O, and the solid was collected by filtration to afford 4-(2-chlorobenzamido)benzoic acid (2.72 g, 54.2% yield). ESI m/z=276.1 (M+H+).
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH2:18][CH:19]=[CH2:20])[O:13][CH2:14][CH:15]=[CH2:16])[P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].C(Cl)Cl.C[N:28](C=O)C>C1COCC1>[NH2:28][CH:1]([P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6])[P:12](=[O:21])([O:13][CH2:14][CH:15]=[CH2:16])[O:17][CH2:18][CH:19]=[CH2:20]
Reactant: CN(C)C=O
Reactant: C=CCOP(=O)(CP(=O)(OCC=C)OCC=C)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)C(N)P(=O)(OCC=C)OCC=C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of bisphosphonate 23 (2.0 g, 5.95 mmol) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 254 mg, 6.35 mmol) portionwise. The solution was stirred for 45 min at room temperature and added to a solution of O-(diphenylphophinyl)hydroxylamine (1.35 g, 5.77 mmol) in THF (40 mL), cooled in a dry ice/acetone bath. The resulting mixture was stirred for 10 min at the same temperature then 18 h at room temperature. CH2Cl2 (40 mL) was added, the solids were removed by filtration and washed with several portions of CH2Cl2. The combined filtrates were concentrated in vacuo and purified by flash chromatography on silica gel using a gradient of 0-5% MeOH/EtOAc to provide aminobisphosphonate 24 as a clear yellow oil (1.24 g, 3.53 mmol, 59%). 1H NMR (400 MHz, CDCl3) δ 1.69 (bs, 2H), 3.52 (t, J=20.8 Hz, 1H), 4.64-4.67 (m, 8H), 5.24-5.27 (m, 4H), 5.36-5.42 (m, 4H), 5.92-6.02 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[C:18](OC(NC(=NC(OC(C)(C)C)=O)SC)=O)(C)(C)C.C(O)(=O)C>CO>[NH2:1][C:2]1[C:6]([CH3:18])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c(-c2ccccc2)cc1N
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c(-c2ccccc2)c(C)c1N
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a 25-mL, round-bottomed flask was added ethyl 3-amino-5-phenylpyrrole-2-carboxylate (Example 66 (b)) (1.1 g) and MeOH (5 mL). To the reaction flask was added 1,3-bis(tertbutoxycarbonyl)-2-methyl-2-thiopseudourea (Aldrich Chemical Company) (1.6 g, 5.5 mmol), followed by glacial acetic acid (1.43 mL, 25 mmol). The reaction mixture was stirred at room temperature under N2 for 28 h. A heavy precipitate formed and was collected by filtration, washed with H2O (3×10 mL) and dried in a vacuum oven overnight to give 0.71 g (32% from Example 66 (a)) of the title compound as an off-white solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.38 (t, 3, J=7.00), 1.44 (s, 9), 1.46 (s, 9), 4.38 (q, 2, J=6.97), 7.31-7.46 (m, 3), 7.76 (d, 2, J=7.86), 11.06 (br s, 1), 11.25 (s, 1), 11.61 (s, 1), 11.95 (br s, 1); MS m/z: 473 (M+1), 471 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([C:16]#[N:17])=[C:5]2[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(O)cc23)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCc4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89 %

Procedure:
To a solution of 6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (1.5 g, 4.7 mmol) and benzyl bromide (0.61 g, 5.1 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (0.71 g, 5.1 mmol), and the mixture was stirred at room temperature for 17 hrs. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (100 ml). The aqueous layer was separated and extracted with ethyl acetate (50 ml). The organic layer and the extract were combined and the mixture was washed with saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, and crystallized from n-hexane-ethyl acetate to give 6-(benzyloxy)-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (1.7 g, yield 91%) as pale-yellow crystals.