Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:4][OH:5])[CH3:3].[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([CH:22]([CH3:26])[C:23](Cl)=[O:24])=[CH:21][C:8]1=2>N1C=CC=CC=1.O1CCCC1>[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([CH:22]([CH3:26])[C:23]([N:4]([CH2:2][CH3:3])[OH:5])=[O:24])=[CH:21][C:8]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CCNO
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN(O)C(=O)C(C)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A stirring solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 8.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 400 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight (16 hours) with continued stirring. The reaction was quenched with 500 ml of water and concentrated in vacuo to remove solvents. The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na2SO4) and concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated twice via preparative HPLC to give 2.65 g of 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-2-yl)-N-ethyl-N-hydroxypropanamide, as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11]CC)=[O:10])[CH2:4][C:3]1=[O:20].[OH-].[Li+]>C(O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([OH:11])=[O:10])[CH2:4][C:3]1=[O:20]
Reactant: CCOC(=O)C(c1ccccc1)N1CCN(C)C(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(C(C(=O)O)c2ccccc2)CC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.1 %

Procedure:
Ethyl 2-(4-methyl-3-oxopiperazin-1-yl)-2-phenylacetate (250 mg, 0.90 mmol) was dissolved in ethanol (8.6 ml) and water (4.3 ml). Lithium hydroxide (28.2 mg, 1.18 mmol) was added and the reaction was stirred at room temperature for three days. A second portion of lithium hydroxide (4.33 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 24 hours. EtOH was evaporated and 1N HCl was added to the aqueous solution till pH 7. The water was evaporated and the residue was suspended in acetonitrile and filtered on a buckner funnel washing with acetonitrile to obtain 170 mg of desired compound as a white solid. The compound was used in the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([CH3:12])[C:6]=1[C:7](OCC)=[O:8].O.[CH:15]([NH2:17])=O>>[CH3:12][C:5]1[C:6]2[C:7]([OH:8])=[N:17][CH:15]=[N:1][C:2]=2[S:3][C:4]=1[CH3:13]
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc(C)c1C
Solvent: O
Product: Cc1sc2ncnc(O)c2c1C
Temperature: 180 °C
Yield: 85 %

Procedure:
The mixture of ethyl 2-amino-4,5-dimethylthiophene-3-carboxylate (30 g, 0.15 mol) in 150 mL of formamide was heated at 180° C. for 4 h and cooled down. The mixture was poured into 200 mL of water and filtered. The solid was collected and recrystallized from ethanol to afford 5,6-dimethylthieno[2,3-d]pyrimidin-4-ol as yellow solid (23 g, 85%).
Reaction SMILES: [Na+].[Cl-].O[C:4]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:5]=1[C@@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:10]([O:16]C)=[CH:11][CH:12]=2)[O:7]1.C[OH:29]>>[CH3:21][C:20]([CH3:22])=[CH:19][CH2:18][C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[C:13]([C:14](/[CH:15]=[CH:6]/[C:5]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][CH:4]=2)=[O:29])[C:8]=1[OH:7]
Reactant: CO
Reactant: COc1ccc2c(c1CC=C(C)C)O[C@H](c1ccc(O)cc1O)CC2
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)=CCc1c(O)ccc(C(=O)/C=C/c2ccc(O)cc2)c1O

Procedure:
Yellow powder; mp 75-76° C.; UV (MeOH) λmax (log ε) 368 (4.09), 206 (4.08) nm; IR (NaCl) γmax 3395, 2921, 1635 cm−1; 1H NMR (CD3OD, 500 MHz) δ 1.63 (3H, s, H-5″), 1.77 (3H, s, H-4″), 3.34 (2H, d, J=7.2 Hz, H-1″), 5.26 (1H, m, H-2″), 6.53 (1H, d, J=8.8 Hz, H-5′), 6.92 (2H, d, J=8.5 Hz, H-3), 7.72 (2H, d, J=8.4 Hz, H-2), 7.74 (1H, d, J=15.2 Hz, H-1), 7.82 (1H, d, J=15.3 Hz, H-β), 7.96 (H, d, J=8.9 Hz, H-6′); 13C NMR (CD3OD, 125 MHz) δ 17.9 (C-4″), 22.2 (C-1″), 25.8 (C-5″), 107.9 (C-5′), 114.4 (C-1′), 116.0 (C-3′), 116.7 (C-3), 118.5 (C-α), 123.2 (C-2″), 127.6 (C-1), 130.3 (C-6′), 131.5 (C-3″), 131.7 (C-2), 144.9 (C-β), 160.9 (C-4), 162.6 (C-4′), 164.7 (C-2′), 192.5 (CO); EIMS m/z 324 (M+, 100), 281 (83), 269 (22), 176 (22) 161 (36), 149 (96), 120 (31).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)O1.[NH2:19][C:20]1[C:29]2[C:24](=[C:25](Br)[C:26]([CH2:30][CH3:31])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:33]([NH2:35])=[O:34]>>[NH2:19][C:20]1[C:29]2[C:24](=[C:25]([C:9]3[CH:17]=[C:16]4[C:12]([CH:13]=[N:14][NH:15]4)=[CH:11][CH:10]=3)[C:26]([CH2:30][CH3:31])=[CH:27][CH:28]=2)[N:23]=[N:22][C:21]=1[C:33]([NH2:35])=[O:34]
Reactant: CCc1ccc2c(N)c(C(N)=O)nnc2c1Br
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Product: CCc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2cn[nH]c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole and 4-amino-8-bromo-7-ethylcinnoline-3-carboxamide. ESI-MS m/z [M+H]+ 333.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[NH:6]2.[CH2:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH3:20].C(N(CC)CC)C>C(O)C>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([N:24]1[CH2:25][CH2:26][N:21]([CH2:19][CH3:20])[CH2:22][CH2:23]1)[N:10]=[C:9]([CH3:11])[N:8]=2
Reactant: CCN1CCNCC1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3Cl)[nH]c2n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCN(c2nc(C)nc3[nH]c(-c4ccccc4Cl)nc23)CC1
Yield: 41.2 %

Procedure:
Heat a solution of 6-chloro-8-(2-chloro-phenyl)-2-methyl-9H-purine (0.5 g, 0.0017 mol), N-ethyl piperazine (0.22 g, 0.0019 mol), and triethyl amine (0.22 g, 0.0022 mol) in ethanol (10 mL) at 90° C. for 8 h. Alternatively, heat the reaction with microwave irradiation. Upon reaction completion, concentrate the reaction mixture under reduced pressure. Dissolve the residue in dry dichloromethane and wash with saturated sodium bicarbonate solution, water, and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give a residue. Purify the residue on a silica gel column using MeOH:DCM (2:98) as eluent to give 8-(2-Chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.25 g). Add HCl (2 M solution in ethanol) (1.0 eq) into the mixture of 8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.25 g, 0.0007 mol) in dry ether (2.5 mL) at 0° C. and stir for one hour at room temperature. Filter the precipitate, wash with ether and DCM. Dry under vacuum to give the title compound (0.275 g) as a white solid. ES/MS m/z 357 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]([CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:6])[CH3:5].[PH3:13]>>[CH3:12][CH:2]([CH2:3][C:4]([CH3:6])([CH3:5])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:1][P:13]([CH2:1][CH:2]([CH3:12])[CH2:3][C:4]([CH3:5])([CH3:6])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:1][CH:2]([CH3:12])[CH2:3][C:4]([CH3:5])([CH3:6])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)=CC(C)(C)CC(C)(C)C
Reactant: P
Product: CC(CP(CC(C)CC(C)(C)CC(C)(C)C)CC(C)CC(C)(C)CC(C)(C)C)CC(C)(C)CC(C)(C)C

Procedure:
Triisobutylene is reacted with phosphine according to Example 1 and the reaction mixture is subjected to vacuum stripping to remove unreacted triisobutylene and mono 2,4,4,6,6-pentamethylheptylphosphine. The residue is reacted with 1-dodecene according to Example 1 and a mixture is obtained of predominantly bis(2,4,4,6,6-pentamethylheptyl)-ndodecylphosphine and tris(2,4,4,6,6-pentamethylheptyl) phosphine. The above mixture is oxidized with hydrogen peroxide and the corresponding mixture of symmetrical branched and unsymmetrical branched tertiary phosphine oxides is obtained, useful as a metal extractant commposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([C:24](O)=[O:25])[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:27][N:28]([CH3:39])[S:29]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:24]([OH:25])[C:13]3[C:12](=[C:17]([C:18]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([S:29](=[O:31])(=[O:30])[N:28]([CH3:27])[CH3:39])=[CH:33][CH:34]=4)=[O:20])[CH:16]=[C:15]([N+:21]([O-:23])=[O:22])[CH:14]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Product: CN(C)S(=O)(=O)c1ccc(NC(=O)c2cc([N+](=O)[O-])cc3c(O)nc(Nc4ccc(Cl)c(Cl)c4)nc23)cc1

Procedure:
The title compound was prepared in a manner analogous to Example 1 from 2-((3,4-dichlorophenyl)amino)-4-hydroxy-6-nitroquinazoline-8-carboxylic acid and 4-(N,N-dimethyl)sulfamoylaniline. 1H NMR (300 MHz, DMSO-d6):. 11.87 (s, 1H), 10.45 (s, 1H), 8.90 (d, J=2.7 Hz, 1H), 8.80 (d, J=2.7 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H 2.64 (s, 6H). MS (APCI+): m/z 577, 579.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])O1.C(=O)([O-])O.[Na+]>COCCOC.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>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3N)[nH]c2c1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a suspension of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (6.50 g, 19.3 mmol) obtained in the same manner as in the method described in WO03/010140 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (5.08 g, 23.2 mmol) in 1,2-dimethoxyethane (90 ml) and water (45 ml) were added sodium hydrogen carbonate (4.81 g, 57.9 mmol) and tetrakis(triphenylphosphine)palladium (1.12 mg, 0.965 mmol), and the mixture was heated under reflux for 9 hr. The mixture was allowed to cool to room temperature, and water was added to the reaction mixture. The mixture was extracted with ethyl acetate and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1-3:1) to give methyl 2-(2-aminophenyl)-3-cyclohexyl-1H-indole-6-carboxylate (6.48 g, yield 96%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:12][C:13](O)=[O:14].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH:11]1[S:10][C:2]2=[N:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]2[C:13](=[O:14])[CH2:12]1
Reactant: O=C(O)CC(Sc1nc2ccccc2[nH]1)c1ccccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C1CC(c2ccccn2)Sc2nc3ccccc3n21
Temperature: 0 °C
Yield: 51.8 %

Procedure:
3-(2-Benzimidazolylthio)-3-(2-pyridyl)propionic acid (3.7 g) was suspended in dichloromethane (100 ml) and was cooled to 0° C. N,N'-Dicyclohexylcarbodiimide (2.55 g) was added and the mixture was left to stir until t.l.c. showed no starting material. The solvent was removed under reduced pressure and the residue suspended in acetone and filtered. The solvent was removed under reduced pressure and the residue was dissolved in chloroform. The organic solution was washed with dilute sodium hydrogen carbonate solution then water and was dried (MgSO4). The residue was purified on silica using chloroform as eluent to give 2,3 dihydro-2-(2-pyridyl)-[1,3]-thiazino[3,2-a]benzimidazol-4-one 1/4 hydrate (1.8 g,) mp 165.5°-167.5° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:12]1([CH:18]=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=CC1CCCCC1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCCC1

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (2 g, 11.4 mmol) was reacted with cyclohexanecarbaldehyde (1.53 g, 13.6 mmol) (Aldrich) and piperidine (1.35 mL, 13.6 mmol) in methanol to give a mixture of E- and Z-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one as a brown solid (Yield 2.71 g, 91%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl.C([NH:19][CH:20]([C:22]1([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:25][CH2:24][CH2:23]1)[CH3:21])C1C=CC=CC=1.[BH4-].[Na+].Cl>C(O)C.O>[ClH:32].[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:19][CH:20]([C:22]2([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:23][CH2:24][CH2:25]2)[CH3:21])=[CH:3][CH:4]=1
Reactant: CC(NCc1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNC(C)C2(c3ccc(Cl)c(Cl)c3)CCC2)cc1

Procedure:
A stirred mixture of p-anisaldehyde (0.62 ml) and 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (see Example 1 of published British Patent Specification No. 2098602) in the form of its free base (1.22 g) was heated to 130°-135° for 30 minutes. After cooling the residue was dissolved in ethanol (10 ml) and the solution added to a solution of sodium borohydride (1.5 g) in ethanol (200 ml). The mixture was heated under reflux for one hour. Water (10 ml) and then excess 5N HCl were added and the ethanol removed by evaporation. The residue was basified with aqueous sodium hydroxide solution and an ether extraction performed. The extract was dried and evaporated to give an oil. Hydrogen chloride gas was passed through an ethereal solution of the oil to give N-(4-methoxybenzyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 217°-218° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:32])[C:11]([C:28]([O:30]C)=[O:29])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:15](=[O:27])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.O.[OH-].[Li+]>[CH2:1]([O:8][C:9]1[C:10](=[O:32])[C:11]([C:28]([OH:30])=[O:29])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:15](=[O:27])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Yield: 86.5 %

Procedure:
Methyl 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate (420 mg) was dissolved in tetrahydrofuran (8 ml)-water (2 ml), and 4N aqueous lithium hydroxide solution (0.58 ml) was added with stirring. After stirring at 70° C. for 1 hr, the mixture was concentrated. Water (5 ml) and then 5% aqueous potassium hydrogen sulfate solution (15 ml) were added with stirring. The precipitated crystals were collected by filtration to give 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylic acid (352 mg).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[CH3:38][O:37][C:35]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9]1)=[O:36]
Reactant: COC(=O)Cl
Reactant: c1ccc(C(NC2CCCNC2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCCC(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 72.9 %

Procedure:
Add triethylamine (3.73 mL, 26.7 mmol) to a solution of piperidin-3-yl-trityl-amine (7.63 g, 22.3 mmol) in dichloromethane (125 mL), follow by dropwise addition of methyl chloroformate (1.76 mL, 22.7 mmol). Stir the reaction at room temperature under nitrogen overnight. Wash the reaction is wash with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–20% ethyl acetate/hexane) to give 6.51 g of the title compound as a white solid, 73% yield. 1H NMR: consistent with structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][C:21]([N:25]([CH2:29][CH:30]=[CH2:31])[CH2:26][CH:27]=[CH2:28])([CH3:24])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][CH:18]2[CH2:19][CH2:20][C:21]([N:25]([CH2:26][CH:27]=[CH2:28])[CH2:29][CH:30]=[CH2:31])([CH3:24])[CH2:22][CH2:23]2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]
Reactant: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Yield: 35.3 %

Procedure:
Following general procedure F, {6-Bromo-4-[4-(diallylamino)-4-methylcyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (120 mg, 0.248 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (105 mg, 0.372 mmol) to afford the crude product (49 mg) as a brown-green solid: ESI MS m/z 560 [C33H38ClN3O3+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].C(N(CC)C(C)C)(C)C>C1COCC1>[C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:25](=[O:26])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(N)n(C2CCCCC2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(C2CCCCC2)n1
Reaction time: 15 h
Yield: 58.6 %

Procedure:
To a stirred mixture of 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-amine hydrochloride (260 mg, 1 mmol) and potassium carbonate (210 mg, 1.5 mmol) in THF (3 mL) at rt, was added dropwise a solution of phenyl chloroformate (170 mg, 1.1 mmol) in THF (2 mL) and the reaction mixture was stirred for a further 15 h. N,N-Diisopropylethylamine (129 mg, 1 mmol) was added to the reaction mixture and stirring continued for an additional 4 h. The reaction mixture was filtrated, the filtrate concentrated under reduced pressure and the residue partitioned between dichloromethane and water. The organic layer was separated and washed with brine, then concentrated under reduced pressure to give a solid which was recrystallized from diethyl ether to afford crude phenyl 3-tert-butyl-1-cyclohexyl-1H-pyrazol-5-ylcarbamate (200 mg) which was used without further purification. LC-MS (ESI) m/z 342 (M+H)+.
Reaction SMILES: [NH:1]1[C:12]2[C:4](=[CH:5][CH:6]=[C:7]3[C:11]=2[CH:10]=[CH:9][NH:8]3)[CH:3]=[C:2]1[C:13]([OH:15])=O.[CH2:16]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[CH2:16]([CH:23]1[CH2:28][CH2:27][N:26]([C:13]([C:2]2[NH:1][C:12]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[C:7]2[C:11]=3[CH:10]=[CH:9][NH:8]2)=[O:15])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2ccc3[nH]ccc3c2[nH]1
Solvent: CCOCC
Product: O=C(c1cc2ccc3[nH]ccc3c2[nH]1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 1,6-dihydro-1,6-diaza-as-indacene-2-carboxylic acid and 4-benzylpiperidine according to the method described in Example 1/c. Mp.: 186-188° C. (diethyl ether).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][C:10]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])([CH3:25])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[CH2:11][C:10]([NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])([CH3:25])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1=O
Agent: B
Solvent: C1CCOC1
Product: CC1(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccc(F)cc3)ccc2N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
To compound 148H ((75 mg, 0.15 mmol) was added BH3THF (1M, 1.5 mL, 1.5 mmol) at RT under Argon. After addition, the reaction was stirred at RT for 24 h, then quenched by carefully adding MeOH (1 mL). The resulting mixture was stirred at RT for 2 h, then partitioned between saturated aqueous Na2CO3 (10 mL) and EtOAc. The aqueous layer was extracted with EtOAc (15 mL×3) and the combined EtOAc extracts washed with brine, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (0-40%) in hexane to give the title compound as an off-white solid (40 mg, 55%). HPLC: 99% at 8.50 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4), Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 487 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13].[NH4+].[OH-]>O>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1c(F)ccc(F)c1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(F)ccc(F)c1N
Temperature: 70 °C

Procedure:
2-Amino-3,6-difluorobenzonitrile (2.3 g, 15 mmol) was added to concentrated sulfuric acid (5 mL) in a 25 mL 2-necked flask equipped with a thermometer with good stirring. The temperature rose to around 40° C. and the mixture became homogeneous. The solution was heated to 70° C. for 2 hours, cooled to room temperature, poured over ice, neutralized with concentrated NH4OH using water and NH4OH to rinse the flask and adding ice as necessary to keep the mixture cold. The separated solid was collected by filtration, washed with water and dried to give 2-amino-3,6-difluorobenzamide, 2.2 g. A second crop of 0.24 g was collected from the cold, concentrated filtrate, 95% overall. M.P. 121-123° C., LC/MS (ESI) m/z 172, 1H NMR (300 MHz, d6-DMSO) δ 7.70 (bs, 1H), 7.63 (bs, 1H), 7.10 (m, 1H), 6.32 (m, 1H), 6.05 (bs, 2H).