Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH3:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH:13]=O>[Pd].CO.O>[CH2:13]([N:1]([CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])[CH2:12][C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: CC(C)(C)CC=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CC(C)(C)CCN(CCC(C)(C)C)[C@@H](CC(=O)O)C(=O)O

Procedure:
To a slurry of L-aspartic acid (4 g, 0.03 mol) in 1:1 methanol/water (80 mL) was added neat 3,3-dimethylbutyraldehyde (3 g, 0.03 mol), followed by Pd/C (4%, 50% wet, 0.5 g). The mixture was hydrogenated using H2 (50 psi) at room temperature for 2 days. The resulting reaction mixture was filtered through a Celite® bed, and the bed washed with methanol (50 mL) The filtrate and washings were combined and the methanol removed using a rotary evaporator under reduced pressure at 40-50° C. to provide the N,N-di-neohexyl L-aspartic acid as a solid precipitate in water. The solid was filtered, washed with water (2 mL) and dried in a vacuum oven at 50° C. for 4 hrs to provide 3.2 g of N,N-di-neohexyl L-aspartic acid (36%), M.P. 197-198° C., [α]D -3 (c=1, methanol). Anal. Calc'd. for C16H31NO4 ; C, 63.78; H, 10.29; N, 4.65. Found: C, 63.43; H, 10.29; N, 4.70
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[N:27]3[CH2:30][CH:29]([C:31]([O:33]C)=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][CH:22]4[N:27]3[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)C1CN(C2CCc3c(-c4noc(-c5ccc(OC(C)C)c(C#N)c5)n4)cccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4N3CC(C(=O)O)C3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3-carboxylate (6.8 mg, 0.02 mmol) was added 5N NaOH (20 μL). The mixture was stirred at room temperature for 2 hours, dissolved in 250 μL of 1:1 DMSO:MeOH and purified by preparative HPLC. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5; found 445.1 [M+H]+, tR=6.52 min (Method 2).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:22][C:23]([F:33])([F:32])[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.C(#N)C.[I-].[Na+]>C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:29][C:28]4[CH:30]=[CH:31][C:25]([O:24][C:23]([F:22])([F:32])[F:33])=[CH:26][CH:27]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 150 °C

Procedure:
In a 5 ml microwave vial was combined 4-chloro-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.113 g, 0.000356 mol), 4-(trifluoromethoxy)aniline (0.0964 mL, 0.000711 mol), acetonitrile (2 mL, 0.04 mol), and sodium iodide (0.00533 g, 0.0000356 mol). The mixture was heated at at 150° C. for 10 minutes and reduced in vacuo. The remaining solid was taken up in ethyl acetate (10 mL) and washed with saturated sodium bicarbonate (2×10 mL) and water (1×10 mL). The organic layer was dried over magnesium sulfate and reduced in vacuo to yield an off white solid. The mixture was purified by flash chromatography using an ethyl acetate:hexanes (0-50%) gradient to yield the desired product as an off white solid (0.105 g).
Reaction SMILES: C([CH:3]1[C:12]2[C:11]([C:13]([N:15]([O:17][CH3:18])[CH3:16])=[O:14])=[N:10][N:9]([CH3:19])[C:8]=2[C:7](=O)/[C:6](=[CH:21]/N(C)C)/[CH2:5][CH2:4]1)C.S(O)(O)(=O)=O.[CH3:30][O:31][C:32](=[NH:34])[NH2:33].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:18][O:17][N:15]([CH3:16])[C:13]([C:11]1[C:12]2[CH2:3][CH2:4][CH2:5][C:6]3[C:7](=[N:34][C:32]([O:31][CH3:30])=[N:33][CH:21]=3)[C:8]=2[N:9]([CH3:19])[N:10]=1)=[O:14]
Reactant: CCC1CC/C(=C\N(C)C)C(=O)c2c1c(C(=O)N(C)OC)nn2C
Reactant: COC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: COc1ncc2c(n1)-c1c(c(C(=O)N(C)OC)nn1C)CCC2
Yield: 59.5 %

Procedure:
To a solution of ethyl (7E)-7-[(dimethylamino)methylidene]-N-methoxy-N,1-dimethyl-8-oxo-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazole-3-carboxamide (1.62 g, 5.3 mmol) in CH3CN (130 ml), O-methylisourea sulphate (5.22 g, 21.2 mmol) and K2CO3 (3 g, 22.2 mmol) were added. The reaction mixture was stirred at reflux for 16 h, then it was filtered to remove salts and the solvent was evaporated. The residue was suspended in DCM and washed with water; the organic phase was dried on Na2SO4, filtered and concentrated. The crude was purified by flash-chromatography in silica gel (hexane/AcOEt:1/1) to afford 1 g (62% yield) of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH2:7])([O-:3])=[O:2].N1C=CC=CC=1.[C:20](Cl)(=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>ClC(Cl)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)([O-:3])=[O:2]
Reactant: CCCCCCCCC(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CCCCCCCCC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
3,5-Dinitroaniline, 10.0 g (0.055 mole), is dissolved in 200 ml dichloroethane, containing 25 ml pyridine. The solution is stirred at room temperature while nonanoyl chloride, 10.3 g (0.058 mole), is added slowly. The solution is stirred for 2 hours. Excess pyridine is removed by washing the product with 4N hydrochloric acid. The product is obtained by crystallization at -20° C. and recrystallized from 95% ethanol. There is obtained N-(3,5-Dinitrophenyl) nonanamide (M.P. 72.5°-73.0° C.). Analysis shows 12.69% nitrogen as against a calculated value of 12.61% for C15H21N3O5.
Reaction SMILES: C(O[CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)(C)(C)C.C(Cl)Cl.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>>[F:18][C:19]([F:24])([F:23])[C:20]([O:22][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:21]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OCCOC1CCOCC1
Solvent: ClCCl
Product: O=C(OCCOC1CCOCC1)C(F)(F)F

Procedure:
4-(2-tert-Butoxyethoxy)tetrahydropyran (24 g, 0.12 mol) was stirred in a mixture of methylene chloride/trifluoroacetic acid (150 ml/150 ml) at ambient temperature overnight. The solvents were evaporated off and the residual trifluoroacetic acid was azeotroped off with, toluene. The crude oil was purified by flash chromatography using successively petroleum ether, petroleum ether/methylene chloride (1/1) and methylene chloride. The organic phase was washed with water, brine, dried (MgSO4), filtered and the solvent evaporated. Evaporation of the solvent gave 4-(2-trifluoroacetoxyethoxy)tetrahydropyran which was hydrolysed with potassium hydrogen carbonate (48 g, 0.48 mol) in methanol (700 ml) and water (300 ml) at ambient temperature for 3 hours. The solution was neutralised to pH 7 and the solvents evaporated off. The residue was extracted with ethyl acetate, the organic phase washed with water and brine, dried (MgSO4) and the solvent evaporated off to give 4-(2-hydroxyethoxy)tetrahydropyran (6 g, 35%) as a light brown oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:24][CH2:23][CH2:22][N:21]3[CH3:25])=[CH:16][N:15]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].CC(O)=O>CO>[CH3:25][N:21]1[CH2:22][CH2:23][CH2:24][C@H:20]1[C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]2)=[N:15][CH:16]=1
Reactant: COC(=O)[C@H]1CC[C@H](CCCc2ccc([C@@H]3CCCN3C)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC[C@H]1c1ccc(CCC[C@H]2CC[C@H](C(=O)O)CC2)nc1

Procedure:
A mixture of 6 (0.11 g, 0.3 mmol) and KOH (0.025 g, 0.45 mmol) in 50% aqueous MeOH (10 mL) was heated under reflux for 30 min. The reaction mixture was acidified with HOAc to pH 8 and the solvents were evaporated in vacuo. The crude product was purified by column chromatography (silica gel, CHCl3/MeOH, gradient of MeOH 10% to 50%) to afford 0.077 g (74%) of 7.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[OH:19])[C:14]#[N:15].[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[C:14]#[N:15]
Reactant: COCCOCCl
Reactant: N#Cc1ccc(O)c(Br)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
Diisopropylethylamine (21.8 mL, 151.5 mmol) was added slowly to a magnetically stirred solution of 3-bromo-4-hydroxybenzonitrile (10 g, 50.5 mmol) and 2-methoxyethoxymethyl chloride (6.9 mL, 60.6 mmol) in dichloromethane (100 mL) and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with 5% citric acid solution until the washings were acidic, dried and concentrated. Product was purified from the residue by chromatography (silica gel, 30% ethyl acetate/hexanes) gave 3-bromo-4-(2-methoxyethoxymethoxy)-benzonitrile (11.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12](#[N:14])[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:13][C:12]#[N:14])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1Br
Reactant: CC#N
Product: COc1ccc(C(O)CC#N)cc1Br

Procedure:
Alkylation of 3-bromo-4-methoxybenzaldehyde with acetonitrile following the method used in Example 115 gave 3-(3-bromo-4-methoxyphenyl)-3-hydroxypropanenitrile as a pale orange oil. Yield (10.32 g, 96%): 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.8, 2.0 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 5.93 (d, J=4.4 Hz, 1H), 4.85-4.81 (m, 1H), 3.81 (s, 3H), 2.86 (ABd, J=16.4, 4.8 Hz, 1H), 2.79 (ABd, J=16.8, 6.8 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[H-].[Na+].Cl.Cl[CH2:33][C:34]1[N:35]=[C:36]([CH3:39])[S:37][CH:38]=1>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:33][C:34]3[N:35]=[C:36]([CH3:39])[S:37][CH:38]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cn2c(N3CCCN(C(=O)OC(C)(C)C)CC3)nc3ccccc32)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
Treat a solution of 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.89 g, 2.77 mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride (0.15 g, 3.05 mmol, 49% dispersion in oil ) at room temperature. After 15 minutes, add slowly a solution of 4-chloromethyl-2-methylthiazole hydrochloride (0.56 g, 3.05 mmol, Lancaster Synthesis) and dimethylformamide (10 mL). After stirring 12 hours at room temperature, add water (10 mL) slowly and extract with dichloromethane.(150 mL). Wash the organic phase with water (3×10 mL), dry (Na2SO4) the organic layer, filter, concentrate the filtrate to remove the solvent and purify the residue by chromatography on silica gel eluting with 5% methanol in dichloromethane. Concentrate the desired fractions to afford 1.02 g of 4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])(=O)C.[Na+]>C(O)CO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([Cl:12])[CH:14]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1cccc(Cl)c1

Procedure:
A mixture of 50 g of 2,4-dichloro-1-nitrobenzene, 40 ml of 3-chloroaniline and 43 g of anhydrous sodium acetate in 220 ml of ethylene glycol is refluxed for 72 hours. After cooling, the precipitate formed is filtered off and washed with water to give 39 g of the expected product after crystallization from iso ether. M.p.=112° C.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:5]1([CH2:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:1]([Cl:4])=[O:2])[CH2:18][CH2:19]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCC(CCCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Phosgene is passed into 150 ml. of dry toluene at 0° C. until 17 g. of gas has been absorbed. The cooling bath is removed, and to the phosgene solution is added, dropwise, with stirring, during 1 hour, a solution prepared from 27.6. g. of 4-(3-phenylpropyl)piperidine, and 12.3 ml. of pyridine and 100 ml. of toluene. After the end of the addition, the reaction mixture is stored at ambient temperature for 16 hours. At this point, the reaction mixture is filtered, and the filtrate is evaporated in vacuo, leaving 39 g. of the title compound in crude state. The product is contaminated with toluene, but it is sufficiently pure for coupling with alkenesulfonamides.
Reaction SMILES: CS(O[CH:6]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH:7]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)=O.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[N:10]1([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12][CH:6]=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:8][CH2:9]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1OS(C)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CCOC(=O)C1=CCCN(C(=O)OC(C)(C)C)CC1
Yield: 95.5 %

Procedure:
A solution of example 42C (0.77 g, 2.1 mmol) in 30 mL of benzene was treated with DBU (0.9 ml ) at 60° C. for 1 hour. After cooling, the reaction mixture was concentrated and the residue was purified by flash column chromatography (30% EtOAc in hexane) to give the title product (540 mg, 95% yield). MS (DCI/NH3) m/z 270 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([NH2:17])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH:18](O)=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([NH:17][CH:18]=[O:19])=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: CNc1nc(Nc2ccc(Cl)cc2)ncc1N
Reactant: O=CO
Product: CNc1nc(Nc2ccc(Cl)cc2)ncc1NC=O

Procedure:
200 mg of 2-(4-chlorophenylamino)-4-methylamino-5-amino-pyrimidine are refluxed in 5 ml of formic acid for 5 hours. The reaction mixture is evaporated to dryness and then the residue is stirred with 15 ml of water. The solid is suction filtered, washed with water, briefly boiled with 15 ml ethanol, cooled, suction filtered again, then washed with hot ethanol and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH3:8][O:7][C:5](=[O:6])[C:4](=[CH:9][NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:15][CH:16]=1)[C:3]([O:2][CH3:1])=[O:18]
Reactant: COC(=O)C(=CNc1ccc(O)cc1)C(=O)OC
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1ccc(NC=C(C(=O)OC)C(=O)OC)cc1
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a mixture of 7 g (28 mMol) of 2-(4-Hydroxy-anilinomethylene)-propanedioic acid dimethyl ester, 3.9 g (28 mMol) of Potassium carbonate in 50 ml of dimethylformamide, 7.3 g (28 mMol) of Butyl iodide were added dropwise with stirring at room temperature. The reaction mixture was heated at 80° C. for 24 hours. Then the reaction mixture was poured into 50 ml of water and extracted three times with ethyl acetate. The organic layer was washed with a solution of sodium hydroxyde (15%) and thereafter with water, dried and evaporated and gave 4.5 g of the title compound which is a white solid melting at 46-47° C., UV 328 nm (E=685).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: C1CCNC1
Product: COc1cc2c(C(=O)N3CCCC3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Yield: 64 %

Procedure:
As described in example 1E, 100 mgs of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid was coupled with pyrrolidine to give 74 mgs (64%) of [6,7-dimethoxy-4-(pyrrolidine-1-carbonyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester: 1H NMR (CDCl3) δ 1.51 (s, 9H), 1.83-1.92 (m, 2H), 2.02-2.07 (m, 2H), 3.20-3.29 (m, 2H), 4.03 (m, 6H), 4.92 (br s, 2H), 6.17 (br s, 2H), 7.23-7.24 (m, 1H), 7.38 (br s, 1H), 8.31-8.33 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[NH:19]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:20]([NH2:22])=[NH:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:21]=[C:20]([NH:19][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[N:22]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N=C(N)NCCCC(=O)O
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Product: O=C(O)CCCNc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 4-guanidino butyric acid were converted to I-19 (6%): HRMS Calcd. for C16H15ClN4O3: 347.091, Found 347.092.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[OH-].[Na+]>C(O)C>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccsc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccsc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-(3-thienyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (400 mg, 1.268 mmol), Ethanol (5 mL) THF (1 mL), and sodium hydroxide (2.114 mL, 6.34 mmol). The final product was collected as 370 mg (100%). LCMS E-S (M+H)=287.9. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.8 Hz, 6 H), 5.34 (quin, J=6.6 Hz, 1 H), 7.72 (dd, J=5.0, 3.0 Hz, 1 H), 7.93 (dd, J=5.0, 1.3 Hz, 1 H), 8.15 (s, 1 H), 8.34 (s, 1 H), 8.49 (dd, J=3.0, 1.3 Hz, 1 H), 13.97 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:9]([NH:11][CH2:12][CH2:13][C:14]3[CH:28]=[CH:27][C:17]([O:18][C:19]4[N:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.Cl.[O:30]([NH2:32])[CH3:31]>C(O)C.O>[CH3:31][O:30][N:32]=[CH:25][C:22]1[CH:23]=[N:24][C:19]([O:18][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][NH:11][C:9]3[C:10]4[C:2]([Cl:1])=[CH:3][S:4][C:5]=4[N:6]=[CH:7][N:8]=3)=[CH:28][CH:27]=2)=[CH:20][CH:21]=1
Reactant: CON
Reactant: O=Cc1ccc(Oc2ccc(CCNc3ncnc4scc(Cl)c34)cc2)nc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CON=Cc1ccc(Oc2ccc(CCNc3ncnc4scc(Cl)c34)cc2)nc1
Yield: 77 %

Procedure:
A solution of 6-{4-[2-(5-Chlorothieno[2,3-d]pyrimidin-4-ylamino)ethyl]phenoxy}pyridine-3-carbaldehyde (0.2 g, 0.5 mmol) and methoxylamine hydrochloride (0.2 g, 2.5 mmol) in ethanol (10 mL) was heated at reflux for 1 hour. After cooling, the reaction was diluted with water and the solid collected by filtration and air dried affording product, 0.17 g, 0.4 mmol, 77 percent yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19](OCC)=[O:20])[CH:15]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[OH:8].[NH3:24].CO>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]3[C:18]=2[N:17]=[C:16]([C:19]([NH2:24])=[O:20])[CH:15]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CCOC(=O)c1ccc2cncc(-c3ccc(O)c(F)c3)c2n1
Reactant: N
Solvent: CO
Product: NC(=O)c1ccc2cncc(-c3ccc(O)c(F)c3)c2n1
Temperature: 80 °C
Yield: 56 %

Procedure:
Ethyl 8-(3-fluoro-4-hydroxyphenyl)-1,6-naphthyridine-2-carboxylate (100 mg, 0.32 mmol) synthesized in Example 1 (1a) was dissolved in a 7M ammonia-methanol solution (10 mL), followed by stirring while heating at 80° C. for three hours. After cooling the resulting reaction liquid to room temperature, a precipitated solid was collected by filtration to give the desired title compound (51 mg, yield 56%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[C:17]([F:28])[C:16]=2[F:29])=[C:11]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][CH:31]=2)[S:10][N:9]=1>>[Cl:7][C:8]1[C:12]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[C:17]([F:28])[C:16]=2[F:29])=[C:11]([C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH3:37])=[CH:34][CH:35]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(-c2snc(Cl)c2COc2ccc(CCCO)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 156 following Step 2 by LAH reduction of ethyl 3-(4-((3-chloro-5-(4-ethylphenyl)isothiazol-4-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=8.8 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 6.86 (t, J=9.0 Hz, 2H), 6.77 (t, J=9.2 Hz, 2H), 5.01 (s, 2H), 3.69 (t, J=8.5 Hz, 2H), 2.75 (m, 4H), 1.88 (m, 2H), 1.52 (br, s, 1H), 1.26 (t, J=9.0 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[N:3]1[CH2:14][CH:15]=O.[C:17]([O:21][C:22]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl.CO>[C:12]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2](=[O:1])[N:3]2[CH2:14][CH2:15][N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:30][CH2:29]2)=[CH:8][CH:7]=1)#[N:13]
Reactant: N#Cc1ccc2ccc(=O)n(CC=O)c2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(C#N)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A solution of 2-oxo-1-(2-oxoethyl)-1,2-dihydro-7-quinolinecarbonitrile (0.60 g, 2.8 mmol) and 4-t-butoxycarbonylaminopiperidine (0.68 g, 2.8 mmol) in chloroform (30 ml) and MeOH (20 ml) was stirred at 60° C. for 1 h. The mixture was then treated with NaBH(OAc)3 (1.8 g, 8.5 mmol), stirred at rt for 1 h, more 4-t-butoxycarbonylaminopiperidine (340 mg, 1.4 mmol) and NaBH(OAc)3 (1.2 g, 5.7 mmol) were then added and the reaction stirred at rt for 1 h. The solvents were then removed and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford the desired compound (1.1 g, 98%).