Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH:9]12[CH2:10][N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH:13]1[CH2:14][CH2:15][NH:8]2
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2CCNC2C1

Procedure:
21.2 g (77.3 mmol) of ethyl 2-benzyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 400 ml of ethanol are hydrogenated at 100° C. and 100 bar on 3 g of palladium-active carbon (10% Pd). The catalyst is filtered off, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:25]O.C[O-].[Na+]>OCC(CO)O>[CH3:25][O:23][C:1](=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC/C=C\CCCCCCCCCCCC(=O)O
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: OCC(O)CO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Reaction time: 0.5 h

Procedure:
Behenic methyl esters are made from hydrogenated high erucic acid rapeseed oil. About 870 grams of hydrogenated high erucic acid rapeseed oil, about 174 grams of methanol, and about 12.2 grams of sodium methoxide solution (25% in methanol) are added to a spherical 3-liter glass reactor. The reactor has a heating mantle, thermometer, temperature controller, reflux condenser, variable speed agitator, vacuum take-off, and bottom outlet. The mixture is reacted at about 65° C. for approximately 1.5 hours,while refluxing the methanol. The agitation is stopped, and the glycerin isallowed to settle for about 30 minutes. The glycerin settles to the bottom of the reactor, and is removed through the bottom outlet. About 30 additional grams of methanol, and about 5.2 grams of sodium methoxide solution (25% in methanol) are added to the glass reactor, and the mixtureis reacted at about 65° C. for about 30 minutes. The agitation is stopped, the glycerin is settled for about 30 minutes, and removed throughthe bottom outlet. About 100 grams of water are added to the mixture, stirred, allowed to settle, and removed through the bottom outlet. The water-washing procedure is repeated two more times. The reflux condenser is removed, and vacuum is broken, and a fractionation column is added to the reactor. The reactor is heated to about 170°-200° C. under a vacuum of about 0.3-1.0 mm Hg. Approximately 50% of the first material to evaporate from the column is collected and discarded. The next40% (approximately) of the material to evaporate from the column is collected as product. This product is approximately 92% by weight methyl behenate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:10]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO>[CH2:19]([CH:18]([N:9]1[C:8]2[CH:23]=[CH:24][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Temperature: 110 °C

Procedure:
To 0.69 g of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 4 ml of methanol and 4 ml of 1 M aqueous sodium hydroxide solution were added and the reaction was heated in a microwave reactor to 110° C. for 5 min. The reaction mixture was adjusted to pH 5 by the addition of 2M aqueous hydrochloric acid and was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. After crystallization from diisopropylether 0.46 g (96%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: [CH:1]([C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=O.C(O)(=O)C.[NH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C([O-])(O)=O.[Na+]>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:38])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[CH:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]1([CH2:1][NH:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[CH2:20][CH2:19]2
Reactant: NCCN1CCCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCN3CCCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (0.1 g, 0.167 mmol) in DCE (2 ml) was added acetic acid (0.019 ml, 0.334 mmol) and N-(2-aminoethyl)piperidine (0.048 ml, 0.334 mmol). The mixture was stirred at rt for 2 h then sodium triacetoxyborohydride (0.177 g, 0.835 mmol) was added. The mixture was stirred at rt for three days then was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step with no additional purification. LCMS: m/e 711.2 (M+H)+, 3.32 min (method 6).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14](I)[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1.C(Cl)Cl.C(N(CC)CC)C.[C]=O>CO>[NH2:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:26][CH:25]3[CH:20]([N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24]3)[CH2:19]2)[C:5]2[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[C:14]([C:27]([O:29][CH3:30])=[O:28])[CH:15]=[CH:16][C:8]=3[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCOc3cc(I)ccc3-4)CC21
Agent: [C]=O
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)OCCc1c-2nc(N)nc1N1CC2CCCN(C(=O)OC(C)(C)C)C2C1

Procedure:
A mixture of the product from Example 102A (55 mg, 0.098 mmol), PdCl2(pddf).CH2Cl2 (4 mg, 0.0049 mmol), triethylamine (0.027 mL, 0.19 mmol) and MeOH (2 mL) was heated at 100° C. in an atmosphere of carbon monoxide at a pressure of 60 psi for 3 hours. The mixture was cooled and filtered to remove the solids. The filtrate was concentrated and purified by chromatography on silica gel using a gradient of 4:1 to 0:1 CH2Cl2:EtOAc to provide the title compound. 1H NMR (CDCl3) δ 1.31-1.43 (m, 1H), 1.49 (s, 9H), 1.54-1.86 (m, 4H), 2.21-2.33 (m, 1H), 2.54-2.68 (m, 1H), 2.75-2.89 (m, 2H), 3.45 (d, J=11.1 Hz, 1H), 3.60-3.78 (m, 2H), 3.85-3.92 (m, 1H), 3.94 (s, 3H), 4.01-4.10 (m, 1H), 4.50-4.68 (m, 2H), 4.79 (s, 2H), 7.80 (d, J=1.6 Hz, 1H), 7.98 (dd, J=7.9, 1.6 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H);
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CS(C)=O>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:5]1
Reactant: CC1CNCC(C)N1
Reactant: CCOC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Product: CCOC(=O)c1ccc(N2CC(C)NC(C)C2)cc1
Temperature: 120 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
2,6-Dimethylpiperazine (3.43 g, 30.00 mmol) was added to ethyl 4-fluorobenzoate (1.101 mL, 7.5 mmol), in DMSO (10 mL) warmed to 120° C. under nitrogen. The resulting solution was stirred at 120° C. for 20 h. The reaction mixture was cooled and the solvent was evaporated. The crude product was purified by silica column chromatography, eluting with 10% methanol in dichloromethane containing 1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (1.490 g, 76%) as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Br)ccc2[N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (500 mg, 2.27 mmol) in DMF (6 mL) was added (4-methoxyphenyl)methanamine (342 mg, 2.5 mmol) and TEA (345 mg, 3.4 mmol). The reaction mixture was then stirred at 120° C. for 30 min under microwave heating. After cooling, the mixture was diluted with water (40 mL) and the resulting precipitate collected by filtration, washed with water and dried in vacuo to give the desired product (750 mg, crude, 97% yield) which was used in next step without further purification. LCMS (m/z): 338.1 [M+H]+
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:20]([CH3:21])=[C:19]([CH3:22])[NH:18][C:5]2=[C:6]([N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:9])[N:7]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:20]([CH3:21])=[C:19]([CH3:22])[N:18]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=3)[C:5]2=[C:6]([N:8]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH3:9])[N:7]=1
Reactant: Cc1[nH]c2c(N(C)Cc3ccc(F)cc3)nc(Cl)cc2c1C
Reactant: Fc1cccc(CCl)c1
Product: Cc1c(C)n(Cc2cccc(F)c2)c2c(N(C)Cc3ccc(F)cc3)nc(Cl)cc12
Yield: 69 %

Procedure:
In accordance with the same procedures as in Example 657, except for using N-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-(4-fluorobenzyl)-methylamine prepared in Step 1 and 3-fluorobenzyl chloride, the titled compound was obtained as a pale yellow solid. (Yield: 69%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:19]#[C:20][NH2:21].OS(C(F)(F)F)(=O)=O>C1COCC1>[C:20](=[NH:19])([O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)=[CH:11][CH:12]=1)[NH2:21]
Reactant: Cc1ccc(Oc2ccc(CCO)cc2)cc1F
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(CCOC(=N)N)cc2)cc1F
Temperature: 55 °C
Yield: 25.8 %

Procedure:
To a solution of 2-{4-[(3-fluoro-4-methylphenyl)oxy]phenyl}ethanol (1 g, 4.06 mmol) and cyanamide (0.205 g, 4.87 mmol) in dry THF (15 mL) under nitrogen was added triflic acid (0.433 mL, 4.87 mmol). The mixture was heated at 55° C. for 2 h. Purification via reverse phase flash chromatography afforded the title compound (420 mg, 1.047 mmol, 25.8% yield) as white solid. LCMS: rt=2.61 min, [M+H+]=229
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:8]3=[CH:7][C:6]=2[CH2:5]1)[CH3:3].[Cl:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[N:25]([CH3:40])[C:26]([C:29]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]3)=[N:27][N:28]=1>>[ClH:19].[CH3:3][CH:2]([N:4]1[C:12](=[O:13])[C:11]2[CH:10]=[C:9]3[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][S:23][C:24]4[N:25]([CH3:40])[C:26]([C:29]5[CH:38]=[CH:37][CH:36]=[C:35]6[C:30]=5[CH:31]=[CH:32][C:33]([CH3:39])=[N:34]6)=[N:27][N:28]=4)[CH2:17][CH2:18][C:8]3=[CH:7][C:6]=2[CH2:5]1)[CH3:1]
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Reactant: CC(C)N1Cc2cc3c(cc2C1=O)CCNCC3
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6c(cc5CC4)C(=O)N(C(C)C)C6)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-(1-methylethyl)-3,5,6,7,8,9-hexahydroazepino[4,5-f]isoindol-1(2H)-one (80 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline (130 mg) and was obtained as a colourless slightly hygroscopic solid (120 mg).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:38](O)=O)[CH2:37][CH2:36][O:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1COCC1>[C:25]([O:29][C:30](=[O:31])[NH:32][C:33]1([C:38]2[NH:23][C:20]3[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=3[N:24]=2)[CH2:37][CH2:36][O:35][CH2:34]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Nc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2nc3cc(Cl)ccc3[nH]2)CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
N,N′-Dicyclohexylcarbodiimide (1.75 g, 8.5 mmol) is added portionwise at 0° C. to 4-chloro-o-phenylenediamine (1.21 g, 8.5 mmol) and 3-tert-Butoxycarbonylamino-tetrahydro-furan-3-carboxylic acid (1.97 g, 8.5 mmol) in THF (50 mL). After stirring overnight at rt, the reaction mixture was filtered and evaporated under reduced pressure to give a residue that is purified by flash chromatography (eluent 0-5% EtOH/DCM) to furnish [3-(5-Chloro-1H-benzoimidazol-2-yl)-tetrahydro-furan-3-yl]-carbamic acid tert-butyl ester (2.35 g, 78%).
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27](OCC)=O)[CH:23]=[CH:24][CH:25]=1.Cl>C(O)C.O>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCOC(=O)Cc1cccc(OC)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccc(OC)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Sodium (1.19 g) was dissolved in ethanol (85 mL) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (5.7 g, 26 mmol) and then ethyl 3-methoxyphenylacetate (10 g) were added. The reaction mixture was refluxed overnight, cooled to room temperature and the solvent was stripped. Water was added to the residue, followed by 2N HCl and the precipitate which formed was collected by filtration and recrystallized from ethyl acetate to afford 5.08 g of 1-cyclopentyl-3-ethyl-6-(3-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 148°-150° C.
Reaction SMILES: ClCC1C=NC=CN=1.C(N)CN.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[CH2:19][NH:20][CH2:21][CH2:22][NH2:23].[C:24]([NH:26][C:27](=[N:30][CH3:31])SC)#[N:25]>>[C:24]([NH:26][C:27]([NH:30][CH3:31])=[N:23][CH2:22][CH2:21][NH:20][CH2:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][N:13]=1)#[N:25]
Reactant: CN=C(NC#N)SC
Reactant: NCCNCc1cnccn1
Agent: ClCc1cnccn1
Solvent: NCCN
Product: CNC(=NCCNCc1cnccn1)NC#N

Procedure:
Reacting 2-chloromethylpyrazine with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(2-pyrazinylmethyl)ethylenediamine with N-cyano-N',S-dimethylisothiourea by the procedure of Example 3 gives the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[O:24][C@@H:25]1[C@@H:65]([CH2:66][O:67]C(=O)C)[O:64][C@@H:28]([O:29][N:30]2[CH:34]=[C:33]([CH2:35][O:36][C@H:37]3[CH2:61][CH2:60][C@@:59]4([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]5[C@@H:58]4[CH2:57][CH2:56][C@@:55]4([CH3:63])[C@H:43]5[CH2:44][CH2:45][C@@H:46]4[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]3)[N:32]=[N:31]2)[C@H:27]([O:71]C(=O)C)[C@H:26]1[O:75]C(=O)C)(=O)C.C[O-].[Na+]>C1COCC1.CO.CO>[C@H:6]1([O:24][C@@H:25]2[C@@H:65]([CH2:66][OH:67])[O:64][C@@H:28]([O:29][N:30]3[CH:34]=[C:33]([CH2:35][O:36][C@H:37]4[CH2:61][CH2:60][C@@:59]5([CH3:62])[CH:39]([CH2:40][CH2:41][C@@H:42]6[C@@H:58]5[CH2:57][CH2:56][C@@:55]5([CH3:63])[C@H:43]6[CH2:44][CH2:45][C@@H:46]5[C@H:47]([CH3:54])[CH2:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:38]4)[N:32]=[N:31]3)[C@H:27]([OH:71])[C@H:26]2[OH:75])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](On3cc(CO[C@H]4CC[C@@]5(C)C(CC[C@H]6[C@@H]7CC[C@H]([C@H](C)CCCC(C)C)[C@@]7(C)CC[C@@H]65)C4)nn3)O[C@@H]2COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4C[C@@H](OCc5cn(O[C@@H]6O[C@H](CO)[C@@H](O[C@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)nn5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Peracetate 95 (190 mg) was dissolved in THF/MeOH (1:1). NaOMe in MeOH (11M, 20 μL) was added and the solution was stirred at room temperature for 3 hours. The solution was neutralised with H+ resin, filtered and the solvent evaporated to give 125 mg (90%) of the off-white solid product which was reacted on without further purification or characterisation.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>C(O)C>[F:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: NN
Reactant: Fc1cccnc1Cl
Solvent: CCO
Solvent: O
Product: NNc1ncccc1F
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of 9.59 g of 2-chloro-3-fluoropyridine in 6 ml of ethanol there was added 6 ml of hydrazine monohydrate, and the mixture was stirred at 60° C. for 3 days. The solution was adsorbed onto 50 g of NH silica gel and purified by NH silica gel column chromatography (ethyl acetate-heptane) to give the title compound (403 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)CCC.CCOC(C)=O.Cl>CN(C=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.O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(I)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 120 °C
Yield: 25.8 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-1-iodo-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (105 mg, 0.24 mmol), 3-tributylstannanyl-pyridine (133 mg, 0.36 mmol), and PdCl2(PPh3)2 (34 mg, 0.048 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under N2 atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 24 mg of the title compound. MS: (+) m/z 388.33 (M+1).
Reaction SMILES: O=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C.Cl.[NH2:38][OH:39].C([O-])(=O)C.[Na+]>O>[N:38](=[C:2]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C@@H:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:39]
Reactant: NO
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCC(=O)c2ccccc2)[C@H]1c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccccc1CN[C@H]1CCCN(CCCC(=NO)c2ccccc2)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
Under a nitrogen atmosphere in a round bottom flask were placed 445 mg (1 mmol) of (2S,3S)-1-(4-oxo-4-phenylbut-1-yl)-3-(2methoxybenzylamino)-2-phenylpiperidine and 6 ml of ethanol. To the system were added 209 mg (3.2 mmol) of hydroxylamine hydrochloride and 417 mg (5 mmol) of sodium acetate in 6 ml of H2O, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between chloroform and water. The layers were separated, and the aqueous phase was extracted two times with chloroform. The combined organic extracts were dried (sodium sulfate) and concentrated to 368 mg of gold oil. The crude product was purified by flash column chromatography using 7% in chloroform as the eluant to obtain 174 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:7]1=[C:6]2[CH:17]=O.C([O-])(=O)C.[NH4+].[N+:24]([CH2:27][CH3:28])([O-:26])=[O:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:7]1=[C:6]2[CH:17]=[C:27]([N+:24]([O-:26])=[O:25])[CH3:28]
Reactant: CC[N+](=O)[O-]
Reactant: COc1ccc2c(c1)c(C=O)c1n2CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc2c(c1)c(C=C(C)[N+](=O)[O-])c1n2CCCCC1
Temperature: 25 °C

Procedure:
A stirred solution of 2-methoxy-7,8,9,10-tetrahydro-6H-azepino[1,2-a]indole-11-carboxaldehyde and ammonium acetate in nitroethane is heated to 100° C. for 1 h, cooled to room temperature and partitioned between ethyl acetate and water. The combined organic extracts are washed (water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.