Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+:3]([CH2:8][CH3:9])(CC)CC)C.[NH2:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH2:27])=[CH:13][CH:12]=1.[C-]#N.[Na+].[N+:31](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].[S]>O.CN(C)C=O>[NH2:10][C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14]([NH2:27])=[C:13]([C:12]#[N:31])[C:9]=1[C:8]#[N:3]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: CC[N+](CC)(CC)CC
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Agent: [C-]#N
Agent: [Na+]
Agent: [S]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)c2c(c(N)c1C#N)C(=O)c1ccccc1C2=O
Reaction time: 11 h

Procedure:
20 parts of tetraethylammonium ethosulfate and 48 parts of 1,4-diaminoanthraquinone are introduced into 400 parts by volume of dimethylformamide and the mixture is heated to 120° to 125° C. At this temperature there is introduced in the course of thirty minutes 50 parts of sodium cyanide and then 24 parts of sodium m-nitrobenzenesulfonate is added in about twenty minutes. 6 parts of powdered sulfur is added and the whole is stirred at 120° to 125° C. until all the 1,4-diaminoanthraquinone has been used up, this being the case after from 10 to 12 hours. After the whole has cooled to about 50° to 60° C. the reaction mixture is poured into 2000 parts of water, air is passed through the mixture to oxidize leuco compound still present and finally the excess sodium cyanide is destroyed by adding 35 parts of 30% hydrogen peroxide at from 60° to 70° C. while stirring. Suction filtration is carried out while the mixture is still warm and the filter cake is washed well with water and finally washed with methanol until the liquid running away is colorless. After drying, 47 parts of 1,4-diaminoanthraquinone-2,3-dinitrile is obtained which agrees chromatographically with the product obtained according to the process of German Pat. No. 1,108,704 and which has a melting point above 350° C. Recovery of the solvent may be carried out as described in Example 2 (b). An equally good product is obtained when an equivalent amount of trimethylbenzylammonium chloride is used instead of tetraethylammonium ethosulfate.
Reaction SMILES: Br[CH2:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[OH:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29]>CN1CCCC1=O>[C:6]1(/[CH:5]=[CH:4]/[CH2:3][CH2:2][O:18][N:19]2[C:20](=[O:29])[C:21]3=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]3[C:23]2=[O:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCC/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCC/C=C/c1ccccc1
Yield: 56 %

Procedure:
Example 1 was repeated to react 67 g (0.32 mol) of E-4-bromo-1-phenyl-1-butene with 29 g of potassium carbonate (0.21 mol) and 51.9 g of N-hydroxyphthalimide (0.32 mol) in 320 ml of N-methylpyrrolidone. The crude product, precipitated by means of ice-water, was taken up in dichloromethane and washed twice with dilute sodium hydroxide solution. A customary working up gives the product in a 56% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH2:10])=[O:4].[N:11]([O-])=O.[Na+]>Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[NH:10][NH2:11])=[O:4]
Reactant: COC(=O)c1scnc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1scnc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of 4-aminothiazole-5-carboxylic acid methyl ester (15.3 g) in concentrated hydrochloric acid (90 ml) there was added dropwise an aqueous solution (10 ml) containing sodium nitrite (7.32 g) at 0-10° C. The mixture was then stirred at 0° C. for 30 minutes. To this mixture there was added dropwise a concentrated hydrochloric acid solution (100 ml) containing stannous chloride (73.2 g) at 0-10° C., and the mixture was stirred at the same temperature for 2 hours. The mixture was filtered, and the filtrate was carefully added to a suspension of potassium carbonate and celite in ethyl acetate (3 liters) with stirring, with regular addition of potassium carbonate to prevent solution acidic. After adding the filtered substance to a solution of this mixture in ethyl acetate, it was rendered basic with a 5N aqueous sodium hydroxide solution. The mixture was allowed to stand, and then most of the supernatant (organic layer A) was separated off. The remaining suspension was filtered through celite and the filtrate was separated into organic layer B and aqueous layer A. Ethyl acetate (500 ml) and anhydrous magnesium sulfate were added to the filtered substance, and the mixture was stirred and then filtered. Aqueous layer A was re-extracted with the resulting filtrate. Washing of the filtered substance and re-extraction of aqueous layer A were repeated 4 times in the same manner. Organic layer A and organic layer B were combined with the obtained organic layer, and the mixture was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-methanol) to give the title compound (11.6 g) as a light yellow solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]=[C:16]=[O:17].P([O-])(OCCCC)(OCCCC)=O>C1(C)C=CC=CC=1>[CH3:14][NH:15][C:16]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:17]
Reactant: CN=C=O
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CCCCOP(=O)([O-])OCCCC
Solvent: Cc1ccccc1
Product: CNC(=O)N(c1ccccc1)c1ccccc1
Temperature: 100 °C

Procedure:
0.5 mole of diphenylamine was taken together with 0.53 mole of methyl isocyanate and 0,6 g of di-n-butyl phosphate in 150 ml of toluene. The mixture was heated at 100° C. for 10 hours, with stirring. After cooling to room temperature, the N-methyl-N',N'-diphenylurea formed was filtered off wtih suction. The filtrate was made up to 150 ml with toluene, and 0.5 mole of diphenylamine and 0.53 mole of methyl isocyanate were added. The mixture was heated again at 100° C. for 10 hours, with stirring, and then cooled to room temperature. Recycling of the filtrate and subsequent addition of in each case 0.5 mole of diphenylamine and 0.53 mole of methyl isocyanate was repeated a further three times. After these five reactions with only a single addition of catalyst, 2.4 moles of N-methyl-N',N'-diphenylurea were obtained. The urea was washed with in each case 100 ml of cold toluene after each reaction. Melting point: 170°/yield: 96% of theory.
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[OH:9][C@@H:10]([C:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=1[CH3:24])[C@@H:11]([OH:13])[CH3:12].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[Si:5]([O:13][C@@H:11]([CH3:12])[C@H:10]([C:14]1[O:18][N:17]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:15]=1[CH3:24])[OH:9])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: CCOC(=O)c1noc([C@H](O)[C@H](C)O)c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc([C@H](O)[C@H](C)O[Si](C)(C)C(C)(C)C)c1C
Temperature: 25 °C

Procedure:
tertbutyldimethylsilyl chloride (6.3 g, 41.5 mmol) was added portionwise to ethyl 5-((1R,2S)-1,2-dihydroxypropyl)-4-methylisoxazole-3-carboxylate (Intermediate B)(8.65 g, 37.7 mmol), 4-dimethylaminopyridine (1.38 g, 11.32 mmol) and triethylamine (5.80 mL,) in DMF (100 mL) at 0° C. and the reaction was allowed to warm to room temperature. After 18 h the reaction was partitioned between EtOAc and brine, washed with saturated aqueous ammonium chloride, brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 15% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)c1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (2.3 mL of a 0.31M stock solution, 0.71 mmol) cooled to −78° C. was treated with a solution of 4-methoxycarbonylmethyl-benzoic acid methyl ester (66 mg, 0.31 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.85 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (86 mg, 0.40 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was then stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and stirred at 25° C. for 18 h. At this time, the reaction mixture was quenched by the slow addition of a saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was then poured into water (50 mL). This solution was extracted into ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 4-(2-cyclopentyl-1-methoxycarbonyl-ethyl)-benzoic acid methyl ester (60.5 mg, 65.7%) as a clear oil: EI-HRMS m/e calcd for C17H22O4 (M+) 290.1518, found 290.1518.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH3:14]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:14]
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: N
Solvent: O
Product: Nc1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
Into a 1000 ml high-pressure reaction vessel add 200 g 3,4,5-Trichlorobenzotrifluoride and 145 g water, enclose the reaction vessel, fill liquid ammonia 380 g, close the valve, start agitation, slowly increase temperature to 160° C. and pressure to 10.0 MPa, make timed temperature-retention under controlled temperature 165° C. and controlled pressure 11.5 MPa for 8 h, then release the pressure and discharge ammonia.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:26]([N:28]=[C:29]=[O:30])[CH3:27]>C1COCC1.CN(C=O)C>[CH2:26]([NH:28][C:29](=[O:30])[O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)=[O:17])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:27]
Reactant: CCN=C=O
Reactant: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)[C@H]1CN2CCC1CC2
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCNC(=O)OCc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
35 mg (0.10 mmol) of (3R)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo-[2.2.2]octane-3-carboxamide are dissolved in 1 ml of a 1:1 THF/DMF mixture. 17 mg (0.21 mmol) of ethyl isocyanate are added, and the mixture is stirred at 60° C. overnight. The solvent is removed under reduced pressure, and the crude product is purified by preparative HPLC. 24 mg (55% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=4)[CH2:16][CH2:15][N:14]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CCC2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
1-(4-Chlorophenyl)-N-[2-(4-methoxyphenyl)ethyl]cyclobutanecarboxamide (10.58 g, 30.8 mmol) was treated with toluene (100 mL). Phosphoryl trichloride (4.72 g, 30.8 mmol) was added and the reaction mixture was heated under reflux for 8 h. After cooling to room temperature the reaction mixture was concentrated in vacuo and then slowly poured in ice water. Ethyl acetate was added and the organic layer was washed with water (2×), dried (MgSO4) and concetrated in vacuo to give an orange oil. Yield: 10.25 g.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH:9]=[C:8]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=2)[CH:7]=1.[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31].[C:32](=O)([O:38]C(C)(C)C)[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C(N(CC)CC)C>CN(C)C(=O)C>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH:9]=[C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH3:25])[N:19]=3)[CH:7]=[C:6]2[NH:5][CH2:4][CH2:3][CH2:2][N:31]([CH2:30][CH2:29][CH2:28][O:27][CH3:26])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CNc1nccc(-c2cc(NCCCBr)c3cc(OC)ccc3c2)n1
Reactant: COCCCN
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CNc1nccc(-c2cc(NCCCN(CCCOC)C(=O)OC(C)(C)C)c3cc(OC)ccc3c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.2 %

Procedure:
A mixture of 4-(4-((3-bromopropyl)amino)-6-methoxynaphthalen-2-yl)-N-methylpyrimidin-2-amine (189) (0.10 g, 0.25 mmol) and N,N-dimethylacetamide (2 mL) were treated with 3-methoxypropan-1-amine (0.10 mL, 1.0 mmol). The resulting mixture was stirred at room temperature 16 h. The reaction mixture was dried down and treated with di-tert-butyl carbonate solution (1 mL of 0.6 M solution in methanol, 0.6 mmol) and triethylamine (0.5 mL, 3.6 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated (rotary) and dissolved in ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated (rotary). The residue was purified by column chromatography (silica gel) using 85% ethyl acetate/hexanes as the eluent to afford tert-butyl (3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)propyl)(3-methoxypropyl)carbamate (190) as an orange oil (0.05 g). The residue was dissolved in dioxane (1 mL) and then treated with HCl (4 M in dioxane, 0.5 mL, 7.2 mmol). The reaction mixture was stirred at room temperature and then filtered to afford N-{7-methoxy-3-[2-(methylamino)pyrimidin-4-yl]-1-naphthyl}-N′-(3-methoxypropyl)propane-1,3-diamine was isolated as a red-orange solid. M.p.=130-132° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.88 (br s, 2H), 8.44 (d, J=6.3 Hz, 1H), 8.11 (br s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.66-7.56 (m, 2H), 7.28-7.24 (m, 2H), 3.96 (s, 3H), 3.56-3.41 (m, 4H), 3.22 (s, 3H), 3.20-2.95 (m, 7H); Experimental Elemental Analysis (3.2 equivalents of HCl)=52.49% C, 6.19% H, 12.82% N; Calculated Elemental Analysis 52.50% C, 6.55% H, 13.31% N; LCMS (m/z): 410 [M+H].
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1O)(=[O:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[C:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)(=[O:31])[CH3:30]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1O[C@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.9 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.2 mg, 0.0137 mmol), 2-acetylphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (1.70 mg, 24.9% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.65 (m, 1H), 7.55 (s, 1H), 7.30–7.20 (m; 5H), 7.20 (m, 3H), 6.97 (m, 2H), 6.76 (apparent d, 1H), 5.49 (apparent dd, 1H, J=4.3, 8.0 Hz), 3.38 (m, 2H), 2.93 (m, 2H), 2.71 (s, 3H), 2.60 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=7.6 Hz), 2.30–2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 498.8 (M+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([O-:12])(=[O:11])[CH3:10].[NH4+:13].C(O)(=O)CC(O)=O>CC(O)C>[NH2:13][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:10][C:9]([OH:12])=[O:11]
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Reactant: O=Cc1cccnc1
Agent: O=C(O)CC(=O)O
Solvent: CC(C)O
Product: NC(CC(=O)O)c1cccnc1

Procedure:
To 3-pyridine carboxaldehyde (300 ml) in 2-propanol (3 liters) was added ammonium acetate (297 g) followed by malonic acid (398 g). The reaction mixture was stirred at reflux for 5 hours. The precipitate was filtered while hot and washed with hot isopropanol (2 liters). The resulting white solid was then dried to yield DL-3-amino-3-(3-pyridyl)propionic acid (220 g) as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH3:15])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH2:17][CH3:18].CS(O)(=O)=O>O>[CH:1]1([N:6]2[C:10]3=[N:11][C:22]([C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[O:19][CH2:16][CH2:17][CH3:18])=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH3:15])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CCCOc1ccccc1C=O
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCOc1ccccc1-c1nc2n(C3CCCC3)[nH]c(C)c-2c(=O)n1
Temperature: 180 °C
Yield: 39.9 %

Procedure:
A mixture of 1-cyclopentyl-3-methyl-5-amino-1H-pyrazole-4-carboxamide (3.98 g, 0.019 mol), 2-propoxybenzaldehyde (6.35 g, 0.038 mol), xylenes (150 ml) and methanesulfonic acid (0.5 ml) was heated at reflux for 39 hours with azeotropic removal of water. The reaction mixture was concentrated in vacuo and the residue was treated with 10% K2CO3 and ether. The layers were separated, the aqueous layer was extracted with ether and the combined ether layers were concentrated in vacuo. Analysis of the reaction mixture by TLC indicated that the reaction was not yet complete, therefore, the mixture was heated at 180° C. on an oil bath. The residue was dissolved in chloroform, and purified by column chromatography on silica gel eluting with hexane (100%) followed by ether (100%) to afford 2.67 g (41%) of 1-cyclopentyl-3-methyl-6-(2-propoxyphenyl)-pyrazolo[3,4-d]pyrimidin-4-one, m.p. 130°-132° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=S)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2F)[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[NH2:23][NH2:24]>C(O)CCC>[N+:17]([C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:24][N:23]=[C:10]2[NH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])([O-:19])=[O:18]
Reactant: N#Cc1cccc(NC(=S)c2cc([N+](=O)[O-])ccc2F)c1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: N#Cc1cccc(Nc2n[nH]c3ccc([N+](=O)[O-])cc23)c1
Yield: 63.1 %

Procedure:
To a solution of N-(3-Cyano-phenyl)-2-fluoro-5-nitro-thiobenzamide (8.56 g; 0.028 mol) in n-butanol (300 mL) was added hydrazine hydrate (2.54 mL; 0.053 mol) and the solution refluxed for 3 hours. The reaction mixture was concentrated in vacuo and triturated with hot ethanol to afford the title compound as a red solid (4.93 g; 62%). 1H NMR (400 MHz, DMSO-d6) δH 7.30 (1H, d), 7.45–7.60 (2H, m), 7.90 (1H, d), 8.20 (1H, d), 8.25 (1H, s), 9.20 (1H, s), 9.85 (1H, s). Mass Spectrum (ES−) m/e=278.28.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:8]=[C:9]3[N:18]([CH3:19])[CH:17]=[CH:16][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])[CH2:4]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:15][C@H:13]([C:12]2[N:11]=[C:10]3[CH:16]=[CH:17][N:18]([CH3:19])[C:9]3=[CH:8][C:7]=2[N:5]2[CH2:6][CH:3]([O:2][CH3:1])[CH2:4]2)[CH3:14])[N:22]=1
Reactant: COC1CN(c2cc3c(ccn3C)nc2[C@H](C)N)C1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC1CN(c2cc3c(ccn3C)nc2[C@H](C)Nc2nc(N)nc(N)c2C#N)C1
Temperature: 120 °C
Yield: 15 %

Procedure:
(S)-1-(6-(3-Methoxyazetidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (469 mg, 1.80 mmol), 2,4-diamino-6-chloropyrimidine-5-carbonitrile (367 mg, 2.16 mmol), and N-ethyl-N-isopropylpropan-2-amine (628 μl, 3.60 mmol) were combined in acetonitrile (1.8 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours. Additional 2,4-diamino-6-chloropyrimidine-5-carbonitrile (367 mg, 2.16 mmol) and N-ethyl-N-isopropylpropan-2-amine (628 μL, 3.60 mmol) were added. The reaction mixture was heated in a microwave reactor at 120° C. for 1 hour and then concentrated in vacuo. The residue was taken up in DMF and purified by preparative HPLC (basic mode) eluting with 25-50% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was added to a silica gel column and was eluted with EtOAc. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (106 mg, 15%). 1H NMR (500 MHz, CD3OD) δ ppm 1.49 (d, J=6.83 Hz, 3 H), 3.40 (s, 3 H), 3.70-3.74 (m, 1 H), 3.82 (s, 3 H), 3.89 (dd, J=7.32, 4.39 Hz, 1 H), 4.15-4.20 (m, 1 H), 4.32-4.40 (m, 2 H), 5.64 (q, J=6.83 Hz, 1 H), 6.51 (dd, J=3.42, 0.98 Hz, 1 H), 7.20 (s, 1 H), 7.31 (d, J=2.93 Hz, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394.2; found 394.5.
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:6][C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[C:10]3[CH:32]=[C:33]([O:38][CH3:39])[C:34]([O:36][CH3:37])=[CH:35][C:9]=3[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2nc(CC3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(CC3CCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1OC

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclopentylmethyl-5,6-dimethoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.