Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]1([C:18]2([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>O.CC(C)=O>[CH2:33]([O:32][C:30]([N:21]1[CH2:20][CH2:19][C:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 144 h
Yield: 66.1 %

Procedure:
A mixture of 151 g of 4-phenylpiperidine-4-carboxylic acid p-toluenesulfonate and 213 g of aqueous 30% NaOH solution in 500 ml of water is cooled to 5° C. A solution of 68.2 g of benzyl chloroformate in 150 ml of acetone is added dropwise and the mixture is stirred for 6 days while allowing the temperature to return to rt. 150 ml of acetone are added and the reaction mixture is poured onto a mixture of 200 g of concentrated HCl solution, 300 ml of water and 300 ml of acetone precooled on an ice bath. The precipitate formed is filtered off by suction and washed with water and then with ether. 89.7 g of the expected product are obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH3:33]>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromoanisole
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:48][CH:49]([CH3:51])[CH3:50])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][C:31](O)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[ClH:58]>C(OCC)(=O)C>[ClH:58].[ClH:58].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:48][CH:49]([CH3:51])[CH3:50])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:29][CH:30]=[C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:32][CH2:33]3)=[O:27])[CH2:23][NH:22][CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC(O)(c3ccccc3)CC2)CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CC=C(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-[(4-hydroxy-4-phenylpiperidin-1-yl)carbonyl]piperidine-1-carboxylate (100 mg) was dissolved in ethyl acetate (5 ml), 4 N hydrogen chloride-ethyl acetate solution (7 ml) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure to give the object compound (80 mg).
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]3[C:20]([CH:21]=2)=[N:19][N:18]2[CH:22]=[C:23]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]5([NH:36]C(OC(C)(C)C)=O)[CH2:35][CH2:34][CH2:33]5)=[CH:28][CH:27]=4)=[N:25][C:17]=32)=[CH:11][CH:10]=[N:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[C:44]1([C:23]2[C:24]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([NH2:36])[CH2:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:25][C:17]3[N:18]([CH:22]=2)[N:19]=[C:20]2[C:16]=3[CH:15]=[CH:14][C:13]([C:12]3[NH:8][N:9]=[CH:10][CH:11]=3)=[CH:21]2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5ccc(-c6ccnn6C(=O)OC(C)(C)C)cc5nn4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4c5ccc(-c6ccn[nH]6)cc5nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
206.7 mg Crude 5-[2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylpyrimido[1,2-b]indazol-8-yl]pyrazole-1-carboxylic acid tert-butyl ester, intermediate example Int-3-0, were dissolved in 15 mL 4 M hydrogen chloride in dioxane. The reaction mixture was stirred over night at room temperature. After evaporation of the solvent the residue was dissolved in methanol and given on a PoraPak Rxn CX column. The column was washed with 100 mL methanol, and the product was eluted with methanol/ammonia. The solvent was removed, and the residue was purified by HPLC yielding 32.8 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[NH:19][C:18](=O)[N:17]=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:21].O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:18]1[N:19]=[C:14]([C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:21])[CH:4]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:15]=[CH:16][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ncccc2-c2ccnc(=O)[nH]2)ccc1F
Product: Cc1cc(-c2ncccc2-c2ccnc(Cl)n2)ccc1F
Temperature: 25 °C

Procedure:
6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)pyrimidin-2(1H)-one (0.83 g) and POCl3 (3 mL) were heated at 130° C. under nitrogen. The reaction mixture was cooled to room temperature upon completion of the reaction (2 h). The volatiles were removed and quenched the concentrate with ice. The semi-heterogeneous slurry was neutralized with aq. NaHCO3 solution while stirring, warmed to room temperature and diluted with EtOAc (200 mL). The organic layer was separated, stirred over MgSO4, filtered, concentrated and purified by flash chromatography (Combiflash® companion System® with RediSep® silica gel column 12 g and 10-50% EtOAc/Hexanes as eluting solvent) to obtain 2-chloro-4-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)pyrimidine as a clear viscous liquid.
Reaction SMILES: Cl.[CH:2]([NH2:4])=[NH:3].C([O:7][CH:8]=[C:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])C.C(OCC)(=O)C.Cl>C(O)C.O>[O:7]=[C:8]1[NH:4][CH:2]=[N:3][CH:15]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnc[nH]c1=O
Temperature: 120 °C

Procedure:
A mixture of formamidine hydrochloride (4.02 g, 49.9 mmol) and diethyl ethoxymethylenemalonate (5 ml, 24.95 mmol) in ethanol (4.99 ml) was heated to 120° C. (by microwave irradiation) for 15 h. After the reaction mixture was cooled to room temperature, ethyl acetate, hydrochloric acid (1M), and water were added. The aqueous layer was washed with ethyl acetate and then extracted with 3:1 chloroform:isopropanol. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to afford ethyl 6-oxo-1,6-dihydropyrimidine-5-carboxylate as an orange solid. LRMS (ESI) calc'd for (C7H9N2O3) [M+H]+, 169.1; found 169.1.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH:8]1([NH2:11])[CH2:10][CH2:9]1>CO>[OH:7][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH:11][CH:8]1[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: C1CCC2OC2C1
Solvent: CO
Product: O[C@@H]1CCCC[C@H]1NC1CC1

Procedure:
Cyclohexene oxide (143 ml) and cyclopropylamine (82 g) are dissolved in methanol (1 liter), and the mixture is refluxed for 5 hours. The mixture is concentrated under reduced pressure to remove the solvent, and the resulting residue is distilled under reduced pressure to give trans-N-(2-hydroxycyclohexyl)-N-cyclopropylamine (126 g) as a colorless oil.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[C:13]([O:24][CH2:25][C@@H:26]([C:35]([OH:37])=O)[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1.CN(C=O)C>CCOC(C)=O>[O:37]=[C:35]1[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:13]=2[O:24][CH2:25][C@@H:26]1[NH:27][C:28](=[O:29])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1-c1ccccc1)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1COc2c(cccc2-c2ccccc2)NC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.2 %

Procedure:
0.136 ml of diethyl cyanophosphonate (147.8 mg, 0.906 mmol) is introduced, at 0° C., into a 25 mL three-necked flask containing 284 mg of 36 (0.763 mmol) and 6.2 mL of DMF, followed 10 minutes later by 0.102 ml of TEA (0.731 mmol). The reaction medium is stirred at 0° C. for 2 h. 20 ml of AcOEt are added and then the mixture is washed with twice 20 mL of distilled water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 160 mg of expected product 37 are obtained.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(Cl)=[S:17]>O1CCCC1>[CH2:1]([N:8]=[C:16]=[S:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=NCc1ccccc1
Temperature: -10 °C
Reaction time: 2.75 h

Procedure:
A solution of benzylamine (5.4 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and filtered. The filtrate was treated with charcoal, then filtered and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column using hexane:ethyl acetate (90:10) as the eluant to yield benzyl isothiocyanate as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8](#[N:12])[CH2:9][C:10]#[N:11].C(N(CC)CC)C>C(Cl)Cl>[C:1]([CH:9]([C:8]#[N:12])[C:10]#[N:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: N#CCC#N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(C#N)C#N

Procedure:
Pivaloyl chloride (60 g) and malononitrile (33g) were dissolved in methylene chloride (500 ml) and were placed in a flask equipped with a stirrer and a dropping funnel. Triethylamine (100 g) was added slowly with cooling over a period of 45 minutes. The triethylamine hydrochloride was removed and the filtrate was concentrated to about half volume. The solution was poured onto ice, acidified strongly with concentrated hydrochloric acid and the resulting product was filtered off and air dried.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:19]([CH2:18][CH2:17][C:4]1[C:3]2[C:7](=[CH:8][C:9]([I:11])=[CH:10][C:2]=2[I:1])[NH:6][C:5]=1[C:12]([OH:14])=[O:13])([OH:21])=[O:20]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(I)cc(I)c12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(I)cc(I)c12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 4,6-diiodo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (1.71 g, 5 mmol) was dissolved in 15 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 0.63 g of lithium hydroxide trihydrate (3 equiv.) in 15 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×15 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 280-282° C. 1H-NMR (DMSO-d6) δ 2.48 (m, 2H, 2′-H); 3.49 (m, 2H, 1′-H); 7.78 (dd, 2H, J=1.7 Hz, 5-H, 7-H); 11.80 (s, 1H, NH); 12.68 (b, 2H, 2CO2H). 13C-NMR (DMSO-d6) δ 18.9 (C-2′); 36.4 (C-1′), 88.3 (C-4); 89.5 (C-6); 121.4 (C-7); 122.0 (C-3); 126.2 (C-2); 126.4 (C-3a); 137.8 (C-7a); 138.1 (C7); 162.7 (2′-CO2H); 173.58 (2-CO2H). LC-MS (m/z): 503 [M+NH4+]+, 486 [M]+, 484 [M]−. Purity (LC-MS): 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26](Cl)=[O:27])=[C:19]2[N:18]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([NH:13][C:12]3[C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH3:15])=[N:9][N:10]([CH3:14])[CH:11]=3)=[O:27])=[C:19]2[N:18]=1
Reactant: Cc1ccc(Cl)cc1-c1nn(C)cc1N
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2ccc(Cl)nc12
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a solution of 3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-amine (182.9 mg, 0.4826 mmol, 1.2 equiv) in dichloromethane (5 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (91.2 mg, 0.411 mmol, 1.0 equiv) and triethylamine (0.30 mL, 2.2 mmol, 5.2 equiv) at room temperature. After 16 hours, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 143.1 mg (87%) of 5-chloro-N-(3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was carried forward without purification. LCMS (ESI) m+H=401.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Product: CCC(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 80.6 %

Procedure:
Following the general method as outlined in Example 89, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 370 mg; 0.80 mmol) and propionyl chloride (179 mg; 1.93 mmol), 310 mg (80%) of the title compound was obtained as a yellow oil, which was used directly without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH2:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH2:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N[C@@H]2CCN(Cc3ccccc3)C2)nc1
Temperature: 100 °C
Reaction time: 10 h
Yield: 68.2 %

Procedure:
A mixture of methyl 6-chloronicotinate (8.0 g), (3R)-(−)-1-benzyl-3-aminopyrrolidine (9.86 g), CuO (371 mg) and K2CO3 (8.38 g) in DMF (60 ml) was stirred at 100° C. for 10 hours under atmospheric pressure of nitrogen. The reaction mixture was poured into a mixture of AcOEt and water and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (97:3). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}nicotinate (9.9 g).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[NH:4][C:5](=[S:20])[N:6]([CH2:9][CH2:10][C:11]2[NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[N:12]=2)[C:7]=1[NH2:8].[C:22](O)(=O)C.C(N)=N>CS(C)=O>[NH:12]1[C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=[C:11]1[CH2:10][CH2:9][N:6]1[C:7]2[N:8]=[CH:22][NH:1][C:2]=2[C:3](=[O:21])[NH:4][C:5]1=[S:20]
Reactant: Nc1c(N)n(CCc2nc3ccccc3[nH]2)c(=S)[nH]c1=O
Reactant: CC(=O)O
Agent: N=CN
Solvent: CS(C)=O
Product: O=c1[nH]c(=S)n(CCc2nc3ccccc3[nH]2)c2nc[nH]c12
Temperature: 80 °C
Yield: 11.7 %

Procedure:
To 5,6-diamino-1-[2-(1H-benzimidazol-2-yl)ethyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.29 g, 0.96 mmol, obtained from Example 12(c)) in DMSO (2 mL) was added formamidine acetate (0.15 g, 1.4 mmol) and the reaction was heated to 80° C. for 2 h. Purification of the crude product using preparative HPLC gave the title compound (0.035 g, 12% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[F:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[C:17]([F:16])[CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1cccc(F)c1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-3-fluorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 3-fluorobenzoyl chloride in a similar manner as described above to give a white solid (24% yield). 1H-NMR (DMSO-d6): δ 11.04 (s, 1H), 8.97 (d, 1H), 7.85-7.81 (m, 1H), 7.81-7.74 (m, 1H), 7.62 (d, 1H), 7.59-7.50 (m, 1H), 7.46-7.37 (m, 1H), 7.29 (d, 1H), 7.17 (dd, 1H), 5.38 (m, 1H), 2.68 (m, 2H), 2.08 (m, 2H), 1.87 (m, 2H); MS m/z 387 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:28]([O-])=O.[NH4+].[Cl-]>CO.[Fe]>[NH2:28][C:3]1[CH:4]=[C:5]([C:8]2[C:17]([N:18]3[CH2:22][CH2:21][CH2:20][C@@H:19]3[CH3:23])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:14]=3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COC(=O)c1ccc2nc(-c3ccc(N)c([N+](=O)[O-])c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1ccc2nc(-c3ccc(N)c(N)c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-methyl 2-(4-amino-3-nitrophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (1.0 g, 2.45 mmol) in methanol (40 mL) was added Fe (1.38 g, 24.6 mmol) and NH4Cl (1.3 g, 24.30 mmol). After the resulting solution was stirred for 6 h at 60° C., the solids were filtered out. The filtrate was concentrated under vacuum and dissolved in water (200 mL), extracted with dichloromethane (3×80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to afford (S)-methyl 2-(3,4-diaminophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as yellow solid (970 mg, crude).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[O:33][C:32](=[O:34])[N:31](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:30]=2)=[CH:19][CH:18]=1>CN(C)C=O.O.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:33][C:32](=[O:34])[NH:31][N:30]=3)=[CH:19][CH:18]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: O=c1oc(-c2ccccc2-c2ccc(CBr)cc2)nn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2-c2n[nH]c(=O)o2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 27.6 %

Procedure:
To an ice-cooling solution of 2-butyl-4-chloroimidazole-5-carbaldehyde (0.19 g) in N,N-dimethylformamide (1 ml) was added sodium hydride (60% in oil; 44 mg), and the mixture was stirred for 10 minutes. To the mixture was then added 5-(4'-bromomethylbipenyl-2-yl)-2,3-dihydro-3-triphenylmethyl-1,3,4-oxadiazol-2-one (0.57 g). The reaction mixture was stirred for 1.5 hour at room temperatures, which was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel. The crude product thus obtained was dissolved in trifluoroacetic acid (4 ml), and the solution was stirred for 30 minutes at 60° C. Trifluoroacetic acid was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with an aqueous solution of sodium hydrogencarbonate and dried. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel. Crude crystals thus obtained was recrystallized from ethylacetate-hexane to afford the title compound as colorless prisms (0.12 g, 27%), m.p.178°-179° C.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH2:12][CH2:11]1>CN(C)C=O>[O:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: C1=COCC1
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Yield: 60 %

Procedure:
In 20 ml of dimethylformamide were dissolved 1.3 g of 5-fluorouracil. To this solution were added 1.4 g of 2,3-dihydrofuran and the mixture was reacted in an autoclave for 5 hours at 170° C. After completion of the reaction, the reaction liquid was treated in the same manner as described in Example 1 whereby 0.35 g of the starting 5-fluorouracil was recovered as a substance insoluble in chloroform and 1.20 g of 1-(2-tetrahydrofuryl)-5-fluorouracil were obtained. The yield of the end product was 82% based on the consumed 5-fluorouracil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21](F)=[C:22]([CH:25]=3)C#N)=[N:14][C:12]=2[N:13]=1.O.[NH2:35]N>CCO>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@@H:28]2[CH3:33])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[C:22]([NH2:35])[CH:21]=[CH:20][CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccc(F)c(C#N)c3)nc2n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3cccc(N)c3)nc2n1

Procedure:
To a 0.3M solution of 5-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-fluoro-benzonitrile (example lay) (1 equiv) in EtOH was added hydrazine hydrate (5 equiv). The mixture was refluxed for 90 minutes whereupon it was cooled and partitioned between CH2Cl2 and water (1 reaction volume of each). The organic extract was removed. The aqueous phase was further extracted with CH2Cl2 (2×1 reaction volume). The combined organic extracts were then dried (MgSO4), filtered and concentrated in vacuo to give a yellow slurry which was further purified by flash chromatography (SiO2) using EtOAC/Hexanes as eluent to give the title compound as a yellow powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.