Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[C:17]([CH2:24]I)[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]2[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=1.O>CN(C)C=O>[O:3]=[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]1[CH2:24][C:17]1[C:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:15]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[C:14]2[C:19](=[CH:20][C:21]([O:22][CH3:23])=[C:12]([O:11][CH3:10])[CH:13]=2)[N:18]=1
Reactant: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Cn2ccccc2=O)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.8 %

Procedure:
Oily sodium hydride (60%, 0.117 g) was added to a solution of 2-hydroxypyridine (0.277 g) in N,N-dimethylformamide (DMF)(10 ml), and the mixture was stirred at room temperature for 15 minutes. To this solution was added ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-iodomethylquinoline-3-carboxylate(1.2 g) . The mixture was stirred at room temperature for 8 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated. The residual oil was subjected to column chromatography on silica gel. The fractions eluted with chloroform/ethyl acetate (10/1, v/v) gave ethyl 2-(1,2-dihydro-2-oxopyridine-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (0.64 g, 57%) which was then recrystallized from ethanol. Colorless prisms. mp. 154°-156° C.
Reaction SMILES: [CH3:1][C:2]([NH2:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O.C(O)(C)C>C1(C)C=CC=CC=1.[Pt]>[NH2:19][C:2]([CH3:18])([CH3:1])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(N)CNc1c(N)cnc2ccccc12
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 2-methyl-N1-(3-nitroquinolin-4-yl)propane-1,2-diamine (2.45 g, 9.42 mmol), in 100 mL of toluene and 50 mL of isopropanol was treated with 0.5 g of 5% Pt on carbon and shaken under H2 (3 atm, 3 Kg/cm2) for 3 h. The solution was then filtered through a Celite pad and concentrated to give 2.17 g of crude N4-(2-amino-2-methylpropyl)quinoline-3,4-diamine as a light brown foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([CH:14]=O)=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[BH3-]C#N.[Na+]>ClC(Cl)C.[Zn+2].[I-].[I-]>[CH2:1]([O:3][C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([CH3:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C=O)sc2[nH]1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc2cc(C)sc2[nH]1
Reaction time: 168 h
Yield: 49.7 %

Procedure:
Using a procedure by C. K. Lau et. al. (J. Org. Chem., 51: 3038-3043 (1986)), a mixture of 2-formyl-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (Soth, S. et al., Bull. Soc. Chim. Fr., 2511-2515 (1975); 500 mg, 2.24 mmol), ZnI2 (1.08 g, 3.36 mmol), and NaBH3CN (1.06 g, 16.8 mmol) in dichloroethane (25 mL) was stirred for 7 d and quenched with saturated aqueous NH4Cl (25 mL). The resultant biphasic mixture was stirred for an additional 30 min, extracted with ethyl acetate, dried over Na2SO4, and concentrated. The product was purified by Chromatotron-chromatography (3:2 hexanes:ether) and obtained as a white foam (233 mg, 50%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][S:16][C:17]1[C:22]([NH:23][C:24](=[O:27])[CH2:25]O)=[C:21]([S:28][CH3:29])[CH:20]=[C:19]([CH3:30])[N:18]=1.I(O)(=O)=O.[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[NH:37][C:36]=1[S:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>CN(C)C=O.C(OCC)(=O)C.O>[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[NH:37][C:36]=1[S:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][N:50]([CH2:25][C:24]([NH:23][C:22]2[C:17]([S:16][CH3:15])=[N:18][C:19]([CH3:30])=[CH:20][C:21]=2[S:28][CH3:29])=[O:27])[CH2:49][CH2:48]1
Reactant: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: [O-][I+2]([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 94 %

Procedure:
Diisopropyl azodicarboxylate (0.770 mL, 1.52 mmol) was added dropwise to a solution of N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hydroxyacetamide (131 mg, 0.508 mmol), 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine iodate (933 mg, 1.88 mmol) and triphenylphosphine (470 mg, 1.79 mmol) in dimethylformamide (3 mL) under stirring with water cooling over 5 minutes. The resultant mixture was stirred at room temperature for 60 minutes, and water (10 mL) was added thereto. Subsequently, 1 mol/L hydrochloric acid (10 mL) and ethyl acetate (30 mL) were added the reaction mixture, to thereby collect the aqueous layer. The organic layer was extracted with 1 mol/L hydrochloric acid (10 mL×2). The obtained aqueous layers were combined, and the thus-combined aqueous layer was washed with ethyl acetate (30 mL×2). The pH of the resultant mixture was adjusted to 8 to 9 with a 1 mol/L aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (30 mL×3). The organic layers were combined, and the thus-combined organic layer was washed with saturated brine. The thus-washed organic layer was dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure. The crude product was purified through silica gel column chromatography (silica gel: 40 g, developer: chloroform:methanol=100:3), to thereby yield 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide (240 mg, yield: 94%).
Reaction SMILES: [O:1]=O.[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=C)=[CH:8][C:7]=1[OH:14].CSC>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:1])=[CH:8][C:7]=1[OH:14]
Reactant: O=O
Reactant: C=Cc1ccc(C(=O)OC)c(O)c1
Solvent: CSC
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)cc1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A steady stream of O2 (g) is passed through a cold (−78° C.) solution of 2-hydroxy-4-vinyl-benzoic acid methyl ester (3.28 g, 0.0184 mol) in CH2Cl2 (50 ml). After 5 minutes, O3 (g) is bubbled into the solution until the solution's color turns blue/gray. The solution is then purged with O2 (g) for 5 minutes, treated with DMS (4.05 ml, 0.0552 mol) and allowed to warm to room temperature overnight. All volatiles are removed in vacuo and the crude product is purified with silica gel column chromatography (0-100% ethyl acetate in hexanes gradient) to afford 4-formyl-2-hydroxy-benzoic acid methyl ester: ESMS m/z 181.0 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[Mg].[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[CH:18]=[C:19]([CH3:21])[CH3:20]>C1COCC1>[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[CH2:18][C:19]([CH3:21])([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([CH3:13])[O:12][CH2:11][CH2:10][O:9]2)[CH:3]=1)[CH3:20]
Reactant: CC(C)=CC(=O)C(F)(F)F
Reactant: CC1(c2cccc(Br)c2)OCCO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2(C)OCCO2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 43.1 %

Procedure:
To a solution of 2-(3-bromophenyl)-2-methyl-[1,3]dioxolane (1 g) in THF (5 mL) was added portionwise magnesium metal (0.2 g) and the reaction heated at refluxed for 30 minutes. The mixture was cooled to room temperature and CuBr-DMS complex (846 mg, 4.11 mmol) was added. The mixture was stirred 3 minutes at room temperature, cooled to 0° C. and 1,1,1-trifluoro-4-methylpent-3-en-2-one (62 mg, 4.11 mmol) in 20 mL of THF was added dropwise. The mixture was stirred for 30 minutes at 0° C., warmed to room temperature, stirred overnight and quenched with aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford a residue that was purified by flash chromatography. Concentration in vacuo of the product-rich fractions afforded 0.56 g of 1,1,1-trifluoro-4-methyl-4-[3-(2-methyl-[1,3]dioxolan-2-yl)phenyl]pentan-2-one.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:34])[OH:33])=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1.[CH3:39][C:40]([CH3:58])([CH2:43][N:44]1[CH:48]=[C:47]([B:49]2[O:53][C:52]([CH3:55])([CH3:54])[C:51]([CH3:57])([CH3:56])[O:50]2)[CH:46]=[N:45]1)[CH2:41]O.CN1C=CN=C1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCCl>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:36]=[CH:35][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][PH:32](=[O:33])[O:34][CH2:39][C:40]([CH3:58])([CH3:41])[CH2:43][N:44]4[CH:48]=[C:47]([B:49]5[O:53][C:52]([CH3:55])([CH3:54])[C:51]([CH3:57])([CH3:56])[O:50]5)[CH:46]=[N:45]4)=[CH:26][C:25]=3[O:37][CH3:38])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CO)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Agent: Cn1ccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CCCC[PH](=O)OCC(C)(C)Cn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
A suspension of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinic acid (Compound 74B, 0.500 g, 0.810 mmol) and 2,2-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 47B, 227 mg, 0.809 mmol) in 1,2-dichloroethane (24.4 mL) and 1-methylimidazole (0.967 mL, 12.1 mmol) was charged with (benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (2530 mg, 4.85 mmol). After stirring at 60° C. for 16 hours, the reaction mixture was quenched with water (10 mL) and extracted with DCM (20 mL). The organic layer was washed with NaHCO3 (10 mL), washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a brown oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using 1:1 DCM-EtOAc/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield an off-white foam (318.1 mg, 45%). MS (ESI): m/z 879.93/881.94 [M+H]+. UPLC: tR=1.67 min (UPLC-TOF: polar—2 min).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[O:32][CH3:33])=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[O:4].[CH:34]1([NH2:37])[CH2:36][CH2:35]1>ClCCl>[CH:34]1([NH:37][CH2:2][C:3]([NH:5][C:6]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[O:32][CH3:33])=[N:24][NH:23][C:20]4=[N:21][CH:22]=3)=[CH:13][C:7]=2[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[O:4])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)CBr)c(C(=O)N(C)C)c3)cc12
Solvent: ClCCl
Product: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(NC(=O)CNC4CC4)c(C(=O)N(C)C)c3)cc12
Reaction time: 19 h
Yield: 38.5 %

Procedure:
20 mg (39 μmol) of 2-(2-bromo-acetylamino)-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 3 mL of dichloromethane. 14 μL (12 mg, 0.2 mmol) of cyclopropylamine was added at room temperature and the resulting mixture left at ambient temperature for 19 h. The resulting solution was evaporated and the residue purified by mass-triggered reverse-phase HPLC to afford 7.1 mg (15 μmol, 38%) of 2-(2-cyclopropylamino-acetylamino)-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 13.82 (s, 1H), 10.00 (s, 1H), 8.87 (d, 1H), 8.35 (d, 1H), 8.33 (d, 1H), 7.82 (dd, 1H), 7.72 (d, 1H), 7.65 (dd, 1H), 7.47 (dd(m), 1H), 7.23 (d(m), 1H), 7.11 (ddd, 1H), 3.84 (s, 3H), 3.30 (s, 2H), 3.04 (s, 3H), 2.94 (s, 3H), 2.17 (m, 1H), 0.40 (m, 2H), 0.32 (m, 2H), MS: m/z 485.2 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[CH:11](O)[CH2:12][C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.O=S(Cl)[Cl:26]>>[Cl:26][CH:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[CH2:12][C:13]1[CH:22]=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: OC(Cc1cnc2ccccc2n1)c1cnc2ccccc2n1
Reactant: O=S(Cl)Cl
Product: ClC(Cc1cnc2ccccc2n1)c1cnc2ccccc2n1

Procedure:
A solution of 1,2-di(quinoxalin-2-yl)ethanol (0.05 g, 0.166 mmol) in SOCl2 (2 mL) was stirred at room temperature for 1 hour. The solution was then concentrated to afford 2,2′-(1-chloroethane-1,2-diyl)diquinoxaline (0.05 g) as a yellow solid. MS (ESI) m/z 321.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O.CC(OC)(C)C>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.9 %

Procedure:
To a flask equipped with a nitrogen inlet, addition funnel, thermowell, and mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and dimethylacetimide (9.6 L). The mixture was cooled to −5° C. in an ice/brine bath and sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions as a solid. The mixture went to a dark solution during 15 minutes and trimethylsilylethoxymethyl chloride (2, 763 mL, 4.31 mol, 1.1 equiv) was added slowly via an addition funnel at a rate that the temperature did not exceed 5° C. The reaction was stirred for 30 minutes, determined to be complete by TLC and HPLC, and water (1 L) was slowly added to quench the reaction. The mixture was then diluted with water (12 L) and MTBE (8 L). The layers were separated and the aqueous was re-extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L), dried over sodium sulfate (NaSO4), and solvents removed under reduced pressure. The residue was dissolved in heptane (2 L), filtered and loaded onto a silica gel (3.5 kg) column eluting with heptane (˜6 L), 95% heptane/ethyl acetate (˜12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The pure fractions were combined and concentrated under reduced pressure to give 4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (3a, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil that partially solidified to an oily solid on standing at room temperature. For 3a: 1H NMR (DMSO-d6, 300 MHz) δ ppm 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H); 13C NMR (DMSO-d6, 100 MHz) δ ppm 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:23][NH:24][C:25]([NH2:27])=[NH:26].[ClH:28]>C(O)C>[ClH:28].[ClH:28].[C:2]1([C:1](=[N:23][NH:24][C:25](=[NH:26])[NH2:27])[CH2:9][CH2:10][C:11](=[N:23][NH:24][C:25](=[NH:27])[NH2:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCC(=O)c1ccccc1)c1ccccc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CCO
Product: N=C(N)NN=C(CCC(=NNC(=N)N)c1ccccc1)c1ccccc1

Procedure:
1,2-dibenzoylethane (4.76 g), aminoguanidine bicarbonate (5.45 g), and concentrated hydrochloric acid (3.33 mL) were heated in 50% ethanol (60 mL) for 24 hr. Cooling, concentration and filtration gave 4.3 g of 2,2′-(1,4-diphenyl-1,4-butanediylidene)bis(hydrazinecarboximidamide) dihydrochloride, mp 285-6° C.
Reaction SMILES: [C:1]1([S:7]([CH3:9])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)C=[CH:24]1.C(N(CC)CC)C>C(Cl)Cl.O>[C:1]1([S:7][C:9]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)c1ccccc1
Reactant: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(Sc2c[nH]c3ccccc23)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of methyl phenyl sulfoxide (4.0 g, 147 mmol) in CH2Cl2 is cooled to −78° C., treated dropwise with trifluoroacetic anhydride (4.0 mL, 5.99 g, 28.5 mmol), stirred for 30 min at −78° C., treated with a solution of indole (1.82 g, 15.6 mmol) in CH2Cl2, stirred for 30 min at −78° C., treated with triethylamine (20 mL, 145 mmol), stirred for 4 days at ambient temperatures and diluted with water. The phases are separated. The organic phase is dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed (1:99 methanol:CH2Cl2) to give the title product as a white solid, 3.08 g (88% yield), mp 149–151° C., characterized by mass spectral and HNMR analyses.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(O)(=O)C>CC#N>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[C:19]([F:29])=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: F[B-](F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)O
Solvent: CC#N
Product: Cn1cc(-c2cc3ncc(F)n3c(-c3cnn(C(CC#N)C4CC4)c3)n2)cn1
Temperature: 80 °C
Yield: 20 %

Procedure:
3-Cyclopropyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 2; 0.200 g, 0.558 mmol), Selectfluor® (0.395 g, 1.12 mmol) and acetic acid (0.320 mL, 5.58 mmol) were suspended in MeCN (20 mL) and heated to 80° C. overnight. The reaction mixture was cooled to ambient temperature and the reaction mixture partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The combined organic extracts were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 1-2% (9:1 MeOH:NH4OH)/dichloromethane to provide the 3-cyclopropyl-3-(4-(3-fluoro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.042 g, 0.112 mmol, 20% yield). MS (apci) m/z=377.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([Mg]Cl)(C)C.CN(C)[CH:18]=[O:19]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[O:19])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(F)cc(I)c1=O
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1cc(F)cc(C=O)c1=O
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
5-Fluoro-3-iodo-1-methyl-1H-pyridin-2-one (32, 120.5 g, 476 mmol) was dissolved in 2381 mL of tetrahydrofuran and cooled to −40° C. in a dry ice acetone bath. Isopropylmagnesium chloride (310 mL, 619 mmol) was added dropwise and the mixture was stirred for 30 minutes. Then 92 mL of N,N-dimethylformamide was added and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding 200 mL of 10% aqueous hydrochloric acid, then concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 100% ethyl acetate. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound as a yellow solid (33, 35 g, 226 mmol, 47.4%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[CH2:16][CH2:17][NH2:18].CCN(CC)CC.CO>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([CH2:16][CH2:17][NH:18][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCc1cccc(Br)c1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCc2cccc(Br)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
TsCl (11 g, 57.5 mmol, 1.15 eq.) was dissolved in DCM (150 mL) and cooled to 0° C. To this solution was added a solution of 3-bromo-phenethyamine (10 g, 50 mmol) in DCM (50 mL), followed by Et3N (18 mL). The solution was stirred at r.t. overnight when TLC (5% MeOH in DCM) showed that the reaction was complete. LCMS: t=4.158, MS 354/356. 3 g of polymer-supported-amine was added, stirred for 1 h at r.t. The solution was filtered through a Celite pad, rinsed with DCM and the solvent was evaporated to dryness, re-dissolved in DCM (100 mL) and water (20 mL). The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with 1N H3PO4 (2×20 mL) and sodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with DCM (TLC: DCM) to get 17.89 g (100%) of the title compound as a off-white solid, on standing.
Reaction SMILES: C(N)CN.C(C1OC=NC=1CCl)C1C=CC=CC=1.[CH2:19]([C:26]1[O:30][CH:29]=[N:28][C:27]=1[CH2:31][NH:32][CH2:33][CH2:34][NH2:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37]=[C:38]=[S:39]>>[CH3:36][NH:37][C:38]([NH:35][CH2:34][CH2:33][NH:32][CH2:31][C:27]1[N:28]=[CH:29][O:30][C:26]=1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:39]
Reactant: CN=C=S
Reactant: NCCNCc1ncoc1Cc1ccccc1
Agent: ClCc1ncoc1Cc1ccccc1
Solvent: NCCN
Product: CNC(=S)NCCNCc1ncoc1Cc1ccccc1

Procedure:
Reacting ethylenediamine with 5-benzyl-4-chloromethyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]3[S:29][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:27][CH:26]=3)[CH2:20][CH2:19]2)=[O:15])=[C:11]([CH3:36])[C:10]=1[C:37]#[N:38])=O)(C)(C)C.[ClH:39]>CO.ClCCl>[ClH:39].[ClH:39].[ClH:39].[NH2:8][C:9]1[S:13][C:12]([C:14]([O:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][C:25]3[S:29][C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[N:27][CH:26]=3)[CH2:22][CH2:23]2)=[O:15])=[C:11]([CH3:36])[C:10]=1[C:37]#[N:38]
Reactant: Cc1c(C(=O)OCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)sc(NC(=O)OC(C)(C)C)c1C#N
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1c(C(=O)OCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)sc(N)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound prepared in Example 223 (0.026 g) was suspended in methanol (2 mL) and dichloromethane (2 mL). Hydrogen chloride solution (4 M in 1,4-dioxane) (3.0 mL) was added and the reaction mixture stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to afford the title compound (0.027 g), which was used without further purification possessing the following physical data.