Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:39])C1C=CC=CC=1.[H][H].C(O)C>C1COCC1.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[CH:35]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:39]
Reactant: [H][H]
Reactant: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1O

Procedure:
0.4 g of 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine are hydrogenated in a hydrogen atmosphere at normal pressure and about 40° C. for 10 h in 20 ml of THF and 10 ml of ethanol in the presence of 0.2 g of 5% palladium/carbon. After filtration through Celite and crystallization of the residue from methylene chloride, 5-(4-hydroxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-aminopyrrolo[2,3-d]pyrimidine having an m.p. of 202°-204° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:15]=1[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:9]
Reactant: COc1ccc(OC)c(N)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Product: COc1ccc(OC)c(NC(=O)c2cc(Br)ccc2O)c1
Yield: 39.7 %

Procedure:
Using 5-bromosalicylic acid and 2,5-dimethoxyaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13].CN1CCCC1=O.Cl>[Fe](Cl)(Cl)Cl.O>[C:12]([C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(N)c(F)c1
Yield: 57.2 %

Procedure:
21 g of 4-bromo-2,6-difluoroaniline, 11 g of copper (I) cyanide, and 70 ml of N-methyl-2-pyrrolidone were placed in a flask for three hours to form a reaction mixture. The reaction mixture was poured into a solution of 41 g of iron (III) chloride mixed with 13 ml of concentrated hydrochloric acid and 50 ml of water. The mixture was extracted with chloroform and washed with water and 10% potassium hydroxide and the chloroform was removed by distillation. The residue was distilled under reduced pressure (bp 90° to 110° C. at 4 mmHg) and recrystallized with a mixture of hexane and chloroform to yield 8.9 g of 4-cyano-2,6-difluoroaniline.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:36])[CH2:32][CH2:33][CH2:34][NH2:35]>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH2:36])[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: NCCCCN
Product: NCCCCNc1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Yield: 28 %

Procedure:
Following the procedures Example 271, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and butane-1,4-diamine were reacted and the product was deprotected to give 283 as a yellow solid (20 mg, 28%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.19-9.21 (m, 1H), 9.12-9.13 (m, 2H), 8.53-8.60 (m, 2H), 7.60-7.63 (m, 1H) 7.51-7.54 (m, 1H), 7.44-7.46 (m, 1H), 6.53 (d, J=6.4 Hz, 1H), 3.65 (t, J=1.2 Hz, 2H), 2.93 (t, J=1.2 Hz, 2H), 1.80-1.85 (m, 4H). ESI MS m/z=360 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][CH2:8][C@@H:7]([C:10]([OH:12])=O)[CH2:6]1)=[O:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[C:26]1[S:27][CH:28]=[CH:29][N:30]=1>ClCCl>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[C:10]([C@@H:7]1[CH2:8][CH2:9][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:12]
Reactant: COC(=O)[C@H]1CC[C@@H](C(=O)O)C1
Reactant: C[Si](C)(C)c1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@H](C(=O)c2nccs2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1R,3S)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (130 mg, 0.76 mmol) in dichloromethane (3 mL) was added DMF (5.85 μL, 0.08 mmol). The solution was cooled to 0° C. oxalyl chloride (73.0 μL, 0.83 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature for one hour. The reaction was re-cooled to 0° C., 2-(trimethylsilyl)thiazole (178.0 mL, 1.13 mmol) was added and the mixture was stirred at room temperature for two hours. The mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to afford (1S,3R)-methyl 3-(thiazole-2-carbonyl)cyclopentanecarboxylate. MS ESI calc'd. for C11H14NO3S [M+H]+ 240. found 240. 1H NMR (500 MHz, DMSO-d6) δ 8.21 (d, J=3.0 Hz, 1H), 8.14 (d, J=3.0 Hz, 1H), 3.58 (s, 3H), 2.96-2.89 (m, 1H), 2.27-2.20 (m, 1H), 1.74-2.04 (m, 6H)
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[K+].O>CS(C)=O>[C:1]([C:5]1[NH:6][C:7]2[CH:8]=[CH:9][C:10]([N+:15]([O-:17])=[O:16])=[C:11]([C:18]#[N:19])[C:12]=2[CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2c(F)c([N+](=O)[O-])ccc2[nH]1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc2c(C#N)c([N+](=O)[O-])ccc2[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a solution of 2-tert-butyl-4-fluoro-5-nitro-1H-indole (4.0 g, 17 mmol) in DMSO (30 mL) was added KCN (3.4 g, 51 mmol). The mixture was stirred at 70° C. for 3 hours, and poured into water (80 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (7% EtOAc in petroleum ether) to afford 2-tert-butyl-5-nitro-1H-indole-4-carbonitrile (2.2 g, 53%). 1H NMR (DMSO, 300 MHz) δ 12.23 (br s, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 6.50 (s, 1H), 1.38 (s, 9H). MS (ESI) m/z: 244.2 [M+H+].
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)(=[O:3])[CH3:2].[CH2:29](O)C.C(OCC)C>>[C:1]([N:4]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[CH3:29])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)n1c(C(=O)c2cccc(C)c2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCOCC
Product: CC(=O)N(C)c1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared from 3-acetylamino-6-chloro-1-ethoxycarbonyl-2-(3-methylbenzoyl)indole (Example 22, step 1) according to the procedure described in Example 146. m.p.: 166-171° C. (ethanol/diethyl ether)
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])=O>O>[OH:23][C:17]1[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]=1[CH2:14][CH2:13][NH:6][C@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: N[C@@H](CS)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@H](CS)NCCc1ccc(O)cc1O
Reaction time: 1 h

Procedure:
Ingredients. (1) Water 97.3 (2) Sodium Bicarbonate 0.9 (3) L-Cysteine 1.2 (4) Resacetophenone 1.5. Procedure. Mix (1) to (3). Heat to 70 to 80 C. Add (4). An instantaneous reaction occurs and a clear yellow solution is obtained. The mixing and heating is continued for 1 hour, and then hydrogenated over Pt catalyst. After filtration of catalyst, solution of N-[(2,4-dihydroxyphenyl)ethyl]cysteine Sodium in water is thus obtained, pH 8.5. Water is evaporated to ⅓ in volume and the solution allowed to cool. The pH is adjusted to 6.5 with citric acid (2.0 grams of 50% solution). N-[(2,4-dihydroxyphenyl)ethyl]cysteine is obtained as a pale, yellow solid.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.CN(C)[CH2:26][CH2:27]CN=C=NCC.C(O)C.CN(C1C=CC=CN=1)C>ClCCl>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:13]([O:15][CH2:26][CH3:27])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C

Procedure:
5 g of Boc-Phe(4-NO2)-OH, 3.09 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 5 ml of ethanol and 2 g of dimethylaminopyridine were stirred in dichloromethane for 3 days. The obtained substance was washed with 1N hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and saturated NaCl solution, and dried with magnesium sulfate. The solvent was removed to obtain the title compound.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[CH3:33][C:34]1([O:37][CH2:36]1)[CH3:35]>>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([CH2:33][C:34]([CH3:36])([OH:37])[CH3:35])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Reactant: CC1(C)CO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(CC(C)(C)O)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-9H-purin-6-yl)morpholine and isobutylene oxide were reacted at room temperature to give 534. LCMS m/z: 253.2 (2M+H+)
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[NH:14]1[C:22]2[C:17](=[C:18]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15]1.O1CCCC1>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11]([N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[CH:20][CH:21]=[C:22]4[C:17]=3[CH:16]=[CH:15][NH:14]4)[CH2:24][CH2:25]2)=[O:13])=[CH:2]1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: O=C(O)Cc1coc2ccccc12
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cc1coc2ccccc12)N1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
A mixture of 2-(3-benzofuranyl)acetic acid (0.95 g), 1-(1H-indol-4-yl)piperazine (1.3 g), and N,N-dicyclohexylcarbodiimide (1.3 g) in a mixture of dry tetrahydrofuran (50 mL) and dry dimethylformamide (10 mL) was stirred for 16 h at room temperature. Filtration and removal of solvent in vacuo gave an oil which was purified by flash chromatography (eluent: ethyl acetate/heptane/triethylamine 10:9:1) giving 1-(3-benzofuranyl)methylcarbonyl-4-(1H-indol-4-yl)piperazine (0.5 g) as an oil. The oil was dissolved in tetrahydrofuran (20 mL) and treated with a suspension of lithium aluminium hydride (0.26 g) in tetrahydrofuran (20 mL) at room temperature under a nitrogen atmosphere followed by reflux for 4 hours. The reaction mixture was cooled to 0° C. and treated subsequently with water (1 mL), 15% aq. sodium hydroxide (0.5 mL), and water (2.5 mL). After stirring for 30 min the mixture was filtered and concentrated. The remaining oil was dissolved in acetone followed by addition of oxalic acid and filtration, giving the title compound as a crystalline material (0.4 g). Mp 130-32° C. 1H NMR (DMSO-d6): 3.05-3.15 (m, 2H); 3.15-3.30 (m, 6H); 3.35 (s, 4H); 6.45 (s, 1H); 6.55 (d, 1H); 7.00 (t, 1H); 7.10 (d, 1H); 7.20-7.40 (m, 3H); 7.60 (d, 1H); 7.75 (d, 1H); 7.90 (s, 1H); 11.10 (s, 1H). MS m/z (%): 346 (MH+, 3%), 214 (31%), 199 (19%), 171 (14%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:18]1([NH2:22])[CH2:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH:18]1([NH:22][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([N:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Reactant: NC1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)N1CCN(c2ccc(CNC3CCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.6 %

Procedure:
To a solution of 4-(4-acetylpiperazin-1-yl)benzaldehyde (150 mg, 0.64 mmol) and cyclobutylamine (75 mg, 0.77 mmol) in dichloroethane (1.5 mL) was added sodium triacetoxyborohydride (216 mg, 0.96 mmol), followed by acetic acid (0.055 mL, 0.96 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was then quenched with 1 N aqueous NaOH, diluted with dichloromethane and the dichloromethane layer was isolated with a phase-separator cartridge and concentrated to give 1-(4-(4-((cyclobutylamino)methyl)phenyl)piperazin-1-yl)ethanone (185 mg). The product was used without purification. LCMS (m/z) ES+ 288 [M+1]+.
Reaction SMILES: C(OC([N:11]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[O:14]1[C:13]2([CH2:18][CH2:19][NH:11][CH2:12]2)[O:17][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCC2(C1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: C1CC2(CN1)OCCO2
Reaction time: 0.33 h

Procedure:
A mixture of 1d (34.8 g, no more than 124 mmol) and 10% Pd—C (14 g) in EtOH (90 mL) was hydrogenolyzed (60 psi) in a Parr shaker apparatus at room temperature for 1.5 h. The catalyst was filtered off, the solvent was evaporated in vacuo and the residue was pumped under high vacuum for 20 min to yield 1e (15.9 g, quant. yield). Rf 0.14 (EtOAc-iPrNH2, 95:5, v/v); 1H NMR (200 MHz, CDCl3) δ 4.00 (s, 4H), 3.10 (t, J 7 Hz, 2H), 2.90 (s, 2H), 2.00 (t, J 7 Hz, 2H); 13C NMR (50 MHz, APT, CDCl3) δ 64.5 (+), 55.0 (+), 45.5 (+), 37.0 (+); IR (film) 3292 cm−1.
Reaction SMILES: [CH3:1][C:2]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[N:5]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]([O:13][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:19][CH3:20])([CH3:12])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5]1
Reactant: CC[Si](CC)(CC)OC(C)(C)Cn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC[Si](CC)(CC)OC(C)(C)Cn1ccc(N)n1

Procedure:
In a Parr shaker bottle was placed 1-(2-methyl-2-triethylsilanyloxy-propyl)-3-nitro-1H-pyrazole (197 mg, 0.65 mmol), 10% palladium on activated carbon (25 mg) and ethanol (10 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 1 h. The reaction was then filtered through a pad of celite and washed with ethanol, concentration in vacuo afforded 1-(2-methyl-2-triethylsilanyloxy-propyl)-1H-pyrazol-3-ylamine (191 mg, 100% (wet with some ethanol)) as a clear colorless oil: ES-HRMS m/e calcd for C13H27N3OSi (M+H)+ 270.1996, observed 270.1995; 1H NMR (300 MHz, CDCl3) δ ppm 0.56 (q, J=7.9 Hz, 6H, 3×SiCH2), 0.92 (t, J=7.9 Hz, 9H, 3×CH3), 1.21 (s, 6H, 2×CH3), 2.63 (br.s., 2H, NH2), 3.83 (s, 2H, NCH2), 5.59 (d, J=2.4 Hz, 1H, Ar), 7.22 (d, J=2.4 Hz, 1H, Ar).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.CCN(C(C)C)C(C)C.[C:24]1([NH:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([NH:33][CH2:32][CH2:31][NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: NCCNc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(NCCNc2ccccc2)nc(N2CCOCC2)n1
Temperature: 75 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4,6-dichloropyrimidin-2-yl)morpholine (prepared as described in Method 22; 932 mg, 4.0 mmol) and DIEA (0.7 mL, 4.0 mmol) in ACN (40 mL), neat N1-phenyl-ethane-1,2-diamine (0.523 mL, 4.0 mmol) was slowly added. The reaction mixture was stirred at 70-80° C. under nitrogen. After 20 hours, the reaction mixture was cooled down, and the solvent was removed under reduced pressure. The crude product was partitioned between EtOAc (120 mL) and 0.1 M NaHCO3 (50 mL). The organic layer was washed with additional 0.1 M NaHCO3 (2×50 mL), brine (50 mL), dried, filtered and concentrated to give N1-(6-chloro-2-morpholinopyrimidin-4-yl)-N2-phenylethane-1,2-diamine, as an off-white solid (1.29 g, 96%). LC/MS (m/z): 334.0 (MH+), Rt 1.94 minutes.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:13]=1[N+:14]([O-])=O)([C:3](OCC)=[O:4])=[O:2].O>C(O)(=O)C.[Zn]>[C:17]1([C:11]2[S:10][C:9]3[NH:8][C:1](=[O:2])[C:3](=[O:4])[NH:14][C:13]=3[CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)Nc1sc(-c2ccccc2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(-c3ccccc3)sc2[nH]c1=O

Procedure:
2-Ethoxalylamino-5-phenyl-3-nitrothiophene (641 mg, 2 mmol) was suspended in 35 ml of 80% acetic acid, and 1.31 g (20 mmol) of zinc dust was added in one portion with stirring. After 2 hours 70 ml of water was slowly added to the suspension, and the precipitate was isolated by filtration (483 mg). This crude product was purified by suspending in 20 ml of methylene chloride, filtering, and subsequent crystallisation by dissolving in 50 ml of boiling acetic acid and slow addition of 30 ml of water. The yield was 87 mg (17.8%) of the title compound as crystals, melting over 300° C. 1H-NMR (DMSO-D6, δ): 7.05 (s, 1H), 7.3 (t, 1H), 7.4 (t, 2H), 7.6 (d, 2H), 11.9-12.5 (broad, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[N:7]=1)=[O:5])[CH3:2]>[Pt]=O.C(O)C>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:10][N:9]=1
Reactant: CCOC(=O)c1nc(Cc2ccccc2[N+](=O)[O-])n[nH]1
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(=O)c1nc(Cc2ccccc2N)n[nH]1
Reaction time: 2 h

Procedure:
A mixture of 1 g of 5-ethoxycarbonyl-3-(o-nitrobenzyl)-1,2,4-triazole, 10 ml of ethanol and 25 mg of platinum oxide is hydrogenated at 3 atmospheres pressure for 2 hours, filtered and evaporated to give 3-(o-aminobenzyl)-5-ethoxycarbonyl-1,2,4-triazole.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1>>[C:1]([C:11]1[NH:10][CH:14]=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1c[nH]cn1
Product: O=C(c1ccccc1)c1ncc[nH]1
Yield: 71 %

Procedure:
Benzoyl imidazole was prepared by the above procedure using benzoyl chloride (28.1 grams, 200 mmole) and imidazole (14.3 grams, 210 mmole), in an amount of 24.3 grams (71% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(CBr)cc1
Reactant: Oc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(F)c(Br)c2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 3-bromo-4-fluorophenol (0.59 g) in tetrahydrofuran (7 ml) under nitrogen was added sodium hydride, 60% dispersion in mineral oil (0.13 g). The solution was stirred at room temperature. After 30 minutes a solution of 4-methoxybenzylbromide (0.62 g) was added in tetrahydrofuran (5 ml). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was partitioned between dichloromethane and brine, then dried (MgSO4), the solvents were removed in vacuo to give a crude residue. This crude residue was purified using flash chromatography to give 2-bromo-1fluoro-4-(4-methoxy-benzyloxy)-benzene (0.71 g). To a solution of 2-bromo-1fluoro-4-(4-methoxy-benzyloxy)-benzene (0.33 g) in tetrahydrofuran (10 ml) under nitrogen was added triisopropylborate (0.29 ml). The mixture was cooled to −78° C. and 2.5M n-butyllithium solution in hexanes was added. The reaction mixture was stirred at −40° C. for 1 hour, then warmed to 20° C. and quenched with 2M hydrochloric acid (aq) (2 ml). The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was adjusted to pH 7 using saturated sodium bicarbonate solution, then partitioned between ethyl acetate and water, dried (MgSO4) and the solvents removed in vacuo to yield a crude residue (0.31 g). A mixture of this crude residue and pinacol (0.25 g) in toluene (10 ml) were stirred under reflux overnight in a Dean-Stark apparatus. The solvents were removed in vacuo, the residue was then partitioned between ethyl acetate and water, the combined organics were washed with water then brine and dried (MgSO4), the solvents were removed in vacuo to yield 2-[2-fluoro-5-(4-methoxy-benzyloxy-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxyborolane (0.28 g)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:24](OC(C)(C)C)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27]>C1(C)C=CC=CC=1>[O:27]=[C:26]([CH3:28])[CH2:25][C:24]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:29]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 88.8 %

Procedure:
A solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (1.0 g, 3.12 mmol) and t-butyl acetoacetate (0.494 g, 3.12 mmol) in 8 mL of toluene was heated at 90° C. for 2 h, then cooled. The resulting solid was filtered and air-dried to give 1.12 g (89%) of 3-oxo-N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)-butanamide as a tan solid (B10); mp 159-164° C. 1H NMR (CDCl3) δ 9.35 (s, 1H), 8.55 (s, 1H), 8.19-8.09 (d, J=8.7 Hz, 2H), 7.83-7.74 (d, J=9.1 Hz, 2H), 7.74-7.63 (d, J=8.7 Hz, 2H), 7.43-7.32 (d, J=8.3 Hz, 2H), 3.62 (s, 2H), 2.34 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 205.34, 163.43, 163.02, 148.34, 141.49, 138.84, 135.55, 127.37, 126.50, 122.37, 121.67, 121.16, 120.03, 49.56, 31.36; ESIMS m/z 581 ([M+H]+).