Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: CC#N
Product: CC(C)CNc1c(N)cnc2cc(Br)ccc12
Reaction time: 1 h

Procedure:
A solution of (7-bromo-3-nitroquinolin-4-yl)-(2-methylpropyl)amine (30.9 g, 105 mmol) in acetonitrile (1.8 L) and isopropanol (200 mL) was added to a Parr vessel. A mixture of 5% platinum on carbon (3.0 g) and acetonitrile:isopropanol (20 mL) was added, and the vessel was purged with nitrogen. The vessel was placed under hydrogen pressure (40 psi, 2.8×105 Pa) for two hours. After one hour, the pressure had decreased to 20 psi (1.4×105 Pa) and was readjusted to 40 psi (2.8×105 Pa). The reaction mixture was filtered through a layer of CELITE filter aid, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 7-bromo-N4-(2-methylpropyl)quinoline-3,4-diamine as an oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[O:4][N:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[N:6]=[C:5]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])[O:4][N:3]=1
Reactant: Cc1noc(N)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: Cc1noc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 208° C. and MS: m/e=307 (M+) was prepared in accordance with the general method of example 44a from 3-methyl-[1,2,4]oxadiazol-5-ylamine and 9H-xanthene-carboxylic acid chloride.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[C:15]([C:26]([NH:28][CH2:29][CH2:30][OH:31])=[O:27])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.O>N1C=CC=CC=1>[CH3:32][N:33]([CH3:38])[CH2:34][C:35]([O:31][CH2:30][CH2:29][NH:28][C:26]([C:15]1[N:14]=[N:13][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)=[O:27])=[O:36]
Reactant: CN(C)CC(=O)O
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCO)c2COc2cccc(F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NCCOC(=O)CN(C)C)c2COc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-[(3-fluorophenoxy)methyl]-N-(2-hydroxyethyl)-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 498 in pyridine (10 ml) were added dimethylglycine (181 mg) and WSC (336 mg), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column (ethyl acetate/hexane=1/1 to 2/1) and recrystallized from ethyl acetate to give the title compound as a colorless powder (432 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.[H-].[Na+].[CH3:13]I.[NH4+].[Cl-]>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[CH3:13][O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][CH2:4]1
Reactant: OCC1CCC(CO)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COCC1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
1,4-bis(Hydroxymethyl)cyclohexane (5 g, 0.0347 mol), cis/trans mixture 1:3, in anhydrous DMF (20 cm3) was added dropwise to NaH (1.6 g, 0.0366 mol, 55%) washed with hexane, under atmosphere of nitrogen. The mixture was stirred at room temperature for 1/2 h, then CH3I (5 g, 0.0352 mol) dissolved in DMF (20 cm3) was added dropwise. After the addition was complete the solution was stirred at room temperature for 2 h; NH4Cl solution was added then thoroughly extracted with ether, to which Na2SO4 was added and dried under reduced pressure. Chromatography on silica gel eluting with hexane/ethyl acetate (55/45) gave 4-methoxymethyl-cyclohexylmethanol (1.8 g, 0.0113 mol) out of 4.1 g of residue. Such compound was dissolved in ether (10 cm3), cooled to -70° C. and was added dropwise with PBr3 (1.2 g, 0.0044 mol). After the addition was complete the solution was stirred to room temperature for 2 h, was extracted with ether and cautiously added with satured NaHCO3 solution. After the two layers were separated, the organic phase was added with Na2SO4 and dried under reduced pressure. Chromatography on silica gel eluting with hexane gave 4-methoxymethyl cyclohexylmethyl bromide, cis trans mixture 1 3. Such product was employed in the example 8.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)ccc1F

Procedure:
To a solution of 2-fluoro-5-methylbenzoic acid (20.0 g, 0.13 mol) in MeOH (100 mL) is added thionyl chloride (1.9 mL, 26.0 mmol) dropwise, via syringe, and the solution is refluxed overnight. After cooling, the solvent is evaporated, and the residue is taken up in ethyl acetate (200 mL), extracted with sat'd aq. NaHCO3 (50 mL), brine (50 mL), water (50 mL), dried (MgSO4), and chromatographed (silica, 5% EtOAc/hexane) to yield methyl 2-fluoro-5-methylbenzoate, as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[N:12]2)[CH:5]=1.CO.NN>C(OCC)(=O)C.[Ni].O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[CH:5]=1
Reactant: COC(=O)c1cccc(Cn2ccc([N+](=O)[O-])n2)c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(Cn2ccc(N)n2)c1
Yield: 69.1 %

Procedure:
The 3-(3-nitro-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.78 g, 6.82 mmol) was dissolved in ethyl acetate (5 mL) and methanol (5 mL) was added. While stirring, a 50% slurry of raney nickel in water (1 mL) was added followed by hydrazine (1.5 mL). Immediate effervescence was observed. The reaction continued to stir and bubble for 30 min. The reaction was passed through a plug of celite and concentrated in vacuo to give a yellow oil. The oil was taken up in ethyl acetate (100 mL), washed with water (2×20 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 3-(3-amino-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.09 g, 69%) as a beige solid: H1-NMR (400 MHz, DMSO-d6) δ 3.83 (3H, s), 4.57 (2H, bs), 5.09 (2H, s), 5.41 (1H, d, J=2.0 Hz), 7.44-7.46 (3H, m), 7.76 (1H, bs), 7.82-7.84 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH2:21])[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c(OC)c1
Agent: [Pd]
Product: COc1ccc(-c2cccc3c2OC(CN)C3)c(OC)c1
Yield: 54 %

Procedure:
Treatment of (+)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.660 g, 1.57 mmol) with palladium on carbon (0.066 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.242 g (48%) of (−)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a pale yellow solid, hydrochloride salt. [α]D25=−4.7 (c 10.0 in methanol); mp 166-168° C.; Anal. calcd. for C17H19NO3HCl: C, 63.45; H, 6.26; N, 4.35. Found: C, 60.84; H, 6.51; N, 3.98.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[OH:10][CH:11]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[CH:22])[CH2:16][C@@H:15]1[C:23]([O:25][CH3:26])=[O:24].O>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][CH:11]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1)[CH2:12][CH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]#[C:22][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=2)[CH2:16][C@@H:15]1[C:23]([O:25][CH3:26])=[O:24]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C#CCN1CC[C@@H](CCC(O)c2ccnc3ccc(OC)cc23)[C@@H](C(=O)OC)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CN(CC#Cc2cc(F)cc(F)c2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 80 °C

Procedure:
0.138 g of tetrakis(triphenylphosphine)palladium, 0.046 g of cuprous iodide, and 0.42 cm3 of 1-bromo-3,5-difluorobenzene were added to a mixture, stirred at a temperature in the region of 20° C. under an inert atmosphere, of 0.95 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-(prop-2-ynyl)piperidine -3-carboxylate in 9.5 cm3 of triethylamine. The mixture was heated at a temperature in the region of 80° C. for 3 hours. After cooling to approximately 20° C., the reaction mixture was taken up in 30 cm3 of ethyl acetate and 30 cm3 of water and stirred for 5 minutes. The organic phase was separated by settling, while the aqueous layer was extracted with 2 times 30 cm3 of ethyl acetate. The organic extracts were combined, washed with 3 times 30 cm3 of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 2.3 cm; 40 g), elution was carried out with pure ethyl acetate. 2 fractions of 100 cm3 were first collected and then 20-cm3 fractions were obtained. Fractions 8 to 40 were combined and evaporated under the above conditions. 0.967 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate was obtained in the form of a foam with an orange color.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]1[O:16][C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=3[C:19]=1[C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:9]=[CH:8]2>C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]1[O:16][C:17]3[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=3[C:19]=1[CH:20]([OH:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH:9]=[CH:8]2
Reactant: CCCCC(=O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCC(O)c1c(-c2ccc3cc(OC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
Sodium borohydride ((7.56 g, 200 mmol) was added portion-wise to the stirring mixture of 1-[2-(6-methoxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (17.9 g, 50 mmol) in ethanol (600 mL). The mixture was stirred at room temperature for 2 hours then filtered. The solids were dissolved in methylene chloride and 2N hydrochloric acid solution. The organic phase was washed with water, dried over anhydrous magnesium sulfate and solvent evaporated to give the title compound (16.6 g). 1HNMR (300 MHz, DMSO-d6): δ8.2 (s, 1H), 7.98-7.92 (m, 2H), 7.9-7.82 (m, 2H) 7.62 (d, 1H, J=7.5 Hz), 7.38 (s, 1H), 7.35-7.22 (m, 3H), 5.46 (d, 1H, J=3.6 Hz), 5.15-5.07 (m, 1H), 3.92 (s, 3H), 2.12-1.97 (m, 1H), 1.95-1.82 (m, 1H), 1.44-1.21 (m, 3H), and 0.69 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([NH:9][C:10](=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])SC)#[N:8]>C(O)C>[C:7]([NH:9][C:10]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[N:13][CH2:14][CH2:15][S:16][CH2:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23])#[N:8]
Reactant: NCCCCO
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: Cc1nc[nH]c1CSCCN=C(NC#N)NCCCCO
Yield: 38.6 %

Procedure:
4-Aminobutanol (2.7 g) and N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (4.05 g) were refluxed in ethanol (30 ml) for 4 hours. The reaction mixture was evaporated to yield an oil which was chromatographed on a silica gel column and eluted with chloroform and chloroform/methanol (20:1) to give the title compound as a colourless oil (1.8 g). (Found: C, 50.4; H, 7.4; N, 26.8; S, 10.1%. C13H22N6OS requires: C, 50.3; H, 7.2; N, 27.1; S, 10.3%). n.m.r. analysis in DMSO-d6 at 100 mHz:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[CH:30]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=1[N:40]1[C:44](=[O:45])[CH2:43][S:42]/[C:41]/1=[N:46]\[C:47](=O)[O:48]C1C=CC([N+]([O-])=O)=CC=1)([CH3:32])[CH3:31]>>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[N:15]=3)=[CH:12][CH:13]=2)[C:47](/[N:46]=[C:41]2\[S:42][CH2:43][C:44](=[O:45])[N:40]\2[C:34]2[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:33]=2[CH:30]([CH3:31])[CH3:32])=[O:48])[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CCNCC4CC4)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)N(CCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC2CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using N-(cyclopropylmethyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB27) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red-orange oil (0.127 g, 60%).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][NH:46][CH2:45]2)[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:40])([F:41])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][N:46]([C:3]3[N:8]4[N:9]=[C:10]([CH:12]5[CH2:17][CH2:16][N:15]([CH:18]([CH3:19])[CH3:20])[CH2:14][CH2:13]5)[N:11]=[C:7]4[CH:6]=[C:5]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=4[Cl:28])[N:4]=3)[CH2:45]2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Reactant: Nc1nc(NC2CCCNC2)ccc1C(=O)C(F)(F)F
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(N4CCCC(Nc5ccc(C(=O)C(F)(F)F)c(N)n5)C4)n3n2)CC1
Temperature: 130 °C

Procedure:
80 mg (0.17 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidine hydrochloride, 64.9 mg (0.2 mmol) of 1-[2-amino-6-(piperidin-3-ylamino)pyridin-3-yl]-2,2,2-trifluoroethanone hydrochloride (Example 22A) and 0.17 ml (0.99 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 32 mg (28% of theory) of the product as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: C1CNCCN1
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 48.1 %

Procedure:
1-Bromo-4-t-butylbenzene (2.38 mL, 14 mmol), piperazine (1.8 g, 21 mmol), sodium t-butoxide (1.95 g, 20.3 mmol) and dichlorobis(tri-o-tolylphosphine)palladium(II) (330.1 mg, 0.42 mmol) were dissolved in anhydrous toluene and reacted for 3 hours while heating at 100° C. After identifying complete disappearance of 1-bromo-4-t-butylbenzene by TLC, the reaction solution was filtered with celite. The filtrate was concentrated and purified by separation through column chromatography (CH2Cl2/MeOH, 1:1). A target compound (1.47 g, 6.732 mmol, 48.2%) was yielded.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:17](=[O:18])[C:16]3[C:11]4=[C:12]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[N:10]4[CH:9]=2)[CH:13]=[CH:14][N:15]=3)[CH:2]=1.[CH:25](=O)C1C=CC=CC=1>>[CH2:7]([C:8]1[C:17](=[O:18])[C:16]2[C:11]3=[C:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[N:10]3[CH:9]=1)[CH:13]=[CH:14][N:15]=2)[C:3]1[CH:2]=[CH:25][CH:6]=[CH:5][CH:4]=1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccccc3c3ccnc1c32
Reactant: O=Cc1ccccc1
Product: O=c1c(Cc2ccccc2)cn2c3ccccc3c3ccnc1c32
Yield: 58.2 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) produced in Example 26<step 2> was reacted with benzaldehyde (153 mg) to obtain the title compound (116 mg; 42%).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1I.[CH2:19]([Li])CCC.IC>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH3:18])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[C:6]=1[CH3:19]
Reactant: Cc1nc(I)c(I)n1-c1ccc(C(F)(F)F)cc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1nc(I)c(C)n1-c1ccc(C(F)(F)F)cc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
4,5-Diiodo-2-methyl-1-(4-trifluoromethyl-phenyl)-1H-imidazole (1.0 g, 2.1 mmol) was dissolved in 15 ml THF and cooled to −75° C. n-Butyllithium (1.6M in Hexane) (1.60 ml, 2.5 mmol) was added, and the mixture stirred for 60 min at −75° C. Iodomethane (0.19 ml, 3.0 mmol) was added and stirring was continued 30 min. at −75° C. and then 1 h without dry ice bath. The reaction mixture was quenched with sat. NaHCO3− solution and extracted with water and ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (heptane/ethylacetate 100:0→60:40 gradient) and by recrystallization from little ethyl acetate and cyclohexane. The desired compound was obtained as a white solid (197 mg, 26%), MS: m/e=367.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-])=O)=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:23])[CH:3]=1>C(O)C.CC(O)=O.[Fe]>[NH2:1][C:2]1[C:19]([NH2:20])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([Cl:23])[CH:3]=1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1N
Temperature: 25 °C

Procedure:
A solution of 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (2 mmol; see Example 154) in ethanol (5 mL) and AcOH (1 mL) was added with iron powder (10 mmol). The reaction mixture was then heated to reflux for 6 h. The contents were cooled to RT, filtered through Celite pad, and the pad was washed with ethanol. The filtrates were combined and concentrated in vacuo. The residue obtained was purified on a silica gel column chromatography using MeOH/DCM as eluent to afford 4,5-diamino-2-chloro-N-(1H-indazol-6-yl)benzamide.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[CH3:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:10]>C(O)C.C(OCC)C>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH3:8])=[CH:12][CH:13]=1
Reactant: OC(CCl)CCCl
Reactant: CC(=O)c1ccc(O)cc1
Solvent: CCOCC
Solvent: CCO
Product: CC(=O)c1ccc(OCC(O)CCCl)cc1

Procedure:
Utilizing the procedure of Preparation 16, 1,4-dichloro-2-butanol was reacted with 4-hydroxyacetophenone to give cream colored solid, m.p. 75°-77° C. Recrystallizing solvent was a mixture of ethanol-diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.ClC1C=C(Cl)C=CC=1C1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)[N:21]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]1[C:25]([C:26]2[NH:30][CH:29]=[CH:28][N:27]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][N:36]=2)[N:21]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(F)cc3Cl)n2)nc1

Procedure:
[4-(2-chloro-4-fluorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 2-chloro-4-fluorobenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)=O)=[N:4][S:5][N:6]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:27]2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7](=[S:27])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)=[N:4][S:5][N:6]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Nc1nsnc1C(=O)Nc1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1nsnc1C(=S)Nc1ccc(F)c(Br)c1
Yield: 55.7 %

Procedure:
A solution of 4-amino-N-(3-bromo-4-fluorophenyl)-1,2,5-thiadiazole-3-carboxamide (225 mg, 0.7 mmol) and 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane (570 mg, 1.4 mmol) in toluene (6.8 mL) was stirred at 95° C. for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL) and the insoluble salts were filtered. The filtrate was concentrated to a crude residue which was purified on silica gel to give the desired product (130 mg, 55%). LCMS for C9H7BrFN4S2 (M+H)+: m/z=332.8, 334.9.