Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:9](=O)[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C[OH:38]>>[C:1]([O:5][C:6](=[O:34])[CH:7]([OH:38])[CH:8]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:9][CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(=O)COc1c(F)c(F)cc(F)c1F
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)C(O)C(CCOc1c(F)c(F)cc(F)c1F)NC(=O)OCc1ccccc1
Yield: 81 %

Procedure:
To a dry round bottom flask equipped with a magnetic stir bar was added composition 12 (189 mg, 0.38 mM, 1 equiv) and MeOH (20 mL). With constant stirring was added NaBH4 (8 mg, 0.228 mmol, 0.6 equiv). Upon addition gas bubbles were produced and the resulting clear colorless solution was stirred at 0° C. for 30 minutes. Solvent was removed in vacuo and the resulting solid was purified via column chromatography (silica gel, 2:1, hexanes/EtOAc) to give 13 as a sticky white solid. (165 mg, 0.34 mmol, 81% yield) ESMS: 488.2 (M+H+), 510.8 (M+Na+).
Reaction SMILES: [CH:1]12[NH:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH:3]([NH:10][C:11]([C:13]1[N:17]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]4[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=4[F:31])[C:16]3=[N:15][C:14]=1[CH3:32])=[O:12])[CH2:2]2.[CH2:33]1COC[CH2:34]1.[H-].[Na+].ICC>C(OCC)(=O)C>[F:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([F:31])[C:24]=1[CH2:23][O:22][C:21]1[C:16]2[N:17]([C:13]([C:11]([NH:10][CH:3]3[CH2:2][CH:1]4[N:9]([CH2:33][CH3:34])[CH:5]([CH2:6][CH2:7][CH2:8]4)[CH2:4]3)=[O:12])=[C:14]([CH3:32])[N:15]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: C1CCOC1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1CC2CCCC(C1)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCI
Product: CCN1C2CCCC1CC(NC(=O)c1c(C)nc3c(OCc4c(F)cccc4F)cccn13)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60 mg of N-(9-azabicyclo[3.3.1]non-3-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]-pyridine-3-carboxamide (Example 27, 0.14 mmol) were initially charged in 1.4 ml of abs. THF, 4.2 mg of sodium hydride (purity 95%, 0.16 mmol) were added and the mixture was stirred at RT for 15 min. 0.011 ml of iodoethane (0.14 mmol) were then added dropwise, and the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed twice with water. The organic phase was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered. The filtrate was concentrated and dried. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were concentrated and the residue taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated and lyophilized. This gave 35 mg of the title compound (55% of theory).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][O:32]2)[CH2:12][C@@H:11]1[OH:37].[Br:39]N1C(=O)CCC1=O>C(Cl)Cl.CN(C)C=O>[CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH:7]([Br:39])[CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(C(Br)CCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Under an atmosphere of nitrogen, a solution of 3.4 g of (5Z,13E)-(9α,11α,15S)-9-hydroxy-11,15-bis(tetrahydropyran-2-yloxy)prosta-5,13-dienoic acid methyl ester in a mixture of 30 ml of methylene chloride and 6 ml of N,N-dimethylformamide was added dropwise to a suspension of 1.35 g of N-bromosuccinimide in 50 ml of methylene chloride at -20° to -10° C. and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was then poured into ice-water and extracted with diethyl ether. The extract was washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (4:1) as eluent to give 3.43 g of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]([Si:5]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[S:23](N)([NH2:26])(=[O:25])=[O:24]>O1CCOCC1>[C:1]([Si:5]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:6][CH:7]1[CH2:8][N:9]([S:23]([NH2:26])(=[O:25])=[O:24])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)[Si](OC1CNC1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](OC1CN(S(N)(=O)=O)C1)(c1ccccc1)c1ccccc1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 15 step (i) using 3-(tert-butyl-diphenyl-silanyloxy)-azetidine (prepared according to patent WO 2003/072557) (0.93 g), dioxane (20 ml) and sulfamide (0.34 g). Isolation was by filtration to remove excess sulfamide, the filtrate was then reduced in vacuo to give the subtitle compound as a brown oil. Yield: 1.2 g
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12.[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:8]([C:7]2[C:2]([OH:1])=[C:3]3[S:15][CH:14]=[CH:13][C:4]3=[N:5][CH:6]=2)=[O:10])=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Reactant: NCc1ccc(Cl)cc1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccsc2c1O
Temperature: 190 °C

Procedure:
A mixture of ethyl 7-hydroxythieno[3,2-b]pyridine-6-carboxylate (223 mg) prepared as described in the literature (Elliott, R. L.; O'Hanlon, P. J.; Rogers, N. H. Tetrahedron 1987, 43, 3295-3302) and 4-chlorobenzylamine (1.2 mL) was heated to 190° C. for 1 h. The crude product was purified by column chromatography (CH2Cl2/methanol, 100/1; 50/1; 33/1) and the resulting solid was recrystallized from glacial acetic acid/water to afford 84 mg of the title compound as a tan solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[C:14]([F:21])=[CH:15][C:16]([F:20])=[C:17]([NH2:19])[CH:18]=3)[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1.[CH3:22][NH2:23]>CCOC(C)=O>[NH2:19][C:17]1[C:16]([F:20])=[CH:15][C:14]([F:21])=[C:13]([C:7]2[C:8]([CH3:12])=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][N:3]=[C:2]([NH:23][CH3:22])[CH:11]=3)[CH:18]=1
Reactant: CN
Reactant: Cc1nc2cc(Cl)ncc2cc1-c1cc(N)c(F)cc1F
Solvent: CCOC(C)=O
Product: CNc1cc2nc(C)c(-c3cc(N)c(F)cc3F)cc2cn1
Temperature: 120 °C
Yield: 98.1 %

Procedure:
Heat a solution of 5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2,4-difluorobenzenamine (0.55 g, 1.799 mmol) in methylamine (33% in EtOH, 10 mL, 1.799 mmol) at 120° C. with microwave irradiation for 12 h. Add additional methylamine (33% in EtOH, 2 mL), heat the mixture at 120° C. for 12 h, add more methylamine (33% in EtOH, 2 mL) and irradiate at 120° C. for 15 h. Dilute the mixture with EtOAc, wash with satd. NaHCO3 (2×), dry and evaporated to yield the title compound (0.53 g, 98%). MS(ESI) m/z: 301.1 (M+H+).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[S:26][C:27]([CH3:30])=[N:28][N:29]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1nnc(N)s1
Product: Cc1nnc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)s1
Yield: 62.1 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-methyl-1,3,4-thiadiazole (39.2 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(5-methyl-1,3,4-thiadiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (40.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][CH:10]([C:13]#[N:14])[C:11]#[N:12])=[O:8])=[CH:5][CH:4]=1.Cl.O>C(O)(=O)C>[NH2:12][C:11]1[O:8][C:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=2)=[CH:9][C:10]=1[C:13]#[N:14]
Reactant: COc1ccc(C(=O)CC(C#N)C#N)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(C#N)c(N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a suspension of α-((4-methoxybenzoyl)methyl)malononitrile (9.66 g, 45.1 mmol) in acetic acid (50 ml) was added conc. hydrogen chloride (11,3 ml). The mixture was stirred at room temperature for 2 hours, and then poured into water. The resultant precipitation was filtrated, washed with water and ethanol, and dried under reduced pressure to give the Intermediate of Example 2(A) (5.54 g, 56%) as a solid. 1H NMR (400 MHz, CDCl3) ppm 3.83 (s, 3H), 4.74 (brs, 2H), 6.39 (s, 1H), 6.90 (m, 2H), 7.42 (m, 2H).
Reaction SMILES: [CH2:1]([OH:8])[C@@H:2]([C@@H:4]([CH2:6][OH:7])[OH:5])[OH:3].[C:9]([O:28]C)(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C[O-].[Na+]>[C:9]([O:3][C@H:2]([C@@H:4]([CH2:6][O:7][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[O:5][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: OC[C@@H](O)[C@@H](O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OC[C@H](OC(=O)CCCCCCC/C=C\CCCCCCCC)[C@@H](COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC

Procedure:
Erythritol and a five-fold molar excess of methyl oleate are heated at 180° C. under vacuum, with agitation, in the presence of sodium methoxide catalyst over two reaction periods of several hours each. The reaction product (predominately erytiritol tetraoleate) is refined in petroleum ether and crystallized three times from several volumes of acetone at 1° C.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH:8](O)([CH3:10])[CH3:9]>>[CH:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH:4]=[CH:3]1)([CH3:10])[CH3:9]
Reactant: O=C1C=CC(O)N1
Reactant: CC(C)O
Product: CC(C)OC1C=CC(=O)N1
Reaction time: 3 h

Procedure:
A mixture of 3 g of 1,5-dihydro-5-hydroxy-2H-pyrrol-2-one, 1.5 g of Amberlite IR 120 H and 60 cm3 of isopropanol is taken to 45°-50° C. for 3 hours. After cooling, filtering and evaporating to dryness, 1.8 g of the expected product is obtained, m.p. 79°-81° C., crystallized from isopropanol.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[N:57]=CC(N)=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[N:57][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:54]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CN1CCN(c2ccc(NC(=O)Nc3ccc(-c4nc(N5CC6CCC(C5)O6)c5cnn(C)c5n4)cc3)cn2)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(4-methylpiperazino)-3-pyridinamine as the aniline component. (16%, MS=555.3 (M+H))
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC([O-])(C)C.[K+]>CC(O)C>[C@@H:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a 100 mL autoclave with a stirrer, RuCl[(R)-dm-segphos][(S)-daipen] obtained from Example 5 above (3.5 mg, 0.003 mol, 1/1,000 molar fold of 1-tetralone) were added. After purging with nitrogen, 2-propanol (3 mL), 1-tetralone (439 mg, 3 mmol) and 2-propanol solution of t-BuOK (0.1 mol/L, 0.3 mL, 0.03 mmol) were added. Subsequently, purging with hydrogen, the mixture was stirred at 25° C. for 15 hours under hydrogen pressure of 1 MPa. As a result of analysis of the reaction solution by using gas chromatography (Chirasil-DEX CB), it was found that the conversion rate is 99% or more and the optical purity is 96% ex.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
16 g of carbazole was dissolved in 80 ml of N,N′-dimethylformamide. To this was added 18 g of N-bromosuccinimide and allowed the reaction to stir at room temperature overnight. The reaction mixture was poured into water and the precipitated white solid was filtered, washed with methanol and dried under vacuum to obtain 20 g of 3-bromocarbazole. It was further converted to its acetyl derivative by refluxing with acetic anhydride (3 vol) with traces of conc. sulfuric acid. Aqueous workup yielded an off-white solid, which was then washed with n-hexane and dried under vacuum to obtain 23 g 9-acetyl-3-bromocarbazole, quantitatively.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34]([OH:36])=O.CCN(C(C)C)C(C)C.[CH:46]1([C:52]2[CH:53]=[CH:54][C:55]([O:72][CH3:73])=[C:56]([C:58]3[N:59]=[C:60]([NH:63][C:64]([CH:66]4[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]4)=[O:65])[S:61][CH:62]=3)[CH:57]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(#N)C>[CH:46]1([C:52]2[CH:53]=[CH:54][C:55]([O:72][CH3:73])=[C:56]([C:58]3[N:59]=[C:60]([NH:63][C:64]([CH:66]4[CH2:67][CH2:68][N:69]([C:34]([C:29]5[CH:30]=[N:31][CH:32]=[CH:33][N:28]=5)=[O:36])[CH2:70][CH2:71]4)=[O:65])[S:61][CH:62]=3)[CH:57]=2)[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51]1
Reactant: O=C(O)c1cnccn1
Reactant: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(C2CCCCC2)cc1-c1csc(NC(=O)C2CCN(C(=O)c3cnccn3)CC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.7 %

Procedure:
0.32 g of BOP, 0.08 g of pyrazinecarboxylic acid and then 0.37 mL of DIPEA are added, at a temperature of 0° C., to a solution of 0.25 g of the compound prepared in step 1.2 in 3 mL of acetonitrile. The medium is stirred at room temperature for 12 hours and then concentrated. The medium is taken up in EtOAc and washed 3 times with 10% Na2CO3 solution and then with saturated NaCl solution. After drying over MgSO4, the solution is concentrated and then purified by flash chromatography to give 0.23 g of a dark yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=O)=[CH:11][CH:10]=2)[CH2:3]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH2:37])[NH:35][N:36]=2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1.C[Al](C)C>ClCCl>[CH3:29][O:28][C:26]1[CH:25]=[C:24]([CH2:30][CH2:31][C:32]2[CH:33]=[C:34]([NH:37][C:13](=[O:15])[C:12]3[CH:11]=[CH:10][C:9]([N:4]4[CH2:5][C@H:6]([CH3:8])[NH:7][C@H:2]([CH3:1])[CH2:3]4)=[CH:19][CH:18]=3)[NH:35][N:36]=2)[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1
Reactant: CCOC(=O)c1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4C[C@@H](C)N[C@@H](C)C4)cc3)[nH]n2)cc(OC)c1
Yield: 50.2 %

Procedure:
N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]-4-[(3R,5 S)-3,5-dimethylpiperazin-1-yl]benzamide was prepared following the procedure as for Example 155, but starting with ethyl 4-((3R,5S)-3,5-dimethylpiperazin-1-yl)benzoate (0.525 g, 2 mmol), 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.495 g, 2.00 mmol) and 2M trimethylaluminium (2.5 ml, 5.0 mmol in toluene). The crude mixture was chromatographed on a SCX column, eluting with 7N ammonia in methanol. Fractions containing product were combined and evaporated to give an oil. The oil was suspended in dichloromethane (20 ml) and product slowly crystallised out. This was filtered to give the title compound (0.465 g, 50.2%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C(O)C>[CH2:13]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCBr
Reactant: Oc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCOc1ccccc1

Procedure:
Phenol (0.5 mole) was added to a solution of sodium ethoxide in ethanol (2 N; 250 ml) and 1-bromopentane (0.5 mole) was added dropwise while stirring. The mixture was heated under reflux for three hours and most of the solvent was then distilled off. Water was added to the residue and the organic layer was separated, washed twice with 10% aqueous NaOH, water, dilute H2SO4 and water, and was then dried over MgSO4. It was distilled in vacuo to give the title compound, b.p. 97°-101° C. at 14 mm Hg pressure. The identity and purity was confirmed by thin layer chromatography (TLC) and NMR and IR spectroscopy.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)=[CH:4][C:3]=1[Cl:38].[S:39]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40]1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.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>[Cl:38][C:3]1[CH:4]=[C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:20][C:19]([C:21]5([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:26][O:25][C:24]([CH3:28])([CH3:27])[O:23][CH2:22]5)=[CH:18][C:17]=4[CH:37]=3)[N:9]=2)[CH:6]=[CH:7][C:2]=1[C:41]1[CH:42]=[CH:43][S:39][CH:40]=1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(Br)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2cc3cc(-c4noc(-c5ccc(-c6ccsc6)c(Cl)c5)n4)ccc3o2)COC(C)(C)OC1
Reaction time: 2 h
Yield: 71.3 %

Procedure:
To a stirred mixture of the product of Example 38, Step C (0.09 g, 0.15 mmol) and 3-thiophene-boronic acid (0.028 g, 0.22 mmol) in a mixture of dioxane and H2O (5 ml:1 ml), Pd(PPh3)4 (0.03 g) was added at 80° C., followed by the NaHCO3 solution (0.065 g in 1 ml H2O) and this was stirred for 2 h. The solvent was distilled off and the residue was diluted to 20 ml with EtOAc, washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by FCC (SiO2, hexane/EtOAc), to give the title compound (0.065 g, 71%), as pale paste. 1H-NMR (CDCl3) 8.45 (d, 1H, J=1.53 Hz); 8.25-8.22 (m, 2H); 7.94 (dd, 1H, J=8.7, 1.8 Hz); 7.55-7.42 (m, 3H); 7.38-7.37 (m, 2H); 6.78 (s, 1H); 5.43 (bs, 1H); 4.29-4.13 (m, 4H); 1.46 (s, 9H); 1.27 (b, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[N:7][N:6]=[CH:5]2.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24]([F:35])([F:34])[F:23])=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)=[CH:14][CH:15]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(Nc2nncc3cc(Br)ccc23)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1ccc(Nc2nncc3cc(-c4ccccc4C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Combine (6-bromo-phthalazin-1-yl)-(4-tert-butyl-phenyl)-amine (60 mg, 0.19 mmol), 2-(trifluoromethyl)phenyl-boronic acid (50 mg, 0.26 mmol) in 1,2-dimethoxyethane (10 mL) and bubble nitrogen into the mixture for 10 minutes. Add tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) and 2M Na2CO3 (1 mL) and heat at 80 C. for 48 hours. Let the mixture cool to room temperature, dilute with water (10 mL), and extract twice with EtOAc (10 mL each). Dry (Na2SO4), evaporate, and purify on a preparative silica gel plate (2000 micron) eluting with 75% hexane-EtOAc to provide (4-tert-butyl-phenyl)-[6-(2-trifluoromethyl-phenyl)-phthalazin-1-yl]-amine as a straw colored solid. Mass Spec. 421.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[CH2:23]([N:26]=[C:27]=[S:28])[CH2:24][CH3:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[S:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCN=C=S
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)NCCC
Yield: 66.7 %

Procedure:
Using the general method of Example 150, 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) was reacted with propyl isothiocyanate (560 mg, 5.55 mmol) to provide 1.34 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-propylthiourea as a crystalline solid, m.p. 144.5-145.5° C. Analysis: Calculated for C21H30N6S. 0.56H2O: %C, 61.72; %H, 7.68; %N, 20.56; Found: %C, 61.72; %H, 7.67; %N, 20.56.