Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.C1(N(C)C2CCCCC2)CCCCC1.Br[C:22]1[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=1.O1CCOCC1>O>[F:28][C:23]1[C:22]([C:3]2[CH2:4][CH2:5][C:1](=[O:6])[CH:2]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Fc1ncccc1Br
Reactant: O=C1C=CCC1
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C1C=C(c2cccnc2F)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a round bottom flask was added bis(tri-t-butyl)phosphine palladium (0.591 g, 1.156 mmol) before sealing and evacuating and backfilling with nitrogen. Subsequently, cyclopent-2-enone (7.48 mL, 93 mmol), N-cyclohexyl-N-methylcyclohexanamine (14.73 mL, 69.4 mmol), and 3-bromo-2-fluoropyridine (4.07 g, 23.13 mmol) were added before adding dioxane (25 mL). The reaction mixture was stirred under nitrogen at 110° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate before drying over magnesium sulfate, filtering, and concentrating under reduced pressure. The crude compound was purified by column chromatography (ethyl acetate/dichloromethane) to give 3-(2-fluoropyridin-3-yl)cyclopent-2-enone as an orange solid. MS (ESI, pos. ion) m/z: 178.0 (M+1).
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)[C:31]([F:42])=[CH:30][N:29]=1.[NH2:43][C:44]1[CH:52]=[C:51]2[C:47]([CH:48]=[CH:49][NH:50]2)=[CH:46][CH:45]=1>>[F:42][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([OH:41])[CH:36]=2)=[N:33][C:28]([NH:43][C:44]2[CH:52]=[C:51]3[C:47]([CH:48]=[CH:49][NH:50]3)=[CH:46][CH:45]=2)=[N:29][CH:30]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: Nc1ccc2cc[nH]c2c1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Oc1cccc(Nc2nc(Nc3ccc4cc[nH]c4c3)ncc2F)c1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 6-aminoindole were reacted to yield 5-fluoro-N4-(3-hydroxyphenyl)-N2-[(1H)-indol-6-yl]-2,4-pyrimidinediamine. LCMS: ret. time: 18.13 min.; purity: 96%; MS (m/e): 336 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]=1[Cl:10])[C:5]#[N:6].Cl[C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:10][C:9]1[C:8]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[NH:1][C:19]1[N:24]=[C:23]([N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:22]2=[N:38][CH:39]=[C:40]([C:41]#[N:42])[N:21]2[N:20]=1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: N#Cc1cc(N)c(Cl)c(CN2CCOCC2)c1
Agent: [Fe+2]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(CN4CCOCC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 3-amino-4-chloro-5-(morpholinomethyl)benzonitrile (32 mg, 0.13 mmol), 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate 9)(47 mg, 0.13 mmol), Cs2CO3 (85 mg, 0.262 mmol), DPPF (7.3 mg, 0.013 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (7.6 mg, 0.013 mmol) in a microwave vial was flushed with nitrogen. Dioxane (1 mL) was added and the vial was sealed and heated at 100° C. for 4 hr. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed and radial silica gel chromatography eluting with hexane containing 5 to 40% EtOAc afforded 2-((2-chloro-5-cyano-3-(morpholinomethyl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (33 mg, 44% yield) as an oil. This was dissolved in DCM (1.5 mL) and anisole (0.158 mL, 1.447 mmol) and TFA (0.9 mL) were added. After stirring at room temperature overnight, the solvent was removed and the residue was dissolved in MeOH and applied onto a SCX column. This was washed with MeOH and then eluted with 2 N NH3 in MeOH with DCM. Silica gel radial chromatography eluting with DCM containing 1% MeOH gave the title compound (19 mg) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:16][NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C@@H:38]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[CH:32]=3)=[CH:22][CH:21]=2)=[CH:11][C:10]=1[NH:62][S:63]([CH3:66])(=[O:65])=[O:64])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[Si:55]([O:54][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:62][S:63]([CH3:66])(=[O:64])=[O:65])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C@@H:38]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:39][CH2:40][N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])[CH:32]=2)=[CH:24][CH:25]=1)([C:58]([CH3:61])([CH3:59])[CH3:60])([CH3:57])[CH3:56]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(NS(C)(=O)=O)c3)cc2)ccc1O)C(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
N-{2-(benzyloxy)-5-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]phenyl}methanesulfonamide (Preparation 14, 200 mg, 0.2 mmol), and palladium hydroxide (20% by weight on carbon, 50 mg, 0.07 mmol) were dissolved in ethanol (5 ml), then ammonium formate (74 mg, 1.2 mmol) was added and heated to 80° C. for 5 minutes then stirred at 75° C. for 1 hour. Reaction was cooled to room temperature and the mixture was filtered through Arbocel™ and the solvent removed in vacuo. to yield the title compound as a white foam, 190 mg.
Reaction SMILES: [CH2:1]([C:8]1[CH:25]=[CH:24][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][C:16]=2[F:23])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>CC#N>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:16]=2[F:23])=[O:13])=[CH:24][CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CO)cc1F)c1ccc(Cc2ccccc2)cc1
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1ccc(NC(=O)c2ccc(Cc3ccccc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-benzyl-N-(2-fluoro-4-(hydroxymethyl)phenyl)benzamide (200 mg, 0.60 mmol), 4-methylmorpholine N-oxide (140 mg, 1.2 mmol), and 4 A molecular sieves (1 g) in 10 ml of CH3CN was treated with tetrapropylammonium perruthnate (10 mg, 0.03 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The solids were filtered and the filtrated was concentrated. The residue was purified on ISCO system (80% hexane in dichloromethane) to give a pure product as a white crystalline: 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.80 (t, J=8.0 Hz, 1H), 8.25 (s, 1H), 7.84 (d, J=7.2 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.69 (d, J=10.8 Hz, 1H), 7.19-7.37 (m, 6H), 4.07 (s, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>COCCOC.O.CCOC(C)=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>[OH:30][C:31]1[CH:36]=[CH:35][C:34]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=[CH:10]3)=[CH:33][CH:32]=1
Reactant: CCOC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: OB(O)c1ccc(O)cc1
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: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of ethyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthalenecarboxylate (0.3 g, 0.861 mmol), tetrakis(triphenylphosphine)palladium (0) (0.04 g, 0.0345 mmol), 2 M Na2CO3 (4 mL) and 4-hydroxyphenyl boronic acid (0.143 g, 1.03 mmol) in ethylene glycol dimethyl ether (5 mL) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature, diluted with water and EtOAc. The EtOAc layer was separated, washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as oil. The crude material was purified by flash chromatography over SiO2 with a Hex:EtOAc (0 to 50% EtOAc) gradient to afford 0.23 g (92%) of the title compound as an oil. 1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1 H), 8.76 (d, J=9.0 Hz, 1 H), 8.20 (m, 2 H), 8.07 (d, J=7 Hz, 1H), 7.93 (m, 1 H), 7.66 (d, J=9 Hz, 2 H), 7.58 (t, J=8 Hz, 1H), 6.88 (d, J=9 Hz, 2 H), 4.42-4.37 (m, 2 H), 1.37 (t, J=7 Hz, 3 H).
Reaction SMILES: [SH:1][SiH3:2].C(OC[C:7]1([CH2:13][O:14][CH:15]=[CH2:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=C>>[SH:1][SiH3:2].[CH2:16]=[CH:15][O:14][CH2:13][CH:7]1[CH2:8][CH2:9][CH:10]([CH2:15][O:14][CH:13]=[CH2:7])[CH2:11][CH2:12]1
Reactant: C=COCC1(COC=C)CCCCC1
Agent: [SiH3]S
Product: C=COCC1CCC(COC=C)CC1

Procedure:
Mercaptosilane (SI263 made by Degussa) in 196.4 g (1 mole) and cyclohexane dimethanol divinyl ether (CHDVE made by Nippon Carbide Industries) in 98.2 g (0.5 mole) were reacted in the presence of a phosphoric acid ester catalyst at room temperature for 3 hours to obtain a blocked mercaptosilane (SI263/CHDVE) shown by the following formula:
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15]([I:18])=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2S(C)(=O)=O)=[CH:3][CH:2]=1.[CH2:30]([O:32][C:33]([CH:35]1[CH2:38][CH:37]([OH:39])[CH2:36]1)=[O:34])[CH3:31].C1CCN2C(=NCCC2)CC1>CN(C=O)C.CCOC(C)=O.O>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:19])[C:15]([I:18])=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:39][CH:37]2[CH2:38][CH:35]([C:33]([O:32][CH2:30][CH3:31])=[O:34])[CH2:36]2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1nc2c(F)c(I)c(F)cc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C1CC(O)C1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CC(Oc2nc3c(F)c(I)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Temperature: 80 °C

Procedure:
To a solution of 1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-iodo-2-(methylsulfonyl)-1H-benzimidazole (Intermediate 5, 0.457 g, 0.872 mmol) and 3-hydroxy-cyclobutanecarboxylic acid ethyl ester (Intermediate 12, 0.503 g, 3.49 mmol) in 2.9 mL of DMF was added DBU (0.526 mL, 3.49 mmol) dropwise via syringe. The reaction was heated at 80° C. for 1 h, and then diluted with EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude residue was purified on silica gel (eluted 2-15% then 15% then 15-20% EtOAc/hexanes: gradient elution) to give the desired product. LCMS: calculated for C27H23F2IN2O3 588.38, observed m/e 588.9 (M+H)+ (Rt 2.55/4 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4][CH:3]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: COC(=O)c1cncc(Cl)n1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(-c2ccco2)n1
Yield: 62.5 %

Procedure:
To a solution of 0.10 g of methyl 6-chloropyrazine-2-carboxylate in 2.9 mL of dioxane, 65 mg of 2-furanboronic acid, 74 mg of lithium chloride, 0.57 g of cesium carbonate, 21 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 24 mg of tris(dibenzylideneacetone)dipalladium(0) were added, and the mixture was heated under reflux for 2 hours. To the reaction mixture, water and ethyl acetate were added, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=87:13 to 83:17 to obtain 74 mg of methyl 6-(2-furyl)pyrazine-2-carboxylate as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5]([O:7]CC)=O.[C:12]1(/[CH:18]=[CH:19]/[C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[F:11][C:4]([F:3])([F:10])[C:5](=[O:7])[CH2:21][C:20](=[O:22])[CH:19]=[CH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)/C=C/c1ccccc1
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Product: O=C(C=Cc1ccccc1)CC(=O)C(F)(F)F
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Sodium hydride (547 mg, 60% dispersion in mineral oil, 13.68 mmol) was added to ethyl trifluoroacetate (1.63 mL, 13.68 mmol). (Note: Carefulness is required. The reaction caught fire upon adding sodium hydride to ethyl trifluoroacetate.) Trans-4-Phenyl-3-buten-2-one (1 g, 6.84 mmol) was added, and the reaction was stirred for 3 hours at 40° C. The reaction was cooled to room temperature and quenched with water, then diluted with 1 N HCl. The mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated. The reaction was assumed to be quantitative. LC-MS (C12H9F3O2 calculated 242) m/z 243 (M+H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11].Cl.C1C(=O)N([O:23][C:24]([O:26][CH2:27][CH:28]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)=O)C(=O)C1>C(=O)([O-])O.[Na+].COCCOC>[NH:8]([C:24]([O:26][CH2:27][CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[C:40]1=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:23])[C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
Under cooling on ice, sodium hydride (3.19 g, 133 mmol) was added to a solution of Boc-Ser (12.3 g, 53.9 mmol) in DMF (300 ml) and stirred at room temperature for 1.5 hours. Octane iodide (11.0 ml, 60.9 mmol) was added thereto and stirred at room temperature for 16 hours. After water (40 ml) was added dropwise to the reaction solution under cooling on ice, the solvent was evaporated under vacuum. The resulting residues were purified by applying them to silica gel column chromatography (gel; Art9385, Merck Co., Ltd, eluent; dichloromethane:methanol:acetic acid=120:10:1), to give 6.88 g Boc-Ser (C8H17) (yield, 36.2%) as pale yellow oily matter. Trifluoroacetic acid (120 ml) was added to this product, Boc-Ser (C8H17) (6.88 g, 21.7 mmol), under cooling on ice and stirred for 0.5 hour at room temperature. After the trifluoroacetic acid was evaporated, the resulting residues were dissolved in diethyl ether (120 ml), and 4N HCl-dioxane (22 ml) was added thereto and stirred for 1 hour under cooling on ice. The precipitated crystals were recovered by filtration to give 5.23 g H-Ser (C8H17) HCl (yield, 96.3%) as colorless crystals. After triethylamine (1.40 ml, 10 mmol) was added to a suspension (50 ml) of this product H-Ser (C8H17).HCl (2.54 g, 10.0 mmol) in 10% sodium hydrogen carbonate, a solution of Fmoc-Osu (5.00 g, 14.8 mmol) in 1,2-dimethoxyethane (20 ml) was added dropwise thereto over the period of 10 minutes and stirred at room temperature for 16 hours. The insolubles were filtered off, then dichloromethane was added to the filtrate, and the organic phase was separated and washed with 13% NaCl solution. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The resulting residues were purified by applying them to silica gel column chromatography (gel; BW-300, Fuji Silicia Co., Ltd, eluent; dichloromethane:methanol=93:7), to give 2.75 g Fmoc-Ser (C8H17) (yield: 62.6%) as colorless crystals. Rf=0.45 (CHCl3: MeOH=9:1, Silica gel 60F254, MERCK CO., Ltd). Fmoc-DSer(C8H17): Rf=0.45 (CHCl3: MeOH=9:1, Silica gel 60F254, MERCK Co., Ltd).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.N1C=CC=CC=1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31]>ClCCl>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(C2(C)C3CN(CCCc4ccccc4)CC32)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.5 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 110 mg, 0.36 mmol) in dichloromethane (4 ml), at 0° C. under nitrogen was added pyridine (56 μl, 0.72 mmol) then dropwise over 5 minutes ethanesulfonylchloride (67 μl, 92 mg , 0.72 mmol). The mixture was allowed to warm to room temperature and was stirred for 16 hours. Further pyridine (56 μl, 0.72 mmol) and ethanesulfonylchloride (67 μl, 92 mg , 0.72 mmol) were added and the mixture was stirred for 2 hours. The crude mixture was purified by silica (40 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (48 mg, 34%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH:18]([CH2:23][C:24]([NH2:26])=O)[CH2:19][C:20]([NH2:22])=O)[CH:17]=3)[N:10]3[CH:27]=[CH:28][N:29]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.C(Cl)Cl.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH:18]([CH2:23][C:24]#[N:26])[CH2:19][C:20]#[N:22])[CH:17]=3)[N:10]3[CH:27]=[CH:28][N:29]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC(N)=O)CC(N)=O)c3)n2)cn1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C(CC#N)CC#N)c3)n2)cn1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
3-(4-(7-(1-Methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanediamide (0.047 g, 0.12 mmol) was partially dissolved in DMF (0.3 mL) and DCM (0.5 mL) and triethylamine (0.08 g, 0.79 mmol) was added. 2,2,2-trichloroacetyl chloride (0.08 g, 0.44 mmol) was added at 0° C., and the reaction was stirred for 1 hour. Additional reagents (40 mg Et3N and 30 mg acid chloride) were added and the reaction was complete. The reaction was concentrated and pumped to dryness. A minimum amount of water was added (1.5 mL) to dissolve the crude product. Excess sodium chloride was added to the aqueous layer and this mixture was extracted with EtOAc (10×10 mL) to recover the desired product. The organic phase was dried using MgSO4 and concentrated to provide 3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)pentanedinitrile (42 mg, 98% yield). MS (apci) m/z=358.1 (M+H). 1H NMR (d6-DMSO) δ 9.12 (s, 1H), 8.59 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.17 (s, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 5.30-5.29 (m, 1H), 3.91 (s, 3H), 1.22-1.10 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].N1C=CC=CC=1.F[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[C:25]#[N:26])[CH:3]=2)[NH:7][CH:6]=1
Reactant: N#Cc1ccccc1F
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: CN(C)CCc1c[nH]c2ccc(Nc3ccccc3C#N)cc12
Yield: 2 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 2-fluorobenzonitrile were used. Pyridine was used as base, 2-fluorobenzonitrile was used as solvent, and the reaction was stirred at reflux for 8 hours. Chromatography afforded the title compound (2%) as a clear, pale brown oil: 1H NMR (CD3OD) δ7.43 (dd, J=7.7 and 1.5 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.30-7.23 (m, 1H), 7.07 (s, 1H) 6.97 (dd, J=8.6 and 1.9 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.73-6.67 (m, 1H), 4.91 (s, 2H), 2.92-2.86 (m, 2H), 2.65-2.59 (m, 2H), 2.30 (s, 6H); HRMS calculated for C19H20N4 304.1690, found 304.1682.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][CH2:13][SH:14].[H-].[Na+]>C1COCC1>[Cl:11][C:4]1[N:3]=[C:2]([S:14][CH2:13][CH3:12])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 2.25 h
Yield: 52.8 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (2.24 g, 11.6, 1.0 eq.) and EtSH (0.86 mL, 11.6 mmol, 1.0 eq.) in THF (60 mL) under nitrogen at 0° C. was added NaH (95%; 0.33 g, 13.1 mmol, 1.1 eq.). After 2.25 hr, the solution was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water, saturated aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using hexanes:EtOAc (10:0.05) as eluent afforded 6-chloro-2-(ethylthio)-3-nitropyridine as a yellow solid (1.34 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].N>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:30][CH2:29][CH2:28][CH:27]=[CH2:26])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: C=CCCCBr
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(Cl)c1
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (23 mg, 67%) from (7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 5-bromo-1-pentene (25 mg, 0.16 mmol). MS (CI, NH3): 427.1 (base, M+H).