Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[N:18]=[C:17]2[CH:19]=[C:20]([F:24])[C:21]([F:23])=[CH:22][C:16]2=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:21]1[C:20]([F:24])=[CH:19][C:17]2=[N:18][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=3)[N:15]=[C:16]2[CH:22]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1nc2cc(F)c(F)cc2n1
Product: FCc1cccc(C#CCCn2nc3cc(F)c(F)cc3n2)n1
Yield: 31.7 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (50 mg, 0.32 mmol) and 2-(but-3-ynyl)-5,6-difluoro-2H-benzo[d][1,2,3]triazole (60 mg, 0.29 mmol, Example 153(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 29 mg (92 μmol, 32%) of 5,6-difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a grey solid (M.P.=104-105° C.).
Reaction SMILES: [O:1]([C:8]([NH:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:22](=[O:23])[C@H:21]3[CH2:24][CH2:25][CH2:26][C@H:20]3[NH:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:33][CH2:34][C:35]([N:19]1[C@@H:20]2[CH2:26][CH2:25][CH2:24][C@@H:21]2[C:22](=[O:23])[N:16]([CH2:15][C:14]2[CH:31]=[CH:32][C:11]([NH:10][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:9])=[CH:12][CH:13]=2)[C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]1=2)=[O:36]
Reactant: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1)Oc1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CCl)c3ccccc32)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(phenoxycarbonylamino)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (1.61 g, 3.8 mmol) in DMF (20 mL) was added chloroacetyl chloride (0.36 mL, 4.5 mmol) and the mixture was stirred at room temperature for 2 hours. This reaction mixture was diluted with saturated aqueous NaHCO3 solution and extracted with 3 portions of chloroform. The pooled organic layer was washed with 2 portions of water and, then, with saturated aqueous NaCl solution. This solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was crystallized from chloroform-diethyl ether to provide 0.90 g (yield 47%) of the compound. m.p. 207-210° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7]C[CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:4]1)[CH3:2].C[C@H](OC1N=C2C(N=C(OC)N2CC2CCNCC2)=C(N)N=1)CCC.ICC>>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:9]([CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Agent: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine and iodoethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[S:8][C:7]=2[CH:33]=1.[H-].[Na+].[CH3:36]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]([CH3:36])[C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[S:8][C:7]=2[CH:33]=1
Reactant: CI
Reactant: CCOC(=O)/C=C/c1ccc(Nc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(N(C)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
To a solution of (E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)amino)phenyl)acrylate (69.0 mg, 0.15 mmol) in DMF (6.0 mL) at room temperature was added NaH (60% suspension in oil, 139 mg, 3.48 mmol). After 15 min, methyl iodide (0.272 mL, 4.35 mmol) was added and the resulting solution was allowed to stir at room temperature for 45 min after which time the reaction was quenched with brine and diluted with water. The resulting solution was then extracted with EtOAc (3×) and the combined organic layers were washed with brine (2×), passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford ((E)-ethyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)(methyl)amino)phenyl)acrylate (25.5 mg, 0.05 mmol, 36% yield) as a white solid. LC/MS (m/z, MH+): 474.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]I)=[CH:8][O:9][C:5]=2[CH:4]=1.[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([CH3:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2c(CCI)coc2c1
Product: COc1ccc2c(CCN3CCN(c4cc(C)cc5cccnc45)CC3)coc2c1

Procedure:
8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 9, step 6, starting from the step of 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil Yield: 210 mg (52%); (M+H): 402; 1HNMR (400 MHz, CDCl3):δ 8.81˜8.80 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.02˜7.99 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H) 7.46˜6.88 (m, 7H); 3.9 (s, 3H); 3.60˜2.82 (m, 12H); 2.5 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccn1
Reactant: Brc1ccc(OCc2ccccc2)cn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(COc2ccc(Nc3ccccn3)nc2)cc1
Yield: 91.4 %

Procedure:
Compound I (370 mg, 1.40 mmol), 2-aminopyridine (145 mg, 1.54 mmol), tBuOK (235 mg, 2.10 mmol), (±)-BINAP (35 mg, 0.01 mmol) and Pd2(dba)3 (32 mg, 0.006 mmol) were stirred in toluene (5 mL) at 90° C. under Ar(g) for 17 h. The reaction mixture was then diluted with CH2Cl2 (5 mL), and silica was added followed by the removal of the solvent under reduced pressure. The resulting dry loaded material was purified by silica gel column chromatography eluting with hexane/EtOAc (60:40 then 50:50) to furnish II as a colourless oil (355 mg, 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=1.C([Li])CCC.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:25][C:26](N(OC)C)=[O:27])=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:25][C:26]([C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[C:4]([CH3:11])[CH:3]=2)=[O:27])=[CH:22][CH:23]=1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Reactant: COc1c(C)cc(Br)cc1C
Agent: [Li]CCCC
Product: COc1c(C)cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)cc1C

Procedure:
In analogy to example 151, step 1, 4-bromo-2,6-dimethylanisole was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) to give the title compound as a light yellow solid, MS (ESI+): m/z=437.4 [M+H]+.
Reaction SMILES: C1([Mg]Br)CCCCC1.C(C1C=CC=C(C(C)C)C=1N=CC(C)C)(C)C.ClC(P)Cl.[Li:30]CCCC.Br[C:36]1[C:41]([CH:42]([CH3:44])[CH3:43])=[CH:40][C:39]([CH:45]([CH3:47])[CH3:46])=[CH:38][C:37]=1[CH:48]([CH3:50])[CH3:49]>C(OCC)C.C1COCC1>[CH:48]([C:37]1[CH:38]=[C:39]([CH:45]([CH3:47])[CH3:46])[CH:40]=[C:41]([CH:42]([CH3:44])[CH3:43])[C:36]=1[Li:30])([CH3:50])[CH3:49]
Reactant: CC(C)c1cc(C(C)C)c(Br)c(C(C)C)c1
Reactant: [Li]CCCC
Agent: Br[Mg]C1CCCCC1
Agent: CC(C)C=Nc1c(C(C)C)cccc1C(C)C
Agent: PC(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: [Li]c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexylmagnesium bromide (1.05 mL of a 2.0 M solution in ethyl ether, 2.1 mmol, Aldrich) was added to a solution of isobutyraldehyde 2,6-diisopropylphenylimine (0.462 g, 2.0 mmol) in THF (5 mL) at −78° C. The yellowish solution was warmed to RT, stirred for 1 h and then added to a solution of dichloromethylphosphine (0.19 mL, 2.1 mmol, Strem) in THF (5 mL) at −78° C. The solution was stirred for 10 min at −78° C., warmed to RT and stirred for 30 min. Assay by 31P-NMR (crude reaction mixture) showed the presence of a single major product (+110.4 ppm). The solution of 2,4,6-triisopropylphenyllithium was prepared by addition of BuLi (1.6 mL of a 1.6 M solution in hexanes, 2.6 mmol, Aldrich) to a solution of 1-bromo-2,4,6-triisopropylbenzene (0.63 mL, 2.5 mmol, Lancaster) in THF (8 mL) at −78° C. followed by stirring for 2 h. The solution of arylLi thus formed was added to the solution of chlorophosphine keeping both flasks at −78° C. The solution was stirred for 20 min at −78° C., warmed to RT and stirred for 30 min. Assay by 31P-NMR (crude reaction mixture) showed the presence of a single major product (−37.9 ppm). The solution was evaporated and CH2Cl2 (10 mL) was added to the residue. Filtration through a 2.2×2 cm plug of silica gel using CH2Cl2 (20 mL) and then ethyl ether (10 mL) as an eluent followed by evaporation of the solvent afforded crude product as a yellowish oil. To the crude ligand was added NiBr2(DME) (0.124 g, 0.40 mmol) and CH2Cl2 (10 mL). The red-brown solution was stirred for 1 h at RT, solution was evaporated and the residue washed with diethyl ether (3×20 mL) and hexanes (20 mL). A brown, insoluble solid (0.310 g, 107% based on Ni) was obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[CH2:35][OH:36])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:37][CH3:38])=[CH:34]/[CH:35]=[O:36])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si:18]([C:21]([CH3:23])([CH3:24])[CH3:22])([CH3:20])[CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC/C(=C\CO)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC/C(=C\C=O)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Reaction time: 12 h

Procedure:
2.8 g (5 mmol) of (E)-3-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}phenyl)pent-2-en-1-ol are dissolved in 50 ml of dichloromethane. 4.3 g (50 mmol) of manganese dioxide are added, and the reaction medium is stirred for 12 hours, then filtered and concentrated under reduced pressure. The desired product is obtained in the form of yellow oil (m=2.8 g; Y=100%).
Reaction SMILES: F[C:2]1[N:23]=[CH:22][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=3)[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CS(C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([NH:31][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[N:23]=[CH:22][C:5]=3[N:6]=[CH:7][N:8]=2)=[CH:12][C:13]=1[C:18]([F:20])([F:19])[F:21]
Reactant: Fc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(F)c(C(F)(F)F)c4)ncnc3cn2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A stirred solution of compound 163 (14.30 g, 43.87 mmol) in DMSO (90 mL) was treated with slow addition of 4-methoxybenzylamine (57.3 mL, 482.52 mmol) under nitrogen at 70° C. The resultant mixture was stirred at 70 to 75° C. for 48 h, then cooled to room temperature and poured into a beaker of ice-water (1 L) with stirring. The resulted solid was collected by filtration, washed with water and dried in a vacuum oven (45° C.) for 2 h. The crude product was triturated with CH2Cl2 to provide N4-(4-fluoro-3-(trifluoromethyl)phenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (166) (14.40 g, 74%) as a yellow solid, m.p. 202-204° C. 1H NMR [(CD3)2SO] δ 9.83 (s, 1H), 8.77 (s, 1H), 8.38 (s, 1H), 8.27-8.30 (m, 1H), 8.21-8.24 (m, 1H), 7.55 (t, J=9.7 Hz, 1H), 7.28-7.34 (m, 3H), 7.17 (s, 1H), 6.86-6.90 (m, 2H), 4.50 (d, J=6.3 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C22H17F4N5O: C, 59.59; H, 3.86; N, 15.79%. found: C, 59.31; H, 4.07; N, 15.46%.
Reaction SMILES: [S:1]1[C:5]([C:6]([O:8]C)=O)=[CH:4][N:3]=[CH:2]1.[C:10](#[N:12])[CH3:11].[H-].[Na+:14].C(OC)(C)(C)C>C1COCC1>[C:10]([CH:11]=[C:6]([C:5]1[S:1][CH:2]=[N:3][CH:4]=1)[O-:8])#[N:12].[Na+:14]
Reactant: CC#N
Reactant: COC(=O)c1cncs1
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: N#CC=C([O-])c1cncs1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (10.5 mmol) of methyl 1,3-thiazole-5-carboxylate and 430 mg (10.8 mmol) of acetonitrile in 15 ml of THF was added dropwise to a suspension of 419 mg of sodium hydride (60% strength suspension in mineral oil) in 16 ml of THF which was heated under reflux. The reaction mixture was heated under reflux for 20 h. After cooling, 50 ml of methyl tert-butyl ether were added and the mixture was stirred for 30 minutes. The resulting precipitate was filtered off with suction through a frit and dried under oil pump vacuum. This gave 1.71 g (94% of theory) of the title compound which was combined with the product (3.48 g, 95% of theory) from a second batch starting with 3.0 g (21 mmol) of methyl 1,3-thiazole-5-carboxylate. This material was used without further characterization for the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/[CH:11]=[C:12]2[C:17](=[O:18])[O:16]C(C)(C)[O:14][C:13]2=O)=[CH:4][CH:3]=1.C[O-].[Na+].Cl.C(Cl)Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:17]([OH:16])=[O:18])=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C(=C/C=N/Nc2ccc(F)cc2)C(=O)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 87.5 %

Procedure:
A mixture of (E)-5-(2-(2-(4-fluorophenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.60 g, 2.05 mmol) and NaOMe (0.133 g, 2.46 mmol) in MeOH (10 mL) was heated under reflux for 15 hours. The salt was treated with cold 1 N HCl solution, extrated with CH2Cl2, dried over MgSO4, and concentrated to afford 0.42 g (87%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 13.57 (br s, 1H), 8.29 (m, 2H), 7.63 (m, 2H), 7.24 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −110.7. LRMS (ESI pos) m/e 235.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH2:18].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH2:17][NH:18][C:9](=[O:10])[C:8]1[CH:12]=[CH:13][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=1
Reactant: CC(C)(C)CCN
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCc1ccc(C(=O)NCCC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4.94 g of 4-butylbenzoylchloride in 20 ml of methylene chloride was added dropwise a solution of 2.53 g of 3,3-dimethylbutylamine and 5.1 g of triethylamine in 80.0 ml of methylene chloride. The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with water, and the organic layer was washed with 6N hydrochloric acid, water, 2N sodium hydroxide, brine, dried, and evaporated to dryness to yield an oil which solidified on standing. The solid was triturated with hexane, collected by filtration, and dried to yield N-[3,3-dimethylbutyl]-4-n-butylbenzamide as a white solid, mp 70°-71° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:32])=[C:21]([C@@:23]2([CH3:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26][O:25][CH2:24]2)[CH:22]=1>>[F:32][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=2)=[O:14])=[CH:22][C:21]=1[C@@:23]1([CH3:31])[NH:29][C:28](=[O:30])[CH2:27][CH2:26][O:25][CH2:24]1
Reactant: C[C@@]1(c2cc(N)ccc2F)COCCC(=O)N1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Product: C[C@@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)COCCC(=O)N1

Procedure:
Starting from 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid and (R) -3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride, the 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [4-fluoro-3-((R)-3-methyl-5-oxo-[1,4]oxazepan-3-yl)-phenyl]-amide was obtained as a light yellow foam. MS (ISP): m/z=446.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:14]=[N:13][N:12]([C@@H:15]3[CH2:19][CH2:18][CH2:17][C@H:16]3[OH:20])[C:4]=2[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:31][C@H:30]2[NH2:32])=[CH:25][CH:24]=1.O[C@H]([C@@H](O)C([O-])=O)C([O-])=O>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[CH2:31][CH:30]2[NH:32][C:2]2[C:3]3[N:14]=[N:13][N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH:16]4[OH:20])[C:4]=3[N:5]=[C:6]([S:8][CH2:9][CH2:10][CH3:11])[N:7]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc([C@@H]2C[C@H]2N)cc1
Reactant: CCCSc1nc(Cl)c2nnn([C@@H]3CCC[C@H]3O)c2n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Product: CCCSc1nc(NC2CC2c2ccc(OC)cc2)c2nnn(C3CCCC3O)c2n1

Procedure:
Prepared using the product from step b) (0.15 g) and (1R,2S)-2-(4-methoxyphenyl)cyclopropanamine, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (0.20 g) (prepared as described in WO 9905143) by the method of Example 1, step d). Purified by chromatography (SiO2, ethyl acetate:dichloromethane 1:9 as eluant) to afford the title compound (0.12 g).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([S:10]([NH:13][C@H:14]([CH2:45][O:46][Si:47]([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:24](=[O:44])[C@H:25]([CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:26][C:27]([O:29][CH3:30])=[O:28])(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:64]1[CH:68]=[C:67]([CH2:69]O)[CH:66]=[N:65]1>C(O)CC(C)C>[S:1]1[C:5]2[CH:6]=[C:7]([S:10]([N:13]([CH2:69][C:67]3[CH:66]=[N:65][O:64][CH:68]=3)[C@H:14]([CH2:45][O:46][Si:47]([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH:23][C:24](=[O:44])[C@H:25]([CH:31]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:26][C:27]([O:29][CH3:30])=[O:28])(=[O:12])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OCc1cnoc1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NS(=O)(=O)c1ccc2ncsc2c1)C(c1ccccc1)c1ccccc1
Solvent: CC(C)CCO
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(Cc1cnoc1)S(=O)(=O)c1ccc2ncsc2c1)C(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
The title compound was prepared in 99% yield from intermediate 35 following the procedure described for the step 9 in scheme 1 corresponding to the synthesis of example 1 but using isoxazol-4-ylmethanol instead isoamyl alcohol. MS: m/z=979.3 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:18]1([C:24]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][O:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: c1ccc(C2(c3ccccc3)CO2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccccc2)c2ccccc2)CCN(C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole (800 g, 4.0 mmol) in DMF (8 mL), sodium hydride [60% dispersion in oil] (480 mg, 12.0 mmol) was added and the reaction mixture stirred for 5 min. 2,2-Diphenyl oxirane (1.176 g, 6.0 mmol) was added dropwise at RT and reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice water and the compound extracted with EtOAc (3×200 mL). The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum to obtain the crude product. The crude compound was crystallized in ether (50 mL) to obtain 950 mg of white solid product as the free base. 100 mg free base was converted to HCL salt. 1H NMR (DMSO, HCl salt) δ (ppm): 7.50 (d, 2H), 7.30 (m, 3H), 7.20 (m, 5H), 7.10 (s, 1H), 7.05 (d, 1H), 6.70 (d, 1H), 6.08 (bs, 1H), 4.80 (m, 2H), 4.50 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.82 (s, 3H), 2.80 (m, 2H), 2.30 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:31]1[C:32]2[C:39]([CH3:41])([CH3:40])[C:38](=[O:42])[NH:37][C:33]=2[N:34]=[CH:35][N:36]=1.N12CCCN=C1CCCCC2>CC(O)C>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:31]4[C:32]5[C:39]([CH3:40])([CH3:41])[C:38](=[O:42])[NH:37][C:33]=5[N:34]=[CH:35][N:36]=4)[CH2:28][CH2:29]3)[N:15]([CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: CC1(C)C(=O)Nc2ncnc(Cl)c21
Reactant: Fc1ccc(-c2cn(CCN3CCCC3)c(C3CCNCC3)n2)cc1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)C(=O)Nc2ncnc(N3CCC(c4nc(-c5ccc(F)c(Cl)c5)cn4CCN4CCCC4)CC3)c21
Yield: 13.5 %

Procedure:
Combine 4-[4-(3-Chloro-4-fluoro-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidine tris hydrochloride (0.3 g; 0.00062 mol), 4-chloro-5,5-dimethyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.16 g; 0.0008 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.76 mL; 0.0051 mol) into IPA (10 mL) and stir at 120° C. for 16 h; cool and concentrate. Quench the reaction with saturated sodium bicarbonate solution and extract with EA. Evaporate the EA layer and purify by column chromatography using 0-5% MeOH/DCM as eluent to afford the title compound (0.045 g; 13.5%). MS (ES+): m/z=538 (M+1).