Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[N:10][C:11]=2[NH2:13])[NH:6][N:5]=1.[Cl:14][C:15]1[C:16]([CH3:37])=[C:17]([CH:26]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)[C:18]([O:24][CH3:25])=[C:19]([CH:21](Cl)[CH3:22])[CH:20]=1>CN(C)C=O.O>[NH2:13][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[N:6]([CH:21]([C:19]3[C:18]([O:24][CH3:25])=[C:17]([CH:26]4[CH2:27][N:28]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])[CH2:29]4)[C:16]([CH3:37])=[C:15]([Cl:14])[CH:20]=3)[CH3:22])[N:5]=[C:4]([CH3:3])[C:12]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 58.6 %

Procedure:
At room temperature, sodium hydride (0.32 g, 8.0 mmol) was added to a suspension of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (from ChemBridge, 0.59 g, 4.0 mmol) in N,N-dimethylformamide (20 mL). The resulting mixture was stirred at room temperature for 25 minutes during which time the suspension became a nearly clear solution. To the resultant mixture was added a solution of tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]azetidine-1-carboxylate (1.35 g, 3.61 mmol, from Example 1, step 5) in N,N-dimethylformamide (10 mL). The mixture was stirred at 50° C. overnight. After cooling, the mixture was diluted with water and extracted with EtOAc (2×). The combined extracts were washed with water and brine, dried over MgSO4 and concentrated. The resulting residue was purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 1.03 g (59%) of the desired product as a yellow gum. The racemic products were applied on a Phenomenex Lux-Cellulose 2 column (21.1×250 mm, 5 micron particle size), eluting with 10% ethanol in hexanes at a flow rate of 18 mL/min, 4 mg/injection, to provide two enantiomers. The retention time of the first peak was 8.34 min and the retention time for the second peak was 10.92 min. Peak 1 (463 mg), LCMS calculated for C24H32ClN6O3 (M+H)+: m/z=487.2; Found: 487.1. 1H NMR (400 MHz, CDCl3): δ 8.21 (s, 1H), 7.37 (s, 1H), 6.30, (q, 1H), 5.40 (s, 2H), 4.23 (m, 2H), 4.17-4.00 (m, 3H), 3.57 (s, 3H), 2.58 (s, 3H), 2.16 (s, 3H), 1.76 (d, 3H), 1.37 (s, 9H) ppm.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]=2[CH:27]1[C:38]([OH:40])=O)=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:41][C:42]1[CH:43]=[C:44]([NH2:53])[CH:45]=[C:46]2[C:50]=1[C:49]([CH3:52])([CH3:51])[CH2:48][CH2:47]2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.O>[F:41][C:42]1[CH:43]=[C:44]([NH:53][C:38]([CH:27]2[N:26]([C:24]([O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:25])[CH2:35][CH2:34][C:33]3[N:32]=[C:31]([O:36][CH3:37])[CH:30]=[CH:29][C:28]2=3)=[O:40])[CH:45]=[C:46]2[C:50]=1[C:49]([CH3:51])([CH3:52])[CH2:48][CH2:47]2
Reactant: CC1(C)CCc2cc(N)cc(F)c21
Reactant: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(n1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 65 °C
Reaction time: 15 h
Yield: 81.2 %

Procedure:
T3P (4.89 mL, 8.22 mmol) was added to a solution of 6-(tert-butoxycarbonyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine-5-carboxylic acid (1.69 g, 5.48 mmol), 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.982 g, 5.48 mmol), DIEA (4.77 mL, 27.41 mmol) and DMAP (0.737 g, 6.03 mmol) in ethyl acetate (40 mL) at room temperature. The mixture was stirred at 65° C. for 15 hr, the reaction mixture was poured into water (150 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with 10% aqueous citric acid solution, aqueous sodium hydrogencarbonate solution, water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained precipitate was washed with hexane to give tert-butyl 5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (2.09 g, 4.45 mmol, 81%) as an off-white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:15]=[C:16]([CH:28]=[CH:29][C:30]=3[S:31][C:32]3[CH:37]=[CH:36][C:35]([O:38]C)=[CH:34][CH:33]=3)[C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26]C)=[O:18])=[N:11][CH:10]=[N:9][C:8]=2[N:40]=1)([CH3:3])[CH3:2].C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(NC3C=CC(C)=CC=3)=O)=NC=NC=2N=1)(C)C>>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:17](=[O:18])[C:16]1[CH:28]=[CH:29][C:30]([S:31][C:32]2[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=2)=[C:14]([NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[N:40][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:15]=1
Reactant: COc1ccc(Sc2ccc(C(=O)Nc3ccccc3OC)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Nc3ccc(C)cc3)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccccc4O)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 55 %

Procedure:
The product from Example 143 was reacted according to the procedure from Example 150 substituting the product from Example 143 for the product from Example 138 to provide a residue which was purified by trituration with methanol and diethyl ether to provide the title compound (26 mg, 55%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.37 (d, J=6.99 Hz, 6H), 3.21-3.43 (m, 1H), 6.83 (s, 1H), 6.84 (d, J=8.82 Hz, 2H), 6.92 (d, J=8.09 Hz, 1H), 7.02 (d, J=8.09 Hz, 2H), 7.32 (d, J=8.46 Hz, 2H), 7.63 (d, J=8.09 Hz, 1H), 7.93 (dd, J=8.46, 1.84 Hz, 1H), 7.99 (s, 1H), 8.94 (s, 1H), 9.08 (d, J=8.46 Hz, 1H), 9.51 (s, 1H), 9.74 (s, 1H), 10.02 (s, 1H); MS (APCI) m/z 524 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:49])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:32])([CH3:31])[C:20]([CH2:33][CH2:34][C:35]([CH3:41])([CH3:40])[CH2:36][C:37](O)=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:83][S:84]([NH2:87])(=[O:86])=[O:85]>C(Cl)Cl>[O:49]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C@:11]23[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:12]2[C@@H:13]2[C@@:26]([CH3:29])([CH2:27][CH2:28]3)[C@@:25]3([CH3:30])[C@@H:16]([C@:17]4([CH3:42])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:31])([CH3:32])[C:20]([CH2:33][CH2:34][C:35]([CH3:40])([CH3:41])[CH2:36][C:37]([NH:87][S:84]([CH3:83])(=[O:86])=[O:85])=[O:38])=[CH:19][CH2:18]4)[CH2:15][CH2:14]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(CCC(C)(C)CC(=O)NS(C)(=O)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
A solution of 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethylpentanoic acid (30 mg, 0.043 mmol) in DCM (2 mL) was treated with HATU (28.6 mg, 0.075 mmol), N,N-diisopropylethylamine (0.026 mL, 0.150 mmol), and methanesulfonamide (5.3 mg, 0.055 mmol). The reaction mixture was stirred at rt for 16 h. The mixture was concentrated and the crude product was purified by prep HPLC (Method 13) to afford 5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-3,3-dimethyl-N-(methylsulfonyl)pentanamide (9.1 mg, 23% yield). LC/MS m/e 776.5 (M+H)+, 2.34 min (ionization peak, no UV) (method 3). 1H NMR (500 MHz, DMSO-d6) δ 5.20 (d, J=5.1 Hz, 1H), 4.69 (s, 1H), 4.55 (br. s., 1H), 3.08 (br. s., 1H), 3.00-2.91 (m, 3H), 2.81 (d, J=2.6 Hz, 3H), 2.74 (s, 3H), 2.64-2.56 (m, 3H), 2.48 (d, J=5.5 Hz, 1H), 2.40-2.32 (m, 1H), 1.95-0.76 (m, 29H), 1.91 (s, 3H), 1.65 (s, 3H), 1.03 (s, 3H), 0.95 (s, 3H), 0.94 (s, 6H), 0.93 (s, 3H), 0.87 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2].[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:22]1[N:23]([CH3:33])[C:24]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[N:25][N:26]=1>>[ClH:17].[CH2:1]([C:3]1[O:4][C:5]2[C:15]([N:16]=1)=[CH:14][C:8]1[CH2:9][CH2:10][N:11]([CH2:18][CH2:19][CH2:20][S:21][C:22]3[N:23]([CH3:33])[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[N:25][N:26]=3)[CH2:12][CH2:13][C:7]=1[CH:6]=2)[CH3:2]
Reactant: CCc1nc2cc3c(cc2o1)CCNCC3
Reactant: Cn1c(SCCCCl)nnc1-c1cccnc1
Product: CCc1nc2cc3c(cc2o1)CCN(CCCSc1nnc(-c2cccnc2)n1C)CC3
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 2-ethyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.25 mmol) and 3-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}pyridine and was obtained as a faint yellow slightly hygroscopic solid (0.12 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH:11]=[CH:10]1.CO.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33](O)[C:34]([OH:36])=[O:35])=[CH:32][C:27]=2[O:26][CH2:25]1>C(#N)C>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33]([C:11]3[C:12]4[C:17](=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=4)[N:9]([CH3:8])[CH:10]=3)[C:34]([OH:36])=[O:35])=[CH:32][C:27]=2[O:26][CH2:25]1
Reactant: O=C(O)C(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Solvent: CC#N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C(C(=O)O)c3ccc4c(c3)OCO4)cn(C)c2c1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Trifluoroacetic acid (1.92 kg) was added portionwise to a stirred suspension of methyl 1-methyl-1H-indole-6-carboxylate (prepared by the same method as 1-methylindole-6-tert-butyl ester in Example 28, International Patent Application WO 97/43260, but using methanol in place of 6-tert-butanol; 1.63 kg) and 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetic acid (1.67 kg) in acetonitrile (16.3 liters) at room temperature under a nitrogen atmosphere. The suspension was heated to reflux for 24 h and allowed to cool to room temperature. Filtration of the precipitated product gave the subtitle compound as a white crystalline solid (2.54 kg, 80.4%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: Cc1cn(-c2ccc(F)cc2C#N)cn1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(F)cc2C#N)c1CN(C)C
Yield: 34 %

Procedure:
As described for example 84b, 5-fluoro-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 24 h at 90° C. Evaporation of the solvent, aqueous workup and crystallization from ethyl acetate/diisopropylether afforded the title compound as a white solid (yield: 34%). MS: m/e=259.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[N:27]=[C:28]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[S:29][C:30]=1[CH3:31])[CH2:6][O:7][C:8]1[C:12]([CH:13]=O)=[CH:11][N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1.[Cl-].[CH2:39]([C:41]1[S:42][CH:43]=[C:44]([CH2:46][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:45]=1)[CH3:40].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:39]([C:41]1[S:42][CH:43]=[C:44](/[CH:46]=[CH:13]\[C:12]2[C:8]([O:7][CH2:6][C:5]3[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]4[N:27]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[S:29][C:30]=4[CH3:31])=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:9][N:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:11]=2)[N:45]=1)[CH3:40]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(/C=C\c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(N4CCOCC4)sc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.6 %

Procedure:
A mixture of 3-({3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.75 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (0.89 g), potassium carbonate (0.29 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give 4-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-thiazol-2-yl]morpholine as colorless crystals (0.25 g, yield 28%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 112-114° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH3:12])[N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Cl>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[Cl:13])=[C:4]([NH:11][CH3:12])[N:3]=1
Reactant: ClCc1ccccc1Cl
Reactant: CNc1nc(Cl)nc2[nH]cnc12
Product: CNc1nc(Cl)nc2c1ncn2Cc1ccccc1Cl

Procedure:
In a manner analogous to that described in Example 17 it is possible, by reacting 2-chloro-6-(N-methylamino)-9H-purine (Example 6) with 2-chlorobenzyl chloride, to obtain the 2-chloro-9-(2-chlorobenzyl)-6-(N-methylamino)-9H-purine, which melts at from 203° to 204° (N,N-dimethylformamide/diethyl ether).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)#[CH:2].C([Li])CCC.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CCCCCC.O.O1CCCC1>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25])#[CH:2]
Reactant: C#Cc1cccc2ccccc12
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1c(CCCCCCCCCCCCCCCCCC)ccc2ccccc12
Temperature: -90 °C
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To 20 mL of a tetrahydrofuran solution of 2.88 g of ethynylnaphthalene was added 25 mL of a 1.6 mol/L hexane solution of n-butyl lithium at −50° C. under a nitrogen atmosphere, and the mixture was cooled to −90° C., and then 12 mL of a tetrahydrofuran solution of 2.3 g of potassium tert-butoxide was added thereto. After stirring at −80° C. for 1 hour, the temperature was raised up to 5° C. At −70° C., 6.90 g of bromooctadecane was dropped to the resulting solution, and stirred overnight at 30° C. 100 mL of water was dropped to the resulting solution at 0° C., and hexane was added thereto to extract the generated compound. The hexane layer was washed with 30 mL of distilled water for 3 times, dried over anhydrous magnesium sulfate for 24 hours, followed by filtration, and the solvent was removed by evaporation. The resulting product was purified on a column by using hexane as a developing solvent, thereby 1.5 g of 1-ethynyl-2-n-octadecylnaphthalene was obtained. The obtained 1-ethynyl-2-n-decylnaphthalene was analyzed by 1H-NMR (270 MHz, CDCl3), and the NMR spectra showed peak at δ 8.3 (1H), 7.8 (2H), 7.5 (3H), 3.6 (1H), 3.0 (2H) 1.7 (2H), 1.3 (32H), 0.9 (3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][C:4]=1[NH:18][C:19](=[O:26])[O:20][C@H:21]([CH2:23][CH2:24][CH3:25])[CH3:22].Br[C:28]1[N:29]=[C:30]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[CH2:40][CH2:39]2)[N:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=12>>[C:46]([NH:45][CH2:44][C@H:41]1[CH2:40][CH2:39][C@H:38]([C:30]2[N:31]3[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]3=[C:28]([C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:26])[O:20][C@H:21]([CH2:23][CH2:24][CH3:25])[CH3:22])=[C:3]([O:2][CH3:1])[CH:8]=3)[N:29]=2)[CH2:43][CH2:42]1)(=[O:48])[CH3:47]
Reactant: CC(=O)NC[C@H]1CC[C@H](c2nc(Br)c3c(C)nccn32)CC1
Reactant: CCC[C@H](C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Product: CCC[C@H](C)OC(=O)Nc1ccc(-c2nc([C@H]3CC[C@H](CNC(C)=O)CC3)n3ccnc(C)c23)cc1OC

Procedure:
(S)-Pentan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-carbamate (20 mg) and N-(((trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)methyl)acetamide (20 mg) were reacted according to the procedure described in example 4 step 4c and purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give (S)-pentan-2-yl 4-(3-((trans)-4-(acetamidomethyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate (16 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](I)[C:7]([F:11])=[CH:6][C:5]=1[O:12][CH3:13])[CH3:2].[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C>C1COCC1>[CH2:1]([O:3][C:4]1[C:5]([O:12][CH3:13])=[CH:6][C:7]([F:11])=[C:8]([B:19]([OH:22])[OH:20])[CH:9]=1)[CH3:2]
Reactant: COB(OC)OC
Reactant: CCOc1cc(I)c(F)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)c(F)cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 89.2 %

Procedure:
To a solution of 64D (324 mg, 1.1 mmol) in THF (5 mL) at −78° C. was slowly added n-BuLi (1.6 M in hexanes, 1.40 mL, 2.2 mmol). The reaction mixture was stirred at −78° C. for 20 min, followed by addition of trimethyl borate (0.31 mL, 2.8 mmol). The mixture was stirred at −78° C. for 3.0 h and then warmed up to rt over 18 h. It was quenched by addition of 1.0 N HCl (2.0 mL). After extraction with EtOAc, washing with a solution of Na2S2O3, brine and drying over Na2SO4, the crude product was purified by silica gel chromatography (eluting with 5% methanol in CH2Cl2) to give 64E (210 mg, 80% yield) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.36 (t, J=6.81 Hz, 3H) 3.86 (s, 3H) 4.00 (q, J=7.03 Hz, 2H) 6.72 (d, J=10.11 Hz, 1H) 6.89 (d, J=5.27 Hz, 1H).
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:18]([NH:22][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)N
Reactant: COCc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Solvent: c1ccncc1
Product: COCc1cc(NC(C)(C)C)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 5.50 g of methyl 4-fluoro-2-(methoxymethyl)-5-nitrobenzoate and 55.0 mL of pyridine was added 7.20 mL of tert-butylamine, followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and to the residue was added water. Then, 1 M hydrochloric acid was added thereto to adjust the pH to about 4, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 6.82 g of methyl 4-(tert-butylamino)-2-(methoxymethyl)-5-nitrobenzoate as a yellow solid.
Reaction SMILES: ClC(N(C)C)=C(C)C.[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([OH:19])=O)[CH2:11]1.[F:20][C:21]([F:42])([F:41])[C:22]1[CH:23]=[C:24]([S:28]([CH2:31][CH2:32][S:33][C:34]2[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][N:35]=2)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1.CCCCCC>C(Cl)Cl.O>[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][C:17]([NH:40][C:39]2[C:34]([S:33][CH2:32][CH2:31][S:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:41])([F:42])[F:20])[CH:23]=3)(=[O:30])=[O:29])=[N:35][CH:36]=[CH:37][CH:38]=2)=[O:19])[CH2:11]1
Reactant: Nc1cccnc1SCCS(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)CC1CCCC(=O)C1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: O=C1CCCC(CC(=O)Nc2cccnc2SCCS(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.4 %

Procedure:
560 μl (4.23 mmol) 1-chloro-N,N,2-trimethylprop-1-en-1-amine were added at 0° C. to a solution of 550 mg (35.2 mmol) 2-(3-oxocyclohexyl)acetic acid in DCM (7 ml). After stirring for 15 min at 0° C., 1.5 g (4.23 mmol) [2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]amine (VPF-001) were added. Then the reaction solution was stirred for a further 16 h at 0° C. It was then diluted with water (30 ml) and extracted with DCM (3×50 ml). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 6:4) of the residue yielded 220 mg (0.44 mmol, 13%) 2-(3-oxocyclohexyl)-N-[2-[2-[[3-(trifluoromethyl)phenyl]sulfonyl]-ethylsulfanyl]-pyridin-3-yl]acetamide. MS: m/z 501.1 [M+H]+.
Reaction SMILES: O.NN.[CH3:4][C:5]1([CH3:20])[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:7]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:6]1=2>[Pd].C(O)C>[NH2:17][C:15]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][CH2:11][C:5]([CH3:20])([CH3:4])[C:6]=2[CH:16]=1
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(=O)Nc2ccc(N)cc21

Procedure:
Added 13 mL of ethanol, 10% Palladium on activated carbon (62 mg), and hydrazine monohydrate (171 ul) to 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (206 mg, 0.8793 mmol). Heated reaction to 60° C. overnight. Filtered reaction through Celite, and purified by normal phase silica gel chromatography eluting with 90/10/1 CH2Cl2/MeOH/NH4OH to obtain an off-white solid to yield 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. mp 168° C.; LCMS: m/z=205.12 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.35 (br s, 1H), 6.78 (d, 1H, J=8.3 Hz), 6.72 (s, 1H), 6.54 (d, 1H, J=8.3 Hz), 3.76 (br s, 2H), 2.32 (m, 2H), 2.06 (m, 2H), 1.35 (s, 6H).