Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].Cl[CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:22]=[CH:21][CH:20]=[CH:19][CH:9]1[CH2:10][CH:11]2[CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:4][CH2:5][CH2:6][O:7][C:8]12[CH:22]=[CH:21][CH:20]=[CH:19][CH:9]1[CH2:10][CH:11]2[CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N+:24]=[N-:25]
Reactant: ClCCCOC12C=CC=CC1CC2CN1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCCCOC12C=CC=CC1CC2CN1CCCCC1
Temperature: 75 °C
Reaction time: 12 h

Procedure:
Sodium iodide (3 g) is added to a stirred solution of 3-(3-chloropropoxy)-1-(1-piperidinylmethyl)benzocyclobutene (0.87 g) in 12 ml of DMF. The reaction mixture is stirred under nitrogen for 12 hours, sodium azide (1.17 g) is added to this solution followed by water (1.2 ml). The resulting suspension is heated at 75° C. for 5 hours. The reaction mixture is partitioned between water and methylene chloride and the organic layer is separated, washed, dried, filtered and evaporated in vacuo yielding the azide product as an oil.
Reaction SMILES: B1([O-])OO1.[OH2:5].O.O.O.[Na+].[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C.C(OCC)(=O)C>[C:10]([O:14][C:15]([C@H:17]([CH2:21][S:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:41]4[O:42][C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=5[C:40]=4[CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28][CH:29]=1)=[O:5])[C:18]([OH:20])=[O:19])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O
Reactant: CC(C)(C)OC(=O)[C@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)[C@H](CS(=O)Cc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Sodium perborate tetrahydrate (42 mg, 0.27 mmol) was added as a solid to a stirred solution of (2R)-2-tert-Butoxycarbonyl-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethyl-sulfanyl)-propionic acid (150 mg, 0.27 mmol), in acetic acid (5 mL) at 40° C. This solution was stirred at 40° C. for 1 hour (HPLC control) and then diluted with ethyl acetate (50 mL), washed with water, brine (2×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by trituration of the product with diethyl ether afforded the title compound as a 1:1 mix of diastereoisomers as a white solid (144 mg, 93%): Rf 0.25 (20% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz) δ 8.19 (1H, d, J=8 Hz, Ar—H), 8.15 (1H, dd, J=8, 1 Hz, Ar—H), 8.01 (2H, d, J=9 Hz, Ar—H), 7.87 (2H, d, J=9 Hz, Ar—H), 7.78 (4H, m, Ar—H), 7.52 (2H, m, Ar—H), 7.44 (4H, m, Ar—H, NH), 4.39 (1H, m, CHN), 4.05-4.27 (2H, m, PhCH2), 3.04 (1H, m, CHHCHN), 2.92 (1H, m, CHHCHN), 1.39 and 1.37 (both 4.5H, s, CMe3 diastereomers); ESI-LCMS e/z calcd for C33H31NO6S 569.675, found 570 (M+H)+, 592 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>C(O)C.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
Ethyl 3-({[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propanoate (1000 mg) which is a synthetic intermediate in Example 148 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 11.5 min were collected, and concentrated. The obtained amorphous compound (487 mg) was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL), 1N lithium hydroxide (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (454 mg, 89%).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH:38]1[CH:42]=[C:41]([CH2:43][C:44](O)=[O:45])[N:40]=[CH:39]1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:44](=[O:45])[CH2:43][C:41]2[N:40]=[CH:39][NH:38][CH:42]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and 4-imidazoleacetic acid hydrochloride (19.5 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.
Reaction SMILES: C(O[CH:4]([O:13]CC)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)C.Cl.[NH2:17][NH:18][C:19]([NH2:21])=[O:20]>C(O)C.O>[NH2:21][C:19]([NH:18][N:17]=[C:5]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:4]=[O:13])=[O:20]
Reactant: CCOC(OCC)C(=O)c1ccccc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: NC(=O)NN=C(C=O)c1ccccc1
Temperature: 120 °C
Yield: 59.3 %

Procedure:
A mixture of 2,2-diethoxy-1-phenylethanone (6.25 g, 0.0300 mol) and semicarbazide hydrochloride (3.34 g, 0.0300 mol) in ethanol-water (1:1 v/v, 50 mL) was heated at 120° C. for 3 h. The mixture was concentrated under reduced pressure. The residue was treated with methanol, filtered, and washed with methanol to give the desired product (3.40 g, 59.3%). Analytical LCMS: (M+H)+=192.1. 1H-NMR (400 MHz, DMSO-D6): δ 11.03 (s, 1H), 7.97-8.01 (m, 2H), 7.61-7.67 (m, 1H), 7.50-7.56 (m, 2H), 7.34 (b, 1H), 6.54 (b, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]2[C:22]3[N:29]([CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)[CH:28]=[CH:27][C:23]=3[N:24]=[CH:25][N:26]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=1.[ClH:40].O1CCCC1>C(O)C>[ClH:1].[ClH:40].[NH2:32][CH2:31][CH2:30][N:29]1[C:22]2[C:21]([NH:20][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]([F:19])([F:18])[F:17])[CH:10]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:26][CH:25]=[N:24][C:23]=2[CH:27]=[CH:28]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl {2-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (173 mg), 2N hydrochloric acid (2.5 mL) and tetrahydrofuran (5.0 mL) was stirred at 60° C. for 6 hrs. Ethanol was added to the reaction system. The solvent was evaporated under reduced pressure. Ethanol was added to the concentrate, and the mixture was further concentrated under reduced pressure. The residual crystals were collected by filtration and the crystals were washed with ethyl acetate to give the title compound (155 mg) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[C:23]([CH:30]=O)=[N:24][N:25]([CH:27]([F:29])[F:28])[CH:26]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:30][C:23]3[C:22]([Cl:21])=[CH:26][N:25]([CH:27]([F:29])[F:28])[N:24]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=Cc1nn(C(F)F)cc1Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde using decaborane yielded (S)-2-amino-6-{5-[(4-chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one as colorless solid. MS (ESI): m/z=443.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH2:21])=[CH:7]2.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[NH:25][CH:26]=[N:27]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[C:8]([CH2:20][NH:21][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3cc2CNc2ncnc3[nH]cnc23)c1

Procedure:
Prepared according to Procedure H using (8-chloro-2-(2-chloro-5-fluorophenyl)-quinolin-3-yl)methanamine (0.050 g, 0.156 mmol), 6-chloropurine (0.027 g, 0.17 mmol, 1.2 eq) and DIEA (0.70 mmol, 2.0 eq) in n-butanol (3 mL). N-((8-chloro-2-(2-chloro-5-fluorophenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=71 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.30 (s, 1H), 8.20 (s, 1H), 7.80 (dd, J=7.58, 0.49 Hz, 2H), 7.69-7.75 (m, 1H), 7.42-7.47 (m, 1H), 7.31-7.37 (m, 1H), 7.11-7.16 (m, 1H), 6.99-7.06 (m, 1H), 4.90-497. (m, 2H), Mass Spectrum (ESI) m/e=440 (M+1)
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([NH:7][C:8]([O:10]C(C)(C)C)=O)=[CH:5][CH:4]=1)#N.S.[C:18]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32](=[S:34])[NH2:33])=[CH:28][CH:27]=1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>N1C=CC=CC=1.CO>[C:21]([O:20][C:18](=[O:19])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:34][CH:16]=[C:3]([C:4]3[C:8](=[O:10])[NH:7][C:6]4[C:5]([CH:5]=3)=[CH:4][CH:3]=[CH:16][CH:15]=4)[N:33]=2)=[CH:30][CH:31]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(N)=S)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Agent: S
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3cc4ccccc4[nH]c3=O)cs2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-cyano-tert-butyloxycarbonylaniline (2.20 g, 10.0 mmol) in 20 mL of pyridine and 5 mL of TEA was purged with H2S gas for 7.0 h. Solvents were removed under vacuum. The resulting crude 4-Boc-aminobenzene-thiocarboxamide (yellow residue, 70% purity) was used directly in the next step. A solution of 4-Bocamino-benzenethiocarboxamide (205 mg, 70% pure, 0.57 mmol) and 3-(2-bromoacetyl)hydroquinolin-2-one (Example 27b, 78 mg, 0.29 mmol) in 50 mL of MeOH was heated at reflux for 4 h. After cooling to RT, the precipitates were collected by filtration to provide the title compound as an off-white solid. MS m/z: 420.2 (M+1). HRMS m/z: 420.1358 (M+H+, C23H21N3O3S Calc'd 420.1376).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(Cl)c1ccc(F)cc1
Yield: 82.8 %

Procedure:
A mixture of 4-fluorobenzoic acid (0.15 mol), thionyl chloride (0.45 mol) and dimethylformamide (5 drops) in chloroform (200 ml) was heated at reflux for 16 hours. Volatiles were removed from the cooled solution in vacuo. The residue was diluted with carbon tetrachloride (100 ml) and the mixture evaporated in vacuo to remove residual thionyl chloride. The residue was distilled affording 19.7 g of a clear oil (83% yield); bp 110°-112° C. at 40 mm of Hg. Spectral data are consistent with the assigned structure.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([N+:21]([O-])=O)=[N:10][CH:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=2)[CH2:4][CH2:3]1.[C:24]([C:26]1[O:30][C:29]([C:31](Cl)=[O:32])=[CH:28][CH:27]=1)#[N:25].C(C1OC(C(O)=O)=CC=1)#N>CN(C=O)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([NH:21][C:31]([C:29]3[O:30][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)=[O:32])=[N:10][CH:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)cnc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Agent: N#Cc1ccc(C(=O)O)o1
Solvent: CN(C)C=O
Product: CC1CCN(c2cc(N3CCN(C)CC3)cnc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 4 %

Procedure:
4-Methy-5′-(4-methyl-piperazin-1-yl)-2′-nitro-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl (as prepared in the previous step) (319 mg, 1.00 mmol) was converted to corresponding amine according to the procedure in Example 55, step (c) and coupled with 5-cyano-furan-2-carbonyl chloride as prepared in Example 4, step (c) (obtained from 137 mg, 1.00 mmol of 5-cyano-furan-2-carboxylic acid as prepared in Example 1) in DMF (2 mL) at 0° C. The product was isolated by flash chromatography on silica (20% EtOAc/hexane-10% MeOH/EtOAc) to obtain the title compound (16 mg, 4%). 1H-NMR (CDCl3; 400 MHz): δ 9.35 (br s, 1H), 7.95 (br s, 1H), 7.33 (d, 1H, J=3.5 Hz), 7.22 (d, 1H), J=3.5 Hz), 7.06 (br s, 1H), 3.21 (m, 4H), 3.06 (m, 2H), 2.71 (m, 2H), 2.58 (m, 4H), 2.37 (s, 3H), 1.84 (m, 2H), 1.7-1.5 (m, 3H), 1.07 (d, 3H, J=6.3 Hz). LC-MS (ESI, m/z); Calcd. for C22H28N6O2, 409.2 (M+H), found 409.2.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([C:18]#[CH:19])([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:4][CH2:3]1.Cl.[C:21]1([O:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(Cl)Cl>[O:27]([C:28]([N:2]1[CH2:3][CH2:4][C:5]([C:18]#[CH:19])([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:7]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: C#CC1(Oc2ccccc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-4-ethynyl-4-(2-nitrophenoxy)piperidine (liberated from 10.0 g of the hydrochloride) in 45 ml of methylene chloride was added dropwise a solution of 5.8 g of phenylchloroformate in 45 ml of methylene chloride. The mixture was stirred at room temperature for 1 hr and at reflux, under nitrogen, for 16 hrs. The solution was allowed to cool to room temperature, poured into water, extracted with methylene chloride, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. Filtration followed by evaporation of solvent provided an oil (13.9 g). A 2.2 g sample of the oil was chromatographed on 150 g of alumina. The column was eluted with three 150 ml volumes of ether. Evaporation of the solvent from the second fraction provided 1.36 g (65%) of product. Recrystallization from isopropyl alcohol provided the analytical sample, mp 76°-80°.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@@:12]1([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[C@H:14]([CH3:15])[O:13]1.C([S:25][C@@H:26]1[CH2:31][O:30][C@@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:28][CH2:27]1)(=O)C>CO.C(O)C>[F:4][C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[C@:12]([OH:13])([C@H:14]([S:25][C@@H:26]1[CH2:27][O:28][C@@H:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:30][CH2:31]1)[CH3:15])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1cccc(F)c1F
Reactant: CC(=O)S[C@H]1CO[C@H](c2ccccc2)OC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1cccc(F)c1F

Procedure:
0.29 ml (1.4 mmol) of a 4.9 M solution of sodium methoxide in methanol were added to a solution of 1.77 g (7.1 mmol) of (2R,3S)-2-(2,3-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Step 7(iv) above] and 2.20 g (9.2 mmol) of trans-5-(acetylthio)-2-phenyl-1,3-dioxane [prepared as described in Japanese Patent Application (Kokai) Hei 8-333350] in 20 ml of ethanol. The resulting mixture was then heated under reflux for 7 hours. After cooling the reaction mixture, it was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure to afford 3.65 g of the crude title compound. An aliquot (0.28 g) of the crude residue was purified by chromatography on a silica gel (15 g) column using a 2:5 mixture of ethyl acetate and hexane as eluent to afford 0.21 g of the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:31]=[N:32][N:33](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:34]=2)[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].O>CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3-c3nnn[nH]3)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.1 %

Procedure:
0.70 g (0.98 mmol) of 2-butyl-4-chloro-1-{[2-[2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]phenyl]quinolin-6-yl]methyl}-1H-imidazole-5-carbaldehyde obtained in Example 8 was suspended in 12 ml of methanol. 12 ml of concentrated hydrochloric acid was added thereto while in an iced water bath followed by stirring at room temperature for 24 hours. The reaction mixture was iced and alkalized with a 10N sodium hydroxide solution. After adding 10 ml of water thereto, the mixture was filter and the filtered cake was washed with 10 ml of a 1N sodium hydroxide solution. The filtrate was acidified by adding concentrated hydrochloric acid dropwise thereto and extracted with 100 ml of ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 0.102 g of 2-butyl-4-chloro-1-{[2-[2-(1H-tetrazol-5-yl)phenyl]-quinolin-6-yl]methyl}-1H-imidazole-5 -carbaldehyde.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H].ClCCl>C(OCC)(=O)C.[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(C#Cc3ccccc3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(CCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, to a solution of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(phenylethynyl)pyrazin-2-amine (7p) (400 mg, 996 μmol) in ethyl acetate (20 mL) was added Palladium/charcoal activated (10% Pd) (80.0 mg) at room temperature. The atmosphere in the reaction flask was replaced with hydrogen gas and the mixture was stirred at room temperature for 3 hours. After replacing the atmosphere of the reaction system again with argon, to the mixture was added dichloromethane (15 mL) and stirred at room temperature for an hour. The catalyst was removed by filtration. After concentration under reduced pressure, the residue was purified by column chromatography (silica gel 40 g, n-hexane/ethyl acetate=2/1) to give Compound 7r (403 mg, 994 μmol, 99.8%) as a brown oily substance. Rf=0.48 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.93 (s, 9H), 2.92 (t, 3H, J=8.0 Hz), 3.05 (t, 3H, J=8.0 Hz), 6.25 (s, 2H), 6.81-6.90 (AA′BB′, 2H), 7.10-7.18 (m, 1H), 7.18-7.35 (m, 4H), 7.75-7.85 (AA′BB′, 2H), 8.27 (s, 1H); 13C NMR (67.8 MHz, DMSO-d6) δ −4.5 (2C), 18.0, 25.6 (3C), 31.7, 34.0, 120.0 (2C), 125.7, 126.1 (2C), 128.2 (2C), 128.5 (2C), 130.9, 135.6, 138.5, 140.1, 141.9, 152.3, 154.6; IR (KBr, cm−1) 507, 635, 677, 698, 750, 781, 841, 914, 1009, 1103, 1146, 1167, 1213, 1254, 1389, 1420, 1454, 1512, 1605, 2857, 2928, 2955, 3061, 3318.
Reaction SMILES: CC1C=CC(N2C3C(=CC=CC=3)C=C2)=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.I[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1>>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]5[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH:36]=[CH:37][CH:38]=5)[CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:47][CH:48]=1
Reactant: COc1ccc(I)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Agent: Cc1ccc(-n2ccc3ccccc32)cc1
Product: COc1ccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)cc1
Yield: 56.1 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-iodo-4-methoxybenzene (46.8 mg, 0.200 mmol) gave the desired product (27 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.70-6.58 (m, 14H), 3.88 (s, 3H), 3.67 (s, 2H), 3.14-3.01 (m, 2H), 2.57-2.41 (m, 2H), 2.25-2.01 (m, 2H), 1.93-1.69 (m, 4H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 482.2 (M+H)+.