Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:22]=[CH:21][C:20]=1[F:34])=[O:18]
Reactant: CC1(C)OCC(COc2ccc(F)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(OCC(O)CO)ccc1F)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 315 was dissolved in TFA:water (3:1, 8 mL) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:2 to 100:0) as the eluent, affording the title compound as a yellow foam. 13C NMR (DMSO-d6) δ 189.3, 158.8 (dd), 155.7 (dd), 154.9 (d), 153.8 (d), 149.5, 133.5, 133.4, 127.8 (d), 126.5 (dd), 126.3, 124.1 (dd), 119.7 (d), 117.1 (d), 114.9 (d), 114.7, 112.0 (dd), 111.7, 105.0 (dd), 70.4, 69.8, 62.5
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][O:5][C:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[CH3:15]S(C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:4]([O:5][C:6](=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:1]#[N:2])[CH3:15]
Reactant: [C-]#N
Reactant: COC(=O)CCCCCCBr
Reactant: CS(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCCCCC#N
Temperature: 50 °C
Yield: 94 %

Procedure:
Add sodium cyanide (12.5 g, 255 mmol) and tetra-n-butylammonium iodide (10 g, 27.0 mmol) portionwise to a solution of 7-bromoheptanoic acid methyl ester (25 g, 105 mmol) in DMSO (300 mL) at room temperature under nitrogen and heat the mixture at 50° C. for 4 hours. Cool the mixture and dilute with water (200 mL) and extract with diethyl ether (2×200 mL). Dry the combined organic extracts over sodium sulfate and remove the solvent under reduced pressure to provide 7-cyanoheptanoic acid ethyl ester (18.2 g, 94%).
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([OH:9])=O)=[O:4].CN1CCOCC1.[NH2:27][CH2:28][CH2:29][CH2:30][OH:31]>C1COCC1.CCOC(C)=O>[N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][CH2:10][C@H:2]1[C:3]([NH:5][CH2:6][C:7]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Reactant: NCCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)NCCCO
Temperature: 25 °C

Procedure:
To a cold (−15° C.) solution of Boc-Pro-Gly-OH (610 mg, 2.24 mmol) and NMM (369 μl, 3.36 mmol) in THF (8 mL) was added ECF (2201 μl, 2.3 mmol) and stirred vigorously. After 2 min. a solution of 1-amino-3-propyl alcohol (220 mg, 2.68 mmol) in THF (2 mL) was added to it followed by NMM (505 mg, 5 mmol) and stirred for further 30 minutes. The mixture was warmed to r.t. and stirred for 8 h. The solvent was removed under reduced pressure to give a residue which was diluted with EtOAc and washed with saturated citric acid, saturated NaHCO3 and the organic layer was dried over Na2SO4 and concentrated under vacuum to give a residue, which was purified by silica gel flash column chromatography (EtOAc:MeOH—50:1) to give the desired product as a thick oil in good yields (633 mg, 80%). TLC (MeOH:DCM—1:4; Rf—0.5).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[CH:16][N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.ClC1C=CC(C=C[N+]([O-])=O)=CC=1>C(N)C1C=CC=CC=1>[CH2:18]([N:17]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[CH:16]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)cn(Cc3ccccc3)c2CC1
Agent: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Solvent: NCc1ccccc1
Product: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CCNCC3)cc1

Procedure:
1-Benzyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-pyrrolo[2,3-d]azepine-6-carboxylic acid tert-butyl ester. The desired compound (54.2 mg) was prepared from the compound of Example 59, Step B (0.56 g), 280 μL of benzylamine, and 0.49 g of 1-chloro-4-(2-nitro-vinyl)-benzene as in Example 1, Step A. MS (ESI): exact mass calculated for C26H29ClN2O2, 436.19. found, m/z 437.2 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:39][C@H:30]([CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.65 (m, 2 H), 1.95–2.10 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.55–3.75 (m, 2 H), 3.96 (d, J=5.2 Hz, 2 H), 4.15–4.25 (m, 1 H), 5.70(brs, 1 H), 6.80 (d, J=9.0 Hz, 2 H), 6.88 (d, J=9.0 Hz, 2 H), 6.90–7.00 (m, 3 H), 7.25–7.35 (m, 2 H), 7.59 (d, J=9.0 Hz, 2 H), 7.69 (d, J=9.0 Hz, 2 H), 9.70 (s, 1 H), 10.37 (s, 1 H), MS (ES) m/z: 539.1 (MH+); HRMS Calcd. for C28H35N4O5S (MH+): 539.2328. Found: 539.2357.
Reaction SMILES: Cl.Br[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16].[CH2:22]([NH:24][CH2:25][CH2:26][OH:27])[CH3:23]>>[CH2:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][OH:27])[CH2:9][CH2:10]1)=[O:16])[CH:19]([CH3:21])[CH3:20]
Reactant: BrCCCCOC1CCNCC1
Reactant: CCNCCO
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Product: CCN(CCO)CCCCOC1CCN(C(=O)OCC(C)C)CC1

Procedure:
In analogy to example 1.4 and 1.5, reaction of 4-(4-Brom-butoxy)-piperidine hydrogen chloride with isobutyl chloroformate and 2-ethylamino-ethanol yielded 4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-piperidine-1-carboxylic acid isobutyl ester, MS: 345 (MH+).
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.C=C1C2[C:64](=[C:65]([O:71][CH:72]([F:74])[F:73])[CH:66]=[C:67]([Cl:70])[CH:68]=2)[O:63][CH2:62]C1.S([O-])([O-])=O.[Na+].[Na+].[C:81]([OH:85])([CH3:84])([CH3:83])[CH3:82]>O>[OH:85][C@@:81]1([CH2:84][OH:22])[C:83]2[C:64](=[C:65]([O:71][CH:72]([F:74])[F:73])[CH:66]=[C:67]([Cl:70])[CH:68]=2)[O:63][CH2:62][CH2:82]1
Reactant: CC(C)(C)O
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=C1CCOc2c(OC(F)F)cc(Cl)cc21
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@@]1(O)CCOc2c(OC(F)F)cc(Cl)cc21
Temperature: 0 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a mixture of tert-butanol (46 mL) and water (46 mL) was added AD-mix-β (18.6 g). The mixture was cooled to 0° C. 4-Methylene-6-chloro-8-difluoromethoxychromane (3.2 g 12.97 mmol, see step (vi) above) in tert-butanol (11 mL) and water (11 mL) was added. The mixture was stirred at 0° C. for 24 h. Sodium sulfite (19.0 g, 150.74 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 1 h. The layers were separated and the aqueous phase was extracted with EtOAc (2×). The combined ethyl acetate phases were dried (Na2SO4) and evaporated. The crude product was chromatographed on silica gel, eluting with methylene chloride:ethyl acetate (4:6), to afford 3.2 g (88%) of the sub-title compound.
Reaction SMILES: N[C:2]1[C:9]([Br:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].OS(O)(=O)=O.N([O-])=O.[Na+].CCOC(C)=O>CCO.O>[Br:10][C:9]1[CH:2]=[C:3]([CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])cc(Br)c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(Br)cc([N+](=O)[O-])c1
Reaction time: 13.5 h
Yield: 82.3 %

Procedure:
To a stirring mixture of 1.2 g (4.96 mmol) of 2-amino-3-bromo-5-nitrobenzonitrile and 2.8 mL of H2SO4 in 28 mL of EtOH at 90° C. was added 2.5 g (36.2 mmol) of NaNO2 in several portions. After 13.5 h, EtOAc and H2O were added. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (5% EtOAc/hexanes) provided 927 mg of 3-bromo-5-nitrobenzonitrile in 82% yield as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1I)[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Cl:21])[CH2:8][C:9]([F:12])([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-(2,2,2-trifluoro-ethyl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Colorless oil (69%). MS (ESI): m/z=403.012 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([N:7]([CH3:9])[CH3:8])[N:3]=1.[C:10]([OH:13])(=O)[CH3:11].O=[C:15]1C[S:18][CH2:17][CH:16]1C(OC)=O>>[CH3:8][N:7]([CH3:9])[C:4]1[N:3]=[C:2]2[N:1]=[C:11]3[C:10](=[O:13])[S:18][CH:17]=[C:16]3[CH2:15][N:6]2[N:5]=1
Reactant: CN(C)c1n[nH]c(N)n1
Reactant: CC(=O)O
Reactant: COC(=O)C1CSCC1=O
Product: CN(C)c1nc2n(n1)CC1=CSC(=O)C1=N2
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
To 19.1 g (0.15 mole) of 5-amino-3-dimethylamino-1H-1,2,4-triazole dissolved in 15 ml of acetic acid 24.3 g (0.15 moles) of methyl 4-oxo-tetrahydrothiophene-3-carboxylate are added and the reaction mixture is boiled for 15 minutes. The product precipitated from the reaction mixture is filtered off from the hot solution, then washed with i-propanol and recrystallized from dimethylformamide. Thus 26.1 g (73.3%) of 2-dimethylamino-6,8-dihydrothieno[3,4-d]-1,2,4-triazolo-[1,5-a]pyrimidine-5(9H)-one are obtained. Melting point: 355°-360° C.
Reaction SMILES: [CH2:1]([N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CC=C.C[N+]1([O-])CC[O:27]CC1.S(S([O-])=O)([O-])=O.[Na+].[Na+].[C:39]([OH:43])(C)([CH3:41])[CH3:40]>[Os](=O)(=O)(=O)=O.CC(C)=O.O>[OH:43][CH:39]([CH2:41][OH:27])[CH2:40][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH3:22])[C:11]1=[O:12]
Reactant: C=CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: CC(C)(C)O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cnc2c1c(=O)n(CCCCCCCC(O)CO)c(=O)n2C
Reaction time: 24 h
Yield: 54 %

Procedure:
A solution of 1-(8-nonenyl)-3,7-dimethylxanthine (810 mg, 2.7 mmol), prepared above, 4-methylmorpholine-N-oxide (340 mg, 2.9 mmol) and 3 drops of 2.5% osmium tetroxide in t-butanol, acetone (20 ml) and water (20 ml) was stirred for 24 hours, followed by addition of saturated aqueous sodium dithionite solution (5 ml). After stirring the resulting mixture for 15 minutes, the reaction mixture was extracted with four 50 ml aliquots of 25% ethanol-dichloromethane. The combined organic layers were dried over sodium sulfate, and the solvent evaporated under vacuum. A resulting solid residue was recrystallized in ethanol-chloroform, producing 490 mg of 1-(8,9-dihydroxynonyl)-3,7-dimethylxanthine (54% yield).
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[Na+].[Na+].CO.Br[CH2:20][CH:21]=[C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:21][CH2:20][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: BrCC=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)(CC=C(c1ccccc1)c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
15.5 gm of sodium phenyl sulfinate and 1.5 gm of sodium carbonate were introduced into 80 cc of methanol. Then 25.6 gm of 1-bromo-3,3-diphenyl-2-propene were added to the reaction mixture under an atmosphere of nitrogen and at room temperature which was then agitated for 1 hour and 30 minutes. Next, the reaction mixture was poured into cold water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, dried and concentrated to dryness. The residue was partly crystallized. The precipitate formed was isolated by vacuum filtering and dried to obtain 25.48 gm of (3,3-diphenyl-2-propenyl)-phenyl sulfone having a melting point of 104° C. A sample of this product, recrystallized from isopropyl ether, had a melting point of 106° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.O[C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20][CH3:21])=O.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2.C12CC3CC(CC(C3)C1=[O:45])C2>C1COCC1>[OH:45][C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[C:26]1=[CH:21][O:20][CH2:18][C:17]1[CH:22]=[CH:23][CH:24]=[CH:15][CH:16]=1)[CH2:32]2
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: C1C2CC3CC1CC(C2)C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OC12CC3CC(CC(C3)C1=COCc1ccccc1)C2
Temperature: 25 °C
Yield: 10 %

Procedure:
A 500 ml three-neck, round bottom flask is fit with a reflux condenser, 125 ml addition funnel, and a nitrogen inlet line with a two-way valve control. After the addition of 200 ml of dry THF, the solution is stirred and cooled under nitrogen on an ice bath. TiCl3 (156 mmol) is added rapidly followed by lithium aluminum hydride (75 mmol) in portions. The ice bath is removed and the solution is permitted to warm to ambient temperature. Upon the addition of triethylamine (86 mmol), the solution is refluxed for 1 h. At this time, a solution of 15-20 mmol of methyl 3-hydroxybenzoate and approximately a 10-20% excess of 2-adamantanone adamantane in about 50 ml of THF are added dropwise over several hours by means of the addition funnel. Refluxing is continued for another several hours. After completion, the cooled solution is quenched by the slow addition of about 50 ml of methanol, then about 100 ml of water. The black mixture is diluted in ether and repeatedly extracted with water until the aqueous phase is no longer colored. The solution is dried over Na2SO4 and concentrated in vacuo. Silica column chromatography is used to purify the desired product, 3-hydroxylphenylmethoxymethylene-adamantane. Ethyl acetate/hexane or methanol/CH2Cl2 solvent systems could be employed. The product (anticipated 10-30% yield; probably an oil) is characterized by NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S@:25]([CH:33]2[CH2:35][CH2:34]2)(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S@:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH:33]1[CH2:34][CH2:35]1)=[O:26])=[O:29])[CH3:32]
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Reactant: CCOC(=O)N=[S@](=O)(c1ccc(N)cc1)C1CC1
Product: CCOC(=O)N=[S@](=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1)C1CC1
Yield: 26 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (185 mg, 0.7 mmol) with (R)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-cyclo-propyl-sulfoximide (167 mg, 0.6 mmol) according to procedure 5a, the desired product is obtained in 26% yield (90 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=O)[CH2:9][CH2:8]1.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.[Mg]>O1CCCC1.CC(C)=O.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:13]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:26][CH:25]=2)([C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]([F:29])([F:28])[F:18])=[CH:22][CH:23]=2)[OH:15])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1CCN(Cc2cccs2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Mg]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2cccs2)CC1
Yield: 4.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step B of Example 3, with 2.0 grams (0.008 mole) of ethyl N-(thien-2-ylmethyl)piperidin-4-ylcarboxylate, 3.5 mL (0.024 mole) of 4-trifluoromethoxyphenyl bromide, and 0.6 gram (0.025 gram-atom) of magnesium turnings in about 69 mL of tetrahydrofuran as reagents. The crude reaction product was subjected to column chromatography on silica gel, with pure methylene chloride, 9:1 methylene chloride: acetone, pure acetone, and then 8:2 methylene chloride:acetone as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.2 gram of N-(thien-2-ylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:37]>>[ClH:1].[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cn1cc(S(=O)(=O)Nc2cccc(-c3nc(C4CCOCC4)sc3-c3ccnc(Cl)n3)c2F)cn1
Reactant: [NH4+]
Agent: [OH-]
Product: Cl
Product: Cn1cc(S(=O)(=O)Nc2cccc(-c3nc(C4CCOCC4)sc3-c3ccnc(N)n3)c2F)cn1

Procedure:
Following a procedure analogous to the procedure described in Example 282 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-1-methyl-1H-pyrazole-4-sulfonamide (720 mg, 1.34 mmol) and ammonium hydroxide (15 ml), the title compound was obtained as a white solid (122 mg, 16%). 1HNMR (MEOD-d4): δ ppm 7.95-7.97 (d, J=8.0 Hz, 2H), 7.52-7.56 (m, 2H), 7.29-7.32 (t, J=6.0 Hz, 1H), 7.21-7.25 (t, J=8.0 Hz, 1H), 6.32-6.33 (d, J=6.4 Hz, 1H), 3.92-3.96 (dd, J1=11.8 Hz, J2=3.2 Hz, 2H), 3.77 (s, 3H), 3.45-3.51 (dd, J1=11.4 Hz, J2=1.2 Hz, 2H), 3.23-3.31 (m, 1H), 1.97-1.99 (d, J=11.2 Hz, 2H), 1.75-1.85 (dd, J1=12.2 Hz, J2=4.0 Hz, 2H); MS: 516 [M+H]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH:15]=2)[C:10]([C:26]([C:29]#[N:30])(C)C)=[CH:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:19]([N:17]([CH3:18])[C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH2:26][C:29]#[N:30])=[CH:9][NH:8]2)=[CH:12][CH:13]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(Cc1ccccc1)c1ccc2c(C(C)(C)C#N)cn(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)c1ccc2c(CC#N)c[nH]c2c1
Yield: 88.2 %

Procedure:
A solution of 6-(benzyl-methyl-amino)-3-(cyano-dimethyl-methyl)-indole-1-carboxylic acid tert-butyl ester (26.4 g, 90%, 58.9 mmol) in DCM-TFA (2:1, 180 mL) was stirred for 20 h at 20° C. Evaporation of solvent gave a crude, which was redissolved in DCM and the solution was washed with water, aqueous sodium bicarbonate and water and dried over MgSO4. Evaporation of solvent gave a solid, which was triturated with hexane to give [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile as a solid (14.3 g). MS (ES): 304 (MH+). [6-(benzyl-methyl-amino)-1H-indol-3-yl]-acetonitrile was then treated in a manner similar to that described in Step 34D-H, but using greater than three equivalents of iodomethane, to give 6-(benzyl(methyl)amino)-1,1-dimethyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester.
Reaction SMILES: C([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)C=C.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15].[CH:22](O)([CH3:24])[CH3:23]>>[CH2:24]([C:10]1[C:9](=[O:11])[C:8]2[CH:15]=[C:14]([CH3:13])[C:16]3[C:21]([C:7]=2[C:6](=[O:12])[C:5]=1[OH:4])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH2:23]
Reactant: C=CCOC1=CC(=O)C=CC1=O
Reactant: CC(C)O
Reactant: C=C(C)c1ccccc1
Product: C=CCC1=C(O)C(=O)c2c(cc(C)c3ccccc23)C1=O

Procedure:
2-Allyloxy-1,4-benzoquinone (10.0 g, 61 mM) and α-Methylstyrene (70 g, 0.59 M) were dissolved in 120 ml of isopropanol to give 3.6 g (14 mM) of 2-Allyl-3-hydroxy-9-methyl-1,4-phenanthrenequinone in the same manner as in Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]([CH3:33])([CH3:32])[O:29][C@@H:28]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC(C)(C)O1

Procedure:
According to the same method as described in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15](=O)([O:17]CC)[NH2:16]>[Cl-].[Zn+2].[Cl-]>[C:8]1([C:7]2[C:6]3[CH:5]=[CH:4][S:3][C:2]=3[NH:1][C:15](=[O:17])[N:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1sccc1C(=O)c1ccccc1
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=c1nc(-c2ccccc2)c2ccsc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 10.0 g of 2-amino-3-benzoylthiophene, 16.57 g of ethyl carbamate and 1.00 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is washed with chloroform, then with water, and filtered to give a solid of 4-phenyl-1,2-dihydrothieno[2,3-d]pyrimidin-2-one. Recrystallization from a mixture of ethanol and dimethylformamide gives crystals having a melting point of 247° - 249°C.