Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[C:3]1=O.C(OCC)(=O)C.O>FC(F)(F)C(O)=O>[CH3:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH3:13])[CH2:3]1
Reactant: COC(=O)C1(C)CCc2c(OC)cccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1(C)CCc2c(cccc2OC)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 211.9 %

Procedure:
To a solution of 2-methyl-2-methoxycarbonyl-5-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene (2.0 g) in trifluoroacetic acid (20 ml) was added triethyls4lane (2.0 ml) at room temperature. After being stirred for 6 hours at room temperature, the solution was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford 2-methyl-2-methoxycarbonyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]([C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[C:12]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:11]=1)=[CH:6]N(C)C)[CH3:2].[H][H]>CCO.[Ni]>[CH2:1]([O:3][C:4]([C:5]1[C:10]2=[N:11][C:12]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:13][CH:14]=[C:15]2[NH:16][CH:6]=1)=[O:27])[CH3:2]
Reactant: CCOC(=O)C(=CN(C)C)c1nc(OC2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c2ccc(OC3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 3-dimethylamino-2-[6-(1-methyl-piperidin-4-yloxy)-3-nitro-pyridin-2-yl]-acrylic acid ethyl ester (3.69 g, 9.76 mmol), RANEY 2400 nickel (3.7 g wet) in EtOH (100 mL) is shaken at room temperature under an atmosphere of hydrogen (50 psi) for a period of 7 h. During this time period, the pressure dropped to 20 psi. The reaction vessel is recharged with hydrogen (50 psi) and shaken at room temperature for a period of 17 h. The reaction mixture is filtered through celite and the filtrate washed with EtOH (300 mL) taking care to never allow the filtrate to become dry. The filtrate is concentrated and purified by chromatography on silica (gradient elution with 10% MeOH/CHCl3 with 0.1% NH4OH to 14% MeOH/CHCl3 with 0.1% NH4OH) to give the title compound as a yellow solid: m.p=231.9° C.; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.64 (d, 1H, J=8.7 Hz), 6.51 (d, 1H, J=8.7 Hz), 5.36-5.28 (m, 1H), 4.26 (q, 2H, J=7.1 Hz), 3.15-3.06 (m, 2H), 3.00-2.90 (m, 2H), 2.61 (s, 3H), 2.30-2.20 (m, 2H), 2.18-2.08 (m, 2H), 1.30 (t, 3H, J−7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 165.0, 159.3, 140.5, 133.7, 125.8, 123.7, 107.3, 106.6, 66.1, 60.0, 51.6, 44.2, 28.5, 14.6; MS (CI) m/z 304.3 (M+1).
Reaction SMILES: C(OC1C(OC)=CC(Cl)=CC=1CC(O)CO)C1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([O:44][CH2:45][CH:46]([OH:65])[CH2:47][C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[C:50]([O:55][CH3:56])[C:49]=2[O:57]CC2C=CC=CC=2)(=[O:43])=[O:42])=[CH:37][CH:36]=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.Cl>N1C=CC=CC=1.[Pd]>[CH3:34][C:35]1[CH:36]=[CH:37][C:38]([S:41]([O:44][CH2:45][CH:46]([OH:65])[CH2:47][C:48]2[CH:53]=[C:52]([Cl:54])[CH:51]=[C:50]([O:55][CH3:56])[C:49]=2[OH:57])(=[O:43])=[O:42])=[CH:39][CH:40]=1
Reactant: COc1cc(Cl)cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c1OCc1ccccc1
Agent: [Pd]
Agent: COc1cc(Cl)cc(CC(O)CO)c1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cc(Cl)cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c1O

Procedure:
Treatment of (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]propane-1,2-diol (32.28 g, 0.1 mol) with p-toluenesulfonyl chloride (21 g, 0.11 mol) in pyridine (1000 mL) generally according to the procedure described for Intermediate 18 provided (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the tosylate with palladium on carbon (5 wt. %, 2.32 g) and hydrogen chloride (19 mL, 4.0 M in isopropanol) generally according to the procedure described for Intermediate 4 gave (±)-3-(5-chloro-2-hydroxy-3-methoxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the phenyl with triphenylphosphine (23.6 g, 0.09 mol) and diisopropyl azodicarboxylate (18.2 g, 0.09 mol) generally according to the procedure described for Intermediate 5 gave 28.2 g (76%) of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow solid. mp 99-102° C.; Anal. calcd. for C17H17ClO5S: C, 55.36; H, 4.65. Found: C, 55.35; H, 4.62.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.[CH:28]([C:31]1[S:32][CH:33]=[C:34]([C:36]([N:38]2[CH2:43][C:42]3([CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[O:41][CH2:40][CH2:39]2)=[O:37])[N:35]=1)([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN1CCCC1=O.O.C(O)(=O)C>[F:20][C:13]1[C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N:46]1[CH2:47][CH2:48][C:42]2([O:41][CH2:40][CH2:39][N:38]([C:36]([C:34]3[N:35]=[C:31]([CH:28]([CH3:29])[CH3:30])[S:32][CH:33]=3)=[O:37])[CH2:43]2)[CH2:44][CH2:45]1
Reactant: CC(C)(C)[Si](C)(C)OCCCc1cccc(C=O)c1F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCCO)c4F)CC3)C2)cs1
Reaction time: 0.25 h

Procedure:
3-(3-(tert-Butyldimethylsilyloxy)propyl)-2-fluorobenzaldehyde (example 88, step c) (0.15 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.19 g) and acetic acid (0.03 mL) in N-methyl-2-pyrrolidinone (10 mL). The resulting mixture was stirred for 15 min then cooled in an ice bath. Sodium triacetoxyborohydride (0.16 g) was then added and the mixture stirred overnight. The reaction was poured into a mixture of saturated sodium hydrogen carbonate solution (20 mL) and water (100 mL). The aqueous was extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (50 mL) and brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was redissolved in THF (10 mL) and a solution of TBAF (1M in THF, 1.52 mL) was added. The resulting mixture was stirred for 2 h and the solvent evaporated. The residue was purified by column chromatography eluting with 4:1 isohexane:ethyl acetate+5% triethylamine to ethyl acetate+5% triethylamine gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 0.22 g.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:24][C:25](O)=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])(=[O:43])[NH:41][NH2:42].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([CH2:24][C:25]([NH:42][NH:41][C:40]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:14][CH:15]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(CCc3cccc(CC(=O)O)c3)nc2)CC1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc(CCc3cccc(CC(=O)NNC(=O)OC(C)(C)C)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a suspension of (3-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)acetic acid (213.4 mg, 0.581 mmol) in anhydrous N,N-dimethylformamide (3 ml) was added 1,1′-carbonyldiimidazole (188.9 mg, 1.165 mmol), and the mixture was stirred at room temperature for 1.5 hrs. tert-Butyl carbazate (460.3 mg, 3.483 mmol) was added, and the mixture was stirred at room temperature for 14 hrs. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred, stood still and partitioned. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified 3 times by silica gel column chromatography (ethyl acetate→methanol: dichloromethane=1:15, methanol:dichloromethane=1:20, methanol:dichloromethane=1:20) to give tert-butyl 2-[(3-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)acetyl]hydrazinecarboxylate (219.4 mg, yield 78.4%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:18][CH2:17]3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([N:16]3[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:21]3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCC1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A mixture containing ethyl 3-[1-[2-[4-(4-pyridyl)piperazin-1-yl]acetyl]piperidin-4-yl]propanoate (50 mg), concentrated hydrochloric acid (1 ml) and dioxan (4 ml) was stirred at 50°-60° C. for 1 hour, then concentrated to give a foam which was triturated with hot isopropanol. Filtration gave the title compound (48 mg) as pale cream prisms, m.p. 188°-190° C. NMR (d6DMSO+d4AcOH): δ1.0-1.3(2H,m); 1.5-1.6(3H,m); 1.8(2H,d); 2.3(2H,t); 2.6-2.8(1H,m); 2.95-3.15(1H,m); 3.5(4H,br.s); 3.6-3.7(1H,m); 4.0-4.2(4H,br.s); 4.3-4.5(3H,m); 7.25(2H,d); 8.35(2H,d); m/e 361(M+H)+ ; calculated for C19H28N4O3. 2HCl. H2O: C, 50.6; H, 7.2; N, 12.4; H2O, 4.0; found: C, 50.3; H, 7.2; N, 12.2; H2O, 4.0%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]([F:17])=[CH:4][C:3]=1[Si:18]([CH3:21])([CH3:20])[CH3:19].[NH2:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[Cl:34].C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:22][C:23]1[CH:28]=[C:27]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([Si:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:5]=2[F:17])[N:26]=[C:25]([C:30]([O:32][CH3:33])=[O:31])[C:24]=1[Cl:34]
Reactant: COC(=O)c1nc(Cl)cc(N)c1Cl
Reactant: CC1(C)OB(c2cc(F)c([Si](C)(C)C)cc2F)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2cc(F)c([Si](C)(C)C)cc2F)cc(N)c1Cl
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 39.4 %

Procedure:
In a microwave vessel, a suspension of (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane (see, e.g., WO 2013003740 A1) (0.6 g, 1.922 mmol), methyl 4-amino-3,6-dichloropicolinate (Head A) (0.354 g, 1.601 mmol), bis(triphenyl phosphine)palladium(II) chloride (0.112 g, 0.160 mmol) and sodium carbonate (0.204 g, 1.922 mmol) in a 3:1 mixture of acetonitrile (4.00 mL) and water (1.334 mL) was stirred under microwave irradiation (120° C., 20 min). The reaction mixture was poured into an half saturated brine solution and was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative reverse phase HPLC (water/acetonitrile gradient) to afford the title compound as a white solid (0.234 g, 0.631 mmol, 39.4%): 1H NMR (400 MHz, CDCl3) δ 7.66 (dd, J=8.7, 5.8 Hz, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.09 (dd, J=10.8, 4.1 Hz, 1H), 4.84 (s, 2H), 4.00 (s, 3H), 0.32 (d, J=0.7 Hz, 9H); 19F NMR (376 MHz, CDCl3) δ −106.56, −106.61, −124.00-124.06; ESIMS m/z 371 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[C:15](C)[C:14](OC)=[C:13](C)[CH:12]=3)[O:8][C:6]=2[N:7]=1.[Br:21]C1C=CC(C(Cl)=O)=CC=1>>[Br:21][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[N:10]=2)=[CH:12][CH:13]=1
Reactant: COc1c(C)cc(-c2nc3cnc(Cl)nc3o2)cc1C
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: Clc1ncc2nc(-c3ccc(Br)cc3)oc2n1

Procedure:
The title compound was prepared analogously as described in example 1, steps (a) and (b), using 4-bromo benzoyl chloride in step (a).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH3:24])[C:13]3[C:18]([S:19][C:20]=2[CH:21]=1)=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3.[CH:25](N1CCCCC1)=[O:26].Cl>C(OCC)C.O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH3:24])[C:13]3[C:18]([S:19][C:20]=2[C:21]=1[CH:25]=[O:26])=[CH:17][C:16]([O:22][CH3:23])=[CH:15][CH:14]=3
Reactant: COc1ccc2c(c1)Sc1cc(OC)ccc1N2C
Reactant: O=CN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Sc1c(ccc(OC)c1C=O)N2C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 179.9 %

Procedure:
16.25 ml of n-butyllithium solution (1.6M in hexane) were added dropwise at -78° under argon to a solution of 5.46 g (10.0 mmol) of 3,7-dimethoxy-10-methylphenothiazine in 100 ml of diethyl ether/tetrahydrofuran (4:1). The reaction mixture was stirred at -70° for 15 minutes, brought slowly to 0°, stirred for 2 hours and then treated at 0° with 3.39 g (30.0 mmol) of N-formylpiperidine. After stirring at 0° for 2 hours the mixture was poured into 500 ml of ice-water, whereupon it was acidified slightly with 0.5N hydrochloric acid solution and extracted with ethyl acetate. The combined organic phases were extracted with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was crystallized from acetone, whereupon, after drying, 5.42 g (90%) of 3,7-dimethoxy-10-methyl-phenothiazine-4-carbaldehyde were obtained as a red solid of m.p. 150°.
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25]/[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2\[C:10](=[O:18])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]\2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Reactant: NC1CCCCC1
Product: O=C1/C(=C(\NC2CCCCC2)c2ccccc2)Sc2ccccc21
Yield: 56 %

Procedure:
Prepared as in Example 31 with a yield of 56% of theory from 2-benzoyl-benzo[b]thiophen-3-ol and cyclohexylamine. Lemon-yellow crystals were obtained, m.p. 122°-123° C. (petroleum ether/ethyl acetate 85:15).
Reaction SMILES: C([C@@H:6]([C@H:8]([C:10]([O:12][CH2:13]C)=O)[OH:9])O)(OCC)=O.C(OO)(C)(C)C.[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1C(=C)[C@H](O)C.[OH-].[Na+].[Na+].[Cl-].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@@:10]1([O:12][CH2:13]1)[C@H:8]([OH:9])[CH3:6]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: C=C(c1ccc(F)cc1F)[C@@H](C)O
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: C[C@@H](O)[C@]1(c2ccc(F)cc2F)CO1
Temperature: -5 °C
Reaction time: 0.42 h
Yield: 73 %

Procedure:
To a solution of diethyl L-(+)-tartrate (4.86 g, 0.0236 mole) in 940 ml of dry CH2Cl2 were added 12 g of activated 3A° molecular sieve powder and cooled the mixture to -5° C. Added a solution of titanium (IV) isopropoxide (14.4 g, .0506 mole) in 76 ml of CH2Cl2 followed by t-butyl hydroperoxide (22.4 g, 0.248 mole) in 150 ml of CH2Cl2 and continue to stir at -5° C. for 25 minutes. To this mixture, a solution of compound 6b, (2R)-3-(2,4-Difluorophenyl)-3-buten-2-ol, (15 g, 0.0815 moles) in 76 ml of CH2Cl2 was added and stirred for 12 hours at 5° C. Cooled the reaction mixture to -40° C., added 4(0 ml of 30% aq. NaOH solution saturated with NaCl and the mixture was allowed to warm to 10° C. Added 40 g of MgSO4, 12 g of celite and continued to stir at 10° C. for 30 minutes. The mixture was suction-filtered over celite. To the filtrate 560 ml of toluene, 450 ml of ether were added and insoluble material removed by filtration. The filtrate was evaporated in vacuo, the residue was dissolved in 400 ml of ether and suction filtered to remove the insoluble material. The filtrate was passed through a bed of silica gel and washed the pad of silica gel with 40 ml of ether. The filtrate was concentrated under reduced pressure to give yellow oil, which was chromatographed on silica gel. Elution with CHCl3 gave title compound 7c as oil (11.9 g, 73%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][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][CH3:38].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1.CO>[CH2:8]([OH:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][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][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCCCCC#CCCCCCCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCC#CCCCCCCCCCO
Reaction time: 3 h

Procedure:
25.6 g (0.048 mol) of 1-tetrahydropyranyloxyhentriacont-10-yne of Example 8 were dissolved in a mixture of 100 ml of THF and 50 ml of methanol, and a catalytic amount (spatula tipful) of p-toluenesulfonic acid monohydrate was added at room temperature. After 3 h at room temperature, the reaction mixture was poured into 1.5 1 of water and stirred for 30 min. The product was filtered off with suction, washed with water and dried under high vacuum.
Reaction SMILES: C[O-].[Na+].[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[BH4-].[Na+].CS(O[CH2:19][CH:20]([O:41][CH3:42])[CH2:21][O:22][CH2:23][CH2:24][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][CH3:40])(=O)=O>O.C1COCC1.CO>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][S:4][CH2:19][CH:20]([O:41][CH3:42])[CH2:21][O:22][CH2:23][CH2:24][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][CH3:40]
Reactant: OCCCCCCS
Reactant: CCCCCCCCCCCCCCCCCCOCC(COS(C)(=O)=O)OC
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(CSCCCCCCO)OC
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To 14 ml of a methanol solution of sodium methoxide (1M solution) are added 2.04 g of 6-mercaptohexanol and 0.24 g of sodium borohydride, to which a THF (20 ml) solution containing 2.18 g of 2-methoxy-3-octadecyloxypropyl methanesulfonate is added dropwise under nitrogen streams with stirring. The mixture is stirred at room temperature for 20 hours and then at 40° C. for 1 hour. After the addition of water, the mixture is extracted with ethyl acetate. The extracted layer is washed with water, dried and concentrated under reduced pressures to obtain an oily product. Purification of the oily product by silica gel column chromatography gives 2.31 g of the captioned compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[CH2:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)=[O:36]>[Cu]I.CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[O:36])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: O=C(CCl)Nc1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(=O)Nc2ccc(F)cc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
The title compound was prepared by following general procedure 7. 3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (100 mg, 0.46 mmol), was taken into DMF. To the above solution CuI (9 mg, 0.046 mmol), L-proline (11 mg, 0.093 mmol), K3PO4 (198 mg, 0.93 mmol) were added and stirred for 10 min. at RT. 2-Chloro-N-(4-fluorophenyl)acetamide (105 mg, 0.56 mmol) was added dropwise. The reaction mixture was heated at 90° C. for 12 h. After completion of reaction, the reaction mixture was filtered through Celite. DMF was evaporated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to obtain 104 mg of 2-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-fluorophenyl)acetamide as the TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL).
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([F:20])[CH2:17][C@@H:16]1[CH2:21][OH:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CS(C)=O.C(OCC)C>[C:8]([O:12][C:13]([N:15]1[CH2:19][C@H:18]([F:20])[CH2:17][C@@H:16]1[CH:21]=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@@H]1CO
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add triethylamine (6.6 mL, 47.7 mmol) and sulfurtrioxide-pyridine complex (3.8 g, 23.9 mmol) to an ice cold solution of 4-(R)-fluoro-2-(R)-hydroxymethylpyrrolidine-1-carboxylic acid tert-butyl ester (2.62 g, 11.9 mmol) in DMSO (12 mL). Stir 30 min, then warm to room temperature and stir 30 min. Dilute with diethyl ether and wash with 5% aqueous citric acid (3×120 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as an oil that is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.CO.O.[NH2:23]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:23]
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=NCC(N)=N2
Reactant: NN
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccccc1)=NCC(NN)=N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.5 parts of 2-amino-7-methyl-5-phenyl-3H-1,4-benzodiazepine, 100 parts by volume of methanol and 1.2 parts of glacial acetic acid is added 2.5 parts of 100% hydrazine hydrate. The mixture is stirred for 1 hour at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-7-methyl-5-phenyl-3H-1,4-benzodiazepine is yielded as crystals. Recrystallization from a mixture of chloroform and diethyl ether affords colorless crystals melting at 240° C to 241° (decomposition).