Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11].C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH2:11])=[O:26]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CSc1ccccc1Cl)c1ccccc1
Solvent: ClCCl
Product: C=C(CS(=O)c1ccccc1Cl)c1ccccc1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
1-[2'-Chlorophenylthio]-2-phenyl-2-propene (1.56 g, 0.006 mole) is dissolved in methylene chloride (50 cc) and cooled to 0° C. 55% strength mCPBA (1.9 g, 0.006 mole) in solution in methylene chloride (15 cc) is added dropwise over 30 min. After 1 hour at 0° C. the solution is washed with saturated sodium bicarbonate (75 cc), brine (2×75 cc) and is dried over MgSO4. The crude (1.6 g) is chromatographed on silica to give 1-[2'-chlorophenylsulphinyl]-2-phenyl-2-propene (1.0 g, 60%) in the form of an oil. nD25 =1.6250.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]3)=[CH:17][CH:16]=2)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:9]([C:10]2[S:41][C:14]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]4)=[CH:17][CH:16]=3)=[N:13][N:12]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCOc1ccc(C(=O)NNC(=O)c2ccc(N3CCC(N(C)C)C3)cc2)cc1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2nnc(-c3ccc(N4CCC(N(C)C)C4)cc3)s2)cc1

Procedure:
A mixture of N′-(4-butoxybenzoyl)-4-(3-dimethylaminopyrrolidin-1-yl)benzohydrazide (100 mg), Lawesson's reagent (191 mg) and toluene (5 ml) was boiled under reflux for 4 hours. Volatiles were removed, and the residue was purified by preparative HPLC. The product with the molecular weight of 422.60 (C24H30N4OS) was obtained in this way; MS (ESI): 423 (M+H+).
Reaction SMILES: COCCOC.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].[CH3:16][C:17]1[C:18](B(O)O)=[CH:19][C:20]2[C:21]([CH3:30])([CH3:29])[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[C:25]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:17]1[C:18]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])=[CH:19][C:20]2[C:21]([CH3:30])([CH3:29])[CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[C:25]=2[CH:26]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1cc2c(cc1-c1cccc(C=O)c1)C(C)(C)CCC2(C)C
Reaction time: 0.17 h

Procedure:
700 ml of DME, 2.4 g (2 mmol) of tetrakistriphenylphosphinepalladium (0) and 8.44 g (45.6 mmol) of 3-bromobenzaldehyde are introduced into a three-necked flask under a stream of nitrogen and the mixture is stirred for 10 minutes. A solution of 17 g (69.1 mmol) of 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid in 25 ml of ethanol are then added, followed by 46 ml (91 mmol) of potassium carbonate solution (2 M) and the mixture is refluxed for four hours. The reaction medium is cooled and filtered and the solid is washed with bicarbonate solution and then with ethyl acetate. The solid obtained is recrystallized from ethanol and 7 g (50%) of the expected aldehyde are collected, with a melting point of 104-5° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[CH2:31][CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:32])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:6][CH2:7][CH2:8][N:9]1[CH2:31][CH2:30][N:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:20][CH:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:25][CH2:26]4)=[CH:17][C:18]=3[CH:19]=[C:11]2[C:10]1=[O:32]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCN(CCO)C2=O)CC1
Yield: 88 %

Procedure:
To a cooled solution of 0.145 g (0.30 mmol) 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one in 3 mL dichloromethane, 1 mL (1.49 g, 13 mmol) trifluoroacetic acid was added and the cooling bath was removed. The solution was evaporated and the residue was taken up in ethyl acetate and was washed with 1M aqueous sodium hydroxide solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give the desired compound as a white foam (88%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][C:3]=1[O:14][CH3:15].C[C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)=O.[H-].[Na+].CC(C)(C)C(=O)CC(=O)C>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])/[CH:11]=[CH:17]/[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=2)=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: COc1cc(C(=O)CC(C)=O)ccc1O
Agent: CC(=O)CC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)CC(=O)c2ccc(O)c(OC)c2)ccc1O
Yield: 39 %

Procedure:
By a similar procedure as described in Example 1 using 1-(4-hydroxy-3-methoxyphenyl)-butane-1,3-dione (prepared by reaction of 4-hydroxy-3-methoxyacetophenone with ethyl acetate in the presence of sodium hydride) in place of 5,5-dimethylhexane-2,4-dione, (E)-1,5-bis-(4-hydroxy-3-methoxyphenyl)-pent-4-ene-1,3-dione (920 mg, 39%) was obtained as yellow needles: mp 170-172° C.; LRMS m/z 342 (M+); 1H NMR (500 MHz, CDCl3) δ 3.95 (3H, s, OCH3), 3.98 (3H, s, OCH3), 5.85 (1H, brs, OH), 6.04 (1H, brs, OH), 6.26 (1H, s, H-2), 6.48 (1H, d, J=15.7 Hz, H-4), 6.94 (1H, d, J=7.2 Hz, H-5″), 6.97 (1H, d, J=8.3 Hz, H-5′), 7.05 (1H, brs, H-2″), 7.12 (1H, brd, J=8.3 Hz, H-6″), 7.51 (1H, brd, J=7.2 Hz, H-6′), 7.56 (1H, brs, H-2′), 7.60 (1H, J=15.7 Hz, H-5), 16.2 (1H, brs, OH) ppm; TLC Rf=0.5 (silica, dichloromethane); HPLC Rt 14 min 99.6% purity.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[O:17][C:18]=1[CH3:19])[CH:7]=[O:8])[CH3:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[O:17][C:18]=1[CH3:19])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 3-ethoxy-4-[[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy]benzaldehyde (20.00 g) in tetrahydrofuran (250 mL)-ethanol (100 mL) was gradually added sodium borohydride (2.31 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol as pale-yellow crystals (18.80 g, yield 93%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][C:2]1([CH3:15])[C:3]2[CH:4]=[C:5]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])[CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC1(C)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2ccc(C(=O)c3ccccc3C(=O)O)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 119.6 %

Procedure:
9,9-Dimethyl-9H-fluorene (40 g, 1 eq, 0.146 mol) and phthalic anhydride (36.5 g, 1.1 eq, 0.161 mol) were placed in a reaction vessel, and dichloromethane (1.5 l) was added thereto. Then, aluminum chloride (29.2 g, 1.5 eq, 0.219 mol) was gradually added at 0° C., and the reaction mixture was stirred at room temperature for 12 hours. After the reaction was terminated, distilled water was gradually added at 0° C., and the resultant solution was extracted with an excess of dichloromethane and several times washed with distilled water. After solvent removal, the resultant solid was placed in a hexane (2 l)-containing vessel, washed, filtered, and dried to give 2-(9,9-dimethyl-9H-fluorene-2-carbonyl)benzoic acid (59.8 g, yield=82%).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[C:9]([CH3:17])[C:8]=2[CH3:18])=[C:4]([N+:21]([O-:23])=[O:22])[CH:3]=1.[CH3:24][C:25]([CH3:27])=O.CC(C)([O-])C.[K+]>CS(C)=O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:17][C:9]1[C:8]([CH3:18])=[C:7]([O:6][C:5]2[C:4]([N+:21]([O-:23])=[O:22])=[C:3]3[C:2](=[CH:20][CH:19]=2)[NH:1][C:25]([CH3:27])=[CH:24]3)[CH:12]=[CH:11][C:10]=1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: CC(C)=O
Reactant: Cc1c(CC(=O)O)ccc(Oc2ccc(N)cc2[N+](=O)[O-])c1C
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c([N+](=O)[O-])c(Oc3ccc(CC(=O)O)c(C)c3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an N2 atmosphere, 2-(4-(4-amino-2-nitrophenoxy)-2,3-dimethylphenyl)acetic acid (0.723 g, 2.29 mmol) was dissolved in DMSO (18 mL) and acetone (0.503 mL, 6.86 mmol) was added. The reaction was treated with potassium tert-butoxide (0.770 g, 6.86 mmol) and allowed to stir at room temperature for 1.5 h. The reaction was diluted with water and citric acid was added to pH 4. The mixture was extracted with ethyl acetate. The aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 9% methanol in dichloromethane, afforded the title compound. LC-MS ESI (neg.) m/z: 353.2 (M−H).
Reaction SMILES: ClC(=C1[C@]2(C)[C@H]([C@H]3[C:27](=CC2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)CC3)CC1)C(Cl)S(C1C=CC=CC=1)=O.C1C[O:36]CC1.C[O-].[Na+].[Cl:41][CH:42](S(C1C=CC=CC=1)=O)[C:43]([O:64]C)=[C:44]1[C@:61]2([CH3:62])[C@H:47]([C@H:48]3C(=[CH:59][CH2:60]2)[C@]2(C)C(=CC(=O)CC2)[CH2:50][CH2:49]3)[CH2:46][CH2:45]1>CO.O.CC(C)=O>[Cl:41][CH2:42][C:43](=[O:64])[C@:44]1([OH:36])[C@:61]2([CH3:62])[C@H:47]([C@H:48]3[C:27](=[CH:59][CH2:60]2)[C@:25]2([CH3:26])[C:20](=[CH:21][C:22](=[O:32])[CH2:23][CH2:24]2)[CH2:50][CH2:49]3)[CH2:46][CH2:45]1
Reactant: C1CCOC1
Reactant: COC(=C1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]12C)C(Cl)S(=O)c1ccccc1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=C(Cl)C(Cl)S(=O)c3ccccc3)CC[C@@H]12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CCl
Reaction time: 1 h

Procedure:
20,21-Dichloro-21-(phenylsulfinyl)pregna-4,9(11),17(20)-trien-3-one (VII, Example 2, 3.0 g), THF (60 ml), methanol (12 ml) and acetone (9 ml) are cooled to 0° under nitrogen and sodium methoxide in methanol (25%, 2.8 ml) are added. After one hour, by TLC analysis, complete conversion to the 20-methoxy derivative (VIII) had occurred. The resulting mixture is brought to 28° and stirred for 22 hours and then warmed to 30°-35° for five hours. The mixture is diluted with water (150 ml) and then extracted with ethyl acetate-methylene chloride (2×75 ml). The organic extracts are combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The concentrate is slurried in methylene chloride (15 ml) and treated with aqueous hydrochloric acid (6 N, 1 ml) at 30°-35° for one hour. The mixture is diluted with methylene chloride (25 ml) and extracted with water (2× 10 ml). The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude product. This material is purified by trituration with hexane/ethyl acetate (7/3, 25 ml) to give the title compound, mp 210.5°-212°; NMR (CDCl3) 0.63, 1.33, 4.47, 5.53 and 5.72δ. ##STR2##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([OH:7])=[O:6]>S(Cl)(Cl)=O.C1CCCCC1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([O:7][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1

Procedure:
A solution of 2,6-dichloroisonicotinic acid (38.4 g, 0.20 mole) in thionyl chloride (60 ml.) and cyclohexane (100 ml) containing a few drops of dimethylformamide is heated at 80° for three hours. The solution is cooled and excess thionyl chloride and cyclohexane are removed in vacuo. The residue is dissolved in chloroform (40 ml.) and added dropwise to a solution of t-butanol (50 ml.) and N,N-dimethylaniline (40 ml.). The solution is heated at reflux for six hours, cooled, diluted with diethyl ether and washed successively with water, water containing 4 ml. of concentrated sulfuric acid, water, dilute sodium carbonate solution and dried over anhydrous sodium sulfate. The solvent is removed under vacuum and the residue is crystallized from a minimum amount of methanol to give 24 g. of product, m.p. 79°-81°.
Reaction SMILES: Br.[F:2][CH:3]([F:27])[O:4][C:5]1[C:6]([OH:26])=[C:7](/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]3[N:19]([C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:17]S3)[CH:8]=[CH:9][CH:10]=1.[CH3:28][C:29](O)=O>>[F:2][CH:3]([F:27])[O:4][C:5]1[C:6]([OH:26])=[C:7](/[CH:11]=[CH:12]/[C:13]2[N:14]=[C:15]3[CH:29]=[CH:28][CH:17]=[CH:18][N:19]3[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Reactant: CC(=O)O
Agent: Br
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2ccccn12

Procedure:
The Step 1 intermediate (4.3 g, 9.674 mmol) was treated with 48% hydrobromic acid (20 mL) in glacial AcOH (20 mL) as described in Intermediate 6 gave 3.1 g of the product as white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.44 (t, J=7.2 Hz, 3H), 4.44 (q, J=7.2 Hz, 2H), 6.92 (d, J=7.8 Hz, 1H), 7.12 (t, J=74.1 Hz, 1H), 7.15-7.22 (m, 2H), 7.48 (d, J=7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.75 (d, J=9.3 Hz, 1H), 7.95 (d, J=16.2 Hz, 1H), 8.08 (d, J=15.9 Hz, 1H), 9.24 (d, J=6.9 Hz, 1H), 9.83 (br, 1H); APCI-MS (m/z) 375.16 (MH)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([OH:11])(=O)[CH2:8][CH3:9].O1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(OCC)C>[CH:13]1[C:15]2[CH2:16][CH2:13][C:14]3[CH:16]=[CH:15][CH:14]=[CH:13][C:15]=3[CH:16]=[C:13]([CH2:9][CH2:8][CH2:7][OH:11])[C:14]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CCC(=O)O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCC1=Cc2ccccc2CCc2ccccc21
Yield: 100 %

Procedure:
To a solution of lithiumaluminum hydride (0.7 g, 18 mmol) in dry tetrahydrofuran (30 ml) the above propionic acid (2.6 g, 9.3 mmol) in dry diethyl ether (30 ml) was added. The reaction mixture was stirred at reflux temperature for 1.5 hour. The reaction was cooled on a ice bath and quenched by addition of water (0.7 ml), and 20% sodium hydroxide (0.7 ml), successively. The resulting mixture was filtered and the filtercake was washed with diethyl ether (2×100 ml). The phases were separated and the organic phase was evaporated in vacuo affording 2.6 g (100%) of 3-(11,12-dihydro-dibenz[a,e]cycloocten-5-yl)-1-propanol as an oil.
Reaction SMILES: [CH2:1]([O:3][NH:4][CH:5]([CH3:16])[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15])[CH3:2].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[CH2:1]([O:3][N:4]([CH:5]([CH3:16])[CH2:6][C:7]1[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=1[Cl:13])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32])[CH3:2]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CCONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
To a solution of O-ethyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (0.5 g, 1.63 mmoles) in dichloromethane (5 ml) was added triethylamine (0.566 ml, 4.07 mmloes) followed by drop wise addition of a solution 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.34 g, 1.79 mmol) in dichloromethane at a temperature of 0° C. After the complete addition of acid chloride the mixture was stirred for 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer were washed with 2N HCl, followed by saturated NaHCO3, then water and finally brine, dried over sodium sulfate and evaporated off solvent under reduced pressure. Resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (0.390 g, 50%) as off white solid. m.p: 111-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3C(=O)C4=CC=CC=C4C3=O)[CH2:21][CH2:20]2)=[N:9][N:8]=1.O.NN>C(O)C>[ClH:1].[ClH:1].[NH2:25][CH:22]1[CH2:21][CH2:20][N:19]([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[C:7]([NH:6][CH2:5][C:4]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:2]([Cl:1])[CH:3]=3)=[N:8][N:9]=2)[CH2:24][CH2:23]1
Reactant: COc1ccc(CNc2nnc(N3CCC(N4C(=O)c5ccccc5C4=O)CC3)c3ccc(C#N)cc23)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(CNc2nnc(N3CCC(N)CC3)c3ccc(C#N)cc23)cc1Cl
Product: Cl
Yield: 30.4 %

Procedure:
A mixture of 4.85 g of the resulting 4-(3-chloro-4-methoxybenzyl)amino-6-cyano-1-(4-phthalimidopiperidino)phthalazine, 4 ml hydrazine monohydrate and 40 ml ethanol was heated under reflux for 1 hr. The reaction solution was evaporated, dissolved in ethyl acetate, and 1 N hydrochloric acid was added thereto to adjust the pH thereof to 3, and the insoluble matters were removed by filtration. The aqueous layer in the filtrate was adjusted to pH 11 with 1 N sodium hydroxide, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and then purified by silica gel column chromatography. The resulting product was suspended in ethanol/water, then 1 N aqueous hydrochloric acid was added thereto and dissolved by heating. After cooling, the resulting crystals were collected by filtration to give 440 mg of the title compound as a yellow powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:36]=[CH:35][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:32]([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>O1CCOCC1.CO>[ClH:37].[CH:32]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:36]=[CH:35][C:17]=43)[CH:21]=2)=[N:30][C:29]([CH3:31])=[N:28]1)([CH3:34])[CH3:33]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C4CCNCC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
To a solution of 4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (569 mg, 1.16 mmol) in dioxane (15 mL) and methanol (5 mL) was added 4M HCl in dioxane (15 mL) and the reaction mixture stirred for 20 h at RT before being concentrated in vacuo. The resultant residue was triturated in a mixture of diethyl ether and methanol to give 2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene Hydrochloride as a tan solid (212 mg, 43%). LCMS: RT=2.34/2.66 min, M+H+=393.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:40]=[O:41])[CH:33]=[CH:32][CH:31]=1>ClCCl>[N:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][C:38]=2[CH:40]([C:6]2[N:5]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:4]=[N:3][CH:2]=2)[OH:41])[CH:33]=[CH:32][CH:31]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=Cc1cccc2cccnc12
Agent: CC[Mg]Br
Solvent: ClCCl
Product: OC(c1cccc2cccnc12)c1cncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-iodo-1-tritylimidazole (commercially available) 5.2 g, 11.94 mmol) in dichloromethane (80 mL) at −10° C. was treated with ethyl magnesium bromide (3.98 mL, 11.94 mmol, 3M in ether) and allowed to react for 45 m. A solution of quinoline-8-carbaldehyde, (Intermediate 11) (1.5 g, 9.55 mmol) in dichloromethane was added via syringe at −10° C. and stirred for 16 h at room temperature. The mixture was quenched with water (50 mL) and a sat. solution of ammonium chloride (50 mL) and subjected to an aqueous work-up. The residue was purified by chromatography on silica gel with 3% NH3-MeOH: CH2Cl2 to give to give quinolin-8-yl(1-trityl-1H-imidazol-5-yl)methanol, (Intermediate 12) as a solid, (3.7 g 82.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH:20]=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[C:5]2[CH2:20][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Product: O=[N+]([O-])c1cc(Cl)cc2c(CN3CCOCC3)c(-c3ccccc3)[nH]c12

Procedure:
5-Chloro-3-formyl-7-nitro-2-phenyl-1H-indole prepared in Step A of Preparation 43 and morpholine were reacted according to the same procedure as Step B of Preparation 43 to give the title compound.
Reaction SMILES: Cl.[CH:2]1[C:15]2[C:14](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:25])[CH2:23][NH2:24])[CH2:18][CH2:17]3)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[O:25]=[C:22]([N:19]1[CH2:20][CH2:21][C:16](=[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[S:7][C:6]3[C:15]2=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:17][CH2:18]1)[CH2:23][NH:24][C:34](=[O:35])[O:36][CH2:37][CH3:38]
Reactant: CCOC(=O)Cl
Reactant: NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCC(=O)N1CCC(=C2c3ccccc3Sc3ccccc32)CC1
Reaction time: 0.25 h

Procedure:
50 mg (0.134 mmol) of 2-[4-(9H-thioxanthen-9-ylidene)-1-piperidinyl]-2-oxoethanamine hydrochloride was dissolved in dichloromethane. 41 mg (0.405 mmol) of triethylamine was added to the obtained solution. A solution of 17.5 mg (0.161 mmol) of ethyl chloroformate in 0.5 ml of dichloromethane was added to the resultant mixture. After stirring for 15 minutes, the product was purified by the thin-layer silica gel chromatography (hexane: ethyl acetate=85:100) to obtain the title compound.