Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([Cl:23])=[O:22])=[CH:17][CH:16]=1.CCOCC>C(O)(C(F)(F)F)=O.CC(C)=O>[ClH:23].[CH3:13][O:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: Cl
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: COc1ccc(C=CC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C)cc1
Reaction time: 4.5 h
Yield: 70 %

Procedure:
7.12 g (0.036 moles) of carnitine hydrochloride are dissolved in 12 mls of CF3COOH, and to the solution an excess (25 mls) of p-methoxy cinnamoyl chloride is added and the mixture kept under stirring at 40°-50° C. for 4-5 hours. At the end of this period of time the mixture is diluted with 90 mls of acetone and some ether is slowly added till complete precipitation. The mixture is filtered and the precipitate which has the tendency to become hygroscopic is quickly washed with ether and dried under vacuum at a temperature not exceeding 50° C; 9 g of a product are obtained (yield 70%) having the following characteristics:
Reaction SMILES: [CH:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH:7](O)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[Si]([C:20]#[N:21])(C)C>C1C=CC=CC=1.[Zn+2].[I-].[I-]>[C:20]([CH:7]1[S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:10]=2[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]1=2)#[N:21]
Reactant: C[Si](C)(C)C#N
Reactant: OC1Sc2ccccc2-c2ccccc21
Agent: [I-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: N#CC1Sc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6H-dibenzo[b,d]thiopyran-6-ol (2.6 g; 12 mmol) was dissolved in anhydrous benzene (50 ml). Trimethylsilylcyanide (4.5 ml; 36 mmol) and a catalytic amount of ZnI2 were added to the solution, then the reaction mixture was stirred for 20 hours at room temperature. The solution was washed with 1N NaOH, dried and evaporated. The residue was crystallized from diethyl ether to give 6-cyano-6H-dibenzo[b,d]thiopyran as white solid (2.3 g; 10 mmol); m.p. 114°-116° C. By proceeding analogously the following compounds were obtained:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C(N(CC)CC)C.[N:21]([C:24]1[N:25]=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=2)=[C:22]=[S:23].C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH3:34][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[N:25][C:24]([NH:21][C:22]1[O:13][C@:5]3([CH2:4][N:3]=1)[CH:10]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]1)[CH2:6]3)=[CH:33]2.[OH:13][C@:5]1([CH2:4][NH:3][C:22]([NH:21][C:24]2[N:25]=[CH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([CH3:34])=[CH:29][CH:28]=3)=[S:23])[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: Cc1ccc2cnc(N=C=S)cc2c1
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2cnc(NC(=S)NC[C@]3(O)CN4CCC3CC4)cc2c1
Product: Cc1ccc2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (65.8 mg, 0.285 mmol) in N,N-dimethylformamide (6 mL) was added triethylamine (0.090 mL, 0.63 mmol) and 3-isothiocyanato-6-methylisoquinoline (57 mg, 0.285 mmol). The suspension was placed into a preheated oil-bath and stirred at 70° C. for 2 h and 30 min. N,N′-diisopropylcarbodiimide (0.177 mL, 1.14 mmol) was then added and the mixture was stirred at 85° C. for 16 h. The mixture was concentrated and purified by silica gel chromatography (0-40% [9:1 methanol:ammonium hydroxide] in chloroform) followed by purification by reverse phase preparatory HPLC (0-40% TFA-methanol-water). The solution of product was filtered through UCT Clean-up CHQAX15M25 cartridge with MeOH (3×10 ml) and concentrated to afford the expected product, (S)-1-((3-hydroxyquinuclidin-3-yl)methyl)-3-(6-methylisoquinolin-3-yl)thiourea, as a tan gum. 1H NMR (400 MHz, MeOD) δ ppm 9.11 (s, 1H), 8.02 (d, J=8.53 Hz, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.47 (d, J=8.53 Hz, 1H), 4.47 (d, J=10.54 Hz, 1H), 4.31 (d, J=10.54 Hz, 1H), 4.10 (d, J=14.81 Hz, 1H), 3.92 (d, J=14.81 Hz, 1H), 3.53-3.71 (m, 2H), 3.27-3.51 (m, 3H), 2.84 (br. s, 1H), 2.55 (s, 3H), 2.48 (m, 1H) 2.10-2.30 (m, 3H). MS (LC/MS) R.T.=1.24; [M+H]+=323.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH2:23])=[C:16]2[N:15]=1.Cl[C:25](=[O:30])[C:26](OC)=[O:27].C[CH2:32][N:33](C(C)C)[CH:34](C)C.CNC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:25](=[O:30])[C:26]([N:33]([CH3:34])[CH3:32])=[O:27])=[C:16]2[N:15]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Reactant: COC(=O)C(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a DCM (1 mL) solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (Preparation B; 50 mg, 0.16 mmol) was drop-wise added methyl 2-chloro-2-oxoacetate (19.4 mg, 0.159 mmol), followed by DIEA (0.0829 mL, 0.476 mmol). After the mild exothermal subsided and the reaction cooled back to ambient temperature, dimethylamine (0.8 mL, 1.6 mmol) [2M, THF] was added. The reaction was heated to gentle reflux for a few minutes, allowed to cool back to ambient temperature and stirred for 1 hour to reach completion. The reaction was concentrated and directly purified by reverse phase column chromatography, eluting with 5 to 60% acetonitrile/water to yield the final product as a pale-yellowish solid (48 mg, 73% yield). MS (apci) m/z=415.1 (M+H).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[CH:7][CH:8]=1.[C:11]([O-:14])([O-])=O.[K+].[K+].CC1C=CC(S([CH2:27][N+:28]#[C-:29])(=O)=O)=CC=1>CO>[CH3:11][O:14][C:7]1[CH:8]=[CH:3][CH:4]=[CH:5][C:6]=1[C:9]1[O:10][CH:29]=[N:28][CH:27]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccccc1-c1cnco1
Temperature: 80 °C
Yield: 83 %

Procedure:
To a solution of Anisaldehyde (2.0 mmol) in MeOH (5.0 mL), was added K2CO3 (2.2 mmol) and TOSMIC (1.10 mmol) and the reaction was allowed to stir at 80° C. in a sealed vial. After the reaction was over, the methanol was removed and the crude product was absorbed in silica gel and purified by column chromatography. The product was isolated in 83% yield as colorless oil. 1H NMR: 3.91 (s, 3H), 6.94 (d, 1H, J=8.4 Hz), 7.01 (t, 1H, J=7.6 Hz), 6.94 (t, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.75 (d, 1H, J=8.0 Hz), 7.53 (s, 1H).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].C(N(CC)C(C)C)(C)C.[CH3:32][C:33]1[C:38]([CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:37][CH:36]=[C:35]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:52])[N:34]=1>O.ClCCl>[CH3:32][C:33]1[C:38]([CH2:39][N:40]2[CH2:41][CH2:42][N:43]([C:5]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:11])[CH2:44][CH2:45]2)=[CH:37][CH:36]=[C:35]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[CH3:52])[N:34]=1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccccc1-c1ccc(CN2CCNCC2)c(C)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 153.8 %

Procedure:
A 100 mL round-bottom flask, was charged with triphosgene (63.0 mg, 0.200 mmol, 0.30 equiv), dichloromethane (10 mL), 1,1,1,3,3,3-hexafluoropropan-2-ol (119 mg, 0.710 mmol, 1.00 equiv). N,N-Di-isopropylethylamine (174 mg, 1.35 mmol, 2.00 equiv) was added drop-wise. The resulting solution was stirred for 2 h at room temperature. 1-[[2-Methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine (200 mg, 0.710 mmol, 1.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (10 mL). The resulting mixture was extracted with dichloromethane (3×10 mL) and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product (230 mg) was purified by preparative HPLC using the following gradient conditions: 20% CH3CN/80% Phase A increasing to 80% CH3CN over 10 min, then to 100% CH3CN over 0.1 min, holding at 100% CH3CN for 1.9 min, then reducing to 20% CH3CN over 0.1 min, and holding at 20% for 1.9 min, on a Waters 2767-5 Chromatograph. Column: Xbridge Prep C18, 19*150 mm 5 um; Mobile phase: Phase A: aqueous NH4HCO3 (0.05%); Phase B: CH3CN; Detector, UV220 & 254 nm. Purification resulted in 146.2 mg (43% yield) of 1,1,1,3,3,3-hexafluoropropan-2-yl 4-[[2-methyl-6-(2-methylphenyl)pyridin-3-yl]methyl]piperazine-1-carboxylate as a off-white solid. 1H NMR 300 MHz (CDCl3) δ 7.62 (d, J=7.8 Hz, 1H), 7.37-7.40 (m, 1H), 7.31-7.35 (m, 3H), 7.19-7.28 (m, 1H), 5.72-5.80 (m, 1H), 3.56-3.59 (m, 6H), 2.64 (s, 3H), 2.51-2.56 (m, 4H), 2.36 (s, 3H). LCMS (ESI, m/z): 476 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21]CC)=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 60 °C

Procedure:
To a solution of 44.0 g (140 mmol) of ethyl (3-{[(benzyloxy)carbonyl]amino}phenyl)acetate) (from Step A) in THF, ethanol, and water (1:1:1, 1500 mL) was added solid LiOH (16.8 g, 700 mmol) and the resulting solution heated to 60° C. via oil bath for 3 h. The mixture was cooled to room temperature overnight and then 40 mL of concentrate HCl was slowly added, keeping the temperature below 25° C., until the solution was about pH of 2-3. Extract with ethyl acetate (3×750 mL) and then combine and wash organics with water and then brine. Dry organics over sodium sulfate, filter and concentrate under vacuum. The title compound (24.7 g, 87%) was used for the next step reaction without further purification. LC-MS: m/z (ES) 286 (MH)+, 308 (MNa)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([CH2:12][C:13](=[O:15])[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>C(=S)=S>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:12][C:13](=[O:15])[CH3:14])=[CH:7][CH:8]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)CCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of aluminium chloride (0.2 mole) in carbon disulphide (200 ml.) at 0° C was added a mixture of benzylacetone (0.1 mole) and p-chlorobenzoyl chloride (0.1 mole) throughout 20 minutes. After a further hour at 0° C, the reaction was allowed to reach room temperature and left overnight. The supernatant carbon disulphide was decanted off and the crude, brown residual oil, was poured carefully onto a mixture of ice and concentrated hydrochloric acid. Work-up in the usual way afforded an oil, which, after trituration with acetone and re-crystallisation from benzene/60°-80° C petrol, gave pure 4-[4-(p-chlorobenzoyl)phenyl]-2-butanone as colourless needles, m.pt. 91° - 2° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1.[ClH:24]>[OH-].[Pd+2].[OH-].C(O)C>[ClH:24].[ClH:24].[O:15]1[CH2:16][CH2:17][N:12]([CH:10]2[CH2:11][NH:8][CH2:9]2)[CH2:13][CH2:14]1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCOCC3)C2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: C1CN(C2CNC2)CCO1
Reaction time: 72 h

Procedure:
A mixture of 1-diphenylmethyl-3-morpholinoazetidine (Preparation 1(c)) (18.6 g, 60.4 mmol), palladium hydroxide (2 g), ethanol (200 ml) and 1N aqueous HCl (52 ml) was stirred under an atmosphere of hydrogen at 345 kPa (50p.s.i.) for 3 days. The catalyst was then removed by filtration and the filtrate evaporated to dryness. Addition of dichloromethane (100 ml) to the residue and trituration gave a solid which was recrystallised from methanol to give the title compound (10.2 g) as a crystalline solid. LRMS m/z=179 (m+1)+.
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:11]([C:14](O)([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:1]1([B:7]2[O:9][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(O)C(C)(C)O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccccc2)OC1(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Phenyl boronic acid (100 g, 0.82 mol, 1 equiv.) and pinacol (96.92 g, 0.82 mol, 1 equiv.) were dissolved in toluene (500 mL) at room temperature. The cloudy solution was then placed on to a rotary evaporator and stirred for 2 hours at 60° C. After this period the solid had dissolved, concurrent with the formation of water (ca. 29.5 mL) as a second layer. The water was then removed in a separating funnel and the crude reaction filtered through Celite. Evaporation of the solvent yielded a clear pale yellow oil which solidified on cooling in a refrigerator to give the title compound in a near-quantitative yield as a white solid (ca. 167 g).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1/[CH:4]=[CH:3]/[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: c1nc[nH]n1
Reactant: ClC/C=C/c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C(=C/c1ccc2ccccc2c1)\Cn1cncn1
Reaction time: 14 h
Yield: 10.3 %

Procedure:
A mixture of (E)-1-chloro-3-(2-naphthyl)-2-propene (0.5 g), 1H-1,2,4-triazole (0.5 g) and K2CO3(1.0 g) in DMF (20 ml) was stirred for 14 hours. The mixture was diluted with ethyl acetate and insolubles were filtered off. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with ethyl acetate to give the titled compound (0.06 g) as colorless powder.
Reaction SMILES: [BH4-].[Na+].O.[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:11][C@H:10]1[CH:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])S(C1C=CC(C)=CC=1)(=O)=O)=[O:8])[CH3:5]>O1CCCC1>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:11][C@H:10]1[CH2:12][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[O:8])[CH3:5]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Sodium Borohydride (2.3 g, 58.55 mol) was suspended in tetrahydrofuran (150 mL) and 4 mL of water was added. (13.3 g, 33.46 mmol) of trans-2-[tert-Butoxycarbonylamino-(toluene-4-sulfonyl)-methyl]-cyclopropanecarboxylic acid ethyl ester was added portionwise (0.8 g portions) and the temperature was kept to 18-30° C. After 1.5 h water (4 mL) and 0.4 g (10.15 mmol) of sodium borohydride were added again. The resulting mixture was quenched with ammonium chloride 2M (300 mL) and 100 mL of 1M K2CO3 and stirring was continued for 0.5 h. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (300 mL) and the combined organic layers were dried over MgSO4 and concentrated to dryness under vacuum and purified with column chromatography on silica with heptane/AcOEt (9/1) to obtain 7.5 g (92.1% yield) of the title compound as a white solid. MS (m/e): 244.1 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5](=O)[CH2:6][O:7][CH3:8].[CH3:11]OC(OC)N(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][NH2:39])=[CH:34][CH:33]=1>C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:4]1[CH:11]=[N:39][N:38]([C:35]2[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=2)[C:5]=1[CH2:6][O:7][CH3:8])=[O:10]
Reactant: COC(OC)N(C)C
Reactant: NNc1ccc(Cl)cc1
Reactant: COCC(=O)CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCc1c(C(=O)OC)cnn1-c1ccc(Cl)cc1
Reaction time: 14 h
Yield: 65.7 %

Procedure:
4-Methoxy-3-oxobutyric acid methyl ester (1.50 g, 10.3 mmol) was mixed with dimethylformamide dimethylacetal (1.83 g, 15.4 mmol) and a catalytic amount of para-toluene sulfonic acid and heated in the microwave for 15 min at 130° C. The mixture was cooled to room temp. and then concentrated in vacuo to afford a red oil. In a second flask para-chlorophenylhydrazine hydrochloride (1.84 g, 10.3 mmol) was placed in acetonitrile (10 mL) and then treated with the above red oil in triethylamine (6 mL). The mixture was stirred for 14 h, concentrated in vacuo and purified by silica chromatography (5% ethylacetate in hexanes) to afford 1-(4-Chloro-phenyl)-5-methoxymethyl-1H-pyrazole-4-carboxylic acid methyl ester (1.90 g, 66%).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:10][C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[N:3][S:4][N:5]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: Cc1ccc(O)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(Oc2nsnc(Cl)c2=O)cn1
Yield: 77.2 %

Procedure:
This compound was prepared in the manner of Example 3, using 14.6 grams (0.08 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one, 8.7 grams (0.08 mole) of 3-hydroxy-6-methylpyridine and 8.9 grams (0.088 mole) of triethylamine in 300 ml of tetrahydrofuran. The crude product was recrystallized from ethanol to give 15.8 grams (77%) of 3-chloro-5-(6-methyl-3-pyridyloxy)-4H-1,2,6-thiadiazin-4-one; m.p. 155°-156° C.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][S:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][S:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][N:41]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: COc1ccc(SCCN)nc1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(SCCNC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)nc1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
4-geranyloxybenzoic acid(1.92 g) was dissolved in chloroform(40 ml) and triethylamine(1.95 ml), and then diphenylphosphinic chloride(1.34 ml) was added thereto while being cooled with ice. After being stirred for 1 hour, the mixture, with 2-(2-aminoethylthio)-5-methoxypyridine(1.29 g) added thereto, was stirred for 17 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 2.84 g of the aimed compound.
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9](=[O:33])[NH:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:22](=[O:23])[C@H:21]3[CH2:24][CH2:25][CH2:26][C@H:20]3[NH:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:36][C:37](Br)=[O:38].C([O-])(O)=O.[Na+].[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.[K]>ClCCl.O>[CH2:1]([N:8]([CH3:34])[C:9](=[O:33])[NH:10][C:11]1[CH:32]=[CH:31][C:14]([CH2:15][N:16]2[C:22](=[O:23])[C@H:21]3[CH2:24][CH2:25][CH2:26][C@H:20]3[N:19]([C:37](=[O:38])[CH2:36][N:49]3[C:48](=[O:50])[C:47]4=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]4[C:45]3=[O:55])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]2=3)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Br)CBr
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(Cc1ccccc1)C(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3Nc3ccccc32)cc1
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccccc1)C(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
To a solution of (3aR*,10aS*)-9-[4-(3-benzyl-3-methylureido)benzyl]-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one (0.30 g, 0.66 mmol) in dichloromethane (5 mL) was added bromoacetyl bromide (58 μL, 0.67 mmol) and the mixture was stirred at room temperature for 30 minutes. After addition of saturated aqueous NaHCO3 solution, the aqueous layer was separated and extracted with dichloromethane. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate=1:11:2) to recover an amorphous fraction containing (3aR*,10aS*)-9-[4-(3-benzyl-3-methylureido)benzyl]-4-(bromoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]-cyclopenta[e][1,4]diazepin-10(1H)-one. This amorphous fraction was dissolved in DMF (1.5 mL) and after addition of potassium phthalimide (93 mg, 0.5 mmol), the solution was stirred at room temperature for 1.5 hours. This reaction mixture was diluted with water and extracted with 3 portions of ethyl acetate. The pooled organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:11:11:2) and crystallized from ethyl acetate-diethyl ether to provide 57 mg (yield 13%) of the title compound. m.p. 156°-158° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([Cl:21])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[H][H]>[Pd].C(O)C>[ClH:21].[C:1]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ncc2ccccc2c1-c1ccccc1
Product: Cl

Procedure:
A mixture of 21.7 g. (0.073 mole) of 3-tert.butyl-1-chloro-4-phenyl isoquinoline, 4.09 g. (0.073 mole) potassium hydroxide, 1.09g 10% palladium on carbon and 1 liter of ethanol is hydrogenated at room temperature and 50 psi until 1 equivalent of hydrogen is absorbed. The catalyst is filtered off and washed with ethanol, combined ethanol portions are evaporated in vacuo. The residue is dissolved in ethyl ether, washed with water, dried, and filtered and the filtrate treated with gaseous HCl. The resulting white solid is filtered and recrystallized from ethanolethyl ether, washed with water, dried, and filtered and the filtrate treated with gaseous HCl. The resulting white solid is filtered and recrystallized from ethanol-ethyl ether (1:1) to give 3-tert.butyl-4-phenyl isoquinoline hydrochloride; m.p. 236°-238° C.