Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:34])[CH2:8][CH2:9][CH:10](Br)[C:11]([CH3:32])=[CH:12][CH:13]([C:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]=1[CH3:31])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])(=[O:3])[CH3:2].N12CCCC1=NCCC2>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:34])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:32])[CH:12]=[C:13]([C:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]=1[CH3:31])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC=C(C)CCC(Br)C(C)=CC(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Agent: C1CN=C2CCCN2C1
Solvent: ClCCl
Product: CC(=O)OCC=C(C)CCC=C(C)C=C(C1=C(C)CCCC1(C)C)S(=O)(=O)c1ccccc1
Reaction time: 5 h
Yield: 84.1 %

Procedure:
A 50 ml flask was charged with 1.38 g (2.5 mmoles) of 1-acetoxy-6-bromo-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene (17) obtained in Example 14, 15 ml of methylene chloride, and 0.6 ml (5 mmoles) of 1,5-diazabicyclo[4.3.0]non-5-ene. The mixture was stirred for 5 hours under reflux. The reaction mixture was worked up by the same operation as in Example 22, to give 0.99 g (yield 84%) of 1-acetoxy-3,7-dimethyl- 9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6,8-nonatriene (19).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9](N1C2CCN(C)CC=2C(C2C=C(F)C(F)=CC=2F)=N1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].[F:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:34]=1[C:43]1[C:47]2[CH2:48][N:49](C(OC(C)(C)C)=O)[CH2:50][CH2:51][C:46]=2[NH:45][N:44]=1.F[C:60]1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F>>[CH3:1][C:2]([CH3:30])([CH3:31])[C@H:3]([NH:8][C:9]([N:45]1[C:46]2[CH2:51][CH2:50][N:49]([CH3:60])[CH2:48][C:47]=2[C:43]([C:34]2[CH:35]=[CH:36][C:37]([C:39]([F:41])([F:42])[F:40])=[CH:38][C:33]=2[F:32])=[N:44]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(C(F)(F)F)cc3F)c2C1
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(C(F)(F)F)cc2F)c2c1CCN(C)C2)C(C)(C)C

Procedure:
Compound 43 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with tert-butyl 3-(2-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate, which was prepared according to the procedure described for the synthesis of intermediate 15 by replacing 3,4-difluorobenzoyl chloride with 2-fluoro-4-trifluoro-benzoyl chloride. 1H NMR (CDCl3) δ 7.92 (d, J=9.4 Hz, 1H), 7.83 (t, J=7.5 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H), 7.42 (d, J=10.3 Hz, 1H), 6.17 (br, 1H), 4.17 (d, J=9.5 Hz, 1H), 3.52 (s, 2H), 3.21-3.28 (m, 2H), 2.79-2.89 (m, 5H), 2.51 (s, 3H), 1.08 (s, 9H). LCMS (+ESI) m/z=470 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH2:17][C:18]([NH2:20])=[NH:19]>CO>[NH2:19][C:18]([NH2:20])=[N:17][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[C:10]([Br:12])=[CH:11][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(Br)cc1C
Reactant: N=C(N)N
Solvent: CO
Product: Cc1cc(Br)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
A solution of 1.8 g of methyl 2-methyl-4-bromo-5-methylsulphonylbenzoate [obtainable in accordance with Ex. 1] and 1.5 g of guanidine in 50 ml of methanol is boiled for five hours, and the solvent is subsequently removed. The residue is treated with water and the remaining crystalline crop is filtered off with suction and treated with dil. sodium hydroxide solution. The solid residue is filtered off and recrystallized from ethanol, and N-diaminomethylene-2-methyl-4-bromo-5-methylsulphonylbenzamide is obtained, m.p. 207°-208°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:41])[C:7]=1[CH:8]([OH:40])[CH2:9][N:10]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12].Cl.[CH3:43][O:44][NH2:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:41])[C:7]=1[CH:8]([OH:40])[CH2:9][N:10]([CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28](=[O:30])[NH:45][O:44][CH3:43])[CH2:26][CH2:27]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12]
Reactant: CON
Reactant: O=C(c1cnn([C@H]2CC[C@H](C(=O)O)CC2)c1C(F)(F)F)N(Cc1cc(F)cc(F)c1)CC(O)c1c(Cl)cncc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3cc(F)cc(F)c3)CC(O)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of compound 5-3 (75 mg, 0.12 mmol) and O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol) in DMF (3 mL) were added HATU (55 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.30 mmol) and mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound 6-1 (65 mg, 82%) as a white foam. LCMS: 650 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH:2]=[CH2:3].C12BC(CCC1)CCC2.FC(F)(F)S(O[C:26]1[CH:35]=[CH:34][C:33]2[CH2:32][CH2:31][C@@H:30]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C@@H:29]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=3)[C:28]=2[CH:27]=1)(=O)=O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:48].[Cl:48][C:44]1[CH:43]=[C:42]([CH:47]=[CH:46][CH:45]=1)[CH2:41][CH:29]1[C:28]2[CH:27]=[C:26]([CH2:3][CH2:2][CH2:1][NH:4][S:5]([CH2:8][CH2:9][CH3:10])(=[O:7])=[O:6])[CH:35]=[CH:34][C:33]=2[CH2:32][CH2:31][CH:30]1[N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C=CCNS(=O)(=O)CCC
Reactant: O=S(=O)(Oc1ccc2c(c1)[C@H](Cc1cccc(Cl)c1)[C@H](N1CCCC1)CC2)C(F)(F)F
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N1CCCC1)CC2
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-allylpropane-1-sulfonamide (0.238 g, 1.456 mmol) is added to a solution of 9-borabicyclo[3.3.1]nonane (0.185 g, 1.519 mmol) in tetrahydrofuran (4 mL). The reaction mixture was stirred for 2 h at room temperature. (7R,8S)-8-(3-chlorobenzyl)-7-(pyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (0.3 g, 0.633 mmol) dissolved in tetrahydrofuran (2 mL), sodium hydroxide (0.063 g, 1.582 mmol in 0.06 mL water) and palladium tetrakistriphenylphosphine (0.073 g, 0.063 mmol) were added. The reaction mixture was heated under reflux over night. The reaction mixture was diluted with ethyl acetate and washed with 1 M sodium hydroxide solution. The aqueous phase was extracted two more times with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and the solvent was evaporated in vacuo. The crude product was purified by preparative thin-layer-chromatography (silica gel, dichloromethane, methanol). The product was dissolved in dichloromethane. Excess 5N hydrochloric acid in ethanol was added. The solvent was evaporated and the product dried in vacuo. Yield: 53 mg (0.108 mmol, 17%).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][N:15](CC4C=CC=CC=4)[CH2:14]3)[CH2:12][C:11](=[O:27])[C:10]=2[CH:28]=1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[Cl:38]C(OC(Cl)C)=O.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[ClH:38].[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:26][C:13]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[CH2:12][C:11](=[O:27])[C:10]=2[CH:28]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)C1)O2
Reactant: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)CC1(CCCNC1)O2
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.7 %

Procedure:
A solution of 7 g (17.47 mmols) of 6-methanesulfonamido-1'-benzyl-3,4-dihydrospiro-[(2H)-1-benzopyran-2,3'-piperidine]-4-one in 250 mL dichloroethane was treated with 5.6 g (43.7 mmole) of diisopropylethylamine, and 6.24 g (43.7 mmoles) of 1-chloroethyl chloroformate. The reaction was stirred at room temperature for 24 hours and then poured into 500 mL saturated sodium bicarbonate, and extracted with ethyl acetate. The ethyl acetate layers were washed with dilute acid to remove excess diisopropylethylamine. The ethyl acetate solution was then dried over MgSO4, filtered and concentrated in vacuo. The crude material was dissolved in 250 mL CH3OH and heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and the solid collected by filtration to give 4.1 g of product, mp=290° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([O:15][Si](C)(C)C)[NH:13][C:12]1=[O:20])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:21](O)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:21]([O:15][C@H:14]1[NH:13][C:12](=[O:20])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1O[Si](C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -35 °C
Reaction time: 22 h
Yield: 60 %

Procedure:
After 155 mg of (3R,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-trimethylsilyloxyazetidin-2-one was dissolved in 1.6 ml of tetrahydrofuran, the mixture was cooled to -35° C. And thereto 0.03 ml (concentration: 1.84% by volume) of acetic acid, 0.5 ml of acetic anhydride and then 20 mg (concentration: 0.92% by weight) of 4-dimethylaminopyridine were added. The mixture was stirred for 22 hours at -35° C. After the same treatment as in Example 16, it was analyzed by means of high performance liquid chromatography used in Example 16 to find 84 mg of (3R,4R)-4-acetoxy-3-[(R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (yield: 60%).
Reaction SMILES: C(Cl)(C)(C)C.Cl.ClC(C)C.Cl[SiH](Cl)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][Si:21]([Cl:29])([Cl:28])CCCCCC.ClCCCCCC>>[CH2:13]=[CH:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:20][SiH:21]([Cl:29])[Cl:28]
Reactant: CCCCCC[SiH](Cl)Cl
Reactant: CCCCCC[Si](Cl)(Cl)Cl
Agent: CC(C)Cl
Agent: Cl
Solvent: CC(C)(C)Cl
Solvent: CCCCCCCl
Product: C=CCCCC
Product: Cl[SiH](Cl)Cl
Yield: 17.9 %

Procedure:
The present experiement was described as shown in the following typical experimental No. 63 in Table 13. The reaction was carried out under the same condition as in Example 3, except that the same amount of t-butyl chloride was, used as the hydrogen chloride source. A mixture of 2-chloropropane and t-butyl chloride having the mixing ratio of 1:6 was reacted with metallic silicon at 280° C. to give 16.1 g of reaction products. The reaction products contained 5.9 g (45.2%) of 1,1-dichloro-1-silaheptane and 1.4 g (9.0%) of 1,1,1-trichloro-1-silaheptane. As other by-products, 31.1 g (13.2%) of 1-chlorohexane which is remained unreacted, 1.1 g (17.9%) of hexene, 2.5 g of trichlorosilane, and unconfirmed materials were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:15])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>CC(=O)CC.O>[CH3:15][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:10][CH:9]=2)[N:6]=1
Reactant: ClCCCN1CCCC1
Reactant: Cc1cc(CO)n(-c2ccc(O)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cc(CO)n(-c2ccc(OCCCN3CCCC3)cc2)n1
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a solution of 4-(5-hydroxymethyl-3-methylpyrazol-1-yl)phenol (326 mg, 1.60 mmol) in 2-butanone (8 mL) was added potassium carbonate (243 mg, 1.76 mmol) and 1-(3-chloropropyl)pyrrolidine (260 mg, 1.76 mmol). The reaction was heated overnight at 80° C. After the reaction was diluted with water and extracted with methylene chloride, the organic layer was dried (MgSO4) and concentrated to give 315 mg of the desired product. LC-MS (C18H25N3O2 calculated 315) m/z 316 (M+H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([Cl:15])=[O:12])[CH:7]=[CH:6][C:5]=12
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nonc2c1
Yield: 79.8 %

Procedure:
In a 500 ml reactor fitted with mechanical stirring, thermometer, addition funnel, reflux condenser and nitrogen inlet, [2,1,3]-benzoxadiazole-5-carboxylic acid (28 g) was suspended in toluene (245 ml). To this suspension was added thionyl chloride (39.4 g) and DMF (0.35 ml). The resulting mixture was heated to reflux and maintained for 3 hours. A short pass column was installed and toluene was distilled (atmospheric pressure, 124 ml) off to remove excess reagent. After cooling the remaining toluene was distilled off, which resulted in a thick oil. This oil was distilled (90° C., 2 mm Hg) to remove impurities and the product crystallized on standing (79.8% yield), mp: 55-58° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)Cl>CS(C)=O>[C:1]([O:5][C:6]([N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:9][CH:10]=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCO)C(C)(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC=O)C(C)(C)C
Yield: 94.8 %

Procedure:
To N-tert-butoxycarbonyl-N-tert-butylethanolamine (7.24 g), triethylamine (13.5 g) and methylene chloride (150 ml) in 500 ml round bottom flask, a solution dissolved sulfur trioxide-pyridine complex (15.9 g) into 150 ml of DMSO was added at a time under cooling with ice and stirring. After stirring for 10 minutes at room temperature, the reaction mixture was poured into 1 liter of saturated saline solution. After the methylene chloride layer was separated, the aqueous layer was extracted with ether and all of the organic layers were combined, which was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by means of silica gel chromatography (chloroform: ethanol=20:1) to obtain 6.80 g of aimed product as a faintly yellow oily product. Yield: 94.8%
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH3:3].[C:14](Cl)(=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[OH2:24]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:14]([OH:22])(=[O:24])[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:10][C:9]1[C:4]([CH:2]([CH3:1])[CH3:3])=[CH:5][CH:6]=[CH:7][C:8]=1[CH:11]([CH3:13])[CH3:12])=[O:20]
Reactant: O
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1OC(=O)CCCCC(=O)O
Reaction time: 2 h
Yield: 40 %

Procedure:
Synthesis of propofol hemiadipate Triethylamine (6.26 ml, 45 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol) in methylene chloride (30 ml) were added to a solution of 2,6-diisopropylphenol (5.2 ml, 28 mmol) and adipoyl chloride (4.4 ml, 30 mmol) in methylene chloride (50) at 0° C. The mixture was allowed to reach room temperature and stirred at that temperature for 2 hr. Water (50 ml) was added, and the two-phase mixture was stirred for 1 hr. The organic phase was washed with 3% aqueous HCl and then dried. Solvents were removed under vacuum, and the oily residue was chromatogrammed on a silica gel column using chloroform-methanol (10:0.1) and then chloroform-methanol-acetic acid (10:0.1:0.01). The fractions containing the ester were pooled and evaporated under vacuum to yield 3.4 g (40% yield) of 2,6-diisopropylphenol hydrogen adipate (propofol hemiadipate) as an oil.
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][N:5]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[C:11]([C:19]#[N:20])=[C:10](SC)[N:9]=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:7]=2[C:6]1=[O:31]>C(O)CCC.CS(C)=O>[NH2:20][C:19]1[C:11]2[C:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:5]([OH:4])[C:6](=[O:31])[C:7]=3[C:8]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[N:9][C:10]=2[NH:3][N:2]=1
Reactant: COc1ccc(-c2nc(SC)c(C#N)c3c2c(=O)n(O)c2ccccc32)cc1
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCO
Product: COc1ccc(-c2nc3[nH]nc(N)c3c3c2c(=O)n(O)c2ccccc32)cc1
Reaction time: 3 h
Yield: 39.7 %

Procedure:
37.4 ml (770 mmol) of hydrazine hydrate is added to a solution of 3 g (7.7 mmol) of 6-hydroxy-4-(4-methoxyphenyl)-2-(methylthio)-5-oxo-5,6-dihydrobenzo[c][2,7]-naphthyridine-1-carbonitrile dissolved in 80 ml of butan-1-ol and 32 ml of dimethylsulfoxide. The reaction medium is carried at 150° C. for 3 hours and then is allowed to rest at room temperature overnight. The precipitate obtained is filtered and then rinsed with methanol to yield 1.14 g (39%) of 1-amino-7-hydroxy-5-(4-methoxyphenyl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one in the form of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][N:2]=1.S(=O)(=O)(O)O.[CH3:15]O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:15])=[O:8])=[CH:3][N:2]=1
Reactant: CO
Reactant: O=C(O)c1ccnnc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnnc1
Reaction time: 16 h

Procedure:
To a solution of pyridazine-4-carboxylic acid (Aldrich, 5.0 g, 40.3 mmol) in methanol (anhydrous, Aldrich, 100 mL) was added sulfuric acid (concentrated, Aldrich, 2 mL). The reaction mixture was then heated to reflux and stirred for 16 hours. The volatiles were removed under reduced pressure. The residue was basified to pH=8-9 with saturated sodium carbonate (20 mL) and then extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (2×20 mL) and dried over magnesium sulfate. The drying agent was filtered off and the organic solution was concentrated and dried to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 3.34 (s, 3H), 8.10 (dd, J=5.2, 2.4 Hz, 1H), 9.52 (dd, J=5.2, 1.2 Hz, 1H), 9.58 (dd, J=2.2, 1.4 Hz, 1H) ppm; MS (DCI/NH3) m/z 139 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:16]>CCOCC.CO>[NH2:16][C:6]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(-c2c(N)ncnc2Cl)cc1

Procedure:
To a solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine (4.14 g) in ether (20 ml) is added 27% ammonia in methanol solution (30 ml), and the mixture is reacted at room temperature for three days in a sealed tube. The mixture is evaporated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:1~ethyl acetate only) to give 4-amino-6-chloro-5-(4-methyl-phenyl)pyrimidine (1.89 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]1([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:22]=[N:23][C:24]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([C:36]([N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[O:37])[CH:34]=5)[C:29]([S:43][CH3:44])=[CH:28]4)=[N:25][CH:26]=3)[CH:16]=2)[CH2:14][CH2:13]1>ClCCl>[CH:12]1([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:26]=[N:25][C:24]([N:27]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([C:36]([N:38]6[CH2:42][CH2:41][CH2:40][CH2:39]6)=[O:37])[CH:34]=5)[C:29]([S:43]([CH3:44])=[O:6])=[CH:28]4)=[N:23][CH:22]=3)[CH:16]=2)[CH2:13][CH2:14]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(-c2ncc(-c3cc(C4CC4)ccn3)cn2)c2cc(C(=O)N3CCCC3)ccc12
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3cc(C4CC4)ccn3)cn2)c2cc(C(=O)N3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
m-Chloroperoxybenzoic acid (77%, 79 mg, 0.35 mmol) was added to an ice cooled solution of 341b) (0.2 g, 0.43 mmol) in dichloromethane (30 mL). The mixture was stirred at room temperature for 1 h and then diluted with dichloromethane (25 mL). The organic phase was washed successively with saturated sodium hydrogen solution (2×15 mL) and brine (1×15 mL), dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography [silica; dichloromethane with 0-2% methanol]. White solid. Yield: 0.08 g (39% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.Cl.[CH3:15][NH:16][O:17][CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:16]([O:17][CH3:18])[CH3:15])=[O:13])=[CH:5]2
Reactant: CNOC
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a mixture of 5-chloro-1H-indole-2-carboxylic acid (15.0 g), N,O-dimethylhydroxylamine hydrochloride (8.97 g), 1-hydroxybenzotriazole monohydrate (14.1 g), triethylamine (25.6 mL) and N,N-dimethylformamide (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.6 g), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, the resulting precipitate was collected by filtration to give the title object compound (15.5 g, 84%) as a pale-brown solid.
Reaction SMILES: C[O-].[Na+:3].[CH3:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:21]=[C:20]([O:30][CH2:31][CH2:32][OH:33])[C:19]=2[O:34][C:35]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].O.C(OCC)(=O)C>CO>[CH3:7][C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N-:17][C:18]2[C:19]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=3[O:41][CH3:42])=[C:20]([O:30][CH2:31][CH2:32][OH:33])[N:21]=[C:22]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)[N:23]=2)(=[O:15])=[O:16])=[CH:10][CH:9]=1)([CH3:4])[CH3:6].[Na+:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1Oc1c([N-]S(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Sodium methoxide solution (30% methanolic solution; 3.9 mL) was added to a mixture of bosentan monohydrate (5 g) in methanol (15 mL). Ethyl acetate (80 mL) was added to the reaction mixture. The reaction mixture was heated to 55° C. and stirred for 30 minutes at 55° C. The reaction mixture was cooled to 25° C. The reaction mixture was stirred for 1.5 hours and the solid was filtered at 10° C. to 15° C., washed with a mixture of ethyl acetate (4 mL) and methanol (1 mL). The wet material obtained was dried at hot air oven at 50° C. to 55° C. to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:8])[S:5][C:6]=1[CH3:7].[CH2:9]([Br:12])[C:10]#[CH:11]>C1(C)C=CC=CC=1.C(OCC)C>[BrH:12].[CH3:1][C:2]1[N:3]([CH2:11][C:10]#[CH:9])[C:4](=[NH:8])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(N)sc1C
Reactant: C#CCBr
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Br
Product: C#CCn1c(C)c(C)sc1=N
Temperature: 85 °C
Yield: 72.6 %

Procedure:
To a solution of 4,5-dimethylthiazol-2-amine (2.5 g, 19.5 mmol) in 10 mL toluene was added propargyl bromide (2.78 g, 23.4 mmol). The reaction was heated at 85° C. for 12 h then cooled. The crude material was diluted with diethyl ether and the solid was collected via filtration to give 3.5 g of the title compound which was used without further purification. m/z 167.1 (M+H)+.