Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]([O:11]CC=C)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])C=C.C(OC(=O)C)(=O)C.[C:22](O)(=O)/[CH:23]=[CH:24]\C(O)=O.[OH-].[Na+]>CN(C)C(=O)C.O.C1(C)C=CC=CC=1>[CH2:24]([CH:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[O:11])[CH:23]=[CH2:22]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: C=CCOC(CCCCC)OCC=C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Product: C=CCC(C=O)CCCC
Temperature: 120.5 °C

Procedure:
1,1-Bis(allyloxy)hexane (118.98 g, 0.60 mol) was dissolved in N,N-dimethylacetamide (320 mL) under a nitrogen atmosphere. To the solution, acetic anhydride (170 mL, 1.80 mol) and maleic acid (3.48 g, 0.03 mol) were added, and the mixture was stirred. The reaction mixture was warmed to 115 to 126° C., stirred at this temperature for 25 hours, and then cooled to 10° C. or lower. To the reaction mixture, toluene (480 mL) and water (720 mL) were added, and a 50% aqueous sodium hydroxide solution (294 mL) was slowly added with stirring to separate an organic layer. The aqueous layer was subjected to extraction with toluene (240 mL), and the extract was combined with the organic layer and then washed with 10% saline (240 mL). The organic layer was dried over sodium sulfate. After filtration, the filtrate was used in the next step without being concentrated or purified.
Reaction SMILES: [NH2:1][C:2](N)=[O:3].[CH2:5]([NH:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH3:7]>C1(C)C(C)=CC=CC=1>[CH2:5]([N:8]([CH2:9][CH2:10][CH3:11])[C:2]([NH2:1])=[O:3])[CH2:6][CH3:7]
Reactant: CCCNCCC
Reactant: NC(N)=O
Solvent: Cc1ccccc1C
Product: CCCN(CCC)C(N)=O
Temperature: 25 °C

Procedure:
180 g (3 mols) of urea are suspended in 500 ml of dry xylene. This is heated to an internal temperature of from 130° to 135° C. and a mixture of 303 g (3 mols) of dipropylamine and 250 ml of xylene is slowly introduced. When the reaction temperature has been reached, more dipropylamine mixture is added, with stirring. When all of the amine solution has been added, the reaction mixture is concentrated to half its volume. It is then left to cool to room temperature and the crystallized reaction product is separated by suction filtration. 345 g (80% of the theoretical yield) of N,N-dipropyl-urea having a melting point of 69° C. are obtained.
Reaction SMILES: C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22](=O)[C:21](=[CH:24]N(C)C)[CH2:20][C:19](=[O:28])[NH:18][C:17]=2[CH:29]=1.[NH:30]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)[C:31]([NH2:33])=[NH:32]>CCO.CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[C:22]3[N:32]=[C:31]([NH:30][C:34]4[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=4)[N:33]=[CH:24][C:21]=3[CH2:20][C:19](=[O:28])[NH:18][C:17]=2[CH:29]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to method I (DMF and NaHCO3 were used in place of EtOH and K2CO3), 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and 4-guanidinobenzoic acid were converted to I-3 (68%): HRMS Calcd. for C19H13ClN4O3: 381.0754, Found 381.0721.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[C:15]([OH:22])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:25])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1c(O)ccc2cccc(Cc3ccccc3)c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 0.5 h

Procedure:
82.7 g of 8-benzyl-1-methoxymethoxy-2-naphthol was dissolved in 300 ml of N,N-dimethylformamide to give a solution. 12.3 g of sodium hydride (55% suspension in oil) was added to the solution at room temperature. The obtained mixture was stirred for 30 minutes, followed by the dropwise addition of 17.5 ml of methyl iodide. The obtained mixture was stirred for one hour and poured onto ice-water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (developer: 3 to 9% ethyl acetate/hexane) to give 79.5 g of the title compound as a yellow oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:3][C:4]2[N:5]=[CH:6][S:7][CH:8]=2)=[CH:13][CH:12]=1
Reactant: ClCc1cscn1
Reactant: CSc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1ccc(OCc2cscn2)cc1

Procedure:
A mixture of 4-chloromethyl thiazole hydrochloride (3.0 g, 17.6 mmol), 4-methylsulfanyl-phenol (2.5 g, 1 eq.) and K2CO3 (6.1 g, 2.5 eq.) in acetone (60 mL) was heated to reflux for 48 hours. After cooling, the solid was filtered off. The filtrate was evaporated to dryness in vacuo. The crude product was redissolved in diethyl ether. The solution was washed twice with 2N NaOH solution and then with H2O. After being dried over Na2SO4, removal of the solvent afforded the desired product as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22](OC)[O:23]C)[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2].Cl>>[C:1]([C:3]1[C:4]([O:27][CH3:28])=[CH:5][C:6]([NH:9][C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[O:23])[N:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])=[N:7][CH:8]=1)#[N:2]
Reactant: COc1cc(NC(=O)N2CCCc3ccc(C(OC)OC)nc32)ncc1C#N
Agent: Cl
Product: COc1cc(NC(=O)N2CCCc3ccc(C=O)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(5-cyano-4-methoxypyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2B, 36 mg, 0.094 mmol) was treated with HCl (4 M in dioxane, 2 ml, 65.8 mmol). The solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was triturated with EtOAc to furnish the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[I:10]Cl.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([I:10])=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(N)nc(N)n1
Reactant: ClI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N)nc(N)c1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
A solution of 8.0 grams (0.064 mole) of 2,4-diamino-6-methylpyrimidine in 30 mL of glacial acetic acid is stirred, and a solution of 13.5 grams (0.083 mole) of iodine monochloride in 20 mL of glacial acetic acid is added dropwise during a 5 minute period. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is diluted with 100 mL of water and then is made basic with 10% aqueous sodium hydroxide. The mixture is then extracted with three 75 mL portions of ethyl acetate. The combined extracts are washed with one 75 mL portion of an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 11.7 grams of 2,4-diamino-5-iodo-6-methylpyrimidine. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:10][C@@H:8]([CH3:9])[CH2:7][C@@H:6]1[OH:11])=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(Cl)Cl>C(OCC)(=O)C.CCCCCC>[CH3:21][S:22]([O:11][C@@H:6]1[C@@H:5]([CH2:4][N:1]=[N+:2]=[N-:3])[O:10][C@@H:8]([CH3:9])[CH2:7]1)(=[O:24])=[O:23]
Reactant: C[C@H]1C[C@H](O)[C@@H](CN=[N+]=[N-])O1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@H](OS(C)(=O)=O)[C@@H](CN=[N+]=[N-])O1
Yield: 48.7 %

Procedure:
The title compound is prepared by the procedure of Example 277 using 0.192 g of product from Example 338, 0.316 g of Hunig's base, 0.280 g of methanesulfonyl chloride and. 0.35 ml of methylene chloride to give after chromatography (Silica gel: 30% ethyl acetate/hexane) 0.140 g of the desired product.
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1.[OH-].[Na+].Cl>CO.O>[F:21][CH:2]([F:1])[C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2cnc3cccnn23)c(C(F)F)s1
Temperature: 50 °C

Procedure:
To a stirred solution of methyl 5-(difluoromethyl)-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (57 mg, 0.18 mmol) in methanol (1 mL) and water (0.5 mL) was added NaOH (2 N, 0.28 mL, 0.56 mmol). The mixture was heated to 50° C. for 1 h, cooled to room temperature, and acidified with 1 N HCl. The resultant mixture was concentrated, and used in the next step without further purification. LRMS (APCI) calc'd for (C12H8F2N3O2S) [M+H]+, 296.0. found 296.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>CC(C)=O.CCOCC>[NH2:12][C:10]([C@H:9]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15])[CH2:13][CH3:14])=[O:11]
Reactant: O=C(Cl)CCCCl
Reactant: CC[C@@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC[C@@H](NC(=O)CCCCl)C(N)=O
Temperature: 0 °C
Yield: 86 %

Procedure:
31.1 g (0.225 mole) of ground potassium carbonate are mixed with 12.47 g (0.09 mole) of (R)-2-aminobutanamide hydrochloride in 160 ml of acetone. The reaction mixture is cooled to 0° C. and a solution of 15.23 g (0.108 mole) of 4-chlorobutyryl chloride in 25 ml of acetone is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 100 ml of anhydrous ether for 15 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 30 ml of ether, and dried in vacuo to obtain 16 g of (R)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide. Melting point: 127°-129° C. [alpha]D25 : +22.2° (c=1, methanol). Yield: 86%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20](=O)[CH2:21][C:22]#[N:23])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl.[C:33]([NH:37][NH2:38])([CH3:36])([CH3:35])[CH3:34]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:21]=[C:22]([NH2:23])[N:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[N:38]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)(c2ccccc2)CC1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2)(c2cc(N)n(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A solution of 1.66 g (5.0 mmol) of 4-(2-cyanoacetyl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester, 2.20 mL (16 mmol) of Et3N and 2.00 g (16 mmol) of tert-butylhydrazine hydrochloride in 20 mL of absolute EtOH was heated to 100° C. in a sealed tube. After 64 h, the reaction mixture was cooled to rt and concentrated. Purification on silica gel using 30:70 EtOAc-hexanes as eluant afforded 4-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6])(=[O:3])[CH3:2].[OH-].[K+]>ClCCl>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:5]([OH:7])=[O:6])(=[O:3])[CH3:2]
Reactant: COC(=O)C(CCCC1CCCCC1)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)C(CCCC1CCCCC1)C(=O)O

Procedure:
Analogously to Example 29A, 450 mg (2.08 mmol) of methyl 2-acetyl-5-cyclo-hexylpentanoate are reacted with 1.5 ml of a 3.5 M potassium hydroxide solution in dichloromethane to give 2-acetyl-5-cyclohexylpentanoic acid.
Reaction SMILES: [C:1]([C@@H:3]([NH:19]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2]>C(O)=O>[NH2:19][C@H:3]([C:1]#[N:2])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]#[N:18])[CH:12]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)Cc1ccc(-c2cccc(C#N)c2)cc1
Solvent: O=CO
Product: N#Cc1cccc(-c2ccc(C[C@H](N)C#N)cc2)c1
Temperature: 50 °C
Yield: 55.5 %

Procedure:
A suspension of (S)-tert-butyl 1-cyano-2-(3′-cyanobiphenyl-4-yl)ethylcarbamate (8.4 g) in formic acid (100 mL) was stirred and heated to 50° C. for 10 min. The mixture was concentrated in vacuo. The crude material was dissolved in methanol (10 mL) and loaded on to an 50 g SCX cartridge. The impurities were washed through with methanol (100 mL) and discarded. The product was eluted with 1N methanolic ammonia (150 mL) and evaporated in vacuo. The residue was further purified by flash chromatography, eluting with ethyl acetate to afford (S)-4′-(2-amino-2-cyanoethyl)biphenyl-3-carbonitrile (3.32 g).
Reaction SMILES: [CH3:1][C:2]1([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12]([OH:14])=O)=[O:8])[CH2:5][CH2:4][CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[CH3:1][C:2]1([O:6][C:7]([NH:9][C@@H:10]2[C:15](=[O:16])[O:17][C:12](=[O:14])[CH2:11]2)=[O:8])[CH2:3][CH2:4][CH2:5]1
Reactant: CC1(OC(=O)N[C@@H](CC(=O)O)C(=O)O)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC1(OC(=O)N[C@H]2CC(=O)OC2=O)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.45 g. of N-(1-methylcyclobutyloxycarbonyl)-aspartic acid in 50 ml. of dioxane is prepared and 2.2 g. of dicyclohexylcarbodiimide is added with vigorous stirring. After stirring at 25°C. for 2 hours, the dicyclohexylurea is removed by filtration and the dioxane removed by evaporation in vacuo. The resulting solid is substantially pure N-(1-methylcyclobutyloxycarbonyl)-aspartic anhydride.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[OH:29][C@@H:30]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43](O)[CH:42]=1)[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37]>>[O:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[CH2:17][CH:13]1[CH2:12][O:11][C:43]1[CH:42]=[C:41]([C@H:30]([OH:29])[CH2:31][CH2:32][NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccccc3O2)cc1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2Cc3ccccc3O2)c1

Procedure:
Reaction between ((2,3-dihydrobenzofuran-2-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) following the method used in Example 12 gave tert-butyl ((3R)-3-(3-((2,3-dihydrobenzofuran-2-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate as a white solid. Yield (65%); 1H NMR (400 MHz, CDCl3): δ 7.24-7.18 (m, 2H), 7.12 (t, J=8 Hz, 1H), 6.94 (t, J=8.4 Hz, 2H), 6.88-6.81 (m, 3H), 5.16-5.13 (m, 1H), 4.87 (s, 1H), 4.71 (s, 1H), 4.20 (dd, J=10.0, 6.8 Hz m, 1H), 4.10 (dd, J=6.0, 4.8 Hz, 1H), 3.41 (s, 1H), 3.39-3.35 (m, 1H), 3.25 (s, 1H), 3.17-3.11 (m, 2H), 1.85-1.80 (m, 2H), 1.45 (s, 9H); MS: m/z 400 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:3]1.CC([O-])=O.[Na+].Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26]N)=[CH:22][CH:21]=1.CC(O)=O>O>[CH3:18][O:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[NH:26][C:2]1[CH2:3][CH:4]([NH:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:6][C:7]2=1
Reactant: CC(=O)NC1CCCC(=O)C1
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c3c(c2c1)CCC(NC(C)=O)C3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.05 mol of N-(3-oxocyclohexyl)acetamide, 0.05 mol of anhydrous NaOAc, 0.05 mol of 4-methoxyphenylhydrazine hydrochloride, and 155 ml of glacial HOAc was stirred for 1 hr at room temperature and then refluxed for 1 hr. The cooled reaction mixture was poured into H2O and the product triturated until solid. Filtration, drying, and recrystallization from ethanol gave the title compound, mp 191°-193°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)#[N:2].[Br:13]N1C(=O)CCC1=O>S(=O)(=O)(O)O.O>[Br:13][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1ccc(CC(=O)O)c(Br)c1
Reaction time: 18 h
Yield: 70.5 %

Procedure:
A solution of 4-cyanophenylacetic acid (1.6 g, 9.93 mmol) in 50% aqueous sulfuric acid (10 mL) was treated with N-bromosuccinimide (1.8 g, 10.11 mmol). The mixture was stirred in the dark for 18 h then diluted with water and extracted with diethyl ether to give 2-bromo-4-cyanophenylacetic acid (2.1 g, 7.00 mmol, 70.5% yield) as a white solid containing about 25% of starting material.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][N:15]2[C:27](=[O:45])[N:28]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]C=C)[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][N:28]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:27](=[O:45])[N:15]1[CH:14]([CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:22])[CH3:21])[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: CCOC(=O)C12CC1C=CCCCCCN(Cc1ccc(OC)cc1)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Yield: 47.9 %

Procedure:
The diene (125) (1 g, 1.6 mmol) was dissolved in degassed DCE (1000 ml), Hoveyda-Grubbs 2nd generation (100 mg, 0.16 mmol) was added and the reaction mixture was refluxed under an atmosphere of argon overnight. The reaction mixture was evaporated on silica and purified by column chromatography on silica gel (30% EtOAc in Heptane→50% EtOAc in Heptane) to give the title compound (470 mg, 0.767 mmol, 48%). M+H=614.
Reaction SMILES: [I-].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N+](C)C3C=CC=CC=3)[S:9][C:5]=2[CH:4]=1.Cl.[NH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8](=[N:21][CH2:22][CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[S:9][C:5]=2[CH:4]=1
Reactant: C[N+](c1ccccc1)=c1sc2ccc(Cl)cc2s1
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2sc(=NCCc3c[nH]c4ccccc34)sc2c1
Yield: 12.2 %

Procedure:
A solution of 5-chloro-N-methyl-N-phenyl-1,3-benzodithiol-2-iminium iodide (8.39g), tryptamine hydrochloride (3.94g) and anhydrous sodium carbonate (2.12g) in 300 ml of anhydrous dimethylformamide is heated at 130° C under a nitrogen atmosphere for 3 hours. After this time the reaction mixture is poured into 1 liter of water and extracted with three 300 ml portions of benzene. The combined benzene extracts are dried over anhydrous sodium sulfate and then concentrated in vacuo to yield an oil. This oil is chromatographed on 600 ml of silica gel eluting first with dichloromethane/pentane (1:1) and finally dichloromethane. The resultant product with Rf =0.36 (silica gel/dichloromethane) is recrystallized from dichloromethane/pentane to yield 840 mg of the title compound, melting point 145°-147° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH3:14][C:15]1[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[N:20]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1cccc(N)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C)n1
Temperature: 140 °C
Yield: 36.7 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (300 mg, 1.36 mmol) and 6-methylpyridin-2-amine (176 mg, 1.63 mmol) were dissolved in acetonitrile (4.1 mL), then heated at 140° C. for 16 h. A second portion of 6-methylpyridin-2-amine (73 mg, 0.67 mmol) was added. After a further 2 d at 140° C. the reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 5 to 40% ethyl acetate in hexanes) gave 6-chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (146 mg, 36%) as a light yellow oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 10.68 (br. s., 1H) 9.21 (s, 1H) 7.59 (t, J=7.7 Hz, 1H) 6.90 (d, J=7.6 Hz, 1H) 6.76 (d, J=7.9 Hz, 1H) 4.57 (q, J=7.2 Hz, 2H) 2.57 (s, 3H) 1.51 (t, J=7.0 Hz, 3H); LCMS (EI/CI) m/z: 315 [M+Na].
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH2:21])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].CO[CH:24]1[CH2:28][CH2:27][CH:26](OC)O1>C(O)(=O)C>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:21]2[CH:24]=[CH:28][CH:27]=[CH:26]2)[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]([OH:10])=[O:9])(=[O:3])(=[O:4])[NH2:2]
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(-n2cccc2)c1Oc1ccccc1

Procedure:
A mixture of 3-sulphamoyl-4-phenoxy-5-amino-benzoic acid (3.08 g=10 mmols); P. W. Feit, J. Med. Chem. 14,432 (1971), 2,5-dimethoxy-tetrahydrofurane (1.32 g=10 mmols) and 5 ml of glacial acetic acid is refluxed for 15 minutes in an oil bath and evaporated to dryness in vacuo and the residue is recrystallised from ethyl acetate; the compound melts at 209°-210° C.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22]([OH:27])[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.Cl[CH2:39][O:40][CH3:41].[Cl-].[NH4+]>ClCCl>[CH3:39][O:40][CH2:41][O:27][CH:22]1[CH2:23][CH2:24][C@@:25]2([CH3:26])[C:20](=[CH:19][CH:18]=[C:17]3[C@@H:16]2[CH2:15][CH2:14][C@@:13]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8])[CH2:21]1
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1CC[C@@]2(C)C(=CC=C3[C@@H]4CC[C@H]([C@@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Commercially available 7-dehydrocholesterol (18.3 g, 47.6 mmol) was dissolved in dichloromethane (150 mL), and N,N-diisopropylethylamine (24.9 mL, 143 mmol) and chloromethylmethyl ether (7.23 mL, 95.2 mmol) were added thereto at room temperature, followed by stirring overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with chloroform twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain (S)-3-methoxymethoxy-5,7-cholestadiene (18.1 g, 89%).