Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]C)=[O:17])=[CH:11][N+:10]=1[O-:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][N+:10]=1[O-:20])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)Cc1ccc(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[n+]([O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)c1ccc(CC(=O)O)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)-5-(2-methoxy-2-oxoethyl)pyridine 1-oxide from step 4 in a mixture of MeOH/THF (20 mL, 1:1) was added 1 N NaOH. The reaction mixture was stirred at room temperature overnight. 1N HCl was added to acidify the solution to pH 4. The aqueous phase was extracted with EtOAc (3×). The combined organic phases were dried and concentrated. The residue was then purified by reverse phase chromatography to afford the product (1.4 g).
Reaction SMILES: Cl.[CH3:2][S:3]([NH:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][CH:12]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:13]2=[O:16])=[CH:9][CH:8]=1)(=[O:5])=[O:4].Br[CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]2[C:30]([CH:34]=1)=[N:31][O:32][N:33]=2.C(=O)(O)[O-].[Na+].[I-].[K+]>C(#N)C>[N:33]1[O:32][N:31]=[C:30]2[CH:34]=[C:26]([CH2:25][CH2:24][N:20]3[CH2:21][CH2:22][CH:17]([CH:12]4[C:13](=[O:16])[C:14]5[C:10](=[CH:9][CH:8]=[C:7]([NH:6][S:3]([CH3:2])(=[O:4])=[O:5])[CH:15]=5)[CH2:11]4)[CH2:18][CH2:19]3)[CH:27]=[CH:28][C:29]=12
Reactant: BrCCc1ccc2nonc2c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(C1CCNCC1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(C1CCN(CCc3ccc4nonc4c3)CC1)C2

Procedure:
In the manner described in Example 14, 6-methanesulfonamido-2-(4-piperidyl)-indan-1-one hydrochloride (0.20 g, 0.58 mmol), 5-(2-bromoethyl)benzofurazan (0.395 g, 1.74 mmol), sodium bicarbonate (0.146 g, 1.74 mmol) and potassium iodide (20 mg), in 20 mL of acetonitrile were heated under reflux for 30 hours. After purification by flask column chromatography on silica gel eluting with 5% methanol in chloroform saturated with ammonia (gas), and treatment with ethanol HCl, crystallization from methanol gave the title compound as a white solid, mp 214°-217° C.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.N1C=CC=CC=1.C(N(CC)CC)C.[F:20][C:21]([F:33])([F:32])[C:22]1[NH:26][N:25]=[CH:24][C:23]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:30]([O:29][C:27]([C:23]1[C:22]([C:21]([F:20])([F:32])[F:33])=[N:26][N:25]([CH:1]2[CH2:3][CH2:2]2)[CH:24]=1)=[O:28])[CH3:31]
Reactant: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)nc1C(F)(F)F
Temperature: 60 °C
Reaction time: 36 h
Yield: 29 %

Procedure:
Cyclopropyl boronic acid (11 g, 127 mmol), Copper acetate (17.4 g, 95.7 mmol), Pyridine (17.7 g, 223 mmol) and triethylamine (22.4 mL, 160 mmol) were added successively to a solution of ethyl 5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Preparation 100, 6.63 g, 31.9 mmol) in THF (70 mL) and the resulting mixture was allowed to stir at 60° C. for 36 hours. The reaction mixture was filtered over a celite bed and filtrate was concentrated in vacuo and diluted with EtOAc (200 mL). The organic layer was washed with 1N HCl (1×25 mL), brine (1×25 mL) and dried (Na2SO4) and evaporated in vacuo. The crude material was purified by silica gel column chromatography eluting with Hexane:EtOAc 85:15 to afford the title compound as brown solid (29%, 2.3 g).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CCN(C(C)C)C(C)C>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH:25][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: Nc1nccs1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(Nc2nccs2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, thiazol-2-ylamine and DIEA to give 2-(thiazol-2-ylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 339 (MH+).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][C:19](OC)=O)=[CH:12][CH:11]=1.O>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[NH:3]1[CH2:2][CH2:1][N:4]=[C:19]1[CH2:18][CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([NH2:9])=[CH:15][CH:14]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: NCCN
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(CCCC2=NCCN2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
Ethylenediamine (6.23 mL, 93.1 mmol) was added dropwise to a stirred solution of AlMe3/Tol (58 mL, 2M), so that the temperature did not exceed −20° C. The reaction mixture was stirred at room temperature for 10 min, then to the mixture was added dropwise a solution of the compound 27 (4.5 g, 23.3 mmol) in Toluene (290 mL). The reaction mixture was stirred at 120° C. for overnight. After cooling, the solution was treated dropwise with water, diluted DCM and CH3OH and filtered with over MgSO4. The filtrate was concentrated and purified with silica gel column chromatography (EtOAc:CH3OH:TEA=3:1:0.2) to give the compound 55 (4.5 g, 96%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ6.96 (d, 2H, J=8.3 Hz), 6.62 (d, 2H, J=8.3 Hz), 3.56 (s, 4H), 2.55 (t, 2H, J=7.4 Hz), 2.23 (d, 2H, J=7.4 Hz), 1.84-1.94 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:22])[C:4]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](NC(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.Cl>ClCCl.O1CCOCC1>[F:22][C:2]1([F:1])[C:4]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH2:6][CH2:5]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)NN1CCC2(CC2(F)F)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: FC1(F)CC12CCNc1ccccc12
Yield: 890.3 %

Procedure:
0.105 g of tert-butyl 2,2-difluoro-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-quinoline]-1′-carbamate is dissolved in 5 ml of dichloromethane and then 7.78 ml of a 4N solution of hydrochloric acid in dioxane are added. Stirring is maintained for 14 hours. After evaporating, the residue is taken up in dichloromethane and then hydrolyzed with a saturated solution of sodium hydrogencarbonate in water. The mixture is extracted twice with dichloromethane. The organic phases are combined, washed with water and then with a saturated solution of sodium hydrogencarbonate in water and then dried over magnesium sulfate and the solvent is evaporated under reduced pressure. 0.588 g of 2,2-difluoro-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-quinoline] is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:27]>CN(C=O)C>[Cl:27][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([S:23][CH3:24])[N:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: CSc1nccc(-c2cc(C#N)c(O)nc2-c2ccc(F)cc2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cc(C#N)c(Cl)nc2-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 60.1 %

Procedure:
A mixture of 6-(4-fluorophenyl)-2-(hydroxy)-5-(2-methylsulfanylpyrimidin-4-yl)pyridin-3-carbonitrile (48.84 g, 144.6 mmol, obtained in reference example 21), POCl3 (166 mL, 1.8 mol) and DMF (2.2 mL) was heated to 100° C. for 2 h. It was allowed to cool to room temperature and concentrated. It was cooled with an acetone-CO2 bath and EtOAc and ice were subsequently added. The organic phase was decanted, washed with saturated NaHCO3, dried over Na2SO4 and concentrated to dryness. The crude obtained was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity, to afford 31.00 g of the title compound (yield: 60%).
Reaction SMILES: [Cl:1][C@@H:2]([CH3:22])[CH2:3][C@H:4]([CH3:21])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)[CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[CH2:23]([C:26]1[CH:31]=[CH:30][C:29]([O:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C@@H:4]([CH3:21])[CH2:3][C@@H:2]([Cl:1])[CH3:22])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)=[CH:28][CH:27]=1)[CH2:24][CH3:25]
Reactant: CCCc1ccc(O)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCc1ccc(OC(=O)c2ccc(-c3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1
Yield: 62.3 %

Procedure:
0.47 g of (S,S)-4-[4'-(3"-chloro-1"-methylbutoxy)-phenyl]benzoic acid, 0.20 g of 4-n-propylphenol, 0.32 g of dicyclohexylcarbodiimide, 0.04 g of 4-pyrrolidino-pyridine and 6 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (17:3) as a developing solvent. Thus 0.4 g of the title compound was obtained.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[N:27]1([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[N:28]1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]5[CH:34]=[CH:33][C:32]([N:27]6[CH:31]=[CH:30][CH:29]=[N:28]6)=[CH:40][CH:39]=5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(-n2cccn2)cc1

Procedure:
The title compound, white solid (112 mg, 90%), MS (ISP) m/z=499.3 [(M+H)+], mp 258.5° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-pyrazol-1-yl-benzoic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(NCCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(NCCc2ccccc2)cc1

Procedure:
A mixture of 15 g. of N-(2-phenylethyl)-p-nitroaniline, 100 ml. of methanol, and 2.5 g. of 10% palladium on carbon catalyst is shaken under 1 to 2 atmospheres of hydrogen until uptake of the hydrogen ceases. The resultant reaction mixture is filtered through celite and washed with methanol. The filtrate is concentrated in vacuo to yield the product, N-(2-phenylethyl)-p-phenylenediamine, as an oil which can be converted to the dihydrochloride, m.p. 247°C. by bubbling hydrogen chloride gas through a solution of the oil in ether for 1/2 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(I)cc1Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(I)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
A solution of 2-chloro-4-iodoaniline (25 g, 96.66 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C. and then treated with acetic anhydride (50.6 g, 500 mmol). The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was then concentrated in vacuo to remove tetrahydrofuran. The residue was crystallized from ether (50 mL) and hexanes (50 mL). The solids were collected and washed with hexanes to afford N-(2-chloro-4-iodo-phenyl)-acetamide (23.87 g, 84%) as a white crystalline solid: EI-HRMS m/e calcd for C8H7ClINO (M+) 295.1526, found 295.1532.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:25][CH2:26][CH3:27])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:7](=[O:9])[CH:8]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:33][C:8]1[C:7](=[O:9])[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:5]([CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCCc1nc(CC)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 4′-[(4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (4.95 g) and sodium acetate (1.25 g) in acetic acid (100 mL) was added bromine (0.78 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (4.3 g, 71%) as a colorless solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15]C)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]=12)=[O:4].Br>C(O)(=O)C>[OH:15][C:7]1[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]2=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1
Reactant: COC(=O)c1cc(OC)cc2c1CC(C)O2
Agent: Br
Solvent: CC(=O)O
Product: CC1Cc2c(cc(O)cc2C(=O)O)O1

Procedure:
To a solution of 35 grams of 2,3-dihydro-6-methoxy-2-methyl-4-benzofurancarboxylic acid methyl ester, prepared in Example 1, in 160 cc of acetic acid, 60 cc of 48%HBr are added and the resulting mixture is refluxed for 16 hours. After this time the reaction mixture is concentrated to dryness and the residue is dissolved in concentrated NaOH. The obtained solution, heated in a hot water-bath for 2 hours, is then cooled, acidified with concentrated HCl and extracted with ether. Evaporation of the ether extract affords a crude residue which is purified by column chromatography using a mixture CHCl3 -MeOH as the eluting system wherein the percentage of MeOH is gradually increased. The compound of the title, recovered from the last fractions (CHCl3 + 3% MeOH), is then crystallized from ethyl ether-petroelum ether. Yield 14.2 g (47 percent of theoretical). M.p. 225°-27° C.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@@H:4]1[C@H:6]([C:7]([OH:9])=[O:8])[C:5]1([CH3:11])[CH3:10].Br[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=1.N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]([C:12]([F:13])([F:14])[F:15])=[CH:3][C@@H:4]1[C@H:6]([C:7]([O:9][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=2)=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Reactant: Fc1cc(CBr)ccn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1ccnc(F)c1
Yield: 77.5 %

Procedure:
By the method of Example 21, 0.970 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylic acid and 0.75 g (0.004 mole) of 4-bromomethyl-2-fluoropyridine (Example 22) were reacted in the presence of 0.609 g (0.004 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 20 ml of acetonitrile to produce 1.09 g of (2-fluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate, compound 28 in the Tables below. The ir, proton nmr, and 19c nmr spectra were all consistent with the proposed structure.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][C@@:17]1([C:25]#[CH:26])[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>>[CH:9]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([OH:8])[C:26]#[C:25][C@:17]2([O:16][CH3:15])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: C#C[C@@]1(OC)CN2CCC1CC2
Product: CO[C@]1(C#CC(O)(c2ccccc2)C2CCCCC2)CN2CCC1CC2

Procedure:
1-cyclohexyl-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propyn-1-ol 201 was prepared as described in 4.1 (method 1) using cyclohexyl(phenyl)methanone and (3R)-3-ethynyl-1-azabicyclo[2.2.2]oct-3-yl methyl ether 53.
Reaction SMILES: [N:1]([C:4](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[C:5]([O:7][CH3:8])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[NH:1][C:15]2[C:10]([CH:9]=1)=[C:11]([Cl:16])[CH:12]=[CH:13][CH:14]=2)=[O:6]
Reactant: COC(=O)C(=Cc1ccccc1Cl)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(Cl)cccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-azido-3-(2-chlorophenyl)-propenoate (3.566 g, 144 mmol) was suspended in toluene (800 ml) and the mixture was heated at reflux for three hours, then cooled and allowed to stir at room temperature overnight. A yellow crystalline material was obtained by filtration and recrystallised from hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=C(C#N)[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1.[ClH:19].[C:20]([OH:23])(=[O:22])[CH3:21]>>[ClH:19].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:21]([C:20]([OH:23])=[O:22])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:18]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(c1)Sc1ccc(N)cc1C=C2
Agent: Cl
Product: Nc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2

Procedure:
850 Mg. 8-amino-3-cyanodibenzo[b,f]-thiepin is refluxed in a mixture of 20 cc. acetic acid and 20 cc. concentrated hydrochloric acid for 48 hours. The suspended solid is filtered, washed with some acetic acid, dried overnight under vacuum at 70° C. to yield 600 mg. pure compound, m.p. 308°-311° C.
Reaction SMILES: [ClH:1].C([NH:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[N:11]=1)(=O)C>C(O)C>[ClH:1].[ClH:1].[NH2:5][CH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[N:13]=[C:14]([N:17]=[C:18]([NH2:20])[NH2:19])[S:15][CH:16]=2)[N:11]=1
Reactant: CC(=O)NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: Cl
Solvent: CCO
Product: NCc1nc(-c2csc(N=C(N)N)n2)cs1

Procedure:
Concentrated hydrochloric acid (72.4 ml) was added slowly to a suspension of 4-(2-acetylaminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole (6.58 g) in ethanol (280 ml). The mixture was refluxed for 2 hours. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 4-(2-aminomethylthiazol-4-yl)-2(diaminomethyleneamino)thiazole dihydrochloride (6.98 g).
Reaction SMILES: P(=O)(O)(O)O.[CH2:6]([O:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:22][C@@H:21]3[C@H:17]2[CH2:18][CH2:19][N:20]3C(OC(C)(C)C)=O)=[N:13][C:12]=1[CH3:30])=[O:10])[CH3:7].O>ClCCl>[C@@H:21]12[CH2:22][N:16]([C:14]3[S:15][C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])=[C:12]([CH3:30])[N:13]=3)[C@@H:17]1[CH2:18][CH2:19][NH:20]2
Reactant: CCOC(=O)c1sc(N2C[C@@H]3[C@H]2CCN3C(=O)OC(C)(C)C)nc1C
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1sc(N2C[C@H]3NCC[C@H]32)nc1C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
85% phosphoric acid (0.44 mL, 3.78 mmol) was added to a solution of tert-butyl (1R,5R)-6-[5-(ethoxycarbonyl)-4-methyl-1,3-thiazol-2-yl]-2,6-diazabicyclo[3.2.0]heptane-2-carboxylate obtained in Example (236b) (278 mg, 0.76 mmol) in dichloromethane (1 mL) at room temperature, followed by stirring for two hours. Water was added to the reaction solution, and the mixture was washed with ethyl acetate. Then, a 1 N aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with an ethyl acetate/methanol mixed solvent. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the solvent was evaporated under reduced pressure to obtain 175 mg of the title compound as a pale yellow oily substance (87%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:20])([C:16]([F:19])([F:18])[F:17])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([Br:21])[C:3]=1[NH:22][C:23](=[O:38])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[C:26]([N+:35]([O-])=O)[CH:25]=1.Cl>C(O)C.O.[Fe]>[NH2:35][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C:23]([NH:22][C:3]1[C:2]([Br:1])=[CH:7][C:6]([C:8]([F:20])([C:16]([F:17])([F:18])[F:19])[C:9]([F:14])([F:15])[C:10]([F:12])([F:13])[F:11])=[CH:5][C:4]=1[Br:21])=[O:38]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1ccc(-n2cncn2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc2Br)ccc1-n1cncn1
Temperature: 80 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of N-[2,6-dibromo-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-phenyl]-3-nitro-4-(1,2,4-triazol-1-yl)benzamide (Example I2) (675 mg, 0.98 mmol) in a mixture of ethanol and water (20 ml and 4 ml, respectively) was added aqueous hydrochloric acid (37% w/v) (0.25 ml) and iron metal powder (5550 mg, 9.8 mmol). The reaction mixture was stirred at 80° C. for 1 hour. The mixture was filtered through a silica gel pad and the filtrate concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:1) to give Compound No. B4 of Table B (372 mg, 58% yield).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]>C(O)C.O=[Pt]=O>[CH2:16]([CH:13]1[CH2:14][CH2:15][CH:10]([CH:7]2[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]2)[CH2:11][CH2:12]1)[CH2:17][CH3:18]
Reactant: CCCc1ccc([C@H]2CC[C@H](CCC)CC2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCCC1CCC(C2CCC(CCC)CC2)CC1

Procedure:
A solution of 24.4 g of trans-1-p-propylphenyl-4-propylcyclohexane in 500 ml of ethanol is hydrogenated over 1 g of PtO2 for 1 hour at 60° and 100 bar, and the mixture is cooled, filtered and evaporated to give 4,4'-dipropylbicyclohexyl in the form of an oily mixture of isomers, which is taken up in 200 ml of boiling methanol. The resulting hot solution is poured into a boiling solution of 70 g of thiourea in 300 ml of methanol. The mixture is cooled to 0°, and the adduct which has been precipitated is filtered off and extracted by boiling with 300 ml of pertroleum ether (b.p. 40°-60°). The undissolved residue is heated with 350 ml of 2N aqueous potassium hydroxide solution for 30 minutes at 50°. The solution is acidified with H2SO4 to give, after customary working up, trans,trans-4,4'-dipropylbicyclohexyl, c.p. 41°.