Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][OH:23])[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCC(CO)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.4 %

Procedure:
To a solution of 6.0 grams (0.01 mole) of (±)-1-S-hexadecyl-2-O-methyl-3-O-tritylthioglycerol in 100 milliliters of chloroform:methanol (3:1) was added 0.2 gram of p-toleunesulfonic acid and the reaction stirred at room temperature for 24 hours. The reaction mixture was neutralized with 1.0 gram of sodium bicarbonate and then extracted three times with 200 milliliter portions of water. The nonaqueous layer was separated and the solvent removed in vacuo to give the crude product as an oil. Silica gel chromatography (CHCl3 eluent) provided 3.1 grams (89%) of pure product as a semi-waxy solid. 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 28H, (CH2)14 ], 2.58 (m, 2H, --S--CH2), 2.62 (m, 2H, CH--CH2 --S--), 3.40(m, 1H, CH), 3.44(s, 3H, CH3 --O--), 3.75(m, 2H, CH2 --OH).
Reaction SMILES: [OH-].[K+].[O:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH2:5][CH2:4]1.[CH3:14][C:15]1[N:19]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:17][C:16]=1[CH:39]=O>CO>[CH3:14][C:15]1[N:19]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:18]=[N:17][C:16]=1/[CH:39]=[C:5]1\[CH2:4][O:3][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]\1=[O:13]
Reactant: O=C1CCOc2ccccc21
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(/C=C2\COc3ccccc3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 3 h
Yield: 95 %

Procedure:
A solution of potassium hydroxide (0.5 g) in methanol (5 ml) was added to a solution of 4-chromanone (0.84 g) and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (2 g) in methanol (25 ml) with warming, and the resulting solution was stirred at 50° for 3 h. The resultant precipitate was filtered off, washed with methanol (25 ml) and dried to give the title compound (2.6 g), m.p. 231°-233°.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(O)[CH2:9]1)(C)(C)C.COCCN(S(F)(F)[F:34])CCOC.CO>C(Cl)Cl>[F:34][C:10]1([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:11][CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCCC(O)(Cc2ccccc2F)C1
Solvent: ClCCl
Solvent: CO
Product: NC1CCCC(F)(Cc2ccccc2F)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl-3-(2-fluorobenzyl)-3-hydroxycyclohexylcarbamate (1 mmol, 323 mg) in DCM was added Deoxo-Fluor® (2 mmol, 370 μL) at room temperature. The reaction mixture was stirred for overnight. Methanol was added dropwise. The desired product was obtained after the removal of solvent by rotary evaporation.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH:15][CH3:16]>CCO>[CH3:14][N:15]([CH3:16])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CNC
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CN(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of 4-fluoro-3-nitrobenzoic acid (1 g; 5.4 mmol) in EtOH (5 mL) was added dimethylamine (730 mg; 16.2 mmol). The resulting mixture was stirred at RT for 18 h and 4 h at 70° C. The reaction mixture was then partitioned between water (10 mL) and Et2O (15 mL), washed with Et2O (10 mL). The aqueous phase was acidified to pH ˜5 with AcOH and washed with Et2O (2×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give the title compound as a yellow powder (1.02 g, 90%). 1H NMR (DMSO-d6, 300 MHz) δ 12.9 (bs, 1H), 8.24 (d, J=2 Hz, 1H), 7.92 (dd, J=8.9, 2 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 2.92 (s, 6H). HPLC (Method A) Rt 2.44 min (purity: 97.2%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16](=[O:21])[CH2:17][C:18](=[NH:20])[NH2:19])[CH3:14]>C(O)C>[CH2:13]([O:15][C:16]([C:17]1[CH:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[C:17]([C:16]([O:15][CH2:13][CH3:14])=[O:21])=[C:18]([NH2:19])[NH:20][C:18]=1[NH2:19])=[O:21])[CH3:14]
Reactant: O=Cc1ccnc2ccccc12
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccnc2ccccc12
Yield: 58 %

Procedure:
Upon heating a solution of 7.8 g quinoline-4-aldehyde and 13.0 g amidinoacetic acid ethyl ester in 200 ml ethanol for 2 hours, 2,6-diamino-4-(quinol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 145° (ethanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Br:11])[C:3]=1[CH:4]=O.Cl.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][NH2:22].C([O-])(=O)C.[Na+]>CO>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][N:22]=[CH:4][C:3]1[C:2]([Br:1])=[CH:9][C:8]([CH3:10])=[CH:7][C:6]=1[Br:11]
Reactant: NNc1ccc(F)cc1F
Reactant: Cc1cc(Br)c(C=O)c(Br)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Br)c(C=NNc2ccc(F)cc2F)c(Br)c1
Yield: 74.9 %

Procedure:
2,6-Dibromo-4-methylbenzaldehyde (89.5 g, 0.322 mol), (2,4-difluorophenyl)hydrazine hydrochloride (58.25 g, 0.322 mol) and sodium acetate (26.9 g, 0.328 mol) were heated in methanol (1.25 L) at reflux for 3.5 hours. The mixture was cooled and the precipitate was collected by filtration and partitioned between ethyl acetate (750 mL) and water (250 mL). The ethyl acetate layer was combined with a second ethyl acetate extract, washed successively with water and brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford the title compound as an off-white solid (97.5 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:25]([OH:37])[C@H:24]([OH:38])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:41][O:42][C:43]1[CH:48]=[CH:47][C:46]([CH2:49]Br)=[CH:45][CH:44]=1>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:25]([O:37][CH2:49][C:46]3[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=3)[C@H:24]([O:38][CH2:49][C:46]3[CH:47]=[CH:48][C:43]([O:42][CH3:41])=[CH:44][CH:45]=3)[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(CCOCc4ccccc4)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Reaction time: 1.5 h
Yield: 50 %

Procedure:
A solution of 132 (12 g, 21 mmol) in DMF (60 mL) was treated with sodium hydride (2.9 g, 84 mmol, 70% dispersed by mineral oil) for 30 minutes at 0° C., followed by addition of PMBBr (25 g, 126 mmol). After additional 1.5 hours at 15° C., the reaction was quenched with water (200 mL), and extracted with dichloromethane (3×100 mL). The combined organic layer was washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 5%-20% ethyl acetate in petroleum ether to afford 133 as light yellow oil (8.5 g, 50%). (ES, m/z) [M+H]+ 809.0; 1H NMR (300 MHz, CDCl3) δ 7.21-7.34 (m, 9H), 6.82-6.89 (m, 4H), 6.08 (d, J=6.3 Hz, 1H), 4.52-4.57 (m, 4H), 4.50 (s, 2H), 4.33-4.35 (m, 1H), 4.05-4.06 (m, 1H), 3.84-3.91 (m, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.58-3.66 (m, 2H), 3.31-3.54 (m, 5H), 1.56 (s, 9H), 0.96 (s, 9H), 0.14 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: Cl.CN(CCCN=C=NCC)C.[NH2:13][CH2:14][C:15]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21]2[C:16]=1[N:17]=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[N:20]2.[CH3:32][O:33][P:34]([CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])([O:36][CH3:37])=[O:35]>C(Cl)Cl>[CH3:29][O:28][C:19]1[C:18]([O:30][CH3:31])=[N:17][C:16]2[C:21](=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:15]=2[CH2:14][NH:13][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][P:34]([O:33][CH3:32])([O:36][CH3:37])=[O:35])[N:20]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Reactant: COP(=O)(CCCC(=O)O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(=O)CCCP(=O)(OC)OC)c2nc1OC
Reaction time: 30 h

Procedure:
163 mg (0.851 mmol) of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride are added at room temperature to a solution of 150 mg (0.568 mmol) of 5-aminomethyl-2,3-dimethoxy-7-nitroquinoxaline and 165 mg (0.738 mmol) of 4-(dimethylphosphono)butyric acid in 3 ml of methylene chloride and the mixture is stirred for 30 hours. The mixture is then diluted with methylene chloride and washed with 0.2N hydrochloric acid and brine and concentrated on a rotary evaporator, and the residue is dried in a high vacuum. The title compound is obtained as a yellow resin.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:16][CH2:17][CH:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:34][CH:35]=4)[CH2:19][CH2:20]3)=[CH:7][CH:6]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)c1ccc(OCCCC2CCNCC2)cc1
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1ccc(OCCCC2CCN(c3ccc(-c4ccc(F)cc4)nn3)CC2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A mixture of 2.1 parts of 3-chloro-6-(4-fluorophenyl)pyridazine, 2.9 parts of ethyl 4-[3-(4-piperidinyl)propoxy]benzoate, 1.1 parts of sodium carbonate and 2 parts of N,N-dimethylacetamide was stirred for 2 hours in an oil bath at 140° C. The reaction mixture was diluted with water while cooling. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 3.4 parts (73.3%) of ethyl 4-[3-[1-[6-(4-fluorophenyl)-3-pyridazinyl ]-4-piperidinyl]propoxy]benzoate; mp. 160.4° C. (comp. 81).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:11])=[C:7]([CH2:9][CH3:10])[CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)[Cl:14].O>CCCCCC>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][CH3:10])=[C:6]([CH3:11])[N:5]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCc1cc(C#N)c(=O)[nH]c1C
Solvent: O
Solvent: CCCCCC
Product: CCc1cc(C#N)c(Cl)nc1C

Procedure:
3-Cyano-5-ethyl-6-methyl-2-(1H)-pyridinone (22.9 g, .141 mol) and phosphorus pentachloride (33.1 g, 0.159 mol) were intimately mixed and heated at 110°-120° C. for one hour. The liquified solids were poured onto crushed ice and water and the semi-solid was extracted into chloroform. This extract was washed with water, saturated aqueous NaHCO3, dried (Na2SO4), filtered and evaporated. This amber oil was dissolved in hexane and the insoluble material was removed when filtered through a pad of charcoal. Removal of the solvent gave a light yellow oil which solidified (17.7 g). Trituration of this solid with cold hexane yielded pure product, m.p. 63°-64° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 29.46 g (170.3 mmol) of 3-bromophenol (distilled) and 16.41 g (20.9 ml, 221.3 mmol) of t-butanol in 100 ml of carbon tetrachloride was added 20.0 ml of conc. sulfuric acid. The clear, colorless solution turned a dark magenta color and became hot. The solution was cooled in water (ambient temperature) and allowed to stir at room temperature for 84 hours. The reaction mixture was neutralized with sat. aqueous NaHCO3 solution (pH -7.0), partitioned between 300 ml of water and 500 ml of dichloromethane, and the organic and aqueous layers were separated. The aqueous phase was washed with 2×500 ml-portions of dichloromethane. All organic phases were combined, washed with 400 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) followed by kugelrohr distillation yielded the title compound as a clear, slightly yellow oil.
Reaction SMILES: OO.B(F)(F)F.CC[O:9]CC.OC([C:16]1[C:17]([CH3:41])=[C:18]2[C:23]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)=[C:22]([C:38]#[N:39])[CH:21]=[N:20][N:19]2[CH:40]=1)(C)C>C(Cl)Cl>[OH:9][C:16]1[C:17]([CH3:41])=[C:18]2[C:23]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:29][CH:30]=3)=[C:22]([C:38]#[N:39])[CH:21]=[N:20][N:19]2[CH:40]=1
Reactant: CCOCC
Reactant: Cc1c(C(C)(C)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Agent: FB(F)F
Agent: OO
Solvent: ClCCl
Product: Cc1c(O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 0.17 h
Yield: 64 %

Procedure:
To a mixture of H2O2 (50% wt in H2O, 0.0115 mL, 0.20 mmol) and CH2Cl2 (2 mL) at −5° C. was added BF3.OEt2. The reaction was stirred at −5° C. for 40 min before a solution of compound 145 (56 mg, 0.14 mmol) in CH2Cl2 (3 mL) was added. The reaction was kept at −5° C. for 10 min and quenched with an aqueous solution of Na2SO3 (2 g, 10 mL). The reaction was diluted with CH2Cl2 and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×10 mL). The CH2Cl2 layers were combined and concentrated in vacuo to give a brown oil. This crude oil was purified by silica gel flash chromatography (eluted with 10% EtOAc/CH2Cl2) to give compound 146 as a yellow solid (32 mg, 64%). HPLC: 90% at 1.89 min (retention time) (Phenom-Prime S5 C18 column, 4.6×30 mm, eluting with 10-90% aqueous methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at 220 nm). MS (ES): m/z 357 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][O:4][C:5]([N:7]1[CH2:27][C@H:26]([OH:28])[CH2:25][C@H:8]1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:49][O:50][CH:51]=[CH:52][C:53]1[CH:58]=[CH:57][C:56](O)=[CH:55][CH:54]=1>C1C=CC=CC=1>[CH3:1][CH:2]([CH3:29])[CH2:3][O:4][C:5]([N:7]1[CH2:27][C@@H:26]([O:28][C:56]2[CH:57]=[CH:58][C:53]([CH:52]=[CH:51][O:50][CH3:49])=[CH:54][CH:55]=2)[CH2:25][C@H:8]1[C:9]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:10])=[O:6]
Reactant: COC=Cc1ccc(O)cc1
Reactant: CC(C)COC(=O)N1C[C@H](O)C[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC=Cc1ccc(O[C@H]2C[C@@H](C(=O)OC(c3ccccc3)c3ccccc3)N(C(=O)OCC(C)C)C2)cc1

Procedure:
A mixture of 1-[(2,2-dimethylethoxy)carbonyl]-(trans)-4-hydroxy-L-proline, diphenylmethyl ester, triphenylphosphine, and 4-(2-methoxyethenyl)phenol is taken up in benzene and evaporated to dryness. The residue is dissolved in dry tetrahydrofuran, cooled to -10° under argon, and treated with diethylazodicarboxylate. The reaction mixture is worked up according to the procedure of Example 1(b) to yield 1-[(2,2-dimethylethoxy)carbonyl]-(cis)-4-[4-(2-methoxyethenyl)phenoxy]-L-proline, diphenylmethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([SH:8])[N:3]=1.[OH-].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17]Cl>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[N:3]=1
Reactant: ClCc1ccccn1
Reactant: Nc1ccnc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccnc(SCc2ccccn2)n1
Temperature: 22 °C

Procedure:
4-Amino-2-mercaptopyrimidine (0.40 g, 3.15 mmol) is slurried in ethanol (2 ml) and 3.25 M NaOH (2.0 ml, 6.5 mmol) is added. The solution is heated to reflux for 10 minutes and after cooling to 22° C., 2-picolyl chloride*HCl (0.49 g, 2.98 mmol) is added. The solution is heated to reflux for an additional 15 minutes. The solution is cooled and concentrated in vacuo. The residue is dissolved in 1 N HCl and diluted with ethyl acetate. The mixture is neutralized with NaOH to pH 8 and the aqueous layer is separated and washed twice with ethyl acetate. The combined organic layers are washed with saturated NaHCO3, saturated NaCl, dried with MgSO4 and concentrated in vacuo, mp 133-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][OH:12].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:12][CH2:11][C:10]([F:14])([F:13])[F:9])[N:5]=[CH:4][N:3]=1
Reactant: OCC(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1cc(Cl)ncn1
Reaction time: 60 h

Procedure:
4,6-dichloropyrimidine (20 g) potassium carbonate (37 g) and 2,2,2-trifluoroethanol (10.3 cm3) were stirred together at ambient temperature in dry dimethyl formamide (DMF) (130 cm3) for seven hours. The mixture was stored at ambient temperature for 60 hours before being poured into water. The product was extracted with diethyl ether and the organic layer was washed with saturated brine and dried over magnesium sulfate. Evaporation under reduced pressure afforded 4-chloro-6-(2,2,2-trifluoroethoxy)-pyrimidine as a 1:1.5 mixture with residual DMF. 1H NMR (CDCl3): δ4.79-4.89(2H,q); 6.93(1H, s); 8.61(1H,s). This was used directly in step 2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:19][C:20]#[N:21])[CH2:16][CH:15]([C:17]#[N:18])[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:17]([CH:15]1[CH2:16][C:13]([N:11]2[CH:12]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[N:7]=3)[CH:9]=[N:10]2)([CH2:19][C:20]#[N:21])[CH2:14]1)#[N:18]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CC(C#N)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: N#CCC1(n2cc(-c3ccnc(Nc4ccc(C(=O)O)cc4)n3)cn2)CC(C#N)C1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)-cyclobutanecarbonitrile (300 mg, 0.00100 mol), p-aminobenzoic acid (206 mg, 0.00151 mol), and p-toluenesulfonic acid (150 mg, 0.00085 mol) in dry 1,4-dioxane (8 mL) was refluxed overnight, cooled to room temperature. The solid was filtered and collected to give the titled compound as a cis- and trans-isomer mixture, which was used directly in next step (310 mg, 77.3%). LCMS (M+H) 400.4.
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#N.[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][N:9]=1>>[OH:7][C:8]1[C:12]([C:13]#[N:14])=[C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:3]([CH3:4])[CH3:1])=[CH:20][CH:21]=2)[S:10][N:9]=1
Reactant: N#CCC(N)=O
Reactant: N#Cc1c(O)nsc1Nc1ccccc1
Product: CC(C)c1ccc(Nc2snc(O)c2C#N)cc1

Procedure:
The title compound was prepared from 1-isothiacyanato-4-isopropyl-benzene and 2-cyanoacetamide by the procedure analogous to Method 2 for 3-Hydroxy-5-phenylamino-isothiazol-4-carbonitrile. 1H NMR (CD3OD) δ: 7.2–7.4 (m, 4H); 2.9 (q, 1H); 1.24 (d, 6H); MS (ES, m/z): 259.8, [M-H]+, 258.3 [M-H]−.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([CH2:18][C:19]([OH:21])=[O:20])[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28]O.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl>[CH3:28][O:20][C:19](=[O:21])[CH2:18][C:10]1[C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO
Reactant: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1c(-c2ccccc2)nn(-c2ccccc2)c1-c1ccccc1
Yield: 91 %

Procedure:
15 grams 1,3,5-triphenyl-pyrazol-4-acetic acid, 50 milliliters methanol, 40 milliliters carbon tetrachloride and 0.64 gram concentrated sulfuric acid were mixed and the mixture heated to the boiling temperature under reflux for 11 hours. The cooled reaction mixture was then extracted, first with sodium carbonate solution and thereafter with water. The organic phase was then dried and evaporated. The residue was recrystallized from a mixture of methanol and water. 14.2 grams 1,3,5-triphenyl-pyrazol-4-acetic acid-methyl ester, melting at 80.5°-81.5° C., were obtained, representing a yield of 91%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8](=[O:10])[NH2:9])=[C:6]([CH3:11])[NH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][C:19]([CH3:21])=O>C(O)C.CCCCCC>[C:8]([C:7]1[C:3]([N:2]=[C:19]([CH3:21])[CH3:18])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:5][C:6]=1[CH3:11])(=[O:10])[NH2:9]
Reactant: CC(C)=O
Reactant: Cc1[nH]c(-c2ccccc2)c(N)c1C(N)=O
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)=Nc1c(-c2ccccc2)[nH]c(C)c1C(N)=O
Yield: 82 %

Procedure:
From the compound of Example 33 and acetone, yield 82%, m.p. 221°-223° C. (from ethanol/hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1.[C:14]([N:16]=[C:17](SC)[S:18][CH3:19])#[N:15]>C(O)C>[C:14]([NH:16][C:17](=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1)[S:18][CH3:19])#[N:15]
Reactant: CSC(=NC#N)SC
Reactant: COc1ccnc(CSCCN)c1
Solvent: CCO
Product: COc1ccnc(CSCCN=C(NC#N)SC)c1
Reaction time: 8 h

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-4-methoxypyridine (3.15 g) in ethanol (25 cc) was added over 1 hour to a stirred solution of dimethyl N-cyano-dithioimidocarbonate (2.215 g) in ethanol (30 cc) at 22° and the mixture was allowed to stand overnight at room temperature. Nitrogen was passed through the suspension and the mixture was filtered to give N-cyano-N'-[2-((4-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea m.p. 91.5°-92.5°. (3.9 g).