Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5](=[O:62])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH:57]([CH3:59])[CH3:58])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:61])[N:7]2[C: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].[I-].[Na+].Br.[OH:66][C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][C:75]=1[OH:76])[CH2:72][NH:71][CH2:70]2.C(N(CC)CC)C>CC(C)=O>[OH:66][C:67]1[CH:68]=[C:69]2[C:73](=[CH:74][C:75]=1[OH:76])[CH2:72][N:71]([CH2:2][C:3]1[CH2:4][S:5](=[O:62])[C@@H:6]3[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH:57]([CH3:59])[CH3:58])/[C:30]4[N:31]=[C:32]([NH:35][C:36]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[S:33][CH:34]=4)[C:25](=[O:61])[N:7]3[C: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])[CH2:70]2
Reactant: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Oc1cc2c(cc1O)CNC2
Agent: Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CN3Cc4cc(O)c(O)cc4C3)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
2.0 g (2.26 mmol) of Benzhydryl 3-chloromethyl-7-[(Z)-2-isopropoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate 1-oxide was dissolved in 40 ml of acetone, and 750 mg (5 mmol) of sodium iodide was added thereto under cooling with ice. The mixture was stirred for 30 minutes. The reaction solution was concentrated under reduced pressure. To the residue, ethyl acetate and water were added. The organic layer was washed with a sodium metabisulfite aqueous solution and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The oily residue was dissolved in 10 ml of N,N-dimethylformamide, and 790 mg (3.4 mmol) of 5,6-dihydroxyisoindoline hydrobromide was added thereto, then 0.47 ml (3.38 mmol) of triethylamine was dropwise added at room temperature. The reaction solution was stirred at the same temperature for 2 hours, and then N,N-dimethylformamide was distilled off under reduced pressure. To the residue, chloroform and water were added. The organic layer was washed with water and with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flush column chromatography (5% methanol-chloroform) to obtain 1.74 g (yield: 78%) of the above-identified compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:8]3[C:15]([CH3:16])=[C:14]([CH3:17])[NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C(#N)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:16][C:15]1[C:8]2[C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])=[CH:3][CH:4]=3)=[N:12][CH:11]=[N:10][C:9]=2[NH:13][C:14]=1[CH3:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1[nH]c2ncnc(Oc3ccc(N)cc3)c2c1C
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Cc1[nH]c2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)c2c1C
Reaction time: 1 h

Procedure:
4-(4-Aminophenoxy)-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine was dissolved in toluene (16 mg) (0.8 ml) and acetonitrile (0.5 ml) under reflux, and then 4-fluorophenylisocyanate (7.9 μM) was added. The mixture was stirred for 1 hour and returned to room temperature, and then the reaction system was concentrated, diethyl ether was added to the residue, and the resulting crystals were filtered out. The crystals were washed with diethyl ether to obtain the title compound (5 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.O.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@H:12]([CH3:14])[CH2:11][C@@H:10]([N:15]([CH3:23])[C:16](=[O:22])[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:34][NH:35]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: NN
Reactant: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: CCO
Solvent: O
Product: C[C@@H]1C[C@@H](N(C)C(=O)CC(C)(C)C)CN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 120 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
To N-{(3R,5R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-3-piperidinyl}-N,3,3-trimethylbutanamide (82 mg, 0.187 mmol) in ethanol (4 mL) was added hydrazine monohydrate (1 mL, 20.4 mmol), and the reaction mixture was stirred for 4 hours at 120° C. into a sealed vessel. The reaction was allowed to cool down to room temperature, and poured onto water (˜120 mL). The resulting aqueous mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (36 mg) as an off-white solid as a 3:2 mixture of rotamers. LC-MS (ES) m/z=451 [M+H]+. 1H NMR (400 MHz, DMSO-d6+1 drop D2O): δ 0.98 (m, 12H), 1.41 and 1.52 (m, 1H), 1.87-2.41 (m, 4H), 2.76 and 2.90 (s, 3H), 2.99-3.25 (m, 2H), 3.84-3.99 (m, 1H), 4.01-4.26 (m, 1H), 4.39-4.66 (m, 1H), 6.57-6.62 (s, 1H), 7.50-7.60 (m, 1H), 7.70 (m, 1H), 7.92 (s, 1H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][C@H:21]([CH3:25])[CH2:22][O:23][CH3:24])[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC[C@@H](C)Oc1cc(N)ncc1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC[C@@H](C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenyl chloroformate (1.53 ml, 12.2 mmol) was added drop wise to a mixture of (R)-6-amino-4-((1-methoxypropan-2-yl)oxy)nicotinonitrile (intermediate 146, 1.37 g, 5.55 mmol) and pyridine (0.99 ml, 12.2 mmol) in THF (60 ml) at 0° C. The reaction mixture was stirred for 12 h at room temperature and additional pyridine (0.98 ml, 12.2 mmol) and phenyl chloroformate (1.53 ml, 12.2 mmol) were added. After stirring for a further 36 h at room temperature the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer washed with saturated brine, dried over MgSO4 and evaporated. The residue was triturated with Et2O and the product obtained by filtration as a white solid. (UPLC-MS 6) tR 1.04; ESI-MS 328.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)Cl)[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[C:1]1([O:3][C:4](=[O:20])[CH:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[C:14]2[NH:23][CH:24]=[CH:25][N:21]=2)[CH:2]=[CH:8][CH:7]=[CH:5][CH:4]=1.[CH2:1]([O:3][C:4](=[O:20])[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[C:22]1[NH:21][CH:25]=[CH:24][N:23]=1)[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)C(Cl)(c1ccccc1)c1ccc(Cl)cc1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)(c1ccc(Cl)cc1)c1ncc[nH]1
Product: O=C(Oc1ccccc1)C(c1ccc(Cl)cc1)c1ncc[nH]1

Procedure:
15.45 g (0.05 mole) phenyl-p-chlorophenyl-chloroacetic acid ethyl ester (prepared from p-chlorophenyl-magnesium bromide and benzoyl-formic acid ethyl ester and subsequent treatment with thionyl chloride: b.p. 160°C./0.2 mm Hg) are boiled with 10 g imidazole in 100 ml acetonitrile for 16 hours. After distilling off the solvent, 50 ml of water are added, and the mixture is extracted with methylene chloride. After drying, the solvent is distilled off in a vacuum and the phenyl-p-chlorophenyl-imidazolyl-acetate acid ethyl ester i.e. phenyl-4-chlorophenyl-imidazolyl-acetic acid ethyl ester is obtained in the form of an oil which solidifies after a fairly long time.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenylacetic acid, 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of dimethylaminopyridine are dissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol) of dicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, the mixture is stirred at 25° C. for 20 h, the precipitated urea is filtered off with suction and washed with 200 ml of dichloromethane, and the organic phase is washed twice each with 500 ml of 2N hydrochloric acid and water. The organic phase is concentrated and distilled.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH2:30]>CN1C(=O)CCC1>[NH2:30][C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[NH:31][C:16]1[S:17][C:13]2[CH:12]=[C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:23])[CH:9]=3)[CH:22]=[CH:21][C:14]=2[N:15]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4N)sc3c2)ccn1
Temperature: 105 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmole) in 400 μL of NMP was added (1R,2R)-cyclohexane-1,2-diamine (17 mg, 150 μmole). The reaction solution was stirred at 105° C. for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give 4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (12 mg, 30 μmole) as white powder. ES/MS m/z 398.1 (MH+).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[N:13]1([CH2:22][N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH2:47][CH3:48])[N:25]=[C:24]2[CH3:49])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1>C(OCC)(=O)C>[N:13]1([CH2:22][N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH2:47][CH3:48])[N:25]=[C:24]2[CH3:49])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(Cn2nnc3ccccc32)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cn2nnc3ccccc32)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.73 g), sodium hydrogen carbonate (1.02 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-{[1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.55 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.23 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.35 g, 56%).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>CN(C=O)C.C(Cl)Cl>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:20])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-phenoxybenzoic acid (500 mg, 2.33 mmol) and DMF (1 drop) in CH2Cl2 (10 mL) under argon was added oxalyl chloride (1.3 mL, 2.0M in CH2Cl2, 2.6 mmol) dropwise. Bubbling of escaping gasses continued for 5 min after addition. The reaction was stirred at room temperature for 1 h, then concentrated in vacuo to give the title compound as a crude pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:11]([O:18][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)COCc1ccccc1

Procedure:
71 ml of ethyl 4-chloro-3-oxobutyrate are reacted with 121.4 g of benzoic acid and 132 ml of triethylamine in 1 l of toluene by the procedure described in Example 4. After removal of the solvent by distillation, the residue is a virtually pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH3:17])=[N:13][C:12]([SH:18])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:19]([O-:22])(O)=[O:20]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH3:17])=[N:13][C:12]([S:18][S:18][C:12]3[N:13]=[C:14]([CH2:15][CH2:16][CH3:17])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:19]([O-:22])=[O:20])=[CH:5][CH:6]=4)[N:11]=3)=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCc1nc(S)nn1-c1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CCCc1nc(SSc2nc(CCC)n(-c3ccc([N+](=O)[O-])cc3)n2)nn1-c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 35 parts of 1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole-3-thiol, 83 parts of concentrated nitric acid solution and 150 parts of water is stirred and warmed to 60° C. While stirring, the mixture is allowed to cool to room temperature and the whole is further stirred overnight at room temperature. The precipitated product is filtered off, washed with water and added to a hot solution of 20 parts of potassium carbonate in 200 parts of water at 100° C. The reaction mixture is allowed to cool to room temperature while stirring. The precipitated product is filtered off, dried and crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 19.8 parts of 3,3'-dithiobis[1-(4-nitrophenyl)-5-propyl-1H-1,2,4-triazole]; mp. 171.5° C.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([Cl:14])([Cl:13])[Cl:12])=[N:9][CH:10]=1)[CH3:4].[N:15]#[C:16][NH2:17].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[Cl:12][C:11]([Cl:14])([Cl:13])[C:8]1[N:9]=[CH:10][C:5]([CH:3]([S:2]([CH3:1])=[N:17][C:16]#[N:15])[CH3:4])=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(Cl)(Cl)Cl)nc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(c1ccc(C(Cl)(Cl)Cl)nc1)S(C)=NC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
To a stirred solution of 5-[1-(methylthio)ethyl]-2-(trichloromethyl)-pyridine (B) (0.55 g, 2.3 mmol) and cyanamide (0.097 g, 2.3 mmol) in THF (7 mL) cooled to 0° C. was added iodobenzene diacetate (0.75 g, 2.3 mmol) in one portion. The resulting mixture was stirred at 0° C. for 1 hr and then at room temperature for 2 hr. The solvent was removed in vacuo and the resulting mixture was purified on silica gel using 50% acetone in hexane (v/v) to give 0.254 g of {1-[6-(trichloromethyl)pyridin-3-yl]ethyl}(methyl)-λ4-sulfanylidenecyanamide (3) as an off-white solid in 40% yield. 1H NMR for the diastereomeric mixture (300 MHz, d6-acetone) δ 8.87 (s, 1H), 8.21-8.25 (m, 2H), 4.65-4.76 (m, 1H), 2.86-2.66 (m, 3H), 1.88-1.92 (m, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14](OC(F)(F)F)=[CH:13][CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].BrC1C(O)=C(C=C(C(C)(C)C)C=1)C=O.[F:39][C:40]([F:51])([F:50])C1C=C(B(O)O)C=CC=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:23]=[O:24])[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:40]([F:51])([F:50])[F:39])[CH:12]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Product: CC(C)(C)c1cc(C=O)c(O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
5-(tert-Butyl)-2-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde was prepared as a yellow oil using the procedure described in Intermediate 5 from 3-bromo-5-(tert-butyl)-2-hydroxybenzaldehyde (Intermediate 4) and 3-(trifluoromethyl)phenylboronic acid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19].C1C(O)=CC=CC=1C>>[F:15][C:11]1[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:18]([N:17]([CH3:20])[CH3:16])=[NH:19])[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1-c1cccc(F)c1
Reactant: CN(C)C#N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: CN(C)C(=N)Nc1ccccc1-c1cccc(F)c1

Procedure:
A mixture of 2-amino-3'-fluorobiphenyl hydrochloride (3.6 g), N,N-dimethylcyanamide (1.7 g) and m-cresol (25 ml) was heated at 90°-95° C. for 8 hours to give N-(3'-fluoro-2-biphenylyl)-N',N'-dimethyl guanidine (m.p. 109°-110° C.) as a colourless solid which was recrystallised from hexane.
Reaction SMILES: [OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:3]([F:6])([F:5])[F:4].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(C(O)(c2nccs2)C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OC(c1cccc(OCc2ccc3ccccc3n2)c1)(c1nccs1)C(F)(F)F
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 2-[1-hydroxy-1-(3-hydroxyphenyl)-2,2,2-trifluoroethyl]thiazole (0.33 g), 2-chloromethylquinoline hydrochloride (0.22 g), potassium carbonate (0.5 g) and dimethylformamlde (5 ml) was stirred at ambient temperature for Z4 hours. The mixture was partitioned between ethyl aceiate and water and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with chloroform/ethyl acetate (9/1 v/v) to give 2-[1-hydroxy-1-[3-(quinol-2-ylmethoxy)phenyl]-2,2,2-trifluoroethyl]thiazole (0.15 g, 30%), m.p. 177° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27][CH2:26]2)=[N:23][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C:19]1[CH:24]=[N:23][C:22]([N:25]2[CH2:26][CH2:27][CH:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:29][CH2:30]2)=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)CC1
Yield: 65.9 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyrimidin-2-yl)piperidin-4-ylcarbamate (440 mg, 1.5 mmol) to afford the desired product (374 mg, 66%) as a yellow solid: ESI MS m/z 567 [C27H31BrN6O3+H]+.
Reaction SMILES: [CH3:1][C@@:2]1([OH:23])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([N+:20]([O-:22])=[O:21])=[CH:11]1.N1C=CC=CC=1.O(Cl)Cl.[O-:33][P:34]([O:37][P:38]([O-:41])([O-:40])=[O:39])(=[O:36])[O-:35].C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C([NH+](CCCC)CCCC)CCC.C[O:95][P:96](OC)(OC)=[O:97]>C1(C)C=CC=CC=1>[CH3:1][C@@:2]1([OH:23])[C@H:6]([OH:7])[C@@H:5]([CH2:8][O:9][P:96]([O:36][P:34]([O:37][P:38]([OH:41])([OH:40])=[O:39])([OH:35])=[O:33])([OH:97])=[O:95])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([N+:20]([O-:22])=[O:21])=[CH:11]1
Reactant: O=P([O-])([O-])OP(=O)([O-])[O-]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc([N+](=O)[O-])c2c(N)ncnc21
Reactant: COP(=O)(OC)OC
Agent: CCCC[NH+](CCCC)CCCC
Agent: ClOCl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@@]1(O)[C@H](O)[C@@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)O[C@H]1n1cc([N+](=O)[O-])c2c(N)ncnc21
Reaction time: 2 h

Procedure:
Compound 101 (57 mg, 1.5 mmol)) was dried by co-evaporation with dry pyridine (2×5 mL) and toluene (2×5 mL) and suspended in trimethylphosphate (5 mL). Phosphoro oxychloride (1.2 eq.) was added and reaction mixture kept for 2 h at 5° C. Tributylammonium pyrophosphate (1 mL of 2N solution in DMF) was added and the mixture was left overnight at 5° C. Reaction was quenched with Et3NHCO3 buffer and separated by RP-HPLC from 0 to 100% B, buffer A—water, buffer B—CH3CN. The major peak was collected, concentrated and repurified by RP-HPLC from 0 to 60% B. Buffers were as mentioned above. The major peak was collected and lyophilized;
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)[OH:5].[CH3:19][N:20]=[C:21]=[O:22].C([O-])(=[O:25])C.C([O-])(=O)C.C([Sn+2]CCCC)CCC>C(Cl)Cl>[CH3:19][NH:20][C:21]([O:25][N:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH:6]1[CH:4]([OH:5])[C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[Cl:1])=[O:22]
Reactant: OC(c1nc2ccccc2o1)c1ccccc1Cl
Reactant: CC(=O)[O-]
Reactant: CN=C=O
Agent: CCCC[Sn+2]CCCC
Solvent: ClCCl
Product: CNC(=O)ON1c2ccccc2OC1C(O)c1ccccc1Cl

Procedure:
A mixture of 2-(o-chloro-α-hydroxybenzyl)benzoxazole (3 g), methyl isocyanate (1.06 mL), a catalytic amount of dibutyltin diacetate and methylene chloride (50 mL) was stirred at room temperature in a pressure bottle overnight, after which the mixture was concentrated in vacuo. The solid residue was partititioned between ethyl acetate-diethyl ether and water. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo to yield the corresponding carbamate. Recrystallization from toluene afforded 2.2 g of crystals, mp. 116°-117° C.