Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([NH:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH2:5]([N:12]([CH2:13][CH2:14][OH:15])[C:1](=[O:3])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Acetyl chloride (0.858 g, 10.8 mmol) was added drop by drop to a solution of N-benzyl ethanol amine (1.5 g, 9.9 mmol) and triethylamine (1.5 g, 14.9 mmol) in dry dichloromethane (20 ml) at 0° C. under nitrogen atmosphere and stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, 10% aq. NaHCO3, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel using 5% methanol in dichloromethane as eluent afforded 0.68 g of the desired product as an oil.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].N1CCC1=O>CO.O>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)N1C(=O)OC[C@@H]1c1ccccc1
Agent: O=C1CCN1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate (1 g, 4.01 mmol) in 35 mL of MeOH was added, at 0° C., 14.3 mL (12.04 mmol) of a 0.84 M solution of LiOH in water. The reaction mixture was then stirred for 3 h. at ambient temperature. Upon complete hydrolysis of the azetidinone, the MeOH was removed by evaporation, the crude residue dissolved in CH2Cl2 and treated with saturated aqueous NaCl. The resulting organic layer was dried (MgSO4) and evaporated to afford the title compound (racemic mixture) as a white solid (0.906 g, 96%); 1H NMR (CDCl3) δ 1.13/1.57 (d/d, J=7.5 Hz, 3H), 3.75/4.50 (q/q, J=7.5 Hz, 1H), 4.10-4.16 (m, 1H), 4.62-4.72 (m, 1H), 4.92-5.03 (m, 1H), 7.32-7.43 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:16]#[N:17])=[CH:5][C:6]([CH2:10][CH2:11][O:12]C(=O)C)=[CH:7]OC.[BrH:19].CC(O)=O>C(O)(=O)C>[Br:19][C:16]1[C:4]([C:3]([O:2][CH3:1])=[O:18])=[CH:5][C:6]([CH2:10][CH2:11][OH:12])=[CH:7][N:17]=1
Reactant: Br
Reactant: COC=C(C=C(C#N)C(=O)OC)CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(CCO)cnc1Br
Temperature: 35 °C

Procedure:
Into a 1L three-neck round-bottom flask with a stirrer bar, nitrogen inlet and condenser were added 20 g (78.974 mmol) of methyl-4-(2-acetyloxyethyl)-2-cyano-5-methoxypenta-2,4-dienoate, which was dissolved in 55 ml acetic acid and heated to 35° C. The solution was slowly treated over a period of ½ h with 85.21 g (237 mmol) HBr/HOAc at 35-40° C. with occasional cooling. After the addition was completed the solvents were evaporated at 40° C. and 30 mm Hg and the residue was charged while stirring with a mixture of 60 ml water and 15 ml methanol. The reaction mixture was treated with 3.3 g charcoal and heated for ½ h at 40° C. The charcoal was filtered off and the methanol was distilled off under reduced pressure. The reaction mixture was evaporated and the residue was chromatographed at 100 g silica gel using a solvent mixture of Heptane:Ethyl acetate (2:1 v/v).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.7 %

Procedure:
To a solution of 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (50 mg, 0.19 mmol) and benzoyl chloride (24 μL, 0.21 mmol) in dichloromethane (1 mL) at 0° C. was added diisopropylethylamine (66 μL, 0.38 mmol). The mixture was stirred at room temperature 15 hours, the solvent removed, and the residue purified by flash chromatography (0-30% ethyl acetate-hexanes) to give 18 mg (26% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.97 (s, 1H), 7.78 (d, 2H), 7.61 (m, 1H), 7.52 (m, 1H), 7.44 (t, 2H), 7.23 (m, 1H), 7.17 (d, 1H), 6.42 (d, 1H), 5.34 (m, 1H), 2.72 (m, 2H), 2.32 (m, 1H), 2.02-1.93 (m, 3H); MS m/z 369 (M−1).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][NH:29][CH2:28]2)=[O:25])=[N:13][CH:14]=1.[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C([BH3-])#N.[Na+]>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH:23][C:24]([O:26][CH:27]2[CH2:31][CH2:30][N:29]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:28]2)=[O:25])=[N:13][CH:14]=1
Reactant: O=C1CCCCC1
Reactant: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OC1CCN(C2CCCCC2)C1
Yield: 96.3 %

Procedure:
Using a similar procedure to that described in Example 9-C, N-(5-chloropyridin-2-yl)-2-[(pyrolidin-3-yloxy-carbonyl)amino]benzamide trifluoroacetate (100 mg, 0.211 mmol), cyclohexanone (0.11 mL, 1.05 mmol), and sodium cyanoborohydride (53 mg, 0.84 mmol) yielded 90 mg (96%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1Br)[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2].[CH2:31]=[N:32]O.N1C(C)=CC=CC=1C.[N+](C1C=CC=CC=1)([O-])=O>[Cu]I>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[N:16]=[N:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([N+:27]([O-:29])=[O:28])=[CH:20][C:19]=1[C:31]#[N:32])[N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: C=NO
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 95 °C

Procedure:
A stirred mixture of 3-acetylamino-4-(2'-bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline(4.8 parts), copper (I) iodide (2.0 parts), formaldoxime trimer (1.75 parts), 2,6-lutidine (2.15 parts), and nitrobenzene (150 parts) was heated to 95° C. for 10 hours when thin layer chromatography showed reaction to be complete. Isolation by the method of Example 1 gave 3-acetylamino-4-(2'-cyano-4',6'-dinitrophenylazo)-N,N-diethylaniline (infra red spectrum identical with that of authentic material). Similar results were obtained when the 2,6-lutidine was replaced by 2,4-lutidine (2.15 parts) and 2,4,6-collidine (2.4 parts).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[Li]CCCC.CCCCCC.[CH2:20]([CH:32]1[CH2:34][O:33]1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>O.CN(P(N(C)C)(N(C)C)=O)C>[OH:33][CH:32]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:34][C:6]#[C:5][CH2:4][CH2:3][CH2:2][C:1]([OH:8])=[O:7]
Reactant: C#CCCCC(=O)O
Reactant: CCCCCCCCCCCCC1CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCC(O)CC#CCCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a dry flask under argon was placed 10.2 g of 5-hexynoic acid, the product of lb, and 100 ml of HMPA (distilled over NaH). The solution was cooled to 0° C. and a solution of n-BuLi in hexane (115 ml, 0.185 mol) was added dropwise. After stirring for 1 hr., 21.7 g (0.118 mole) of dodecyl oxirane, the product of 1 c, was added dropwise. The reaction mixture was allowed to stir at room temperature for 3 days and then poured into 150 ml of ice and water. The aqueous solution was acidified with 5% HCl and then extracted with ether. The ether solution was washed with H2O, saturated with NaCl solution and then dried over MgSO4. Removal of solvent yielded crude product which was recrystallized in cyclohexane to give the title compound, mp 80.5°-81°.
Reaction SMILES: [C:1]([Cu])#[N:2].Cl[C:5]1[N:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=1[CH3:13].CC(OC)(C)C.N>CN(C=O)C>[OH:12][CH2:11][C:8]1[CH:7]=[C:6]([CH3:13])[C:5]([C:1]#[N:2])=[N:10][CH:9]=1
Reactant: Cc1cc(CO)cnc1Cl
Reactant: N#C[Cu]
Agent: N
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CO)cnc1C#N
Temperature: 250 °C
Reaction time: 0.58 h
Yield: 62.7 %

Procedure:
CuCN (54.3 mg, 0.607 mmol) was added to a solution of (6-chloro-5-methyl-3-pyridinyl)methanol (47.8 mg, 0.303 mmol) in anhydrous DMF (2 ml) and the mixture was stirred under microwave irradiation at 250° C. for 35 min. Full conversion was observed by HPLC. TBME and 28% NH3 were added. Extraction, drying (MgSO4), filtration, and removal of the solvent afforded 5-(hydroxymethyl)-3-methyl-2-pyridinecarbonitrile (28.2 mg, 0.190 mmol, 62.8% yield) pure enough to be used in the next step.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1.[BH4-].[Na+].O>CO.O1CCCC1>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]([OH:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:14][C:13]=3[CH:25]=2)[S:3]1
Reactant: O=C1NC(=O)C(Cc2ccc3oc(C(=O)c4ccccc4)nc3c2)S1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC(=O)C(Cc2ccc3oc(C(O)c4ccccc4)nc3c2)S1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
1.3 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl)-2-(benzoyl)benzoxazole are dissolved in a mixture of 30 ml of methanol and 6 ml of tetrahydrofuran, and 0.14 g of sodium borohydride is added thereto. After the mixture is stirred at room temperature for 5 minutes, water is added thereto. The solution is extracted with ethyl acetate, and the extract is evaporated to remove the solvent. The residue is crystallized with ether, whereby 0.64 g of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-(α-hydroxybenzyl)benzoxazole is obtained as colorless crystal.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23]Br)[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.O>C1COCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[C:22][CH2:23][N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:16]=2)=[C:7]([NH:25][C:26]([NH:28][C:29]2[C:34]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=2[CH:38]([CH3:40])[CH3:39])=[O:27])[C:6]1=[O:41])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCNC1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCBr)c2)c2cccnc21
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(C#CCN3CCCC3)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-bromo-1-propynyl)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (400 mg, 0.65 mmol) in THF (5 ml) was added pyrrolidine (139 mg, 1.96 mmol), and the mixture was stirred at room temperature for four hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to give the title compound (340 mg, 0.56 mmol).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[C:21]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]3[CH3:28])=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClCCCl.O>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[C:21]([N:22]3[CH2:27][CH2:26][N:25]([CH3:30])[CH2:24][C@H:23]3[CH3:28])=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Product: C[C@@H]1CN(C)CCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{2-[{2-[2-(dimethylamino)ethoxy]pyridin-3-yl}oxy]ethoxy}-3-[(2R)-2-methylpiperazin-1-yl]pyrazine (from Example 1; 0.48 g, 1.19 mmol) in 1,2-dichloroethane (4 mL) was added sodium triacetoxyborohydride (1.3 g, 6.2 mmol) and 37% aqueous formaldehyde (0.072 g, 2.4 mmol), the slightly exothermic reaction was stirred at ambient temperature overnight. Water was added and the mixture was made basic (pH>13) by addition of 8 M NaOH. After being stirred for five minutes, the phases were separated and the aqueous phase was extracted twice with CHCl3. The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The resulting oil was chromatographed on a column of silica (80 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (95:5:0.2; 100 mL, followed by 90:10:0.2) as eluent to give 0.33 (67%) of the title compound as a colorless oil. HRMS m/z calcd for C21H32N6O3 (M)+ 416.2536. found 416.2523.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[Li]N([Si](C)(C)C)[Si](C)(C)[CH3:28].CI>C1COCC1>[N:10]1[CH:11]=[CH:12][C:7]([NH2:6])=[C:8]([NH2:24])[CH:9]=1.[CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH:24][CH3:28])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Reactant: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC
Product: Nc1ccncc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine (0.250 g, 0.763 mmol) in dry THF (6 ml) was treated with 1M LiN(SiMe3)2 in THF (1.0 ml, 1.0 mmol) at −78° C. and stirred for 10 min. an excess of methyl iodide was added and the resulting mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give a crude material. The crude material was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give N4-(1-ethyl-propyl)-6,N3,N3-trimethyl-2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine and N4-(1-ethyl-propyl)-6,N3-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([CH3:17])[CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[C:3]=1[F:18].O.[NH2:20][NH2:21]>CS(C)=O>[F:18][C:3]1[C:4]([N:10]([CH3:17])[CH2:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[N:5][C:6]([S:8][CH3:9])=[N:7][C:2]=1[NH:20][NH2:21]
Reactant: NN
Reactant: CSc1nc(Cl)c(F)c(N(C)Cc2nccs2)n1
Solvent: CS(C)=O
Solvent: O
Product: CSc1nc(NN)c(F)c(N(C)Cc2nccs2)n1
Temperature: 80 °C
Yield: 43.4 %

Procedure:
6-Chloro-5-fluoro-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine (0.4928 g, 1.621 mmol) was dissolved in 5 mL of DMSO and hydrazine monohydrate (0.63 mL, 12.96 mmol). The reaction vessel was pressure sealed and heated to 80° C. for 2 hours. The reaction mixture was purified by RP-HPLC to provide 5-fluoro-6-hydrazino-N-methyl-2-(methylthio)-N-(1,3-thiazol-2-ylmethyl)-4-pyrimidinamine as a beige solid (0.2112 g, 43%). LCMS: (M+H)+=301.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].OS(O)(=O)=O>C(Cl)Cl.CCCCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Clc1cccc2ncccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCC
Product: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Yield: 49.3 %

Procedure:
In a similar fashion using route 7 general procedure 15, 5-chloroquinoline (1.0 g, 6.13 mmol), potassium nitrate (0.8 g, 7.98 mmol) and H2SO4 (3 ml) gave the title compound (630 mg, 51%) after trituration from DCM/n-pentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=O)[CH:3]=1.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:10])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chloropyridine-2-carboxamide (150 mg, 0.96 mmol) in THF (5 ml) at −15° C. was added NEt3 (331 μl, 2.40 mmol) followed by TFAA (150 μl, 1.08 mmol). After stirring for 2 hours at 0° C. the reaction was concentrated then diluted with EtOAc (30 ml) and washed with water (2×15 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The title compound was obtained as white solid (105 mg, 79%) after purification by FCC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2SC)=[CH:17][C:16]=1[CH3:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]1C=C(C=CC=1)C(OO)=O.O[O:43][S:44]([O-:46])=O.[K+]>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:30])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:44]([CH3:32])(=[O:46])=[O:43])=[CH:17][C:16]=1[CH3:29])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=S([O-])OO
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(C)c1
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2S(C)(=O)=O)ccc1NC(=O)C1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(3-Methyl-2′-methylsulfanyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.57 g, 1.3 mmol) was dissolved in 10 mL EtOAc, added m-chloroperoxybenzoic acid (1.76 g, 6.1 mmol) in one portion and stirred at ambient temperature for 3 hours. Reaction not complete. Concentrated and redissolved in 10 mL acetonitrile and added oxone (1.5 g, 2.4 mmol) in one portion and stirred at ambient temperature overnight and then concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 20% moving to 40% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound. (0.44 g, 72%) APCI (AP−): 457.1 (M−H)−.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[NH:8][CH:7]=[N:6][C:5]=1[CH2:9][CH2:10][NH2:11].[OH-].[Na+].C1(C)C=CC=C(O[C:21](=[NH:25])[NH:22][C:23]#[N:24])C=1.C1C(O)=CC=CC=1C>C(O)(C)C>[C:21]([NH:22][C:23]([NH:11][CH2:10][CH2:9][C:5]1[N:6]=[CH:7][NH:8][C:4]=1[CH3:3])=[NH:24])#[N:25]
Reactant: Cc1cccc(OC(=N)NC#N)c1
Reactant: Cc1[nH]cnc1CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CC(C)O
Product: Cc1[nH]cnc1CCNC(=N)NC#N
Temperature: 25 °C

Procedure:
4.94 g. (0.249 mole) 5-methyl-4-(2-aminoethyl) imidazole dihydrochloride is converted to the free base with NaOH. The free base is combined with 4.36 g. (0.0249 mole) of O-m-tolyl-N-cyanoisourea in 63 ml. isopropanol. This mixture is refluxed for one hour. The mixture is then cooled to room temperature, filtered to remove insoluble material, and the solvent is evaporated to obtain a cloudy oil of the product mixed with m-cresol.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[OH:14][CH2:15][C:16]1[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=1.CN1CCOCC1>C(Cl)Cl>[CH:21]([C:18]1[S:19][CH:20]=[C:16]([CH2:15][O:14][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[N:17]=1)([CH3:23])[CH3:22]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)c1nc(CO)cs1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)c1nc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1.12 g (5.56 mmol) of 4-nitrophenyl chloroformate in 20 ml of CH2Cl2 was cooled to 0° C. and treated sequentially with 0.8 g (5.1 mmol) of 4-(hydroxymethyl)-2-isopropylthiazole and 0.6 ml (5.6 mmol) of 4-methylmorpholine. The resulting solution was stirred at 0° C. for 1 h, diluted with CH2Cl2, washed with three portions of aqueous NaHCO3, dried over Na2SO4, and concentrated in vacuo to give crude 2-isopropyl-4-(p-nitrophenyloxycarbonyloxymethyl)thiazole. A portion (0.53 g, 1.65 mmol) of the residue was taken up in 20 ml of chloroform, treated with 0.23 g (1.67 mmol) of L-alanine methyl ester hydrochloride and 0.36 ml (3.3 mmol) of 4-methylmorpholine, and heated at reflux for 16 h. After being allowed to cool, the solven was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.45 g (94%) of the desired compound, Rf 0.43 (5% methanol in CH2Cl2). 1H NMR (DMSO-d6) δ 1.26 (d, J=8 Hz, 3 H), 1.32 (d, J=7 Hz, 6 H), 3.27 (heptet, J=7 Hz, 1 H), 3.63 (s, 3 H), 4.10 (p, J=8 Hz, 1 H), 5.02 (s, 2 H), 7.47 (s, 1 H), 7.81 (d, J=8 Hz, 1 H). Mass spectrum: (M+H)+ =287.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][S:4][C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:19])([F:18])[F:17])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20].ClC1C=CC=C(C(OO)=[O:31])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:22][C:2]([F:1])([F:21])[CH2:3][S:4]([C:5]1[CH:10]=[C:9]([C:11]2[C:12]([C:16]([F:17])([F:18])[F:19])=[N:13][NH:14][CH:15]=2)[CH:8]=[CH:7][C:6]=1[CH3:20])=[O:31]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1SCC(F)(F)F
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2c[nH]nc2C(F)(F)F)cc1S(=O)CC(F)(F)F
Yield: 37.2 %

Procedure:
To 1.68 g (4.9 mmol) of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluoroethyl sulfide (Compound No. V-292 of the present invention) in 5 ml of chloroform, 1.02 g (5.1 mmol) of m-chloroperbenzoic acid was added at 0° C. with stirring, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was mixed with 10 ml of 10% aqueous sodium sulfite and stirred at room temperature for 10 minutes, and then 20 ml of chloroform was added. The chloroform layer was washed with 20 ml of saturated aqueous sodium hydrogen carbonate three times and dried over anhydrous magnesium sulfate, and the chloroform was distilled off under reduced pressure to obtain 0.65 g of [2-methyl-5-(3-trifluoromethylpyrazolyl)phenyl] 2,2,2-trifluroethyl sulfoxide (yield 37.1%) as a pale yellow solid (m.p. 109-110° C.).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:17][CH2:16][C:8]2[N:9]=[C:10]([NH:12][CH2:13][CH2:14]C)[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2].C(NC1CCC2N=C(NC(=O)CC)SC=2C1)(=O)C>>[C:1]([NH:4][CH:5]1[CH2:17][CH2:16][C:8]2[N:9]=[C:10]([NH:12][CH2:13][CH3:14])[S:11][C:7]=2[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCCNc1nc2c(s1)CC(NC(C)=O)CC2
Agent: CCC(=O)Nc1nc2c(s1)CC(NC(C)=O)CC2
Product: CCNc1nc2c(s1)CC(NC(C)=O)CC2

Procedure:
6-Acetylamino-2-n-propylamino-4,5,6,7-tetrahydrobenzthiazole prepared from 6-acetylamino-2-propionylamino-4,5,6,7,-tetrahydro-benzthiazole at ambient temperature.