Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[NH:8]C(=O)OC(C)(C)C.[ClH:16]>O1CCOCC1>[ClH:16].[NH2:8][N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NN1CCCCC1=O
Agent: Cl
Solvent: C1COCCO1
Product: NN1CCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (2-oxopiperidin-1-yl)carbamate (129 mg) was dissolved in a solution of 4 N hydrogen chloride in dioxane (2 ml), and the reaction solution was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure to obtain 92 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([CH3:22])([CH3:21])[CH:5]2O.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([CH3:22])([CH3:21])[CH2:5]2
Reactant: CC1(C)C(O)c2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a mixture of 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (14.3 g, 43 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) to afford 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (10.5 g, 77%) as a white solid: LC/MS m/e calcd for C17H17ClN2O2 (M+H)+: 317.79, observed: 317.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][NH2:12].CO.[I-].[Na+]>C(O)C>[CH3:11][NH:12][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: OCCOCCOCCCl
Reactant: CN
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CNCCOCCOCCO
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-[2-(2-Chloro-ethoxy)-ethoxy]-ethanol (2.00 mL, 13.8 mmol) was dissolved in ethanol (14.0 mL). A solution of methylamine in methanol (40%, 14.0 mL, 138 mmol) and sodium iodide (103 mg, 0.67 mmol) were added, and the mixture was stirred at 60° C. for 18 hours and then stirred at 75° C. for seven hours in a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure to give 2-[2-(2-methylamino-ethoxy)-ethoxy]-ethanol as a crude product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][S:38]([CH:35]1[CH2:37][CH2:36]1)(=[O:40])=[O:39]
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNS(=O)(=O)C1CC1)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (61 mg, 0.158 mmol), triethylamine (18 mg, 24 μL, 0.174 mmol), cyclopropane sulfonyl chloride (22 mg, 17 μL, 0.158 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-31 (55 mg, 71%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 6.78 (s, 1H), 6.66 (t, J=6.8 Hz, 1H), 6.51 (s, 1H), 6.29 (br s, 2H), 5.91 (s, 2H), 4.31 (t, J=6.0 Hz, 2H), 3.02 (q, J=6.1 Hz, 2H), 2.70 (s, 6H), 2.34-2.38 (m, 1H), 1.95-1.99 (m, 2H), 1.15-1.17 (m, 2H), 0.93-0.96 (m, 2H); 13C NMR (150 MHz, CDCl3): δ 154.9, 153.1, 151.7, 148.4, 147.6, 146.3, 144.8, 119.8, 119.4, 109.6, 102.4, 101.8, 45.4, 40.0, 39.0, 30.4, 30.2, 5.26; HRMS (ESI) m/z [M+H]+ calcd. for C20H26N7O4S2, 492.1488. found 492.1468.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=O)[CH3:4].[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([NH2:17])=[S:16]>C(O)C>[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]1[S:16][C:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:3]([CH3:4])[N:17]=1
Reactant: CC(=O)C(Br)c1ccccc1
Reactant: NC(=S)c1ccccc1Cl
Solvent: CCO
Product: Cc1nc(-c2ccccc2Cl)sc1-c1ccccc1
Yield: 79.1 %

Procedure:
1-Bromo-1-phenyl-2-propanone (10.6 g, 0.050 mole), o-chlorothiobenzamide (8.8 g, 0.051 mole), and ethanol (100 ml) are mixed and, after the initial exothermic reaction has subsided, heated under reflux for two hours. The ethanol is evaporated and the residue is treated with chloroform and aqueous sodium bicarbonate. The chloroform layer is separated and evaporated to leave a yellow oil which solidifies on standing. Recrystallization from acetonitrile yields 11.3 g (79%) of 2-(2-chlorophenyl)-4-methyl-5-phenylthiazole, m.p. 63°-65° C.
Reaction SMILES: Cl[C:2]([F:9])([F:8])C(OCC)=O.[Br:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[OH:21])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH:2]([F:9])[F:8])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC(F)F)c(Br)c1
Temperature: 65 °C
Yield: 49.1 %

Procedure:
Ethyl chlorodifluoroacetate (1.12 ml, 8.7 mmol) was added to a mixture of methyl 3-bromo-4-hydroxybenzoate (Description 64, 2.0 g, 8.7 mmol) and potassium carbonate (1.2 g, 8.7 mmol) in N,N-dimethylformamide (20 ml) and the mixture was heated at 65° C. for 16 h. The mixture was cooled, water (100 ml) was added and the mixture was extracted with ethyl acetate (2×100 ml). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/EtOAc (95:5) to give the title compound as a colorless solid (1.20 g, 49%). 1H NMR (250 MHz, CDCl3) δ8.31 (1 H, d, J 2.0 Hz), 8.22 (1 H, dd, J 8.5, 2.0 Hz), 7.05 (1 H, m), 6.61 (1 H, t, J 73 Hz), and 3.93 (3 H, s).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH:21]([C:28]([O:30]CC)=[O:29])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH:21]([C:28]([OH:30])=[O:29])[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:18](=[O:20])[CH3:19])=[CH:15][CH:16]=2)[C:8]2[CH:33]=[CH:34][CH:35]=[CH:36][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(N(C(C)=O)C(C(=O)OCC)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccccc2n1Cc1ccc(N(C(C)=O)C(C(=O)O)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(α-ethoxycarbonyl)-N-acetyl-benzylamino]benzyl]-benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12](=O)[CH2:13][CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)NC1(c2ccc(Br)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC1(c2ccc(Br)cc2)CC1
Temperature: 5.5 °C
Reaction time: 2 h

Procedure:
To a solution of N-[1-(4-bromophenyl)-cyclopropyl]-propionamide (Intermediate 117, 85.0 mg, 0.32 mmol) in THF (5 mL) at 0° C. was added BH3-Me2S (48.0 mg, 0.63 mmol; 0.31 mL of a 2M solution in THF). The solution was heated to 5.5° C. for 17 hours, cooled to room temperature, saturated aqueous NaHCO3 was added and the resulting mixture was stirred for 2 hours. This mixture was extracted with EtOAc and the combined organic layers were washed with H2O and saturated aqueous Nacl before being dried (MgSO4) and concentrated under reduced pressure. The title compound was isolated by column chromatography (10-30% EtOAc-hexanes).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[N:6]=2.[H-].[Na+].I[CH3:17]>CN(C)C=O>[OH:1][CH2:2][C:3]1[N:4]([CH3:17])[C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[N:6]=2
Reactant: CI
Reactant: Cc1cc(C)c2nc(CO)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2nc(CO)n(C)c2n1
Yield: 53.5 %

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 2.6 g of 2-hydroxymethyl-5,7-dimethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 85), 0.64 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.2 g of iodomethane and 80 ml of dimethylformamide were used. After working up the product as described in Preparation 15, the resulting crude product was purified by column chromatography through silica gel, using a 1:6 by volume mixture of- ethanol and ethyl acetate as the eluent, followed by recrystallization from ethyl acetate, to give 1.5 g of the title compound, melting at 178°-179° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]2([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.CI.[CH3:31]COC(C)=O>CN(C=O)C>[F:3][C:4]1[C:5]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]2([CH2:27][O:28][CH3:31])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2(CO)CCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (20.0 mg 60% in oil, 522 μmol) in DMF (1.0 mL) was slowly added methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-(hydroxymethyl)cyclopentyl)benzoate (75.0 mg, 209.0 μmol) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes and then methyl iodide (296.0 mg, 2087 μmol) was added to the reaction mixture. The resulting mixture was stirred at room temperature overnight. EtOAc (60.0 mL) was added, and the organic layers were washed with brine (20×2 mL) and dried over MgSO4. The product was obtained after filtration and solvent removal. The product was used in the next step. MS ESI (pos.) m/e: 374.0 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.Cl.[CH3:9][C:10]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[N:24][O:25][CH3:26])[C:21]([NH2:23])=[O:22]>O>[CH3:9][C:10]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[C:20](=[N:24]\[O:25][CH3:26])/[C:21]([NH2:23])=[O:22]
Reactant: CON=C(C(N)=O)c1ccccc1COc1cc(C)ccc1C
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CO/N=C(/C(N)=O)c1ccccc1COc1cc(C)ccc1C
Temperature: 85 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
Toluene (4 ml) and conc. hydrochloric acid (0.8 ml) were added to 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (E/Z=15/85) (1.25 g, 4.0 mmol), and the mixture was stirred at 85° C. for 2 hours. After the reaction, water (80 ml) was added. The mixture was extracted with toluene (80 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give crystals. The crystals were recrystallized from n-hexane/ethyl acetate to give (E)-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyiminoacetamide (1.02 g, Yield: 81.6%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:21]=[CH2:22])=[C:9]([NH2:12])[C:8]([F:13])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:6]=1)=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2)c(F)c(N)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)cc2)c(F)c1N
Temperature: 110 °C
Yield: 9.4 %

Procedure:
4-Amino-3-chloro-6-(4-chlorophenyl)-5-fluoropyridine-2-carboxylic acid methyl ester (0.5 g, 1.59 mmol), tributyl(vinyl)tin (1.01 g, 3.17 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.111 g, 0.159 mmol), and tetrabutylammonium triphenyldifluorosilicate (1.71 g, 3.17 mmol) were combined in acetonitrile (3 ml) and heated to 110° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) twice to yield the title compound (46 mg, 5% yield) as an off-white solid, mp 81-83° C. 1H NMR (CDCl3) δ 7.9 (m, 1H), 7.43 (m, 1H), 6.89 (dd, 1H), 5.7 (dd, 1H), 5.57 (dd, 1H), 4.72 (br s, 2H), 3.93 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:21][CH2:22][CH2:23][C:24](Cl)=[O:25].CCCCCCC>C1COCC1>[Cl:21][CH2:22][CH2:23][C:24]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([NH:13][CH3:14])=[O:12])=[O:25]
Reactant: CNC(=O)c1c(N)sc2c1CCCC2
Reactant: O=C(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(NC(=O)CCCl)sc2c1CCCC2
Reaction time: 0.08 h
Yield: 43.8 %

Procedure:
2-Amino-N-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (2.82 g, 13.41 mmol) was completely dissolved in THF (90 mL). Potassium carbonate (2.22 g, 16.09 mmol) was then added and the reaction stirred for 5 min. 3-chloropropanoyl chloride (2.04 g, 1.536 mL, 16.09 mmol) was added and the reaction mixture stirred at RT for 30 min. THF was removed in vacuo. Water was added and the reaction mixture extracted into EtOAc (×3). The combined EtOAc layers were washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo. Purification by flash column chromatography-silica gel and elution with 0-60% EtOAc:heptane gave the desired product (1.76 g, 5.87 mmol, 44%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:24])([F:23])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:13]2=[O:22])=[CH:8][CH:7]=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35](F)[N:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:32][C:33]1[N:34]=[C:35]([N:19]2[CH2:18][CH2:17][C:14]3([C:13](=[O:22])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][C:4]([F:3])([F:23])[F:24])=[CH:7][CH:8]=4)[CH2:16][CH2:15]3)[CH2:21][CH2:20]2)[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Fc1cccc(OCc2ccccc2)n1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccc(OCc3ccccc3)n1)CC2
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a suspension of NaH (9 mg, 0.24 mmol) in DMF (1 mL) at 0° C. was added a solution of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C, 50 mg, 0.16 mmol) and stirring was continued for 30 mins. A solution of 2-benzyloxy-6-fluoro-pyridine (39 mg, 0.19 mmol) in DMF (0.5 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and washed with brine, 1N HCl and again with brine. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to yield the title compound as a light yellow solid (58 mg, 73%). MS (ESI): 498.2 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)C(OC)=O.[OH-].[K+]>C(O)C>[CH3:19][CH:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:4][C:3]([OH:20])=[O:2])=[CH:11][CH:12]=1)[CH3:18]
Reactant: COC(=O)C(Cc1ccc(OC(C)C)cc1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(CCC(=O)O)cc1

Procedure:
2-[[4-(1-Methylethoxy)phenyl]methyl]-propanedioic acid dimethyl ester (23.6 g, 84.2 mmol) is stirred into 2N potassium hydroxide solution (15 ml)/ethanol (25 ml) for 18 hours at boiling temperature.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([Br:12])([F:11])[F:10])[CH:5]=[C:4]([O:18][CH:19]([F:21])[F:20])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[CH:30][CH:29]=[CH:28]2)=[O:24].ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:15])([F:14])[F:16])[C:9]([Br:12])([F:10])[F:11])[CH:5]=[C:4]([O:18][CH:19]([F:20])[F:21])[C:3]=1[NH:22][C:23]([C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N+:31]([O-:43])=[CH:30][CH:29]=[CH:28]2)=[O:24]
Reactant: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F)c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)Br)cc1OC(F)F)c1ccc2c(ccc[n+]2[O-])c1
Yield: 108.2 %

Procedure:
N-[2-Bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]-quinoline-6-carboxamide (0.73 g) was dissolved in dichloromethane (50 ml), added with 3-chloroperbenzoic acid (purity 70%, 0.48 g), and sited at room temperature for S hours. The solvent was distilled off under the reduced pressure and the residue was dissolved in ethyl acetate, Sodium hydrocarbonate solution and potassium carbonate were added thereto. After extracting the mixture twice with ethyl acetate, the organic phases were combined and washed with water, and dried over anhydrous magnesium sulfate. The drying agent (anhydrous magnesium sulfate) was filtered off and the solvent was removed by distillation under the 1.5 reduced pressure to obtain N-[2-bromo-4-(1-bromo-1,1,2,3,3,3-hexafluoropropan-2-yl)-6-(difluoromethoxy)phenyl]quinoline-6-carboxamide-1-oxide (0.81 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([Cl:10])=[C:12]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-chloro-3-trifluoromethylaniline gave 2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=2.1 Hz), 7.96 (d, 1H, J=3 Hz), 7.91 (dd, 1H, J=2.7 Hz and 8.7 Hz), 7.53 (d, 1H, J=8.1 Hz), 7.06 (bs, 1H); 19F NMR (CDCl3): −17892 and −44402; LCMS: purity: 93%; MS (m/e): 326 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][CH2:13][C:14](O)=O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1([NH2:24])[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1>[NH:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:24]=[C:14]1[CH2:13][CH2:12][C:3]1[C:2]([CH3:1])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1nc2ccccc2nc1CCC(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc2ccccc2nc1CCc1nc2ccccc2[nH]1
Temperature: 150 °C
Yield: 6.2 %

Procedure:
3-(3-Methylquinoxalin-2-yl)propanoic acid (98 mg, 0.45 mmol) and benzene-1,2-diamine (98 mg, 0.45 mmol) were suspended in 4 M HCl in 1,4-dioxane (6 mL) and heated in the microwave (150° C., 2.5 h). The crude reaction was poured into saturated aqueous Na2CO3 solution (30 mL) and extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine (1×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by RPLC (Gilson). Fractions containing the compound were combined, diluted with EtOAc and washed with saturated aqueous Na2CO3, dried (Na2SO4), filtered and concentrated to give 2-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-3-methylquinoxaline (8 mg) as an orange oil. LC-MS m/z 289 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=2)[CH:5]=[N+:6]([O-])[CH:7]=1.P(Br)(Br)([Br:22])=O>ClCCCl>[Br:22][C:5]1[C:4]2=[CH:9][N:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[N:11]=[C:3]2[C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: [O-][n+]1cc(Cl)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Reactant: O=P(Br)(Br)Br
Solvent: ClCCCl
Product: Clc1cccc(Cl)c1-n1cc2c(Br)ncc(Cl)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a cooled (0° C.) suspension of 7-chloro-2-(2,6-dichlorophenyl)-2H-pyrazolo[4,3-c]pyridine-5-oxide (2.5 g, 8.0 mmol) in DCE (50 mL) was added phosphorus oxybromide (6.8 g, 24.0 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, warmed to room temperature, and stirred for a further 18 hours. The reaction mixture was partitioned between DCM and sodium carbonate (sat. aq.). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as a white solid (850 mg, 28% yield). LCMS (Method D): RT=3.92 min, m/z: 377 [M+H+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]2[N:10]=[C:11]([N:14]=[C:15]([NH2:17])[NH2:16])[S:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1.[ClH:18].[O-:19][C:20]#[N:21].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[ClH:18].[ClH:18].[NH2:16][C:15](=[N:14][C:11]1[S:12][CH:13]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][NH:1][C:20]([NH2:21])=[O:19])[N:8]=2)[N:10]=1)[NH2:17]
Reactant: N#C[O-]
Reactant: NCc1cccc(-c2csc(N=C(N)N)n2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1cccc(-c2csc(N=C(N)N)n2)n1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of 4-(6-aminomethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.64 g), 1N-hydrochloric acid (5.15 ml) and potassium cyanate (0.21 g) in water (6.4 ml) was stirred for 19 hours at ambient temperature. The solution was made basic with aqueous potassium carbonate and the resulting precipitate was collected by filtration. The free base was converted to the hydrochloride in a usual manner followed by recrystallization from aqueous methanol to give 2-(diaminomethyleneamino)-4-(6-ureidomethylpyridin-2-yl)thiazole dihydrochloride (0.45 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[C:33]=2[CH3:39])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][C:34]1[C:33]([CH3:39])=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:40])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3C)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C)c3C)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2,3-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M130) (0.33 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (160 mg, 61%).