Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[C:10](Cl)(Cl)=[S:11]>O.CO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10]([SH:11])=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1O
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: CO
Product: Sc1nc2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 179.9 %

Procedure:
2-Amino-4-chlorophenol (2.50 kg, 17.4 mol) was charged to a vessel and suspended in water (52 L) and methanol (10.4 L). High dilution was required to prevent slow and difficult filtration of the product. The mixture was stirred, cooled to 0° C., then thiophosgene (2.00 kg, 17.4 mol) was added to the suspension ensuring that the internal temperature remained at 5° C. throughout the addition. Water (8 L) and methanol (2 L) were added to aid stirring and the slurry was warmed to 13° C. for 1 h, followed by aging at 20° C. for a further 1 h. The slurry was then filtered and the solid washed with water (5 L). The batch was repeated and combined to dry in a vacuum oven (T=40° C.) for 15 h to give 9a (5.81 kg, 31.3 mol). The data corresponds to the commercially available material. 1H NMR (400 MHz, d6-DMSO): δ 7.51 (d, 1 H, J=9.2 Hz), 7.3 07.26 (m, 2 H), 13C NMR (100.6 MHz, d6-DMSO): δ 181.2, 147.4, 133.1, 129.7, 123.9, 111.6, 110.8. HRMS (ESI): m/z [M++H] calcd for C7H4ClNOS: 185.9780. found: 185.9785.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Nc1ccc(CCO)cc1
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(CCO)cc3)(CC1)CC2
Yield: 52 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-(4-aminophenyl)ethanol (47.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(2-hydroxyethyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (35.6 mg).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1)=[O:11])(=[O:5])=[O:4].O.[NH2:28][NH2:29]>CCO>[NH:28]([C:16]([C:15]1[CH:20]=[CH:21][C:12]([C:10]([NH:9][C:8]2[CH:22]=[CH:23][CH:24]=[C:6]([S:3]([C:2]([F:26])([F:25])[F:1])(=[O:5])=[O:4])[CH:7]=2)=[O:11])=[CH:13][CH:14]=1)=[O:17])[NH2:29]
Reactant: COC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)Nc2cccc(S(=O)(=O)C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 63 %

Procedure:
To a suspension of methyl 4-({3-[(trifluoromethyl)sulfonyl]anilino}carbonyl)benzoate (390 mg, 1.1 mmol) in EtOH (6 mL) was added hydrazine hydrate (1 mL). After stirring for 15 hrs at reflux, the reaction mixture was cooled to rt and a white solid precipitated out Filtration, washing with EtOH (1×1 mL) and water (3×1 mL), and drying under vacuo at 60° C. for 2 hrs gave 247 mg of the title compound (63%) as a white solid in 95% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [N+](C1C=CC(OC(=O)[C:12](C)=[CH:13][C:14]2[CH:19]=[C:18](OC)[C:17](OC)=[CH:16][C:15]=2N)=CC=1)([O-])=O.C[N:28](C)C=O>>[C:14]1([CH2:13][CH2:12][NH2:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(N)c(C=C(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: CN(C)C=O
Product: NCCc1ccccc1

Procedure:
Into 30 ml of dimethylformamide, 0.72 g (2.0 mmol) of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid p-nitrophenyl ester obtained above and 0.48 g (4.0 mmol) of 2-phenylethylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) were dissolved; and the mixture was reacted at room temperature for one night. The solvent was eliminated under a reduced pressure, and the residue was dissolved in ethyl acetate. After the resulting solution was washed and was dried with magnesium sulfate anhydride, the solvent was eliminated under a reduced pressure, whereby a crude product was obtained. This product was refined by an aminopropyl-modified type silica gel column chromatography (n-hexane/ethyl acetate=1/1), whereby 0.68 g of the aimed compound was obtained (yield: quantitative).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:21][C@@H:22]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>O.C1COCC1>[C@@H:22]1([N:21]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:33](=[O:36])[CH:34]=[CH2:35])[O:30][C@H:29]([CH2:31][OH:32])[C@@H:27]([OH:28])[C@H:25]([OH:26])[C@H:23]1[OH:24]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N(CCCCCCCCCCCCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
A solution of 85 mmol (9 g) of sodium carbonate in 25 ml of water is added to a solution of 13.7 mmol (4 g) of N-tetradecyl-β-D-glucopyranosylamine in 190 ml of THF. A solution of 26 mmol (2.0 ml) of acryloyl chloride in 20 ml of THF is added dropwise over one hour. The THF is evaporated off and the acylamidosugar is then extracted with 300 ml of ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3, dried over MgSO4 and evaporated at reduced pressure.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)(=[O:4])=[O:3]>C(O)(=O)C.[Pt]=O>[CH3:1][S:2]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cnc2ccccc2c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CS(=O)(=O)C1CNc2ccccc2C1

Procedure:
A solution of 6.5 g of 3-methylsulfonylquinoline in 200 ml of glacial acetic acid is hydrogenated in the presence of 690 mg of platinum oxide at 50° C. for 13 h. After the reaction mixture has been filtered over Celite® 545, the filtrate is concentrated and the crude product is purified by means of FC over 200 g of silica gel with a 99:1 mixture of methylene chloride and methanol as the mobile phase: Rf (K)=0.45; anal. calc. for C10H13NO2S: C56.85%, H6.20%, N6.63%; found C56.95%, H6.17%, N6.77%.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10](OCC)=[O:11])=O.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:5][C:6]1[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][CH2:10][OH:11]
Reactant: CCOC(=O)COc1ccccc1CC(=O)NC
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCc1ccccc1OCCO
Temperature: 25 °C
Yield: 28.9 %

Procedure:
At 0° C., a solution of ethyl 2-(2-((N-methylcarbamoyl)methyl)phenoxy)acetate (5.00 g, 19.9 mmol) in tetrahydrofuran (75 ml) was added dropwise to a suspension of sodium borohydride (2.26 g, 59.7 mmol) in tetrahydrofuran (75 ml). A solution of iodine (5.05 g, 19.9 mmol) in tetrahydrofuran (150 ml) was added dropwise. The solution was warmed to room temperature and heated to reflux for 16 h. It was cooled to 0° C. Methanol (150 ml) was added dropwise. The solvent was removed in vacuo. The solid residue was dissolved in 20% aqueous sodium hydroxide solution/tert-butyl methyl ether (150 ml/150 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (3×150 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethane/methanol/10% aqueous ammonia (first: 100:10:1, then 70:30:3) as eluent, to give 1.124 g of 2-(2-(2-(Methylamino)ethyl)phenoxy)ethanol.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([F:13])([F:12])[F:11])=[C:2]=[O:3].[CH3:14][C:15]([CH3:18])([O-:17])[CH3:16].[K+]>C1COCC1>[F:11][C:10]([F:12])([F:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][C:2](=[O:3])[O:17][C:15]([CH3:18])([CH3:16])[CH3:14]
Reactant: CC(C)(C)[O-]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of 1-isocyanato-2-(trifluoromethyl)benzene (4.0 g, 21.4 mmol) in 50 mL of THF at 0° C. was added potassium tert-butoxide (32.0 mL of a 1M solution in THF, 32 mmol) dropwise. The reaction was allowed to stir for 3 h with warming to ambient temperature and then was quenched with 10 mL of water. The mixture was diluted with ethyl acetate and the organics were washed sequentially with 1N HCl, sat'd. aq. NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was taken up in chloroform, filtered through a pad of silica gel and concentrated to afford 2.9 g (52%) of the title compound which was sufficiently pure to be used without further purification. 1H NMR (CDCl3): δ 8.13 (d, 1H, J=8.2 Hz), 7.56 (d, 1H, J=7.7 Hz), 7.52 (t, 1H, J=8.0 Hz), 7.14 (t, 1H, J=7.7 Hz), 6.80 (broad s, 1H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([OH:6])=[O:5].C(=O)(O)[O-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[CH2:16]([O:15][C:13]([N:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(CC(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-methylglycine (7.0 g) was added to water (50 ml) and the pH of the solution adjusted to 9 with solid sodium bicarbonate. The solution was cooled to 0° C. and stirred vigorously, while benzyl chloroformate (19 ml) was added dropwise over 20 minutes. The mixture was stirred for a further 2 hours at 0° C. and an additional 2 hours at room temperature, then extracted with diethyl ether (2×130 ml). The aqueous solution was then acidified to pH 3 with 5N HCl and the product isolated by extraction with ethyl acetate (2×130 ml). The combined organic extracts were dried over anhydrous sodium sulphate and the solution concentrated in vacuo to give N-(benzyloxycarbonyl)-N-methylglycine as a pale yellow oil (16.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CC(C)N=C=O
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.3 mmol) in chloroform (20 mL) was cooled to 0° C., and a solution of isopropyl isocyanate (5.3 mmol) in chloroform (3 mL/g) was added slowly over a period of eight minutes. After one hour, additional isopropyl isocyanate (0.53 mmol) in chloroform was added. Additional isopropyl isocyanate (2.15 mmol) was added again after an additional 2.5 hours. A precipitate was present and was isolated by filtration, washed with cold chloroform, and dried overnight on the filter funnel to provide 1.99 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-(1-methylethyl)urea as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](Br)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:11]>CO>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)(=[O:11])[CH3:9]
Reactant: CC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: Clc1ccc(I)cc1
Solvent: CO
Product: CC(=O)c1ccc(-c2ccc(Cl)cc2)c([N+](=O)[O-])c1

Procedure:
4-Chloroiodobenzene and 4-bromo-3-nitroacetophenone were reacted under Ullmann conditions to give the novel intermediate 4-acetyl-4'-chloro-2-nitrobiphenyl, m.p. 103°-105° C. (from methanol). This compound was reduced with stannous chloride and concentrated hydrochloric acid to give 4-acetyl-2-amino-4'-chlorobiphenyl, m.p. 139°-140° C. (from methanol).This compound was converted to the novel intermediate 4-acetyl-4'-chloro-2-hydroxybiphenyl and thence to the novel intermediate 4-acetyl-4'-chloro-2-methoxybiphenyl, b.p. 167°-170° C./0.4 mm., by diazotization and methylation methods analogous to those described in Example 1.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][NH:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1>O.C(Cl)Cl.O>[CH2:3]([O:10][C:11]([N:13]1[CH2:17][C:16](=[CH2:18])[CH2:15][N:14]1[C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C=C1CNN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Yield: 62 %

Procedure:
Sodium hydroxide (0.12 g, 3 mmol) is dissolved in a 1:2 water/methylene chloride solution (30 mL) with rapid stirring followed by the addition of 4-methylene-pyrazolidine-1-carboxylic acid 1-benzyl ester, 9, (0.62 g, 2.8 mmol) at room temperature. (4-Fluorophenyl)acetyl chloride (0.39 mL, 4.2 mmol) is added and the reaction is allowed to stir for 18 hours after which time the reaction mixture is diluted with water (10 mL) and the layers allowed to separate. The aqueous layer is extracted with methylene chloride, the organic layers combined, dried, and filtered. Concentration in vacuo affords the crude product which is purified over silica (1:3 ethyl acetate/hexane) to provide 0.54 g (62% yield) of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36]>CN(C=O)C>[C:27]1(=[O:36])[N:26]([CH2:25][CH2:24][CH2:23][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]12
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC1CC(=O)NN=C1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc(OCCCN2C(=O)c3ccccc3C2=O)cc1
Yield: 104 %

Procedure:
A mixture of 500 mg (2.45 mmol) of 6-(4-hydroxyphenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (prepared by the method described in Eur. Pat. Appl. EP 178,189 A2), 373 mg (2.70 mmol) of powdered anhydrous K2CO3, and 790 mg (2.95 mmol) of N-(3-bromopropyl)phthalimide in 10 ml of DMF is heated at 100° C. for 2 hrs. The DMF is removed under vacuum, the residue is taken up in 125 ml of EtOAc and 100 ml of water, the organic phase washed once with 75 ml of water, dried (MgSO4), and the solvent removed to give 0.997 g of 6-[4-(3-phthalimidopropyloxy)phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone as a white solid. Yield, 99%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[NH2:16][CH2:17][CH2:18][NH:19][C:20]1[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH3:28])[C:24](=[O:27])[C:25]=1[CH3:26]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:16][CH2:17][CH2:18][NH:19][C:20]2[N:21]([CH3:30])[C:22](=[O:29])[N:23]([CH3:28])[C:24](=[O:27])[C:25]=2[CH3:26])=[CH:7][CH:8]=1)[CH2:14][CH3:15]
Reactant: CCCOc1ccc(OCC2CO2)cc1
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Product: CCCOc1ccc(OCC(O)CNCCNc2c(C)c(=O)n(C)c(=O)n2C)cc1
Yield: 32 %

Procedure:
This compound is obtained in a manner analogous to that described in Example 5 by reacting 4-propoxyphenyl glycidyl ether with 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione. It is obtained in a yield of 32% of theory in the form of colorless crystals which, after recrystallization from methanol, melt at 121°-123° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.192 mmol), 5-methoxy-2-methylaniline (40 mg, 0.288 mmol) similar to Example 76 and isolated as a yellow solid (40 mg, 58%). 1H NMR (CDCl3): 9.75 (d, J=1.2 Hz, 1H), 8.79 (dd, J=1.5, 2.4 Hz, 1H), 8.73 (d, J=2.4 Hz, 1H), 7.28 (d, J=4.5 Hz, 1H), 7.24 (s, 1H), 6.89 (d, J=2.7 Hz, 1H), 6.86 (dd, J=2.7, 8.4 Hz, 1H), 6.73 (s, 1H), 3.82 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[C:34]2([CH2:36][CH2:35]2)[CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:31][C@@H:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:34]3([CH2:35][CH2:36]3)[CH2:33]2)[C:9]([CH3:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC12CC2
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: Cc1c(N2C[C@@H](NC(=O)OC(C)(C)C)C3(CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 20.0 g of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid, 28.9 g of (S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane ([α]D20 -47.2° (c=1, MeOH)) and 80 ml of dimethyl sulfoxide was heated at 100° C. for 36 hours. The reaction mixture was poured into 500 ml of ice water. The deposited crystals were collected by filtration, washed with water and isopropanol, and then recrystallized from a mixture of methylene chloride and methanol to give 14.7 g of the desired compound, which was identified as the compound of Example 19.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5].C(N(CC)CC)C.[Br:18][CH:19]([CH3:23])[C:20](Br)=[O:21]>C(Cl)CCl>[Br:18][CH:19]([CH3:23])[C:20]([NH:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:21]
Reactant: CC(Br)C(=O)Br
Reactant: Cc1cccc(Cl)c1CN
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(Cl)c1CNC(=O)C(C)Br
Temperature: -35 °C

Procedure:
A mixture of 35 parts of 2-chloro-6-methylbenzylamine and 30 parts of triethyl amine in 400 parts of ethylene chloride is stirred and cooled to -35°C. While keeping the temperature between -35° and -20° C., there is added dripwise a solution of 50 parts of 2-bromopropionyl bromide in 160 parts of ethylene chloride. Upon completion, the whole is stirred for one hour at room temperature. The reaction mixture is washed with diluted hydrochloric acid and once with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The solid residue is crystallized from a mixture of 400 parts of ethanol and 150 parts of water, yielding 40 parts of N-(2-bromopropionyl)-2-chloro-6-methylbenzylamine; mp. 168° -169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:16]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[S:25]>O1CCCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH:16]=1)=[C:24]=[S:25]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2sc(-c3cccnc3)nc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=Nc1ccc2sc(-c3cccnc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-2-(3-pyridinyl)benzothiazole, 8.0 g, 0.035 M, is dissolved in 400 cc of tetrahydrofuran and 9.8 cc, 0.070 M, of triethylamine. Thiophosgene, 2.7 cc, 0.035 M is added, and the resulting mixture stirred overnight at ambient temperature. The solids which form are filtered and washed with tetrahydrofuran. The filtrate is concentrated to dryness and chromatographed on Alumina IV; elution with benzene yields 1.0 g of white solid which is recrystallized from acetonitrile to yield the title compound, 0.52 g, m.p. 160°-162° (12% of theory).
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)(=[O:14])=[O:13].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(Cl)Cl>[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:29](=[O:30])[CH2:28][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)(=[O:14])=[O:13]
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(COc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
In a two neck round bottom flask, 1-(naphthalene-2-yl-sulfonyl)piperazine hydrochloride (compound 4, 0.639 moles, 0.200 g) and 2-phenoxyacetylchloride (0.639 moles, 0.109 g) were charged in DCM (20 mL). TEA (2.557 moles, 0.258 g) was added slowly to the reaction flask. The resulting mixture was stirred for 3 h at room temperature. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 4:6, Ethyl acetate/Hexane) to obtain the title compound (0.200 g, 76.33%).