Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5](O)[C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:17])=O.[OH-].[NH4+]>CN(C)C=O>[Cl:17][C:12]1[C:13]2[N:1]=[CH:2][NH:3][C:4]=2[C:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]=2[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ccccc2c2[nH]cnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2cccnc2c2[nH]cnc12

Procedure:
To a mixture of 7.7 g (0.0416 mole) of 1H-imidazo[4,5-c]quinolin-4-ol and 50 mL of N,N-dimethylformamide was added in small portions 12 mL (0.13 mole) of phosphorus oxychloride. The mixture was heated on a steam bath for 1.5 hour, poured onto ice and basified with concentrated ammonium hydroxide. The solid precipitate was separated by filtration, washed with water and dried to provide 4-chloro-1H-imidazo[4,5-]quinoline as a tan powder corresponding to the product of Example 18.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:22][C:6]2=[N:7][C:8]3[C:9]([CH2:10][CH:11]=[CH:12][C:13]=3[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:5]2[CH2:4][CH2:3]1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[CH3:1][C:2]1([CH3:23])[CH2:22][C:6]2=[N:7][C:8]3[C:9]([CH:10]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=[CH:12][C:13]=3[O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:5]2[CH2:4][CH2:3]1
Reactant: CCCCCCCCBr
Reactant: CC1(C)CCC2=C3CC=CC(OCc4ccccc4)=C3N=C2C1
Product: CCCCCCCCC1C=CC(OCc2ccccc2)=C2N=C3CC(C)(C)CCC3=C21
Yield: 93.5 %

Procedure:
Using the procedure of Example 9, the alkylation of 4.3 g of 1,2,3,4-tetrahydro-3,3-dimethyl-6-phenylmethoxy-9H-dibenzo[b,d]pyrrole from Example 59 was reacted with 2.92 g of 1-bromooctane to produce 5.5 g (94%) of 1,2,3,4-tetrahydro-3,3-dimethyl-6-phenylmethoxy -9-octyl-9H-dibenzo[b,d]pyrrole as a white solid after chromatographic purification.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(Cl)cc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-chloro-2-oxindole to give 0.3 g of 5-Chloro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[C:9]=2[C:8]([CH3:23])=[C:7]([NH:24][C:25](=[O:32])OCC(Cl)(Cl)Cl)[C:6]=1[CH3:33].[NH2:34][CH2:35][CH2:36][OH:37]>CCCCCC.C(OCC)(=O)C>[OH:37][CH2:36][CH2:35][NH:34][C:25]([NH:24][C:7]1[C:6]([CH3:33])=[C:5]([CH2:4][CH2:3][CH2:2][OH:1])[C:13]2[O:12][CH2:11][CH:10]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)[C:9]=2[C:8]=1[CH3:23])=[O:32]
Reactant: NCCO
Reactant: Cc1c(CCCO)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(CCCO)c2c(c(C)c1NC(=O)NCCO)C(c1ccc(C(C)C)cc1)CO2
Yield: 53 %

Procedure:
Using 2,2,2-trichloroethyl (7-(3-hydroxypropyl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 141 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 53%. Melting point: 153-154° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]1([C:8]([C:10]([O:12][C:13](=[O:23])[C:14](=[O:22])[C:15]2[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH2:17])=[O:11])=[O:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH2:3].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34])(=O)=O>O=P(N(C)C)(N(C)C)N(C)C>[CH:33]([O:32][CH2:31][CH2:30][NH:3][C:2]1[C:1]([C:8]([C:10]([O:12][C:13](=[O:23])[C:14](=[O:22])[C:15]2[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:17][CH2:30][CH2:31][O:32][CH:33]([CH3:34])[CH3:35])=[O:11])=[O:9])=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Reactant: Nc1ccccc1C(=O)C(=O)OC(=O)C(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)OCCNc1ccccc1C(=O)C(=O)OC(=O)C(=O)c1ccccc1NCCOC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: 3 g of isatic acid anhydride are dissolved in 50 ml of distilled hexametapol(=hexamethylphosphoric acid triamide). The solution is cooled to 5°, and 0.96 g of 55% NaH (freed of oil with hexane) is added. The mixture is stirred for 30 minutes at RT and then 5.67 g of O-(2-isopropyloxyethyl) tosylate are added. The mixture is stirred for 30 minutes at RT and for one hour at 50°. The mixture is left to stand overnight and is poured onto ice, and the organic layer is separated off and washed with water. The mixture is concentrated by evaporation, and the residue is digested with ether and filtered off with suction, yielding N-(2-isopropyloxyethyl)isatic acid anhydride, m.p. 107°-108°.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][O:9][C:10]([C:12]1[N:13]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:14]2[C:19]([C:20](=[O:45])[C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[CH:18][CH:17]=[C:16]([Cl:46])[CH:15]=2)=[O:11]>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:8][O:9][C:10]([C:12]1[N:13]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:14]2[C:19]([C:20](=[O:45])[C:21]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:27][CH:28]=1)=[CH:18][CH:17]=[C:16]([Cl:46])[CH:15]=2)=[O:11]
Reactant: COC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCNCC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of TFA and DCM (1:4, 5 mL) was added to 3-[4-(4-t-butoxycarbonylpiperazine-1-sulfonyl)-benzyl]-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (48 mg, 0.07 mmol) and the resulting mixture stirred at RT for 2 h. The reaction mixture was evaporated under reduced pressure, and the oily solid residue was purified by flash chromatography (DCM/MeOH, 100:0 to 90:10) to afford 7-chloro-4-oxo-1-phenyl-3-[4-(piperazine-1-sulfonyl)-benzyl]-1,4-dihydro-quinoline-2-carboxylic acid methyl ester trifluoroacetate as an off-white powder. MS=552 [M+H]+; MP=203.0-205.0° C.
Reaction SMILES: [CH:1]1([CH3:18])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])[CH2:2]1.[CH3:19][C:20](O)([CH3:22])[CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:20]([O:15][C:14](/[CH:13]=[CH:12]\[C:11]([O:10][CH:3]1[CH:4]([CH:7]([CH3:9])[CH3:8])[CH2:5][CH2:6][CH:1]([CH3:18])[CH2:2]1)=[O:17])=[O:16])([CH3:22])([CH3:21])[CH3:19]
Reactant: CC1CCC(C(C)C)C(OC(=O)/C=C\C(=O)O)C1
Reactant: CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)/C=C\C(=O)OC(C)(C)C)C1
Temperature: 150 °C

Procedure:
2.5 g of maleic acid monomenthyl ester, 1 g of 2-methyl-2-propanol and 0.7 g of p-toluenesulfonic acid in 30 mL of toluene were heated to reflux at a oil temperature of 150° C. for 19 h. Subsequently, the reaction mixture was quenched by the addition of salt saturated sodium bicarbonate solution. The mixture was extracted with ether, the organic layers were combined and washed with salt saturated sodium bicarbonate solution and then with an aqueous solution of sodium hydroxide, salt saturated ammonium chloride solution, and then dried over salt saturated brine and sodium sulfate anhydrous. Finally, the resultant oily product was subjected to distillation under reduced pressure to obtain menthyl 3-t-butoxycarbonyl-2Z-propenoate.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-methyl-3-nitroaniline (3.60 g, 23.7 mmol) in acetic anhydride (28 mL) was allowed to stir at room temperature. After 16 h, the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (25 mL), washed with saturated sodium bicarbonate (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give 4.20 g (Y: 99%) of the title compound; 1H-NMR (CDCl3): δ 8.10 (d, J=1.7 Hz, 1H), 7.75 (dd, J=8.5, 1.7 Hz, 1H), 7.38 (bs, 1H), 7.29 (d, J=8.5 Hz, 1H), 2.56 (s, 3H), 2.21 (s, 3H); MS (DCI) m/e: 195 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[CH:29]([NH2:32])([CH3:31])[CH3:30]>CN(C=O)C>[OH:16][C@H:15]([CH2:17][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CNC(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.6 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and isopropylamine (0.29 ml, 4.65 mmol) in DMF (5 ml) was stirred at 100° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (307 mg, 75%).
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:18])[CH:15]=3)[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:9]2)=CC=1.C(O)(C(F)(F)F)=[O:29]>C(Cl)Cl>[CH2:19]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([Cl:18])=[CH:13][CH:12]=2)[CH2:17][NH:8][C:9]1=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CN2Cc3cc(Cl)ccc3N(Cc3ccccc3)C2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2cc(Cl)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirring mixture of 3-(4-methoxybenzyl)-1-benzyl-6-chloro-3,4-dihydroquinazolin-2(1H-one (0.2 g, 0.68 mmol) in DCM (5.0 mL) was added TFA (4.0 mL). The mixture was stirred at RT for 5 h. The reaction was monitored by MS, and upon completion, the reaction was concentrated. The crude residue was purified using flash column chromatography (100% DCM to 2% MeOH in DCM) to obtain the desired product 1-benzyl-6-chloro-3,4-dihydroquinazolin-2(1H)-one as a white solid. MS m/e 273 (M+H)+.
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([C:21]([F:24])([F:23])[F:22])=[CH2:20])=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1.CC(O)=O>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[N:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3([C:21]([F:24])([F:22])[F:23])[CH2:3][CH2:20]3)=[CH:16][CH:17]=2)[C:12]([C:25]2[N:30]=[C:29]([O:31][C@H:32]3[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37][CH2:36][C:33]43[CH2:35][CH2:34]4)[CH:28]=[N:27][CH:26]=2)=[N:11]1
Reactant: C=C(c1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1)C(F)(F)F
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5(C(F)(F)F)CC5)cc34)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.6 %

Procedure:
Diazomethane (˜0.25M in Et2O (prepared according to Aldrich Technical Bulletin AL-180, Aldrich, St. Louis, Mo.); 1.0 mL, 0.250 mmol) was added (dropwise) to a solution of (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3,3,3-trifluoroprop-1-en-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (41.8 mg, 0.070 mmol) and palladium(II) acetate (1.565 mg, 6.97 μmol) in DCM (1.0 mL) at 0° C., and the resulting solution was stirred at 0° C. for 30 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min. Additional palladium(II) acetate (4.54 mg, 0.020 mmol) and diazomethane (˜0.25M in Et2O; 2×2.0 mL, 2×0.500 mmol) were sequentially added, and the reaction was stirred at 0° C. for 5 min. Additional diazomethane (˜0.25M in Et2O; 2.0 mL, 0.500 mmol) was added, the reaction was stirred at 0° C. for 5 min. HOAc (0.160 mL, 2.79 mmol) was added to quench excess diazomethane, and the resulting mixture was stirred at 25° C. for 12 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (25.2 mg, 0.041 mmol, 59% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (1 H, s), 8.52 (1 H, s), 8.21 (1 H, br. s.), 7.63 (1 H, s), 7.53 (1 H, d, J=8.8 Hz), 5.80 (1 H, d, J=9.0 Hz), 4.69 (1 H, d, J=11.5 Hz), 4.44 (1 H, br. s.), 4.24-4.36 (1 H, m), 4.03 (1 H, d, J=11.5 Hz), 3.71-3.84 (1 H, m), 3.24 (1 H, d, J=14.7 Hz), 2.88-3.03 (1 H, m), 2.56-2.71 (1 H, m), 2.42-2.55 (1 H, m), 2.17-2.29 (1 H, m), 2.12 (1 H, d, J=7.8 Hz), 1.65-1.88 (5 H, m), 1.37-1.55 (9 H, m), 0.81-0.92 (2 H, m), 0.72 (1 H, br. s.), 0.48-0.63 (4 H, m). 19F NMR (377 MHz, CDCl3) δ ppm −70.26 (3 F, br. s.). MS (ESI, pos. ion) m/z: 614.3 (M+1).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1F
Yield: 69 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 2-fluoro-phenylhydrazine according to the method described for Example 1 in 69% yield. MS: M=417.0 (M+H)+
Reaction SMILES: C([O:8][C:9]([C:11]1([N:17]([CH:35]=[CH:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.O>[CH2:40]([O:39][C:37]([CH2:36][CH2:35][N:17]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[C:11]1([C:9]([OH:10])=[O:8])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:38])[CH3:41]
Reactant: CCOC(=O)C=CN(C1(C(=O)OCc2ccccc2)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: [H][H]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCN(C1(C(=O)O)CCOCC1)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of (4.4 mmol) of the product of step D in 25 mL of ethanol is treated with 2.5 g of 50% water wet 10% palladium on carbon catalyst and shaken under 53 psi of hydrogen for 21 hours. The catalyst is removed by filtration and washed with ethanol (4×25 mL). The filtrate and washings are combined and concentrated under vacuum to crude product.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([NH:8][C:15]([C:13]1[N:14]=[C:10]([Br:9])[S:11][CH:12]=1)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: NCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1csc(Br)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzyl amine was loaded to 4-formyl-3,5-dimethoxyphenoxymethyl functionalized polystyrene resin (PAL) via reductive amination to give PAL-benzyl amine resin. See, Ding, S.; Grey, N. S. Wu, X.; Ding, Q.; Schultz, P. G. J. Am. Chem. Soc. 2002, 124, 1594-1596. A reaction flask containing PAL-benzyl amine resin (200 mg, 0.2 mmol), 2-bromothiazole-4-carboxylic acid (83 mg, 0.4 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl) (153 mg, 0.6 mmol) and diisopropylethylamine (0.17 mL, 1 mmol) in DMF (3 mL) was shaken for 24 hr at room temperature. The resin was washed with methanol, dichloromethane and dried in vacuo to give PAL resin-N-benzyl-2-bromothiazole-4-carboxamide, which was then added to a flame-dried reaction vial, followed by 4-aminopyrimidine (95 mg, 1 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and NaOtBu (192 mg, 2 mmol). The vial was sure safe capped and degassed, then charged with argon and anhydrous dioxane (1.5 mL). The reaction was shaken for 24 hours at 90° C. The resin was washed with sodium diethyldithiocarbamate solution (0.05 M in DMF), methanol and dichloromethane and dried in vacuo. The resin was subsequently cleaved with cleavage cocktail TFA:CH2Cl2:H2O (45:55:5) (2 mL) for 2 hr. The resin was filtered, the filtrate was collected and evaporated in vacuo to give the crude which was then purified by HPLC to give the title compound (30 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[K+].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([S:20]([NH-:23])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>CN1CCCC1=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:9][CH3:10])[N:5]=[C:6]([NH:23][S:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:25])[F:24])[CH:15]=2)(=[O:21])=[O:22])[CH:7]=1
Reactant: [NH-]S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: CNc1nc(Cl)cc(Cl)n1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CNc1nc(Cl)cc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)n1
Yield: 45.7 %

Procedure:
0.27 g (0.00155 mol) of (4,6-dichloro-pyrimidin-2-yl)-methylamine and 0.82 g (0.0031 mol) of 3-trifluoromethyl-benzenesulfonamide potassium salt were stirred in 10 ml of 1-methyl-2-pyrrolidone at 150° C. for 8 hours. Then, the solvent was distilled off in a high vacuum, the residue was partitioned in ethyl acetate/water and extracted. The aqueous phase was made acid with 4N HCl and extracted with dichloromethane. The residue was chromatographed over silica gel with cyclohexane/ethyl acetate 2:1 as the eluent. There was obtained 0.26 g (69%) of N-(6-chloro-2-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamide as white/beige crystals; m.p.: 190-193° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][NH:54]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:52][CH2:53][NH2:54])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(O)ccc21
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To 1-(phenylsulfonyl)-1 H-indol-5-ol, (Intermediate 8, 8.0 g, 29 mmol) were 1,1′-azobis(N,N-dimethylformamide) (7.6 g, 44 mmol), triphenylphosphine (15.4 g, 580 mmol), tert-butyl N-(2-hydroxy-ethyl)carbamate (9.4 g, 58 mmol) and DCM (200 mL) added. The reaction mixture was heated at 50° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature and TFA (50 mL) was added. The reaction mixture was stirred for 3 hours and evaporated. The crude material was purified with flash chromatography on silica gel (DCM:MeOH, 95:5) to give the title compound (9.6 g). MS m/z 317 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](Cl)(Cl)=[S:11].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[N:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1)=[C:10]=[S:11]
Reactant: S=C(Cl)Cl
Reactant: Cc1ccc(N)c(C)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N=C=S)c(C)n1
Yield: 66.4 %

Procedure:
The title compound was prepared following the procedure described for intermediate-2 using 2,6-dimethylpyridin-3-amine (1.0 g, 8.26 mmol), thiophosgene (0.949 g, 8.25 mmol) and N-ethyl di-isopropyl amine (3.20 g, 24.80 mmol) in DCM (20 mL) to afford 0.900 g of the desired product. 1HNMR (DMSO-d6): δ 2.44 (s, 6H), 7.18 (d, J=8.1 Hz, 1H), 7.70 (t, J=8.1 Hz, 1H); MS [M+H]+: 165.28.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:20]1[CH2:23][CH2:22][CH2:21]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.CN(C)C=O>[N:20]1([C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13]2)[CH2:23][CH2:22][CH2:21]1
Reactant: C1CNC1
Reactant: O=C(O)CN1CCN(C(=O)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(C(=O)c2ccccc2)CC1)N1CCC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 31.6 %

Procedure:
To (4-benzoylpiperazin-1-yl)acetic acid ethyl ester (8.19 g) were added methanol (300 ml) and water (50 ml), and lithium hydroxide (1.34 g) was added thereto in an ice water bath, followed by stirring for 10 min. The reaction mixture was allowed to warm up to room temperature and stirred for 24 hr. After addition of 1N hydrochloric acid (55.9 ml), the reaction mixture was concentrated under reduced pressure, and ethanol (200 ml) was added to the resultant residue. Precipitated insoluble matter was filtered through celite. The filtrate was concentrated to provide a crude product of (4-benzoylpiperazin-1-yl)acetic acid as a white solid (8.6 g). To (4-benzoylpiperazin-1-yl)acetic acid (2 g) was added N,N-dimethylformamide (80 ml) under a nitrogen atmosphere at room temperature, and azetidine hydrochloride (1.51 g), triethylamine (4.49 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were added thereto in this order, followed by stirring at room temperature for 66 hr. Liquid-liquid separation was carried out after addition of ethyl acetate (100 ml) and a saturated aqueous solution of sodium hydrogencarbonate (50 ml) to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine (50 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, the resultant residue was suspended in diethyl ether (10 ml). The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (731.5 mg).