Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(Cl)Cl.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4]3=[C:5]([C:17](=[O:21])[C:18](=[O:19])[N:3]13)[CH:6]=[CH:7][CH:8]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1=CC(C)(C)Nc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1=CC(C)(C)N2C(=O)C(=O)c3cccc1c32
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,2-dihydro-2,2,4-trimethylquinoline (34.6 g., 0.2 mole) in 50 ml. dry methylene chloride was added slowly dropwise to oxalyl chloride (26.4 g., 0.21 mole) in 300 ml. dry methylene chloride. Addition required 45 min., and when complete the resultant solution was stirred at ambient temperature 4 hrs. and refluxed 2 hrs. The dark red solution was freed of solvent at reduced pressure and the very dark solid residue taken up in chloroform. Dilution with ligroine and chilling produced a total yield of 32.6 g. (71.8%); m.p. 170°-176° C. A sample repeatedly recrystallized from toluene-ligroine (1:4) melted at 176°-177.5° C.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25].CCN(C(C)C)C(C)C.[CH2:36]([N:38]([CH2:44][CH3:45])[CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)[CH3:37]>>[F:1][C:2]1([F:26])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:41]4[CH2:42][CH2:43][CH:39]([N:38]([CH2:44][CH3:45])[CH2:36][CH3:37])[CH2:40]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH:3]1[CH3:25]
Reactant: CCN(CC)C1CCNC1
Reactant: CC1CC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)CCC1(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C1CCN(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)C(C)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, DIPEA and 3-diethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.66 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.19 (m, 3H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.56 (m, 1H), 1.27-1.32 (m, 1H), 1.00 (m, 9H). m/z: 505 [M+H]
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Br:1][C:14]1[C:13]([OH:16])=[CH:12][CH:11]=[C:10]([CH3:9])[N:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(O)c(Br)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
With cooling with ice, N-bromosuccinimide (18 g) was added to a pyridine (75 ml) solution of 6-methylpyridin-3-ol (10 g), and stirred at room temperature for 4 hours. After further stirred overnight at 50° C., the solvent was evaporated away under reduced pressure. The residue was dissolved in ethyl acetate, and washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water. After dried, the solvent was evaporated away, and the residue was crystallized with chloroform to obtain the entitled compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[CH:17][C:11]2=[N:10]1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:33]Br>C(Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:33])=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[CH:17][C:11]2=[N:10]1
Reactant: BrBr
Reactant: CCOc1ccc2nn(-c3cc(C)ccc3O)nc2c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc2nn(-c3cc(CBr)ccc3O)nc2c1
Temperature: 25 °C

Procedure:
2-(2′-hydroxy-5′-bromomethyphenyl)-5-ethoxybenzotriazole was prepared from the bromination of 2-(2′-hydroxy-5′-methyphenyl)-5-ethoxybenzotriazole using azobis isobutyronitrile (AIBN) as an initiator. In a 500 ml three-necked round bottomed flask, 6.275 g (0.0223 mol) 2-(2′-hydroxy-5′-methyphenyl)-5-ethoxybenzotriazole and 100 mg of AIBN were taken and dissolved in 150 ml of dry carbon tetrachloride. In a separate conical flask 4.18 g (1.5 ml, 0.03 mol) of bromine was dissolved in 75 ml of dry carbon tetrachloride and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 2-(2′-hydroxy-5′-methyphenyl)-5-ethoxybenzotriazole was kept in oil-bath with temperature 50° C. Nitrogen was bubbled through the solution for creating inert atmosphere. Cylindrical funnel containing bromine solution was mounted on the three-necked round-bottomed flask. Solution in the flask was continuously stirred with the help of magnetic stirrer. Bromine solution was added, drop-by-drop, from funnel to the flask for a span of 4-5 hours till all the solution was poured out. After that heating was stopped and the final reaction mixture was allowed to cool at room temperature. Product was separated by solvent evaporation. Finally the product was purified by recrystallization from acetone. The yield of 2-(2′-hydroxy-5′-bromomethyphenyl)-5-ethoxybenzotriazole was 6.6 g (85%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].O1CCOCC1>O1CCOCC1>[ClH:27].[CH2:1]([C:8]1[CH:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Cc3ccccc3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Cc2cnc(N3CCNCC3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 152.5 %

Procedure:
To a solution of tert-butyl 4-(5-benzylpyrimidin-2-yl)piperazine-1-carboxylate (8.0 g, 23.0 mmol) in 1,4-dioxane (30 mL) was dropwise added a solution of 4 M HCl-dioxane (20 mL, 80 mmol). The reaction mixture was stirred at RT overnight, and then concentrated to give 5-benzyl-2-(piperazin-1-yl)pyrimidine HCl salt (10.2 g, crude) as a yellow solid, MS (ES+) C15H18N4 requires: 254, found: 255 [M+H-100]+.
Reaction SMILES: O[C:2]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])=[CH:28][CH:27]=2)[C:7]2[CH:8]=[CH:9][C:10]([O:12]COC)=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:12][C:10]1[CH:9]=[CH:8][C:7]2[C:2]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][S:38][CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:44])([F:45])[F:46])=[CH:30][CH:31]=3)=[C:3]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)[CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: Oc1ccc(C2=C(c3ccc(OCCCCCSCCCC(F)(F)C(F)(F)F)cc3)c3ccc(O)cc3OC2)cc1
Temperature: 25 °C

Procedure:
4-Hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]4-[4-(5-(4,4,5,5,5-pentafluoropentylthio)pentyloxy)phenyl]-2,3-dihydro-4H-benzopyran (220 mg, 0.3 mmol) and pyridinium p-toluenesulfonate (789 mg, 3 mmol) were dissolved in methanol (8 mg) and then refluxed for 8 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=1:1) to obtain 142 mg (yield, 78%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=O)[CH3:16])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CCO>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=[N:19][OH:20])[CH3:16])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: NO
Reactant: COC(=O)C1(c2ccc(O)c(C(C)=O)c2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1(c2ccc(O)c(C(C)=NO)c2)CC1
Yield: 98.9 %

Procedure:
To a stirred solution of 1-(3-acetyl-4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (14.6 g, 58.8 mmol) in EtOH (500 mL) were added hydroxylamine hydrochloride (9.00 g, 129 mmol) and sodium acetate (11.6 g, 141 mmol) at room temperature. The resulting mixture was heated at reflux overnight. After removal of EtOH under vacuum, water (200 mL) and EtOAc (200 mL) were added. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-[4-hydroxy-3-(1-hydroxyimino-ethyl)-phenyl]-cyclopropanecarboxylic methyl ester (14.5 g, 98%), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 11.09 (s, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.14 (s, 1H), 6.91 (d, J=8.4 Hz, 1H), 3.63 (s, 3H), 2.36 (s, 3H), 1.62-1.59 (m, 2H), 1.18-1.15 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH:22](OC)O)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[S:27]1[CH:31]=[N:30][N:29]=[C:28]1[NH2:32].C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.Cl[Ti](OC(C)C)(OC(C)C)OC(C)C.CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH2:22][NH:32][C:28]4[S:27][CH:31]=[N:30][N:29]=4)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC(O)C[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Reactant: Nc1nncs1
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2CCNc1nncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a stirred mixture of 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol (18 mg, 0.05 mmol), 1,3,4-thiadiazol-2-amine (10 mg, 0.1 mmol), and anhydrous methylene chloride (0.5 mL) was added chlorotriisopropoxytitanium solution (1 M in hexanes, 0.2 mL, 0.2 mmol) at RT under nitrogen. The mixture was stirred at RT for 15 min before sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added. The mixture was stirred at RT for 1 hr and quenched by the addition of saturated aqueous sodium bicarbonate solution (3 mL). The aqueous layer was separated and extracted with ethyl acetate (3×2 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Prep TLC (silica gel, 50% acetone in ethyl acetate) gave N-(2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)ethyl)-1,3,4-thiadiazol-2-amine (6 mg, 0.015 mmol, 30% yield) as a solid.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:1]1([N:4]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[S:5]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])=[O:12])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCBr
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)NC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCN(C1CC1)S(=O)(=O)c1cccc(C(=O)OCC[Si](C)(C)C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A mixture of 2.12 g of 2-(trimethylsilyl)ethyl 3-(cyclopropylsulfamoyl)benzoate, 1.45 g of ethyl 4-bromobutyrate, 2.57 g of potassium carbonate, and 21 mL of DMF was stirred at 80° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 2.48 g of 2-(trimethylsilyl)ethyl 3-[cyclopropyl(4-ethoxy-4-oxobutyl)sulfamoyl]benzoate as a colorless oily substance. ESI+: 456
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:15][CH2:14]2)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[C:1]([O:5][C:6](=[O:31])[N:7]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[N:16]([C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)[CH:15]=[CH:14]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1cccc2c1N(c1ccncc1)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1cccc2ccn(-c3ccncc3)c12
Temperature: 90 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
Add active manganese dioxide (0.8 g, 9.0 mmol) to a solution of benzyl-[1-(pyridin-4-yl)-2,3-dihydro-1H-indol-7-ylmethyl]carbamic acid tert-butyl ester (0.39 mg, 0.94 mmol) in toluene. Stir the mixture at 90° C. for 16 hours. Cool and filter, then concentrate the filtrate. Purify by chromatography (silica gel; hexane/ethyl acetate; 3:1 to 0:1) to isolate a solid as the title compound (200 mg, 50%). MS (ESI) m/z 414 (M+H)+.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=1[OH:31])[C:11]([NH:13][NH:14][C:15]([C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])=[O:12])=[O:7])(C)(C)C.Cl.C(OCC)(=O)C>>[C:6]([C:8]1[CH:9]=[C:10]([CH:28]=[CH:29][C:30]=1[OH:31])[C:11]([NH:13][NH:14][C:15]([C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])=[O:12])([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1cc(C(=O)NNC(=O)c2occc2-c2ccccc2)ccc1O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NNC(=O)c1occc1-c1ccccc1)c1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
The compound of Example 194 (0.2 g) was mixed with 4 M hydrochloric acid/ethyl acetate and stirred overnight at 25° C. After distilling off the solvent under reduced pressure, the residue was recrystallized from ethyl acetate/hexane, thereby giving 0.14 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Br)cc1Br
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc(Br)cc1Nc1ccccc1
Temperature: 25 °C
Yield: 97.1 %

Procedure:
The product from Step 2 (7.55 g, 26.8 mmol) in THF (80 mL) and triethylamine (3.7 mL, 26.8 mmol) was treated with aniline (2.6 g, 27.9 mmol) and allowed to stir at rt until the reaction was judged complete by TLC. The solvent was removed in vacuo and the residue dissolved in ethyl acetate, washed (3×) with water and brinde, dried over Na2SO4 and concentrated in vacuo to afford the title compound (7.65 g, 97%). MS (ES+) m/e 294/296 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[Cl:19][C:20]1[C:29]2[C:24](=[C:25]([O:34][CH3:35])[C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>C(O)(C)C>[ClH:19].[C:10]([NH:9][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[F:1])[NH:8][C:20]1[C:29]2[C:24](=[C:25]([O:34][CH3:35])[C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc2c(Cl)ncnc2c(OC)c1OC
Reactant: Nc1ccc(F)c(NC(=O)c2ccccc2)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(F)c(NC(=O)c4ccccc4)c3)ncnc2c(OC)c1OC
Temperature: 80 °C
Yield: 52.7 %

Procedure:
N-(2-Fluoro-5-aminophenyl)benzamide (276 mg) was added to a suspension of 4-chloro-6,7,8-trimethoxyquinazoline hydrochloride (293 mg) in isopropanol (8 ml) and the resultant mixture stirred and heated to 80° C. for 18 hours. The mixture was cooled to ambient temperature and the precipitated solid was isolated, washed with isopropanol then diethyl ether to yield the title compound as a solid (257 mg, 53%); NMR: 4.0 (s, 3H), 4.01 (s, 3H), 4.07 (s, 3H), 7.42 (t, 1H), 7.52 (m, 2H), 7.62 (m, 2H), 8.0 (m, 3H), 8.35 (s, 1H), 8.72 (s, 1H), 10.28 (s, 1H), 11.84 (broad s, 1H); m/s: M+H+ 449.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[CH2:13]([O:15][C:16](OCC)([O:22]CC)[C:17](OCC)=O)[CH3:14]>>[CH2:13]([O:15][C:16]([C:17]1[S:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[N:1]=1)=[O:22])[CH3:14]
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1S
Product: CCOC(=O)c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 2-amino-4-trifluoromethyl-benzenethiol (0.7 g) was added ethyl triethoxyacetate (3 eq). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 460 mg of 5-trifluoromethyl-benzothiazole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[C:7]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.[CH2:21]([N:28]([CH2:32][Si](C)(C)C)[CH2:29]OC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:21]([N:28]1[CH2:32][CH2:10][C:9]([C:7]2[CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[N:4]=[C:5]([C:15]([F:18])([F:16])[F:17])[CH:6]=2)([C:11]([F:14])([F:13])[F:12])[CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)C(F)(F)F
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc(C(F)(F)F)n1
Temperature: 25 °C
Yield: 85 %

Procedure:
To the solution of 2,6-bis(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (1.25 g) and N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (5.0 g) in dichloromethane was added dropwise the solution of trifluoroacetic acid (0.038 g) in dichloromethane while cooling with ice. On completion of the dropwise addition, the mixture was warmed to room temperature and stirred over night. The mixture was washed with saturated sodium bicarbonate water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was removed under reduced pressure, and the residue was then purified by silica gel chromatography to yield 4-[1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl]-2,6-bis(trifluoromethyl)pyridine (1.52 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:24]([O-])=[O:25])=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.[NH4+].C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]2[S:14][C:15]([C:24]([NH2:30])=[O:25])=[C:16]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.4 %

Procedure:
To a suspension of the compound of Example 14 (370 mg, 1.02 mmol) in anhydrous DMF (5 mL) was added 1,1′-carbonyldiimidazole (182 mg, 1.12 mmol) and the reaction stirred at r.t. under nitrogen for 20mins. Ammonium hydroxide (2 mL of 28% NH3 in water) was added and the reaction stirred for 72 h. Solvents were removed in vacuo and the crude residue purified by chromatography on silica (0-15% THF in DCM) to give the title compound as a white solid (123 mg). δH (DMSO-d6) 8.74 (1H, s), 7.67-7.34 (3H, m), 7.33-7.27 (2H, m), 7.22-7.00 (5H, m), 6.82-6.71 (3H, m), 6.21 (1H, d, J 9.7 Hz). LCMS (ES+) RT 3.04 minutes, 362 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([Cl:15])[CH:3]=1.C(O)C.[OH-].[Na+]>O>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([Cl:15])[CH:3]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(CC(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To the ethyl (4-amino-2,5-dichlorophenyl)acetate (14) (4.36 g, 17.57 mmol) were added ethanol (30 ml) and 1N NaOH (35 ml), and the mixture was stirred at room temperature for 1 hour. After adding water (30 ml) to the reaction mixture, the reaction mixture was concentrated to about half the volume under reduced pressure. To this concentrate, 1N HCl (36 ml) was added under cooling, and the precipitated crystals were collected by filtration under reduced pressure. After washing the crystals with water, the crystals were air-dried. The resulting crude crystals were dissolved in ethyl acetate:chloroform:methanol (5:5:2, v/v/v, 120 ml), and the solution was filtered under reduced pressure. The filtrate was concentrated under pressure. The precipitated crystals were washed with hexane, and dried under reduced pressure to give (4-amino-2,5-dichlorophenyl)acetic acid (20) (3.69 g, 96%) as fine prism crystals.
Reaction SMILES: ClC(OCC(C)C)=O.CN1CCOCC1.[C:16]([OH:21])(=O)[C:17]#[C:18][CH3:19].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.[Cl-].[Na+].O>[Br:42][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:16](=[O:21])[C:17]#[C:18][CH3:19])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][CH:39]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 35.6 %

Procedure:
Isobutyl chloroformate (0.788 g, 5.75 mmol) and N-methylmorpholine (0.581 g, 5.75 mmol) were added to an ice cold solution of 0.485 g (5.75 mmol) of 2-butynoic acid in 20 mL of tetrahydrofuran under N2. After stirring for 10 min, a solution of 1.50 g (4.42 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of tetrahydrofuran was added and the mixture was stirred overnight at 25° C. A second equivalent of preformed mixed anhydride was then added. After 6 h, the reaction was poured into saturated sodium bicarbonate and brine. The product was collected and washed with hot ethyl acetate and ethanol and dried in vacuo to give 0.638 g of yellow solid; mp 283-285° C. (dec).