Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][C:30]=1[CH3:36])[CH2:24][C:25]([O:27]C)=[O:26])#[N:22]>>[C:21]([CH:23]([C:29]1[CH:34]=[CH:33][C:32]([O:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5]/[C:4](=[N:3]\[O:2][CH3:1])/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:9]=2)=[CH:31][C:30]=1[CH3:36])[CH2:24][C:25]([OH:27])=[O:26])#[N:22]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1C
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)c(C)c2)cc1)c1ccccc1
Yield: 95.69 %

Procedure:
Compound 62 was synthesized from (1Z)-2-[4-(hydroxymethyl)phenoxy]-1-phenylethanone O-methyloxime (0.5 g, 1.85 mmol) and methyl 3-cyano-3-(4-hydroxy-2-methylphenyl)propanoate (0.404 g, 1.85 mmol) by following the procedure described in scheme 18 (0.65 g, yield: 95.69%); Purity: 93.64%.
Reaction SMILES: [F:1][C:2]([F:17])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:10]=2[N:11]=1.IC.[C:20](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:17][C:2]([F:1])=[CH:3][CH2:4][CH2:5][S:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:20])[C:10]=2[N:11]=1
Reactant: Oc1cccc2oc(SCCC=C(F)F)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc2oc(SCCC=C(F)F)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-(4,4-difluorobut-3-enylthio)-4-hydroxy benzoxazole (Compound No. 82, Example 4B(iii), 504mg) in acetone (10 cm3) was added iodomethane (278 mg) and potassium carbonate (270 mg). The reaction mixture was stirred at the ambient temperature for 51/2 hours, then allowed to stand at the ambient temperature for 18 hours. Gc analysis indicated complete consumption of starting material. The reaction mixture was poured into ethyl acetate and and water, the layers separated and the aqueous phase extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried (MgSO4) and evaporated under reduced pressure to a yellow oil. Purification by silica-gel chromatography using 5% ethyl acetate in hexane as the eluent gave 2-(4,4-difluorobut-3-enylthio)-4-methoxy-benzoxazole as a colourless oil (290 mg). 1H NMR (CDCl3) δ7.19(1H,t); 7.08(1H,d); 6.78(1H,d); 4.30(1H,ddt); 3.39(1H,t); 2.55(q).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:24]([O-:26])=[O:25])[NH:21][CH2:20][CH2:19][CH2:18][S:17][C:16]2([CH3:23])[CH3:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:24]([OH:26])=[O:25])[NH:21][CH2:20][CH2:19][CH2:18][S:17][C:16]2([CH3:22])[CH3:23])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)[O-])NCCCSC2(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)NCCCSC2(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2-dimethyl-1,4-thiazepane-3-carboxylate (220 mg, 0.49 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (1.5 mL) and the mixture was stirred for 2 h at room temperature. The solvent was removed in vacuo. Traces of trifluoroacetic acid was removed by adding toluene (1 mL) and removing the solvent to obtain 170 mg (88%) of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl}-2,2dimethyl-1,4-thiazepane-3-carboxylic acid; 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 3H), 1.60 (s, 3H), 1.85 (m, 3H), 1.91 (m, 1H), 2.17 (m, 1H), 2.67 (m, 1H), 2.82 (m, 1H), 3.54 (m, 1H), 3.82 (m, 1H), 4.59 (s, 1H), 4.68 (m, 2H), 7.0 (d, 2H, J=8.7 Hz), 7.75 (d, 2H, J=8.7 Hz); HRMS (C18H23NO5S2)(M+); cald. 397.1018, found 397.0998.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl.[NH2:28][OH:29]>C(O)C.O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:28][OH:29])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Br)cccc1-2
Yield: 86.6 %

Procedure:
12 g (35 mmol) of (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile were stirred at boiling temperature for 2 hours with 9.6 g (94 mmol) of sodium bicarbonate and 7.3 g (105 mmol) of hydroxylamine hydrochloride in 170 ml of ethanol and 40 ml of water. After evaporating the alcohol the suspension obtained was cooled and the crystallizate was filtered off under suction and dried. There were obtained 11.4 g (86%) of (S)-8-bromo-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime of m.p. 235°-237°.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)CCc1ccnc(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1ccnc(O)c1

Procedure:
Ethyl β-(2-methoxy-4-pyridyl)propionate (89.1 g) and ethanolic HCl (200 ml) were stirred under reflux in ethanol (900 ml) for 48 hours. The reaction mixture was evaporated under reduced pressure to give an oily residue which was dissolved in water (300 ml). This solution was taken to pH9 with potassium carbonate solution and extracted into ethyl acetate (6×250 ml). The combined ethyl acetate extracts were washed with water, dried over MgSO4 and evaporated under reduced pressure to afford an oil which solidified to give white crystals of ethyl β-(2-hydroxy-4-pyridyl)propionate which were washed with petroleum ether (40°-60°) and dried in vacuo (59.58 g), m.p. 73°-76.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:46])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCC(=O)NCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (444.5 mg, 1.349 mmol) in a mixture of dichloromethane (20.0 mL) and triethylamine (470 μL, 3.37 mmol) was cooled to 0° C. Myristoyl chloride (367 μL, 1.35 mmol) was slowly added over a period of 10 minutes. The reaction mixture was allowed to stir at 0° C. for 1 hour at which time analysis by thin layer chromatography indicated that there was no starting material left. The reaction mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate solution (2×15 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography (20 g of silica gel eluted with 2% methanol in dichloromethane) followed by recrystallization from ethyl acetate (1.2 mL) and then further purified by column chromatography (25 g of silica gel eluted sequentially with 300 mL of 1% CMA in chloroform, 500 mL of 2% CMA in chloroform, 500 mL of 3% CMA in chloroform, 500 mL of 4% CMA in chloroform, 750 mL of 5% CMA in chloroform, and 600 mL of 6% CMA in chloroform) to provide 9.5 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)tetradecanamide as a white waxy solid, m.p. 85-87° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][C:10]=1[F:17])=[O:5])[CH3:2].B(Br)(Br)Br.CCO>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(OC)cc1F
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(O)cc1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 166.4 %

Procedure:
After 2-(2-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.16 g, 0.67 mmol) obtained in Step B was dissolved in anhydrous DCM (10 mL), 1M BBr3 solution (3.36 mL, 3.35 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, EtOH was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reactant was concentrated under reduced pressure, added with saturated sodium bicarbonate aqueous solution, and extracted with DCM. The organic layer was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex=1/4) to obtain the title compound (0.25 g, 97%).
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([C:22]2([Cl:25])[CH2:24][CH2:23]2)=O)=[CH:14][CH:13]=1.[OH-].[K+]>C(O)(C)(C)C>[Cl:25][C:22]1([C:20]2([CH2:19][CH2:18][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)[CH2:10][O:9]2)[CH2:23][CH2:24]1
Reactant: O=C(CCc1ccc(Cl)cc1)C1(Cl)CC1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: Clc1ccc(CCC2(C3(Cl)CC3)CO2)cc1
Reaction time: 14 h
Yield: 74.4 %

Procedure:
16 ml (0.22 mol) of dimethyl sulphide and 24.2 g (0.19 mol) of dimethyl sulphate are added to 30 ml of tert.-butanol and allowed to stand at 20° C. for 14 hours. A solution of 17 g (0.07 mol) of 1-chlorocyclopropyl 4-chlorophenylethyl ketone in 70 ml of tert.-butanol is first added dropwise to the reaction mixture with stirring and 22 g of potassium hydroxide powder are then introduced, while the temperature of the reaction mixture is kept at 20° to 30° C. The mixture is stirred at 30° C. for 3 hours more, then the dimethyl sulphide is removed under reduced pressure and the reaction mixture is then poured into 50 ml of a 1% aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed with water and concentrated by removing the solvent under reduced pressure after drying over sodium sulphate. In this manner, 13.4 g (75 % of theory) of 2-(1-chlorocyclopropyl)-2-(4-chlorophenylethyl)-oxirane are obtained in the form of an oily product, which is reacted further without additional purification. ##STR64##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:10])=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1.[OH:14]S(O)(=O)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:10])=[C:8]([C:11]([NH2:12])=[O:14])[CH:7]=[N:6][N:5]2[CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cnn2cc(Br)cc2c1Cl
Product: NC(=O)c1cnn2cc(Br)cc2c1Cl
Temperature: 55 °C
Yield: 89 %

Procedure:
To a 50 mL round bottom flask was added 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carbonitrile (12 g, 0.046 mol) and concentrated H2SO4 (60 mL). The reaction mixture was heated at 55° C. for 2 hours then cooled to room temperature and slowly diluted with ice water to precipitate the product which was collected by vacuum filtration, rinsed with water and dried to yield 11.2 g (89%) of the title compound as a yellow solid. HPLC (condition P): retention time=7.780 min. LCMS (condition C): m/z 274.0, 276.0−ve. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.32 (2H, s), 8.05 (1H, s), 7.90 (1H, s), 7.01 (1H, s).
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=1>C(O)C>[C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=2)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1ccccc1
Reactant: Nc1nccc(Cl)n1
Solvent: CCO
Product: C[C@H](Nc1ccnc(N)n1)c1nc2ccccc2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
Into a 25-mL round-bottom flask was placed a solution of (S)-1-(1-phenyl-1H-benzo[d]imidazol-2-yl)ethanamine from Example 4 (238 mg, 1.00 mmol, 1.00 equiv) in ethanol (8 mL) and 4-chloropyrimidin-2-amine (130 mg, 0.99 mmol, 0.98 equiv, 98%). The resulting solution was stirred overnight at 100° C. and concentrated under vacuum. The crude product was applied onto a C18 Column (water/acetonitrile) to afford 150 mg (44%) of 145 as a white solid. LC-MS (ES, m/z): 331 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): δ 7.83 (d, 1H), 7.57 (m, 8H), 6.11 (q, 1H), 5.61 (q, 1H), 1.67 (d, 3H)
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][C:2]1[C:3]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)=[C:4]([O:14][C:15]2[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)c(C)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2c(C)cc3cc(OC)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Yield: 85.5 %

Procedure:
Using the procedure described in Example 1 (Step 10), ethyl ester (47) (0.33 g, 0.69 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.26 g (85%) of compound (48) as an off-white foam. 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 3.77 (s, 3H), 3.92 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.61 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.6 Hz, 2H), 7.00-7.07 (m, 3H), 7.12 (d, J=2.5 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.56 (s, 1H), 7.63 (d, J=15.9 Hz, 1H), 7.68 (d, J=9.2 Hz, 1H). LCMS (APCI): m/z 441 (M+H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.C(C(CCCC)COC(=O)CC[SH:38])C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]1([C:12]2[N:8]3[C:9]4[C:4]([CH:5]=[CH:6][C:7]3=[N:14][N:13]=2)=[CH:3][C:2]([SH:38])=[CH:11][CH:10]=4)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Sc1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Temperature: 80 °C

Procedure:
To 7-Iodo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (1.5 g, 4.0 mmol) in 1,4-dioxane (15 mL) was added iPr2NEt (1.4 mL, 8.1 mmol), and the reaction was degassed with N2 for 10 minutes. 3-Mercapto-propionic acid 2-ethylhexyl ester (975 mg, 4.5 mmol) was added, followed by Pd2dba3 (93 mg, 0.1 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (117 mg, 0.2 mmol). The reaction was sealed and heated overnight at 80° C., and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the thiol intermediate as an oil. The oil was dissolved in THF (9 mL) and cooled to −78° C. Sodium tert-butoxide (780 mg, 8.1 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with 1N NaOH, and the aqueous layer was washed with Et2O. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the crude material was purified by silica gel chromatography (60-100% EtOAc in hexanes) to give the desired product, 10e.
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:31])[F:30])=[CH:4][CH:3]=1.[Cl:33]C1C2SC(I)=NC=2C(C(F)(F)F)=CC=1>>[Cl:33][C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29]([F:32])([F:30])[F:31])=[CH:4][CH:3]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: FC(F)(F)c1ccc(Cl)c2sc(I)nc12
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(Cl)c2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 7-chloro-2-iodo-4-trifluoromethyl-1,3-benzothiazole and conducting the Suzuki coupling at 70° C. for 3 h, the title compound was obtained as a yellow-green solid. 1H NMR (400 MHz, DMSO-d6): δ=2.14-2.36 (m, 4H), 3.05-3.18 (m, 2H), 3.37-3.44 (m, 2H), 4.01 (brs, 2H), 4.45-4.56 (m, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 8.11 (s, 1H), 8.25 (brs, 1H), 8.46 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.86 (brs, 1H), 9.06 (brs, 1H). MS(ES+): m/z=478.98/481.00 (100/76) [MH+]. HPLC: tR=2.37 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Br:12]C(Cl)(Cl)C(Cl)(Cl)Br.O>O1CCCC1>[Br:12][C:3]1[C:2]([Cl:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(Cl)c1Br
Temperature: -75 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
n-Butyl lithium (2.5M solution, 76 ml) was added to a stirred solution of diisopropylamine (28 ml) in dry tetrahydrofuran (THF) at -75° C., and maintained at -30° C. for a further 1 hour, to produce lithium diisopropylamide (LDA). After re-cooling to -75° C., a solution of 3-chloro-4-fluorobenzoic acid (14.4 g) in dry THF was added over 1 hour, and stirring was continued overnight at -75° C. A solution of 1,2-dibromotetrachloroethane (42.77 g) in dry THF was then added over 20 minutes, stirring was continued for 2 hours at -70° C. then at room temperature for 4 hours. Water was added, the organic and aqueous phases were separated and the aqueous phase was washed with ether, then acidified with hydrochloric acid solution and extracted with dichloromethane. The dichloromethane extract was dried (anhydrous magnesium sulphate) and the solvent evaporated to give 2-bromo-3-chloro-4-fluorobenzoic acid (19.54 g) as a beige solid, NMR (DMSO-D6) 7.55(t,1H), 7.75(dd,1H), 13.8(brs,1H).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br>CO>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:2][NH2:3]
Reactant: Clc1ccccc1CBr
Reactant: NN
Solvent: O
Solvent: CO
Product: NNCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.74 g (54.75 mmol) of hydrazine hydrate are introduced into 10 ml of methanol, and a solution of 3.00 g (14.60 mmol) of 2-chlorobenzyl bromide in 5 ml of methanol is added at RT. The temperature rises to 35–40° C. during this, and the mixture is then stirred at RT for 3 hours. The solvent is removed in vacuo, and the residue is taken up in 100 ml of diethyl ether, dried over magnesium sulfate and filtered off.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O.C(Br)(Br)(Br)[Br:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:14]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)CCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCBr
Temperature: 4 °C
Reaction time: 10 h

Procedure:
A solution of crude methyl-8-hydroxy-octanoate (7, 1.24 g, 7.13 mmol, 1.0 equiv.) in CH2Cl2 (15 mL, 0.48 M) at 0° C. was treated successively with CBr4 (3.07 g, 9.27 mmol, 1.3 equiv.) and PPh3 (2.61 g, 9.98 mmol, 1.4 equiv.) and the reaction mixture was stirred at 4° C. for 10 h. The reaction mixture was then concentrated under reduced pressure and washed repeatedly with Et2O (8×10 mL washes). The Et2O washes were combined and concentrated under reduced pressure. Chromatography (SiO2, 5 cm×15 cm, hexanes) afforded 8 as a clear, colorless oil (1.25 g, 1.69 g theoretical, 74.0%): 1H NMR (CDCl3, 250 MHz) δ 3.64 (s, 3H, C(O)OCH3), 3.38 (t, 2H, J=6.8 Hz, CH2Br), 2.29 (t, 2H, J=7.4 Hz CH2C(O)OCH3), 1.83 (p, 2H, CH2CH2Br), 1.63 (m, 2H, CH2CH2C(O)OCH3) 1.47-1.28 (m, 6H, alkyl protons)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17](Cl)=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[N:23]1([CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([Cl:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([O:31][CH2:30][CH2:29][N:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[O:28])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9]
Reactant: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=C1CCCN1CCO
Solvent: c1ccncc1
Product: Cn1nc(-c2cc(C(=O)OCCN3CCCC3=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
A solution of 1 g (2.6 mmol) of 5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-2,4-dichlorobenzoyl chloride and 0.5 g (3.8 mmol) of 2-(2-pyrrolidon-1-yl)ethanol in 20 ml of pyridine was stirred for approximately 15 hours, whereupon the reaction mixture was concentrated. The residue was treated with 10 ml of water and 20 ml of ethyl acetate. The organic phase was then separated off, dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (eluent: initially hexane/ethyl acetate=1:1, then ethyl acetate). Yield: 0.8 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:24])[CH:19]=[N:18][C:17]=2[C:16]([C:30]([OH:32])=O)=[CH:15][CH:14]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>C(Cl)Cl.CO>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:30]([C:16]2[C:17]3[N:18]=[CH:19][C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH3:24])=[N:21][C:22]=3[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])=[CH:14][CH:15]=2)=[O:32])[CH:35]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Reactant: Nc1cccnc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3cccnc3)c3ncc(N(C)CCN(C)C)nc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylic acid (Step 85.1) and 3-aminopyridine. Title compound: ESI-MS: 555.0/557.2 [M+H]+; tR=3.16 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[N:5]=1
Reactant: [I-]
Reactant: Cn1cnc(SCCl)n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cnc(SCI)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 3-chloromethylthio-1-methyl-1,2,4-triazole (981 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 3-iodomethylthio-1-methyl-1,2,4-triazole (1.50 g) as yellow oil.