Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][O:35]C)[CH:31]=1)[C:19]([NH:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH3:28])[N:23]=1)=[O:20].C[Si](I)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Cl:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:37])[CH2:34][OH:35])[CH:31]=1)[C:19]([NH:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH3:28])[N:23]=1)=[O:20]
Reactant: CCn1ccc(NC(=O)c2cc(Oc3ccc4c(c3Cl)OCCN(C)C4=O)cc(O[C@@H](C)COC)c2)n1
Agent: C[Si](C)(C)I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CCn1ccc(NC(=O)c2cc(Oc3ccc4c(c3Cl)OCCN(C)C4=O)cc(O[C@@H](C)CO)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
A solution of 3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-N-(1-ethyl-1H-pyrazol-3-yl)-5-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}benzamide (300 mg, 0.57 mmol) in acetonitrile (10 mL) was treated with trimethylsilyl iodide (0.404 mL) and stirred at RT under argon for 3 hours. Sodium thiosulphate solution (30 mL) was added to quench the reaction and mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated to give a yellow oil. Purification by column chromatography on silica, eluting with 50-100% ethyl acetate in hexanes, gave the desired compound as a pale yellow solid (230 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[N:3][CH:2]=1.Cl.[CH3:16][C:17]1([CH3:24])[CH2:22][NH:21][C:20]([NH2:23])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:16][C:17]1([CH3:24])[CH2:22][N:21]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:23]=[C:20]2[NH:19][CH2:18]1
Reactant: CC1(C)CN=C(N)NC1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC1(C)CNc2nc(-c3ccncn3)cc(=O)n2C1

Procedure:
A mixture containing 5.15 g (26.52 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate, (prepared by analogy to the method described in patent DE 2705582), 4.34 g (26.52 mmol) of 5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride (prepared by analogy to U.S. Pat. No. 4,262,122) and 3.66 g (26.5 mmol) of potassium carbonate in 60 ml of methanol were heated at reflux temperature during 18 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][NH2:12])=[O:10])=[CH:4][CH:3]=1.[CH2:15]=[C:16]1[O:19][C:18](=[O:20])[CH2:17]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][NH:12][C:18](=[O:20])[CH2:17][C:16](=[O:19])[CH3:15])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C1CC(=O)O1
Reactant: CC(C)(C(=O)NN)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NNC(=O)C(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
2-(4-chlorophenyl)-2-methylpropanehydrazide (9.0 g, 42.5 mmol) was dissolved in dry tetrahydrofuran (100 ml), and 4-methyleneoxetan-2-one (3.9 ml, 51 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 18 hours, then solvent removed under resuced pressure, and ethyl acetate was added. The solution was passed through a 120 g silica gel column eluting with ethyl acetate, to provide clean N′-(2-(4-chlorophenyl)-2-methylpropanoyl)-3-oxobutanehydrazide (12.2 g, 97%) as a viscous golden oil. TLC Rf=0.47 using 100% ethyl acetate as eluent on a glass backed silica gel plate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([O:20][CH2:21][C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:25]=[N:24][CH:23]=3)=[N:10][C:9]=2[C:46]#[N:47])[CH:5]=[CH:6][CH:7]=1.CO>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([O:20][CH2:21][C:22]3[NH:26][CH:25]=[N:24][CH:23]=3)=[N:10][C:9]=2[C:46]#[N:47])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(OCc3cncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)nc(C#N)c(-c3cccc(F)c3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2c(OCc3cnc[nH]3)nc(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 2.5 h

Procedure:
4-(3-fluorophenyl)-6-methoxy-1-[(1-trityl-1H-imidazol-5-yl)methoxy]isoquinoline-3-carbonitrile (255 mg) was dissolved in 4 mL of 5% TFA in CH2Cl2 at 0 C to give a bright yellow solution. The reaction was stirred at 0 C for 2.5 h, then at room temp for 1.5 h. MeOH was added, and the reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The aqueous solution was further extracted with CH2Cl2 (3×). The combined organic solutions were dried over MgSO4 and concentrated. The white solid residue was recrystallized from CH2Cl2-EtOAc to give white solid. The mother liquor was concentrated and purified by flash chromatography (0% to 10% MeOH(10% NH4OH) in EtOAc to give additional white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:24](I)[CH3:25]>CN(C)C=O>[CH2:24]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:21])[CH2:19][CH3:20])[CH3:25]
Reactant: CCC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=O)N(CC)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 6.1 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]propanamide in 200 ml of dry dimethylformamide under argon, was added 1.1 g of sodium hydride (50% in oil). The mixture was stirred for one hour, then 1.86 ml of ethyl iodide was added. This mixture was stirred overnight and then treated as described in Example 1. The chromatography fractions containing the product were combined and the solid recrystallized as described in Example 1, giving 4.37 g of the desired product, mp 145°-148° C.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2].[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[CH:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([N:11]2[CH2:16][C:15]3([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[O:14][CH2:13][CH2:12]2)=[O:10])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reaction time: 16 h
Yield: 91 %

Procedure:
To a solution of tert-butyl 4-(2-isopropylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (limiting reagent) (step a) in DCM (5 volumes) was added trifluoroacetic acid (13.4 molar equivalents) in portions at 10-15° C. The solution was allowed to warm to ambient and stirred for 16 hr. Solvent was evaporated and the residue was dissolved in diethyl ether (10 volumes). The solution was cooled in ice and scratched to give precipitation; the slurry was stirred at 0°-10° C. for 0.5 hr then filtered cold. The cake was washed with diethyl ether (5 volumes) and dried in vacuo at 35° C. to give a beige coloured powder. Yield: 91% of theoretical.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([C:18]2[CH:23]=[C:22]([C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:20]([C:33](=[O:45])[NH:34][CH2:35][C:36]3[C:37](=[O:44])[NH:38][C:39]([CH3:43])=[CH:40][C:41]=3[CH3:42])[C:19]=2[CH3:46])[CH2:16][CH3:17])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:41]1[CH:40]=[C:39]([CH3:43])[NH:38][C:37](=[O:44])[C:36]=1[CH2:35][NH:34][C:33](=[O:45])[C:20]1[CH:21]=[C:22]([C:24]#[C:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:18]([N:15]([CH2:16][CH3:17])[C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]2)[C:19]=1[CH3:46]
Reactant: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)[C@H]1CC[C@H](NC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl((trans)-4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydro pyridin-3-yl)methyl)carbamoyl)-2-methyl-5-(3-morpholinoprop-1-yn-1-yl)phenyl)(ethyl)amino)cyclohexyl)(methyl)carbamate (1 equiv.) in DCM at 0° C., TFA (3 equiv.) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with Na2CO3 (aq.) to pH 8 and the aqueous layer was extracted with 20% methanol in DCM. The combined organic layers were dried over Na2SO4 and solvent was removed under reduced pressure to afford the title compound (99% yield) which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:16][CH2:17][CH:18](Br)[CH2:19][CH3:20]>>[CH2:17]([CH:18]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[N:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:19][CH3:20])[CH3:16]
Reactant: CCC(Br)CC
Reactant: COc1ccc(NC(=O)C(C)(C)C)nn1
Product: CCC(CC)c1cc(OC)nnc1NC(=O)C(C)(C)C
Yield: 65.5 %

Procedure:
Using a procedure analogous to Example 17B, from N-(6-methoxy-pyridazin-3-yl)-2,2-dimethyl-propionamide (6.09 g, 29.14 mmol) and Grignard reagent prepared from 3-pentyl bromide (18.1 mL, 160.3 mmol) and Mg (3.84 g, 160.26 mmol) gives the title compound (5.32 g, 19.1 mmol, 65%). 1H NMR (CDCl3): δ. 0.84 (t, J=7.5 Hz, 6H), 1.36 (s, 9H), 1.50-1.72 (m, 4H), 3.50-3.70 (m, 1H), 4.07 (s, 3H), 6.96 (s, 1H) ppm. ES-MS (m/z): calcd for C15H25N3O2 (M+H)+: 280.4. found: 280.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19]Br)[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.[CH3:26][C@H:27]1[O:32][CH2:31][CH2:30][NH:29][C@@H:28]1[C:33]([OH:35])=[O:34]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:13]([CH2:19][N:29]2[CH2:30][CH2:31][O:32][C@H:27]([CH3:26])[C@H:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: C[C@H]1OCCN[C@@H]1C(=O)O
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Product: COC(=O)C1=C(CN2CCO[C@H](C)[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 49.5 %

Procedure:
Methyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.93 g, 1.9 mmol) was reacted with (2R,3S)-2-methyl morpholine-3-carboxylic acid (0.28 g, 1.9 mmol) according to the procedure as described in Example 34 to give the title compound as a yellow solid (0.52 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].[Br:15]Br>C(O)(=O)C>[NH2:9][C:4]1[N:5]=[C:6]([Cl:8])[C:7]([Br:15])=[C:2]([Cl:1])[N:3]=1
Reactant: BrBr
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(Br)c(Cl)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirred mixture of 4,6-dichloro-pyrimidin-2-yl-amine (2.46 g, 15.0 mmol) and sodium acetate (6.15 g, 75.0 mmol) in acetic acid (150 ml) was added bromine (3.24 g, 20.25 mmol) dropwise. The mixture was then stirred at 60° C. for 2 hours. Volatiles were evaporated under reduced pressure. The residue was stirred with water (500 ml) for 1 hour, filtered, and dried under reduced pressure to provide 2-amino-4,6-dichloro-5-bromo-pyrimidine (3.2 g, 88% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][CH2:7][S:6]1)=[O:4].Cl.[NH2:12]O.CCOCC>C(#N)C>[NH2:12][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: NO
Reactant: COC(=O)C1SCCC1=O
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)c1sccc1N

Procedure:
2-Methoxycarbonyl-3-oxotetrahydrothiophene (2 g) was dissolved in acetonitrile (20 ml) with heating and stirring. Hydroxylamine hydrochloride (0.8 g) was added to the refluxing solution and the mixture was refluxed for 11/2hour. After cooling, ether (50 ml) was added and the precipitated straw-coloured solid was filtered off. The solid was dissolved in water and basified with 4M ammonia solution and extracted with dichloromethane (2×25 ml). The combined extracts were washed with water and with brine and dried over sodium sulphate. Filtration and evaporation gave an oil which solidified on cooling and was crystallised from petrol ether bp 60°-80° to afford the title compound, 1.34 g (73%); mp 62°-63°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:17])[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:26]=1[CH2:27]Br.O>CN(C=O)C>[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:26]=1[CH2:27][O:17][C:4]1[C:5]2[N:6]([C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(F)cn12
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(F)cn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
560 mg of ethyl 6-fluoro-8-hydroxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 12A; 2.4 mmol, 1.0 equivalent), 1.7 g of caesium carbonate (5.17 mmol, 2.2 equivalents) and 535 mg of 2,6-difluorobenzyl bromide (2.6 mmol, 1.1 equivalents) were initially charged in 34 ml of dry DMF, and the mixture was heated at 50° C. for 15 min. Water was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water. This gave 560 mg of the title compound (65% of theory).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH3:22].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>CCOC(C)=O>[CH2:21]([O:23][C:24](=[O:37])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:32][CH2:33][N:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=4)=[CH:14][N:15]=3)[CH2:35][CH2:36]2)=[CH:29][CH:30]=1)[CH3:22]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. The product was isolated after silica gel column chromatography with 20-50% EtOAc in hexanes gradient. HRMS m/z calcd for C29H34N4O3 [M+H]+: 487.2704. Found: 487.2701.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11])[CH3:18]
Reactant: CCO
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C(C)=O)s1
Yield: 84 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (17.0 g, 100 mmol) in ethanol (500 mL) was treated with a concentrated H2SO4 solution (10 mL) and heated at reflux for 3 days after which time the reaction was evaporated to approximately ¼ volume and partitioned between EtOAc (300 mL) and water (100 mL). The organic portion was then further washed with a saturated aqueous solution of NaHCO3 (2×100 mL) followed by a brine solution (100 mL), then dried over MgSO4, filtered, and evaporated in vacuo to afford product as light brown colored solid (25.0 g, 84%). 1H NMR (CDCl3) 1.39 (t, J=7.0, 3H), 2.59 (s, 3H), 4.38 (q, J=7.3, 2H), 7.64 (d, J=4.0, 1H), 7.76 (d, J=4.0, 1H). 13C NMR 14.3, 27.1, 61.9, 131.8, 133.3, 140.3, 148., 161.7, 190.9. LC/MS 5.47 min, [M+1]+ 199.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([F:35])([F:34])[S:21](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:23])=[O:22].CCOC(C)=O>CN(C=O)C>[F:19][C:20]([F:35])([F:34])[S:21]([O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1cc(C=O)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C=O)c(C)cc1OS(=O)(=O)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 4-Hydroxy-5-methoxy-2-methylbenzaldehyde (20.0 g, 122 mmol) in DMF (200 mL) at room temperature was added potassium carbonate (33.3 g, 241 mmol) and 4-nitrophenyl trifluoromethanesulfonate (49.0 g, 181 mmol) and the reaction mixture was stirred for 8 hr. EtOAc (600 mL) was added to the reaction mixture and the organic layer was washed three times with water, dried, filtered, and concentrated. The crude compound was then purified by flash chromatography (ethylacetate/hexanes 1:9→3:7) to provide 4-Formyl-2-methoxy-5-methylphenyl trifluoromethanesulfonate. 1H NMR (CDCl3, 500 MHz) δ 10.34 (s, 1H), 7.53 (s, 1H), 7.16 (s, 1H), 3.99 (s, 3H), 2.67 (s, 3H); LC/MS: (IE, m/z) [M+1]+=298.97; tR=3.44 min.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[F:22].[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][C@@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1>>[F:22][C:5]1[CH:6]=[C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)[CH:8]=[CH:9][C:4]=1[C:3]([N:32]1[CH2:33][CH2:34][CH2:35][C@H:31]1[CH2:30][N:26]1[CH2:27][CH2:28][CH2:29][C@H:25]1[CH3:24])=[O:23]
Reactant: COC(=O)c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1F
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(OCc2ccc(S(C)(=O)=O)cc2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure F from 2-fluoro-4-(4-methanesulfonyl-benzyloxy)-benzoic acid methyl ester and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (ES+) 475.2
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([O:19]C)=[CH:17][CH:18]=2)=[CH:4][N:3]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[CH:4][N:3]=1
Reactant: COc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1ccc(Cc2cnc(Cl)c3ccccc23)cn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Under exclusion of moisture, to 500 mg (1.76 mmol) of 1-chloro-4-[(6-methoxy-pyridin-3-yl)methyl]-isoquinoline (step 28.6) in 9 ml of chloroform, 488 μl (3.58 mmol) of Me3Sil are added. Then the mixture is stirred for 8 h at 60° C. Dilution of the mixture with EtOAc and NaHCO3-solution, stirring and filtration of the suspension yields 1-chloro-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline, contaminated with 1-iodo-4-[(6-hydroxy-pyridin-3-yl)methyl]-isoquinoline; FAB-MS: (M+H)+=271chloride/363iodide; HPLC(gradient20-100) tRet=10.2chloride/10.8iodide. From the filtrate, more product can be obtained by extraction with EtOAc.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([Cl:11])[CH:3]=1.[Br:12]Br>O1CCOCC1>[Br:12][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[Cl:11])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Br)cc1Cl
Solvent: C1COCCO1
Product: O=C(CBr)c1ccc(Br)cc1Cl
Reaction time: 3 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(4-bromo-2-chlorophenyl)-1-ethanone (11.58 g, 50 mmol) in dioxane (12 ml) was added a solution of bromine (8.12 g, 51 mmol) in dioxane (46 ml), and the mixture was stirred for 3 hours. Then the volatile was evaporated in vacuo. The residue was used for next reaction without purification. (15.6 g, 99% yield).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[S:24]1(=[O:30])(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[N:3][C:2]([N:25]4[CH2:26][CH2:27][CH2:28][S:24]4(=[O:30])=[O:29])=[CH:7][N:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCS4(=O)=O)cn3)CC2)c(C)c1
Yield: 51.6 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (49 mg) described in Preparation Example 232 and isothiazolidine 1,1-dioxide (16 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (28 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[N:3]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>CC(N(C)C)=O.ClCCl>[CH:21]1([NH:24][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]([F:13])=[C:4]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:3]=2)[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1Cl
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1NC1CC1
Temperature: 90 °C

Procedure:
A solution of ethyl 2-chloro-5-fluoro-6-(4-methylpiperazinyl)-3-pyridine-carboxylate (Example D-2, 1.00 g, 3.314 mmol) and cyclopropylamine (2 mL) in DMA (1 mL) was sealed in a pressure bottle and heated at 90° C. for 60 hours. The reaction mixture was diluted with dichloromethane (30 mL), washed with water, and dried on sodium sulfate. Flash chromatography on silica gel column using dichloromethane as eluent provided compound 0.85 g of the title compound as an oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[C:16]1([S:22]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:12])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: O=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
After a suspension of methyl indole-5-carboxylate (4) (1.00 g, 6.89 mmol), tetrabutylammonium bisulfate (0.35 g, 1.03 mmol) and KOH (0.77 g, 13.78 mmol) in CH2Cl2 (30 mL) was stirred for 20 min, benzenesulfonyl chloride (1.32 ml, 10.33 mmol) was added. The reaction mixture was stirred at room temperature overnight before it was quenched with water and extracted with CH2Cl2 (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a yellow residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:2) to afford 5 (1.79 g) as a white solid. 1H NMR (500 MHz, CDCl3): δ6.78 (d, J=3.6 Hz, 1H), 7.45-7.48 (m, 2H), 7.55-7.58 (m, 1H), 7.67 (d, J=3.7 Hz, 1H), 7.85-7.87 (m, 1H), 7.89 (d, J=7.6 Hz, 2H), 8.06 (s, 1H), 8.11 (d, J=8.6 Hz, 1H), 10.03 (s, 1H).