Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1Cl
Yield: 85.5 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-chlorobenzoic acid (1.02 g, 5.94 mmole)(ACROS, 32525-5000), DMF (50 ml) and 2,3,5,6-tetrafluoro-4-trifloromethylbenzyl bromide (1.16 g, 6.99 mmole), 2.04 g (85.5% yield) of 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino) benzoic acid was obtained as a pale brown solid.
Reaction SMILES: [CH3:1][C:2]1([CH:7]([OH:20])[CH:8]=[CH:9][CH:10]2[CH:17]3[CH:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][CH:11]2[OH:19])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[CH3:1][C:2]1([CH:7]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:8]=[CH:9][CH:10]2[CH:17]3[CH:13]([O:14][C:15](=[O:18])[CH2:16]3)[CH2:12][CH:11]2[O:19][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C(O)C=CC2C(O)CC3OC(=O)CC32)CCCC1
Product: CC1(C(C=CC2C(O[Si](C)(C)C(C)(C)C)CC3OC(=O)CC32)O[Si](C)(C)C(C)(C)C)CCCC1

Procedure:
By the procedure of Example 5 [3aR-[3a alpha,4alpha, (1E,3R*),5beta,6a alpha]]-4-[3-(1-methylcyclopentyl)-3-hydroxy-1-propenyl]hexahydro-5-hydroxy-2H-cyclopenta[b]furan-2-one was reacted with t-butyldimethylsilyl chloride to yield [3aR-[3a alpha,4alpha(1E,3R*),5 beta,6a alpha]]-4-[3-(1-methylcyclopentyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-propenyl]-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-hexahydro-2H-cyclopenta[b]furan-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([O:15]C(C)C)=[O:14])=[C:5]2[CH3:19].[OH-].[Na+].CO>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:19]
Reactant: Cc1c(CCC(=O)OC(C)C)[nH]c2ccc(F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(CCC(=O)O)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 102 %

Procedure:
A mixture of isopropyl 5-fluoro-3-methyl-1H-indole-2-propanoate (0.42 g),1N sodiumhydroxide (6.3 ml) and methanol (20 ml) are stirred at room temperature for 4 hours. The reaction mixture is poured into water, washed with methylene chloride, acidified with 1N HCl and extracted with methylene chloride. The organic layer, dried and evaporated, affords 0.36 g of 5-fluoro-3-methyl-1H-indole-2-propanoic acid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:27]([NH2:29])[CH3:28]>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:29][CH2:27][CH3:28])[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCN
Solvent: CC#N
Product: CCNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1
Temperature: 120 °C

Procedure:
A mixture of [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (1.0 g, 2.51 mmol), ethanamine (2 ml, 70% in water) and ACN (6 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and flash column chromatography (Isooctane/EtOAc/MeOH). Yield: 0.53 g, 78%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 271° C. MS m/z (rel. intensity, 70 eV) 271 (M+, 29), 58 (100), 59 (10), 272 (7), 79 (5). [α]=−66° (MeOH).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][N:14]=[C:15]=S>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:13]([NH:14][CH3:15])[NH:2][C:3]=2[CH:7]=1
Reactant: CN=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: CNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and methyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp >190° C. decomp.; 1H-NMR (DMSO-d6): δ 2.75 (s, 3H), 7.02 (s, 1H), 7.25 (br, 1H), 11.3 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([N-]C(C)C)(C)C.[Li+].[CH3:19][Si:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[CH:34]=[O:35]>O1CCCC1>[F:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[CH:34]([C:26]1[N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:36])([CH3:37])[CH3:19])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=1)[OH:35]
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Reactant: COc1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(O)c2nc3ccccc3n2COCC[Si](C)(C)C)c1F
Temperature: 25 °C

Procedure:
To a solution of 2,4-difluoro-1-methoxybenzene (156 mg) in tetrahydrofuran (5 mL) at −78° C. is added a 2M solution of lithium diisopropylamide in THF (540 μL). After stirring for 45 min a solution of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or U.S. Pat. No. 6,476,041 for example) (300 mg) in tetrahydrofuran (5 mL) is added at −78° C. and the reaction mixture allowed to warm to room temperature. After hydrolysis with aqueous saturated ammonium chloride and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 95/5) to afford (2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.[CH3:26][NH:27][NH2:28]>>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH3:25])=[CH:22][CH:21]=3)[N:27]([CH3:26])[N:28]=2)[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=1[OH:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: Cc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Reactant: CNN
Product: Cc1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)nn(C)c2n1
Yield: 91 %

Procedure:
A mixture of 1.8 g of 4-(2-chloro-6-methylnicotinoyl)-2,6-di-tertiary butylphenol and 0.7 g of methylhydrazine is reacted in a similar manner as Example 1 and the resulting product is recrystallized from ethanol to give 1.6 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenvl)-1,6-dimethyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 178°-181° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH:10]#[C:11][CH2:12][NH:13][C@H:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15]1>O.C(O)(C)C>[CH:10]#[C:11][CH2:12][NH:13][C@H:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15]1.[NH2:1][C@H:2]([C:7]([O-:9])=[O:8])[CH2:3][C:4]([O-:6])=[O:5]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: C#CCN[C@@H]1CCc2ccccc21
Solvent: O
Solvent: CC(C)O
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
82 mg L-aspartic acid was dissolved in 7 ml water at 70° C. A solution of 100 mg (0.58 mmol) rasagiline in 2 ml isopropanol was added at this temperature. The solution remained clear, was cooled to 0° C. and stirred at this temperature for 1 h. Since no turbidity was observed the solvents were removed in vacuo. The residual clear oil partially crystallised on standing. After a slurry wash with acetone, a white crystalline material was obtained (40 mg). Analysis revealed that this material was aspartic acid.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17](O)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:21][C:22]1[C:31]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([N:32]([CH3:34])[CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:18])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Reactant: O=C(O)c1nc(-c2ccccc2)nc2ccccc12
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccccc3)nc3ccccc13)C2
Yield: 9 %

Procedure:
Reaction of 2-phenylquinazolin-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 20 (9% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.66 and 3.18 (2d, 6H), 2.85 and 3.09 (2t, 2H), 3.60 and 4.21 (2t, 2H), 4.50 and 5.09 (2s, 2H), 6.35 and 6.82 (2d, 1H), 6.96 and 7.15 (2d, 1H), 7.53-7.64 (m, 4H), 7.92-8.18 (m, 3H), 8.62-8.68 (m, 2H); MS (ESI) m/z 425 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH3:10])[CH2:7][C:6]=2[CH:11]=1.[CH3:12][S:13]([O:15][Na])=[O:14].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[CH3:10][CH:8]1[CH2:7][C:6]2[CH:11]=[C:2]([S:13]([CH3:12])(=[O:15])=[O:14])[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: CS(=O)O[Na]
Reactant: CC1Cc2cc(Br)ccc2O1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC1Cc2cc(S(C)(=O)=O)ccc2O1
Yield: 49.9 %

Procedure:
A mixture of 5-bromo-2-methyl-2,3-dihydro-1-benzofuran (1.0 g, 4.72 mmol), CH3SO2Na (730 mg, 7.08 mmol), L-proline (110 mg, 0.94 mmol), K2CO3 (120 mg, 0.94 mmol) and CuI (89 mg, 0.47 mmol) in DMSO (10 mL) was irradiated at 140° C. for 2 h under microwave. The mixture was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated to give the crude product that was purified by column chromatography on silica gel (PE/EA=2/1) to give the title compound (500 mg, 50%). 1H NMR (CDCl3, 400 MHz) δ 7.71-7.70 (m, 2H), 6.86-6.82 (m, 1H), 5.08-5.03 (m, 1H), 3.41-3.35 (m, 1H), 3.02 (s, 3H), 2.89-2.83 (m, 1H), 1.56 (d, J=6.4 Hz, 3H).
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:13])(=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:17]=[C:18]([N+:24]([O-:26])=[O:25])[C:19](OCC)=[O:20])C.[N+](CC(OCC)=O)([O-])=O.COC(OC)N(C)C>C(O)C>[N+:24]([C:18]1[C:19](=[O:20])[NH:12][C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:13][CH:17]=1)([O-:26])=[O:25]
Reactant: CCOC(=O)C(=CN(C)C)[N+](=O)[O-]
Reactant: N=C(N)c1ccccc1
Agent: CCOC(=O)C[N+](=O)[O-]
Agent: COC(OC)N(C)C
Agent: C[O-]
Solvent: CCO
Product: O=c1[nH]c(-c2ccccc2)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a mixture of sodium methoxide (8 g) and anhydrous ethanol (100 ml) is added benzamidine hydrochloride (11.7 g) at 0° C. The mixture is stirred at 0° C. for 30 minutes, and thereto is added dropwise a solution of crude ethyl 2-(N,N-dimethylaminomethylene)nitroacetate (14 g), which is obtained by refluxing a mixture of ethyl nitroacetate (10 g) and N,N-dimethylformamide dimethyl acetal (10.7 g) for three hours, followed by concentrating the mixture under reduced pressure, in anhydrous ethanol (50 ml) at the same temperature. After addition, the mixture is stirred at room temperature for 30 minutes, and refluxed for 12 hours. The reaction mixture is concentrated under reduced pressure, and water (150 ml) is added to the residue. The pH value of the mixture is adjusted to pH 4 by addition of conc. hydrochloric acid while the mixture is stirred at 0° C. The precipitates are collected by filtration, washed with water, and recrystallized from ethanol to give the desired compound (7 g), m.p. 264-266° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12]>C(O)C.Cl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:9][C:2](=[O:1])[CH:3]=[CH:4][C:5]2[CH:8]=[CH:13][C:11]([OH:12])=[CH:10][CH:6]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)C=Cc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 150 g (1.23 mole) of 4-hydroxybenzaldehyde and 30 g (0.52 mole) of acetone in 600 ml of absolute ethanol was cooled while passing in hydrogen chloride for 45 minutes. After two hours of stirring, ice water was added and the resulting dark solid was filtered off. It was crystallized from absolute ethanol to give 90 g of brown, crystalline product.
Reaction SMILES: C1COCC1.CO.O[Li].O.C[O:12][C:13]([C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[CH:20][C:21]=2[O:24][C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([C:34](=[O:37])[NH:35][CH3:36])[C:29]([CH3:38])=[CH:28]3)[CH:16]=1)=[O:14]>O>[CH3:38][C:29]1[N:30]([C:34](=[O:37])[NH:35][CH3:36])[C:31]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:24][C:21]1[CH:20]=[CH:19][N:18]=[C:17]3[CH:16]=[C:15]([C:13]([OH:14])=[O:12])[S:23][C:22]=13)=[CH:33][CH:32]=2
Reactant: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)OC)sc34)ccc21
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)n1c(C)cc2cc(Oc3ccnc4cc(C(=O)O)sc34)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A solution of THF (5 mL), MeOH (1 mL) and H2O (1 mL) was used to dissolve LiOH.H2O (0.042 g, 1.0 mmol) and then added 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid methyl ester (0.35 g, 0.89 mmol) added. The solution was stirred at 25° C. for 2 h, quenched with several drops of 1N HCl then concentrated. The precipitate was rinsed with H2O (2×5 mL) and Et2O (2×5 mL), dried under high vacuum for 2 h and used as is to afford 7-(2-Methyl-1-methylcarbamoyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine-2-carboxylic acid (0.25 g, 73%) as yellow solid. HPLC: Rt 3.43 min. (95% area). LCMS (ACPI) M+H+ m/z: 382.1.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]([OH:19])[CH3:18])=[O:14])=[CH:9][CH:8]=1)=[O:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:19])[CH3:18])=[O:14])=[CH:11][CH:12]=1)=[O:5]
Reactant: CC(O)C(NC(=O)c1ccc(NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)C(NC(=O)c1ccc(NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
a mixture of 2-chloro-N-(4-(((2-hydroxy-1-phenylpropyl)amino) carbonyl)phenyl)benzamide (294 mg, 719 μmol) and Dess-Martin periodinane (335 mg, 791 μmol) in 5 mL dichloromethane+1 mL DMF was stirred at room temperature for 2 hours then diluted with 20 mL ethyl acetate and washed with 10 mL each water and brine. The organic layer was stirred over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow solid. The solid was slurried in hot ethyl acetate and left to equilibrate to room temperature. After 48 h, the solid was collected by filtration, rinsing with ethyl acetate and drying over a stream of air (200 mg, 68%). ESI+ m/z=407.0 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:10](=[CH:11][N:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][C:16]1C(C)=NOC=1C.Cl.ClC[CH2:26][N:27](C)[CH3:28].[H-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]2[C:10]([N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6][N:5]2[CH2:15][CH2:16][N:27]([CH3:28])[CH3:26])=[CH:11][N:12]=1
Reactant: CN(C)CCCl
Reactant: Cc1noc(C)c1CN1CCC(=O)N(C)c2cnc(Cl)nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCN1CCC(=O)N(C)c2cnc(Cl)nc21

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 156, on a 0.3 mmol scale, utilising 2 chloroethyldimethylamine hydrochloride (Aldrich; 52 mg, 0.36 mmol) and Sodium Hydride (60% mineral oil dispersion; 36 mg, 0.75 mmol), as a solid (84 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C([O-])([O-])=O.[Na+].[Na+]>CO.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:12]([C:11]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2cc(Br)ccc2s1

Procedure:
A solution of 5-bromo-2-fluorobenzaldehyde (6 g, 29.6 mmol), methyl thioglycolate (2.64 mL, 29.6 mmol), and Na2CO3 (3.14 g, 29.6 mmol) in methanol was heated to reflux for 1 hour, poured into brine, and extracted with ethyl acetate (3×). The combined extracts were washed with brine and filtered through silica gel to provide the desired product. MS (ESI(−)) m/e 270 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[CH:7]=[C:8]([CH:11]=1)[C:9]#[N:10])#[N:2].Cl[C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([O:24][CH3:25])[N:18]=[C:17]([O:26][CH3:27])[N:16]=1.[H-].[Na+]>CN(C=O)C>[C:1]([CH:3]([C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([O:24][CH3:25])[N:18]=[C:17]([O:26][CH3:27])[N:16]=1)[C:4]1[CH:11]=[C:8]([C:9]#[N:10])[CH:7]=[C:6]([CH:5]=1)[C:12]#[N:13])#[N:2]
Reactant: COc1nc(Cl)c(C(C)C)c(OC)n1
Reactant: N#CCc1cc(C#N)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(OC)c(C(C)C)c(C(C#N)c2cc(C#N)cc(C#N)c2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
5-Cyanomethyl-isophthalonitrile (0.285 g, 1.70 mmol) and 4-chloro-5-isopropyl-2,6-dimethoxy-pyrimidine (0.360 g, 1.66 mmol) was dissolved in DMF (8.0 mL) and cooled to 0° C. 60% Sodium hydride (0.136 g, 3.40 mmol) was added portionwise and the reaction was stirred at 0° C. for 2 h, then rt overnight. The reaction was quenched with saturated ammonium chloride solution and pH was adjusted to ˜6.0 with 1N HCl. Mixture was extracted with ethyl acetate and organic layer was dried (MgSO4) and concentrated. The resulting residue was purified by flash column chromatography (silica gel, 10 to 50% ethyl acetate/hexane) to give a white solid (0.2457 g, 43%). 1H NMR (300 MHz, CDCl3): δ 7.90 (s, 3H), 5.46 (s, 1H), 3.96 (s, 3H), 3.89 (s, 3H), 3.05-2.9 (m, 1H), 1.16 (d, J=6.9 Hz, 3H), 1.15 (d, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.F[C:14]1[CH:43]=[CH:42][C:17]([C:18](/[N:20]=[C:21]2\[NH:22][C:23]3[CH:39]=[CH:38][C:37]([CH2:40][OH:41])=[CH:36][C:24]=3N\2[C@@H]2CC[C@H](C(OC)=O)CC2)=[O:19])=[CH:16][CH:15]=1>>[C:18](/[N:20]=[C:21]1\[NH:22][C:23]2[CH:24]=[CH:36][C:37]([CH2:40][OH:41])=[CH:38][C:39]=2[N:1]\1[C@@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)(=[O:19])[C:17]1[CH:42]=[CH:43][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Product: CCOC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccccc3)[nH]c3ccc(CO)cc32)CC1

Procedure:
The title compound was prepared in 6 steps from cis-ethyl 4-aminocyclohexanecarboxylate using a method analogous to the preparation of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate. MS m/z=422.2 [M+H]. Calc'd for C24H27N3O4: 421.2.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][O:6][C:5]2([CH:15]([Br:16])[CH2:14][CH2:13][C:12]3[N:11]([S:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:10]=[CH:9][C:8]2=3)[O:4]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([CH2:2][CH:3]2[CH2:7][O:6][C:5]3([CH:15]([Br:16])[CH2:14][CH2:13][C:12]4[N:11]([S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=5)(=[O:18])=[O:19])[CH:10]=[CH:9][C:8]3=4)[O:4]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CBr)O2)cc1
Reactant: C1CCNCC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CN3CCCCC3)O2)cc1
Yield: 75 %

Procedure:
Heating of 4'-bromomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane with piperidine at 80° C. for 3 hours affords 4'-piperidinomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane in 75% yield.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23](O)=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.[NH2:27][C@@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:27][C@@H:28]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:30][CH2:29]3)=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(OC(F)F)ccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3n2)c2cc(OC(F)F)ccc21

Procedure:
2-(5-(Difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.43 mmol), tert-butyl cis-4-aminocyclohexylcarbamate (102 mg, 0.48 mmol) and HATU (196 mg, 0.51 mmol) in 15 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue was suspended in 50 mL of 0.5N HCl, extracted with ethyl acetate (3×50 mL), dried over sodium sulfate and concentrated to give tert-butyl cis-4-(2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclohexylcarbamate (54 mg, crude). LCMS: (M+H)+=556; (M+Na)+=578. Used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[C:3]=1[CH2:11][CH3:12].[C:13]1([S:23](Cl)(=[O:25])=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[CH2:11]([C:3]1[C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][O:6][C:2]=1[NH:1][S:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:25])=[O:24])[CH3:12]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CCc1c(C(F)(F)F)noc1N
Product: CCc1c(C(F)(F)F)noc1NS(=O)(=O)c1cccc2ccccc12
Yield: 70 %

Procedure:
N-(4-Ethyl-3-trifluoromethyl-5-isoxazolyl)-1-naphthalenesulfonamide was prepared, as described in Example 90, from 5-amino-4-ethyl-3-trifluoromethylisoxazole and 1-naphthalenesulfonyl chloride in 70% yield. Purification was achieved by recrystallization from methanol/water to give an off white solid, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][SH:2].[Cl:3][C:4]1[C:5]([N:16]([CH2:21][CH3:22])[S:17]([CH3:20])(=[O:19])=[O:18])=[C:6]([CH:12]=[CH:13][C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:3][C:4]1[C:5]([N:16]([CH2:21][CH3:22])[S:17]([CH3:20])(=[O:19])=[O:18])=[C:6]([CH:12]=[CH:13][C:14]=1[S:2][CH3:1])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CS
Reactant: CCOC(=O)c1ccc(F)c(Cl)c1N(CC)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(SC)c(Cl)c1N(CC)S(C)(=O)=O
Temperature: -10 °C

Procedure:
A solution of methanethiol (4 ml) in dry DMF was added to a mixture of ethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-fluorobenzoate (7.4 g) and anhydrous potassium carbonate (4.71 g) in DMF at 40° C. The mixture was maintained at −10° C. for 1 hour, then warmed to ambient temperature over 2.5 hours. Water was added and the mixture extracted with ether, washed with brine solution then water, dried (anhydrous magnesium sulphate) and the solvent evaporated to give ethyl 3-chloro-2-(N-ethyl-N-methylsulphonylamino)-4-(methylthio)benzoate (8.3 g) as a white powder, m.p. 109-110.5° C.