Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:37][O:38][C:39]1[CH:45]=[C:44]([CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:43]=[CH:42][C:40]=1[NH2:41]>>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][N:51]([CH3:54])[CH2:52][CH2:53]4)=[CH:45][C:39]=3[O:38][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(CCN2CCN(C)CC2)ccc1N
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3ccc(CCN4CCN(C)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Yield: 67 %

Procedure:
The title compound (0.12 g, 0.17 mmol, 67%) was prepared from 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) and 2-(methyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 131, step D) in an analogous manner to that described for Example 26, step E. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40 (t, J=6.8 Hz, 3H), 2.10 (s, 3H), 2.28 (br. s., 4H), 2.40 (br. s., 3H), 2.49 (d, J=8.4 Hz, 3H), 2.63-2.72 (m, 2H), 3.79 (s, 3H), 4.23 (q, J=6.9 Hz, 2H), 6.57 (d, J=4.9 Hz, 1H), 6.71-6.79 (m, 1H), 6.91-6.99 (m, 2H), 7.16 (t, J=8.1 Hz, 2H), 7.23 (d, J=9.0 Hz, 1H), 7.30-7.37 (m, 1H), 7.37-7.46 (m, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.64-7.74 (m, 2H), 8.02 (s, 1H), 8.23 (d, J=5.3 Hz, 1H), 8.47 (s, 1H), 9.35 (d, J=6.8 Hz, 1H), 9.71 (s, 1H). MS (M+H, ES+) 720.
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13](O)(=[O:22])[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CO>[OH:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:22]
Reactant: C[C@H](N)CCCc1cccnc1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1

Procedure:
Under the conditions outlined in Example 14a, 76.2 g of the amine was reacted with 74.2 g of (S)-mandelic acid in the presence of 105.2 g of 1,3-dicyclohexylcarbodiimide and 78.4 g of 1-hydroxybenzotriazole in 1 L of dimethylformamide. A similar workup furnished 109 g of [S-(S*,S*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 143°-145° C, [α]D25 +27.8° (c, 1.0, MeOH).
Reaction SMILES: [C:1]([NH2:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:52][O:53][CH2:54][CH2:55]Br)[C:47]([O:49]CC)=[O:48])[N:45]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1C=CC=C[CH:23]=1.CS(C)=O>O>[C:21]([NH:40][C:41]1[S:42][CH:43]=[C:44]([C:46](=[N:52][O:53][CH2:54][CH2:55][NH:20][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:47]([OH:49])=[O:48])[N:45]=1)([C:22]1[CH:23]=[CH:3][CH:2]=[CH:1][CH:8]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)C(=NOCCNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Reaction time: 82 h

Procedure:
A mixture of 75 g of tritylamine, 50 g of syn isomer of ethyl 2-(2-tritylamino-4-thiazolyl)-2-(2-bromoethoxyimino)-acetate and 100 ml of dimethylsulfoxide was stirred under argon at 60° C. for 82 hours and after the temperature returned to room temperature, 10 volumes of water were added thereto. The mixture was vacuum filtered and the recovered product was washed with water and dissolved in a liter of chloroform. The solution was washed with water, with an aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure at less than 40° C. The residue was added to a mixture of 320 ml of dioxane, 2 liters of absolute ethanol and 200 ml of sodium hydroxide solution and the mixture was stirred at room temperature for 24 hours and was evaporated to dryness under reduced pressure at not more than 40° C. The residue was empasted 5 times with 60 ml of a 1-7 dioxane-ethanol mixture and was then added to a liter of water and a liter of chloroform. The pH of the mixture was adjusted to 2 by stirring with sufficient N hydrochloric acid and the decanted organic phase was washed with water and with aqueous saturated sodium chloride solution, was dried and evaporated to dryness under reduced pressure at less than 40° C. The residue was suspended in 300 ml of dichloroethane and the mixture was heated at 50° C. for 15 minutes and was then vacuum filtered at room temperature. The product was successively rinsed with dichloroethane, isopropyl ether and ether and dried to a constant weight to obtain 40 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-tritylaminoethoxyimino)acetic acid in the form of a powder melting at 176° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1.[Cl:17][C:18]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][NH:21][CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:17][C:18]1[C:39]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][N:21]([CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)Cc1cccc(OCCCBr)c1
Reactant: FC(F)(F)c1cccc(CNCC(c2ccccc2)c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 96 h
Yield: 81.5 %

Procedure:
A solution of methyl [3-(3-bromopropoxy)phenyl]acetate (1.0 g, 3.48 mmole) and [2-chloro-3-(trifluoromethyl)benzyl]-2,2-diphenylethylamine (1.63 g, 4.18 mmole) in 20 mL of acetonitrile was treated with potassium carbonate (0.72 g, 5.2 mmol). The reaction mixture was heated to reflux and stirred for 4 days. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel cartridge, Biotage 32-63 um, 60A) with 10% ethyl acetate:hexanes as the eluent to afford 1.69 g (81% yield) of the title compound as a viscous oil: 1H NMR (CDCl3, 400 MHz) δ 7.46-7.44 (d, 1H, J=7.7), 7.25-7.14 (m, 12 H), 6.91-6.84 (m, 2 H), 6.666.62 (m, 2 H) 4.154.09 (t, 1 H, J=7.6), 3.78 (s, 1 H), 3.69-3.66 (m, 5 H), 3.59 (S, 2 H), 3.15-3.13 (d, 2 H, J=7.7), 2.72-2.68 (t, 2 H, J=6.6), 1.87-1.80 (m, 2 H); MS (ESI) 597 (MH+); TLC (hexanes:Ethy acetate/9:1) Rf=0.36.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]([C:13]2[C:14]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH:24]=[N:25][NH:26]4)=[CH:22][CH:21]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O[CH:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>>[NH:26]1[C:27]2[C:23](=[CH:22][CH:21]=[C:20]([NH:19][C:14]3[C:13]([C:11]([NH:10][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:1][CH:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH:3]=4)=[O:12])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:28]=2)[CH:24]=[N:25]1
Reactant: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1O
Reactant: CN1CCC(O)CC1
Product: COc1ccc(NC(=O)c2cccnc2Nc2ccc3cn[nH]c3c2)cc1OC1CCN(C)CC1

Procedure:
The title compound was prepared from N-(3-hydroxy-4-methoxyphenyl)[2-(1H-indazol-6-ylamino)(3-pyridyl)]-carboxamide (Example 36) by a method similar to that described in Example 34 using 4-hydroxy-N-methylpiperidine. MS (ES+): 473 (M+H) +; (ES−):471 (M−H). Calc'd. for C26H28N6O3—472.2.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C@H:4]([CH3:23])[CH2:3]1.[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)C>[OH:24][C:25]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[CH2:30][CH2:29][CH:28]([NH:1][C@@H:2]2[CH2:6][N:5]([C:7](=[O:22])[CH2:8][NH:9][C:10](=[O:21])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)[C@H:4]([CH3:23])[CH2:3]2)[CH2:27][CH2:26]1
Reactant: C[C@@H]1C[C@H](N)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(O)(c2ccccn2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)O
Product: C[C@@H]1C[C@H](NC2CCC(O)(c3ccccn3)CC2)CN1C(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
N-{2-[(2R,4S)-4-Amino-2-methylpyrrolidin-1-yl]-2-oxoethyl}-3-(trifluoromethyl)benzamide (200 mg, 0.607 mmol) and 4-hydroxy-4-pyridin-2-yl-cyclohexanone (116 mg, 0.607 mmol) were dissolved in 2-propanol (10 mL). After stirring for 30 minutes, sodium triacetoxyborohydride (257 mg, 1.21 mmol) was added and the mixture was stirred at room temperature overnight. TLC indicated complete conversion to desired products in about a 1:1 ratio of two isomers. The reaction mixture was chromatographed on silica gel eluting with dichloromethane to 10% methanol/dichloromethane/0.5% ammonium hydroxide to give 229 mg (75%) as a mixture of isomers. 1H NMR (CDCl3, mixture of isomers) δ 8.53 (m, 1H), 8.13 (bs, 1H), 8.02 (d, 1H), 7.75 (m, 2H), 7.58 (t, 1H), 7.40 (m, 2H), 7.22 (m, 1H), 4.05-4.38 (m, 3H), 3.80 (m, 1H), 3.56 (m, 1H), 3.42 (m, 1H), 3.19 (m, 1H), 3.04 (m, 1H), 2.65 (m, 1H), 2.47 (m, 1H), 2.16 (m, 2H), 1.40-2.00 (m, 7H), 1.43 (d, 3H). LCMS (M+H)+: Higher Rf isomer m/z 505.2; Lower Rf isomer m/z=505.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:15])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:3]=[CH:4][C:5]=1[F:15])=[O:14]
Reactant: O=C(Nc1cc(Br)ccc1F)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(F)c(NC(=O)C(F)(F)F)c1
Temperature: 60 °C
Yield: 87.4 %

Procedure:
To an oven-dried flask under N2 was added N-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroacetamide (5.6 g, 20 mmol), anhydrous degassed THF (200 mL), dichlorobis(triphenylphosphine)palladium(II) (1.7 g, 2.5 mmol), copper(I) iodide (0.28 g, 1.5 mmol), and trimethylsilylacetylene (7.0 mL, 50 mmol). Next, TEA (27 mL, 197 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography to afford the desired product (5.3 g, 89%) as an off white solid. ES-LC/MS m/z=302 [M−H]−.
Reaction SMILES: Br[C:2]1[O:14][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]([CH3:13])[CH3:12])[C:4]=2[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC1(C)C(C)(C)OB([C:29]2[CH:42]=[CH:41][C:32]([O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>O>[CH:11]([NH:10][C:9]1[C:4]2[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([O:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)=[CH:41][CH:42]=3)[O:14][C:5]=2[N:6]=[CH:7][N:8]=1)([CH3:13])[CH3:12]
Reactant: CC1(C)OB(c2ccc(OCCN3CCCC3)cc2)OC1(C)C
Reactant: CC(C)Nc1ncnc2oc(Br)c(-c3ccccc3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)Nc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Temperature: 75 °C

Procedure:
Into a 16×100 mm vial sparged with argon was placed 6-bromo-N-isopropyl-5-phenylfuro[2,3-d]pyrimidin-4-amine (100 mg, 0.301 mmol), 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)pyrrolidine (120 mg, 0.361 mmol), palladium tetrakistriphenylphosphine (17 mg, 0.015 mmol), potassium carbonate (125 mg, 0.903 mmol), DME (4 mL), and water (1 mL). The vial was sealed and heated to 75° C. for 24 hours.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cnn(Cc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1cnn(Cc2ccccc2)c1
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of (1-benzyl-1H-pyrazol-4-yl)methanol (3.84 g) in methylene chloride (100 mL) were added triethylamine (2.80 mL), 4-dimethylaminopyridine (100 mg) and tert-butyldimethylsilyl chloride (3.80 g) at room temperature, and the mixture was stirred for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and insoluble material was removed by filtration. Ethyl acetate (100 mL) was added to extract the filtrate, and the organic layer was washed with brine. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (6.00 g).
Reaction SMILES: O([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])S(C(F)(F)F)(=O)=O.[Cl:15][C:16]1[CH:23]=[C:20]([CH:21]=[O:22])[C:19](O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[CH2:10][O:9][C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: O=S(=O)(OOCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using a small volume of DMF, the trifluorethoxy triflate thus prepared was added to a mixture of 5-chlorosalicylaldehyde (5 g, 32 mmol) and cesium carbonate (21 g, 64 mmol) in DMF (50 mL) at room temperature. After stirring at room temperature overnight the solids were filtered off and the filtrate concentrated under reduced pressure. The residue was diluted with ether and washed well with water. Drying (Na2SO4) and concentration yielded the title compound as an oil: 1H NMR (CDCl3) δ10.42 (s, 1H), 7.84 (dd, J=2.6 Hz, 1H), 7.54 (m, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.48 (qd, J=1.5, 7.8 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:48]1[CH2:47][CH2:46][CH:45]([C:43]([C:35]2[N:34]([CH2:33][CH2:32][O:31][CH2:30][C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:50][CH2:49]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(c1nc2ccccc2n1CCOCc1ccco1)C1CCNCC1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2CCOCc2ccco2)CC1)c1ccccc1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([SH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: ClCc1cccnc1
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCc2cccnc2)nc1
Yield: 75.8 %

Procedure:
5-nitro-2-pyridinethiol (5.0 g) was dissolved in an aqueous methanol solution (125 ml), and to this solution was added sodium hydroxide (3.84 g) and then, 3-(chloromethyl)pyridine hydrochloride (6.30 g), and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure, and the obtained residue was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[(3-pyridinylmethyl)sulfanyl]pyridine (6.0 g).
Reaction SMILES: Br[C:2]1[C:3]([O:13]C(C)(C)C)=[N:4][C:5]([O:8]C(C)(C)C)=[N:6][CH:7]=1.C([Li])CCC.[CH3:23][C:24]1[O:25][C:26]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:30]=3[C:29](=[O:39])[C:27]=2[N:28]=1>O1CCCC1.C(O)(=O)C>[OH:39][C:29]1([C:2]2[C:3](=[O:13])[NH:4][C:5](=[O:8])[NH:6][CH:7]=2)[C:27]2[N:28]=[C:24]([CH3:23])[O:25][C:26]=2[CH2:33][CH2:32][C:31]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:30]1=2
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: Cc1ccc2c(c1)CCc1oc(C)nc1C2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCc1oc(C)nc1C2(O)c1c[nH]c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
To a solution of the product from example 1 step (vi) (9 g) in dry tetrahydrafuran (100 ml) under nitrogen at −78° C. was added n-butyllithium (2.5M, 14.3 ml) dropwise over 1 min. After 30 min a warm solution of the product from step (v) (6.73 g) in tetrahydrofuran (350 ml) was added rapidly via cannula. After further stirring for 1 h the cooling bath was removed and the mixture allowed to stir at room temperature for 30 min. The reaction mixture was quenched with saturated brine and extracted with ethyl acetate (×2). The combined organic extracts were dried over magnesium sulphate and solvent removed under reduced pressure to leave a pale yellow foam. This was dissolved in acetic acid (100 ml) and stired at room temperature for 16 h. The solvent was evaporated under reduced pressure and the residue azeotroped with toluene (×2) to remove last traces of acetic acid. The remaining residue was triturated with diethyl ether/isohexane mixtures and filtered to give the subtitle product as a beige solid.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][CH:25]([C:29](O)=[O:30])[C:26](O)=[O:27])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:24][C:25]2[C:26](=[O:27])[O:9][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:29]=2[OH:30])[CH2:15][CH2:16]1
Reactant: O=C(O)C(Sc1ccccc1CC1CC1)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: O=c1oc(-c2ccccc2)cc(O)c1Sc1ccccc1CC1CC1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol), and diethyl ester of [[2-(cyclopropylmethyl)phenyl]thio] propanedioic acid (1.00 g, 3.10 mmol) m.p. 165-167° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.25 (dd, 2H), 0.52 (dd, 2H), 1.21 (m, 1H), 2.50 (d, 2H), 6.87 (s, 1H), 6.92 (m, 1H), 7.05 (m, 2H), 7.32 (m, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([C:15]3[C:16]([CH3:22])=[N:17][O:18][C:19]=3[CH2:20][OH:21])=[CH:13][N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:21][CH2:20][C:19]1[O:18][N:17]=[C:16]([CH3:22])[C:15]=1[CH:14]1[CH2:13][N:12]([CH3:23])[N:11]=[C:10]1[C:8](=[O:9])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:34])=[O:33]
Reactant: Cc1noc(CO)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(COS(C)(=O)=O)c1C1CN(C)N=C1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of (4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone (0.05 g, 0.15 mmol) in DCM (10 mL), was added triethylamine (0.1 mL) and methane sulfonyl chloride (0.05 mL) at room temperature. The mixture was stirred for 2 h at room temperature. DCM (50 mL) and saturated sodium bicarbonate solution (20 mL) were added. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the titled product as yellow oil (0.035 g, 56%). LC/MS m/z 409 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cc1

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-methylsulfanyl-phenylboronic acid following a procedure analogous to that described for Example 2; PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex is used as catalyst source. LC (method 3): tR=1.04 min; Mass spectrum (ESI+): m/z=453 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1c(Br)ccc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc(N)c1C#N
Yield: 36.3 %

Procedure:
A stirred solution of 1.7 grams (0.008 mole) of 2-amino-5-bromo-6-methylbenzonitrile, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene was heated at 90° C. for about 20 hours. After this time, the reaction mixture was stirred with 100 mL of water, and the organic layer was separated. The organic layer was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 30/65/5 and 20/60/20 methylene chloride/petroleum ether/ethyl acetate as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 1.0 gram of 2-amino-6-methyl-5-[3,5-di(trifluoromethyl)phenyl]benzonitrile. The NMR spectrum was consistent with the proposed structure.