Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][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]=[N:5]2.[OH:21]O.O>C(O)(=O)C>[Br:1][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[C:6](=[O:21])[NH:5]2
Reactant: OO
Reactant: Brc1ccc2c(c1)ncc1nnc(-c3ccccc3)n12
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2cc(Br)ccc2n2c(-c3ccccc3)nnc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
7-Bromo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoxaline (279 mg, 0.86 mmol) was dissolved in acetic acid (7.5 mL). Hydrogen peroxide (30%, 2.5 mL) was added, and the reaction was heated to 50° C. overnight. The reaction was poured into water (25 mL) and stirred at room temperature for 2 hours. The precipitate was filtered, washed with water, and dried to obtain the desired product, 5z.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:24]Br.O>C(O)(=O)C>[Br:24][CH:13]1[C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:10]([C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:23][CH:22]=2)[CH2:11][CH2:12]1
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccccc2N(C(=O)c2ccc([N+](=O)[O-])cc2)CCC1Br
Temperature: 25 °C
Yield: 87.7 %

Procedure:
A mixture of 0.200 g of 1,2,3,4-tetrahydro-1-(4-nitrobenzoyl)-5H-1-benzazepin-5-one in 2.5 ml of acetic acid is warmed until solution then allowed to cool to room temperature. While stirring, a solution of 0.103 g of bromine in 0.5 ml of acetic acid is added dropwise. After rapid decolorization, the reaction mixture is stirred for 1.5 hours and poured into water. The solid is collected, washed with water and air dried to give 220 mg of the desired product as a crystalline solid, Mass Spectrum; MH+ =389,391.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>C1COCC1.CN(C1C=CN=CC=1)C>[C:22]([O:10][C:9]1[CH:11]=[CH:12][C:4](/[CH:3]=[CH:2]/[C:1]([OH:14])=[O:13])=[CH:5][C:6]=1[O:7][CH3:8])(=[O:24])[CH3:23]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C(=O)O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.9 %

Procedure:
Ferulic acid (10 g, 51 mmol) is solubilised in 100 ml of anhydrous THF under argon. Triethylamine (8.7 ml, 61 mmol, 1.2 eq) is added quickly, then DMAP (3.34 g, 27 mmol, 0.5 eq) at ambient temperature and under argon. Finally acetic anhydride (5.9 mL, 61 mmol, 1.2 eq) is added in 3 min, at ambient temperature. This is kept whilst stirring, at ambient temperature, for 18 h, then the medium is transferred into a separation funnel. This medium is diluted with 100 ml of THF, acidified with 40 ml of HCl 5% v/v and the organic phase is washed with 5×40 ml of H2O. The final organic phase is dried over MgSO4, filtered, then evaporated dry in a rotary evaporator (40° C., 30 mbar). 9.5 g of a crude yellow solid are obtained with a crude yield of 79% and a molar purity measured by NMR of 86%. The product is involved in the following step without purification.
Reaction SMILES: [C:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25](OS(C(F)(F)F)(=O)=O)=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:48]([Sn](CCCC)(CCCC)C=C)[CH2:49]CC>O1CCOCC1.[Cu]I.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>[C:1]([C@H:5]1[C:39](=[O:40])[N:38]2[CH2:41][C@@H:35]([CH2:36][C@H:37]2[C:42]([O:44][CH3:45])=[O:43])[O:34][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]([CH:48]=[CH2:49])=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:46][C@H:9]2[O:8][C:7](=[O:47])[NH:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OS(=O)(=O)C(F)(F)F)O2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC2
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 244 step 1 (100 mg, 0.146 mmol) in dioxane (3 ml) was added tributyl(vinyl)stannane (92 mg, 0.292 mmol), copper (I) iodide (5.55 mg, 0.029 mmol) and tetrakis (33.7 mg, 0.029 mmol). After purging with N2 for 5 min, the reaction was stirred at 80° C. for 16 hours. After cooling to room temperature, water was added and the reaction was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated. Purification by PTLC (30% EtOAc/hexane) provided the desired compound.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH3:8].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([N:2]=[C:3]2[CH2:7][CH2:6][CH2:5][N:4]2[CH3:8])=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Cl)c(Cl)c1

Procedure:
A 6.73 g. (0.05 mole) sample of 2-imino-1-methylpyrrolidine HCl is converted to free base in the usual way. To the K2CO3 -dried, benzene extracts are added a pre-filtered solution of 3,4-dichlorophenylisocyanate (9.4 g.; 0.05 mole). Almost immediately there is a separation of product. After stirring for a short time, the product is collected and recrystallized from acetone-methanol-water and finally from acetone-water to give the pure product, 1-(3,4-dichlorophenyl)-3-(1-methyl-2-pyrrolidylidene)urea. m.p. = 160°-161° C.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=5)=[CH:18]4)=[CH:13][C:12]=3[OH:31])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([NH2:40])=[O:39]>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:21]5[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=5)=[CH:18]4)=[CH:13][C:12]=3[O:31][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:39])[NH2:40])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: COC(=O)c1ccc(-c2ccc3cc(O)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Reactant: NC(=O)CCCCCBr
Product: NC(=O)CCCCCOc1cc2ccc(-c3ccc(C(=O)O)cc3)cc2cc1C12CC3CC(CC(C3)C1)C2
Yield: 65.6 %

Procedure:
Following the procedure of Example 12(a), but reacting 640 mg (1.55 mmol) of methyl 4-[7-(1-adamantyl)-6-hydroxy-2-naphthyl]benzoate with 450 mg (2.32 mmol) of 6-bromohexanamide, 520 mg (65%) of the expected compound were obtained, which compound had a melting point of 209°-10° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([OH:29])=[O:28]>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=4)[C:27]([OH:29])=[O:28])=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: O=C(O)c1cccc(B(O)O)c1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(C(=O)O)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60 and General Procedure C, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and 3-carboxyphenyl boronic acid were reacted to give 144. MS: (ESI+) 490.1
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([NH:14][C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:22])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1.C([O-])([O-])=O.[K+].[K+].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([S:11]([N:14]([C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:15]3[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=3[Cl:21])(=[O:13])=[O:12])[N:10]=[C:4]2[N:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccn2nc(S(=O)(=O)N(C(=O)c3ccccc3)c3c(Cl)cccc3Cl)nc2n1
Yield: 71.1 %

Procedure:
A mixture of 3.00 g (8.37 mmol) of 5-methyl-N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide and 1.16 g (8.37 mmol) of anhydrous powdered K2CO3 in 100 ml of acetone was heated at reflux for 30 minutes. A solution of 1.18 g (8.37 mmol) of benzoyl chloride in 10 ml of acetone was added, and the reaction was heated at reflux for 115 min. The reaction was filtered, and the filtrate was evaporated at reduced pressure. The solid residue was collected by filtration, washed thoroughly with aqueous NaHCO3 and H2O and dried to yield 2.75 g (72%) of the desired product as a solid, mp 187°-189° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:8]=2)[CH2:4][C@H:3]1[NH:26]C(=O)OCC1C=CC=CC=1.C([O-])=O.[NH4+].O>C(O)C>[NH2:26][C@H:3]1[C@H:2]([F:1])[CH2:6][N:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]([CH3:18])[CH3:17])=[C:9]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)[N:8]=2)[CH2:4]1
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(N3C[C@@H](F)[C@H](NC(=O)OCc4ccccc4)C3)nc21
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(N3C[C@@H](N)[C@H](F)C3)nc21
Yield: 94.6 %

Procedure:
A mixture of benzyl ((3R,4R)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)carbamate (390 mg, 0.8 mmol), ammonium formate (514 mg, 8 mmol) in ethanol (20 mL) was degassed for 3 min and 10%-Pd/C (50 mg) was then added. The reaction was stirred and heated to gentle reflux for 45 min. The catalyst was removed by filtration and washed well with ethanol (40 mL). The combined liquors were concentrated to give a residue, which was taken into water (5 mL) and extracted with DCM-isopropanol (9:1, 2×70 mL). The combined organic extracts were washed with saturated NaHCO3 (5 mL), dried over Na2SO4 and evaporated to give the title compound as a light yellow solid (272 mg, 96% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (s, 1 H) 8.00 (s, 2 H) 7.90 (s, 2 H) 7.73 (s, 1 H) 4.89-5.08 (m, 1 H) 4.56-4.66 (m, 1 H) 3.86-4.00 (m, 1 H) 3.81-3.85 (m, 3 H) 3.58-3.80 (m, 3 H) 3.53 (d, J=11.13 Hz, 1 H) 1.51 (d, J=6.72 Hz, 6 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −177.42 (s, 1F). m/z (APCI+) for C16H22FN9 360.2 (M+H)+. Chiral purity was determined as below (using racemic sample to compare):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1.[CH2:17](C([Sn])=C(CCCC)CCCC)[CH2:18]CC>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH:17]=[CH2:18])=[CH:12][N:11]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Fc1cccc(F)c1Nc1ccc(I)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(Nc2c(F)cccc2F)nc1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a mixture of (2,6-Difluoro-phenyl)-(5-iodo-pyridin-2-yl)-amine and Pd(PPh3)4 (approximately 10 mol %) in toluene (approximately. 80 mL/g) at room temperature was added tributylvinyltin (1.1 eq.). The reaction was placed under a N2 atmosphere and heated to 80° C. overnight. The solution was cooled, diluted with ethyl acetate (approximately 80 mL/g) and filtered through a pad of celite. The celite was washed with a further portion of ethyl acetate. The organic layer was dried over MgSO4 and concentrated in vacuo to give the crude reaction product as a yellow oil. Purification by column chromatography, using 10% ethyl acetate:hexane as eluant provided (2,6-Difluoro-phenyl)-(5-vinyl-pyridin-2-yl)-amine (Rf 0.14) in 66% yield.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:21]1[CH:25]=[C:24]([C:26]([NH:28][NH2:29])=[O:27])[N:23]=[CH:22]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:29][NH:28][C:26]([C:24]1[N:23]=[CH:22][O:21][CH:25]=1)=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC(=O)c1cocn1
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1cocn1
Yield: 61.7 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and oxazol-4-carbohydrazide (613 mg, prepared following a procedure analogous to Reference Example 2), 335.2 mg of the title compound was afforded (yield 61.7%).
Reaction SMILES: ClC1N=C2C(NC=N2)=C(Cl)N=1.C(N1C=NC2C1=NC=NC=2)=C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([P:30](=[O:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][N:50]2[CH:53]=[CH2:54])=[C:46](Cl)[N:45]=1>CCO>[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][N:50]2[CH:53]=[CH2:54])=[C:46]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([P:30]([CH3:31])([CH3:32])=[O:33])=[CH:28][CH:29]=2)[N:45]=1
Reactant: C=Cn1cnc2c(Cl)nc(Cl)nc21
Reactant: CP(C)(=O)c1ccc(N)cc1
Agent: C=Cn1cnc2cncnc21
Agent: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21

Procedure:
To a sealed tube were added 2,6-dichloropurine-9-vinyl purine (0.43 g, 2 mmol), 4-aminophenyl-dimethylphosphine oxide (0.37 g, 2.2 mmol), and the solids were dissolved in ˜15 mL anhydrous EtOH under Ar. Then DIEA (1.0 mL, 6 mmol) was added. The reaction was heated at 105° C. for 3 overnights until the starting material 2,6-dichloro-9-vinylpurine had disappeared. Volatiles were removed by rotavaporing and the residue was partitioned between EtOAc/water. The organic layer was washed with water once more and dried over Na2SO4. The final product was purified by silica gel column chromatography (4˜8% MeOH/DCM).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Br:12][C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([S:19]([NH:7][CH2:8][CH2:9][CH2:10][OH:11])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: NCCCO
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=S(=O)(NCCCO)c1cccc(Br)c1

Procedure:
3-Bromo-N-(3-hydroxy-propyl)-benzenesulfonamide (266 mg) obtained from the reaction of pyridine, 3-aminopropanol and 3-bromobenzenesulfonyl chloride in acetonitrile was left to act in di-tert-butyl carbonate (226 mg) and acetonitrile (5 ml) in the presence of DMAP (10 mg), to obtain 3-bromo-N-Boc-N-(3-hydroxy-propyl)-benzenesulfonamide as a colorless oil (267 mg, 72%).
Reaction SMILES: C(N(CC)CC)C.P(Cl)(OCC)(OCC)=O.[CH3:17][C@@H:18]([CH2:22][CH2:23][CH3:24])[C:19]([OH:21])=[O:20].[Si:25]([O:32][C@H:33]1[CH2:42][C@H:41](O)[C@H:40]2[C:35]([CH:36]=[CH:37][C@H:38]([CH3:61])[C@@H:39]2[CH2:44][CH2:45][C@H:46]2[O:51][C:50](=[O:52])[CH2:49][C@H:48]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH2:47]2)=[CH:34]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1(C2C=CN=CC=2)CCCC1>C1C=CC=CC=1>[Si:25]([O:32][C@H:33]1[CH2:42][C@H:41]([O:20][C:19](=[O:21])[C@@H:18]([CH3:17])[CH2:22][CH2:23][CH3:24])[C@H:40]2[C:35]([CH:36]=[CH:37][C@H:38]([CH3:61])[C@@H:39]2[CH2:44][CH2:45][C@H:46]2[O:51][C:50](=[O:52])[CH2:49][C@H:48]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:55])[CH3:56])[CH2:47]2)=[CH:34]1)([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: CCC[C@H](C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Agent: CCOP(=O)(Cl)OCC
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC[C@H](C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
690 mg (6.8 mmol) of triethylamine and 713 mg (4.1 mmol) of diethyl chlorophosphate were added to a solution of 400 mg (3.4 mmol) of (S)-2-methylvaleric acid in 15 ml of dry benzene, and the resulting mixture was stirred at room temperature for one hour. 1.58 g (2.9 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above] and 250 mg (1.7 mmol) of 4-(1-pyrrolidinyl)pyridine were then added to the mixture. The mixture was then stirred at room temperature for 24 hours, after which the mixture was diluted with 20 ml of benzene. The diluted mixture was then washed with 20 ml of water, 20 ml of a 10% w/v aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, in that order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by flash column chromatography through silica gel, using a 6:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.38 g (74% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9](=[C:12](OC)[CH3:13])[C:10]#[N:11])[S:8][C:4]=2[CH:3]=1.O.[NH2:19][NH2:20]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[C:12]([CH3:13])=[N:20][NH:19][C:10]=3[NH2:11])[S:8][C:4]=2[CH:3]=1
Reactant: COC(C)=C(C#N)c1nc2ccc(Br)cc2s1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1n[nH]c(N)c1-c1nc2ccc(Br)cc2s1
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of 2-(6-bromobenzothiazol-2-yl)-3-methoxybut-2-enenitrile (0.96 g, 3.1 mmol) and hydrazine hydrate (0.3 mL, 5.4 mmol) in methanol (30 mL) was heated to reflux overnight. The reaction was then cooled to room temperature. The resulting solid was isolated by filtration and was purified by flash chromatography to yield the title product. MS (m/z, ES+): 308.9 (Br79M+1, 100%), 310.9 (Br81M+1, 100%). Yield=5%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH3:9][C:10]1[CH:14]=[C:13]([Sn](CCCC)(CCCC)CCCC)[O:12][N:11]=1.C1CCC(P(C2C(C3C=CC=CC=3)=CC=CC=2)C2CCCCC2)CC1.CN(C=O)C>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]>[F:8][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[O:12][N:11]=[C:10]([CH3:9])[CH:14]=2)=[CH:7][N:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: Fc1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(F)nc2)on1
Temperature: 90 °C
Yield: 54.3 %

Procedure:
A 48 mL tube was charged with 5-bromo-2-fluoropyridine (1.17 ml, 11.4 mmol), 3-methyl-5-(tributylstannyl)isoxazole (5.29 g, 14.2 mmol), cyclohexyl JohnPhos (0.398 g, 1.14 mmol), Pd2dba3 (0.312 g, 0.341 mmol), and DMF (12.4 ml, 159 mmol), flushed with argon, sealed, then heated at 90° C. for 16 hours. Additional 3-methyl-5-(tributylstannyl)isoxazole (5.29 g, 14.2 mmol) (2 g), Pd2 dba3 (0.312 g, 0.341 mmol), and cyclohexyl JohnPhos (0.398 g, 1.14 mmol) were added and the mixture was stirred at 90° C. for 10 more hours. This was concentrated and the brown residue was purified by MPLC, eluting with 15% ethyl acetate in hexanes isocratic. 2-fluoro-5-(3-methylisoxazol-5-yl)pyridine (1.1029 g, 54.5% yield) isolated as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=2)[CH:6]=1.N[C:19]1([C:31]#[N:32])[CH:24]=[CH:23][C:22](C2C=CC=CC=2)=[CH:21][CH2:20]1.COC1C(CC(OC)=O)CC(OC)O1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:22]3[CH:23]=[CH:24][C:19]([C:31]#[N:32])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1ccn(-c2ccc(F)cc2)c1
Reactant: N#CC1(N)C=CC(c2ccccc2)=CC1
Agent: COC(=O)CC1CC(OC)OC1OC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1ccn(-c2ccc(-c3ccc(C#N)cc3)cc2)c1
Yield: 60 %

Procedure:
According to the procedure described in Example 14(a) for the preparation of 2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-acetic acid methyl ester, 4-amino-4-cyano-biphenyl (commercially available from TCI) and methyl 2-(2,5-dimethoxy-tetrahydrofuran-3-yl)acetate were condensed in 6 hours at 80° C. to give a crude product. Successive flash column chromatography with EtOAc/CH2Cl2/hex gave in 60% yield 2-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid methyl ester as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5]([NH2:7])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S-:19])=[CH:15][CH:14]=1.[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[S:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:5]([NH2:7])=[O:6]
Reactant: [S-]c1ccc(Cl)cc1
Reactant: NC(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a solution of 3,4-dichlorobenzamide (95.0 g, 0.500 mole) in dry dimethylformamide (1 liter) was added in one portion potassium 4-chlorothiophenolate (118.8 g, 0.650 mole). The mixture was stirred under nitrogen at 100° C. for 8 hours and at ambient temperature for 16 hours. Solvent (750 ml) was removed by vacuum distillation at 45° C. and the residue was poured into ice water (3 liters) containing concentrated hydrochloric acid (25 ml). The precipitate was filtered, partially dried, and crystallized from hot ethanol (1.2 liters). The crystals were filtered, washed with ethanol, and dried at 45° C. for 18 hours under vacuum to provide 102.0 g (68%) of 3-chloro-4-(4-chlorophenylthio)benzamide, m.p. 176°-177° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: Cn1cnc2c(N)nc(C#CCCO)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2c(N)nc(CCCCO)nc21

Procedure:
To a solution of 4-(6-amino-9-methyl-9H-purin-2-yl)-but-3-yn-1-ol (1.5 g, 6.88 mmol) in ethanol (30 ml) was added palladium 10% on graphite (1.35 g, 20% in weight). The mixture was stirred for 16 h in autoclave at 50° C. under 4 atm of hydrogen. The catalyst was filtered through a small pad of Celite and the solution obtained was evaporated under reduced pressure, to give a residue that was used for the following reaction without further purification.