Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]1([CH2:32]O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:32][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OCc1cccc2ccccc12
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a stirring solution of 912 mg (3.48 mmol, 1.2 equiv) of triphenylphosphine in 10 mL of CCl4 at 0° C. is added 180 μL (3.48 mmol, 1.2 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 500 mg (3.16 mmol) of 1-Naphthalenemethanol in 5 mL of CCl4 is added over 2 min. The resulting solution is stirred 1.5 h at RT, and the solvent is removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 10/1 as eluent afforded 670 mg of the title compound as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ8.18 (d, 1H), 7.83 (m, 2H), 7.63-7.38 (m, 4H), 4.98 (s, 2H); Rf =0.65 in hexane/EtOAc 5/1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[S-:12][C:13]#[N:14].[Na+].[Cl-].C(C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC)(=O)CCCCCCC>O>[S:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:13]#[N:14]
Reactant: CCCCCCCCCCBr
Reactant: N#C[S-]
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCSC#N
Reaction time: 2 h

Procedure:
A mixture of 100 grams (0.45 mole) of 1-bromodecane, 160 grams (1.98 moles)of sodium thiocyanate, 50 ml water and 10 grams of tricaprylylmethylammonium chloride was heated to 88°-105° C with stirring over a period of 2 hours. Examination of the reaction mixture by gas liquid partition chromatography showed that 100% conversionof the 1-bromodecane had occurred to give 1-thiocyanodecane.
Reaction SMILES: [CH:1]([CH:3]([CH:9]([CH3:13])[C:10]([O-:12])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=O.S(O)(O)(=O)=O.[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)(=[NH:21])[NH2:20].C(O[K])(C)(C)C>>[CH2:28]([N:25]1[CH2:24][CH2:23][N:22]([C:19]2[N:21]=[C:10]([OH:12])[C:9]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:1])=[CH:13][N:20]=2)[CH2:27][CH2:26]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(C=O)C(C)C(=O)[O-]
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: CC(C)(C)O[K]
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 18.4 %

Procedure:
A solution of 2.16 g (10 mmoles) of ethyl 2-formyl-3-methylsuccinate [Zhur. Obshche i Khim., 30, 2250 (1960)] was added to a mixture of 2.67 g (10 mmoles) of 1-amidino-4-benzylpiperazine sulfate, 1.12 g (10 mmoles) of tert-C4H9OK and 12 ml of tert-C4O9OH. The mixture was then refluxed for 6 hours. The reaction mixture was cooled, and extracted by adding water and CHCl3. The CHCl3 layer was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 :CH3OH=95:5) to give 0.68 g (yield 23%) of 2-(4-benzylpiperazino)-5-(1-ethoxycarbonylethyl)-4-hydroxypyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](O)=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[CH2:59]([NH2:66])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](=[O:35])[NH:66][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Reactant: NCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)NCc2ccccc2)C(C)C)ccc1OC

Procedure:
To a stirring solution of (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (70 mg, 0.138 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (42 mg, 0.166 mmol) and triethylamine (77 μL, 0.552 mmol) in CH2Cl2 (3 mL), benzylamine (18 μL, 0.166 mmol) is added. The resulting solution is refluxed for 2 h and then quenched by the addition of aqueous NaHCO3 solution. The organic layer is separated, and the aqueous phase is extracted 3 times with CH2Cl2. The combined organic extracts are dried (Na2SO4), and the solvent is removed in vacuo. The crude material is purified by preparative HPLC (C18-ODB-AQ, 5 μm, 20×50 mm, YMC, eluent: CH3CNIH2O+0.1 % HCOOH flow: 20 mL/min). The HPLC fractions are collected and lyophilized to afford the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.2. MS (LC-MS): 598.0 [M+H]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.60 min.
Reaction SMILES: C(O[C:4]([C:6]1[C:10]([C:11]([O:13]CC)=O)=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[O:8][C:7]=1[NH2:25])=[O:5])C.C[N:27]([CH:29]=O)C.C(O)=O.C([NH2:36])=O>O>[OH:5][C:4]1[C:6]2[C:10]([C:11]([NH2:36])=[O:13])=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)[O:8][C:7]=2[N:25]=[CH:29][N:27]=1
Reactant: CCOC(=O)c1c(N)oc(-c2cccc([N+](=O)[O-])c2)c1C(=O)OCC
Reactant: NC=O
Reactant: CN(C)C=O
Solvent: O
Solvent: O=CO
Product: NC(=O)c1c(-c2cccc([N+](=O)[O-])c2)oc2ncnc(O)c12
Reaction time: 8 h

Procedure:
72.9 g of 2-amino-5-(3-nitrophenyl)furan-3,4-dicarboxylic acid diethyl ester are stirred for ca. 23 h at 140° C. under N2 in 200 ml of formamide, 100 ml of DMF and 40 ml of 98-100% formic acid. After cooling the solution, the reaction mixture is diluted with H2O, left to stand for 8 h and filtered by suction. The residue is dried in a HV, boiled in 300 ml of acetonitrile, filtered by suction, washed with ice-cold acetonitrile and dried in a HV. This second residue is boiled in 200 ml of methylene chloride, filtered by suction whilst warm, washed with methylene chloride and dried in a HV. The residue obtained contains the product; m.p.: 212-220° C. IR: 3528w, 3246m, 3092m, 2985w, 1936w, 1721s, 1589m, 1543s, 1482m, 1429w, 1378s, 1352s, 1323m, 1287m, 1234m, 1196m, 1076m, 1042s. In the product thus obtained, 4-hydroxy-6-(3-nitrophenyl)furo[2,3-d]pyrimidin-5-carboxylic acid amide is obtained as a by-product. This is obtained in analysis-pure form by recrystallisation from DMF; m.p.: ca. 380° C. (decomposition) IR: 3338m, 3180-2810w (multiplett), 1708s, 1676s, 1589w, 1560m, 1526s, 1406w, 1348s, 1220w, 1105w, 1081w, 1041w, 920w, 899w, 880w, 803w, 740w, 676w.
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].N[C:15]1([O:24]O)[CH2:20][CH:19]([CH3:21])[CH2:18][C:17]([CH3:23])([CH3:22])[CH2:16]1>C(O)C>[C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][CH:19]1[CH2:18][C:17]([CH3:23])([CH3:22])[CH2:16][C:15](=[O:24])[CH2:20]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC(=O)[O-]
Agent: O=C1CCCCCC1
Agent: [NH4+]
Solvent: CCO
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
To a stirred mixture of cycloheptanone (73.2 g.) and ethanol (200 cc.), containing ammonium acetate (6.4 g.) and kept at or below 0°C was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (69.2 g.; 76% pure). After the solid had dissolved (5 hours) the solution was stored at 0°C overnight and the product worked up as in the previous Examples. There were obtained unreacted cycloheptanone, and dihydroisophorone, and fractions (57.5 g.) b.p. 124° - 130°/0.3 mm.Hg., peroxide equivalent 283, perchloric acid equivalent 278 shown by mass spectroscopy to contain the peroxide ##SPC30##
Reaction SMILES: Br[CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:3]1.[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN1CCCC1=O.C(Cl)Cl>[CH3:15][C:16]([CH3:20])([C:17]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1)=[O:18])[CH2:19][N:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1
Reactant: CN1CCNCC1
Reactant: CC(C)(C)C=O
Reactant: Cc1ccc(N2CCNC(Br)C2)cc1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)C(C)(C)CN3CCN(C)CC3)CC2)cc1
Temperature: 200 °C
Reaction time: 48 h
Yield: 23.2 %

Procedure:
3-Bromo-1-(4-methylphenyl)piperazine-2,2-dimethylpropan-1-one (6.00 g, 17.68 mmol) was dissolved in N-methylpyrrolidinone (12 mL). N-Methylpiperazine (4.12 mL, 37.94 mmol) was added. The reaction mixture was split into four batches and each was heated at 200° C. for 15 minutes in a Biotage Initiator microwave at high absorption. The reaction mixtures were combined and dissolved in DCM (300 mL), and washed with a 0.5M aq KOH solution (100 mL), water (100 mL), brine (100 mL), and then dried (MgSO4) and concentrated in vacuo. The residue was dissolved in DCM (100 mL) and methyl isocyanate resin (2.0 g) was added, and the reaction mixture was shaken for 48 hours, filtered and then concentrated in vacuo. The resulting residue was purified by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-30%). The resulting residue was dissolved in DCM (100 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo, to give a pale brown oil which was recrystallised from heptane to give 1-{2,2-dimethyl-3-[4-(4-methylphenyl)-piperazin-1-yl]-3-oxopropyl}-4-methylpiperazine (1.47 g, 23.2%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=O.[C:11]([Si:15]([CH3:30])([CH3:29])[O:16][CH2:17][CH2:18]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si]([NH:35][Si](C)(C)C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.C(N(CC)CC)C.C(Cl)(=O)C>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[N:35][C:17]([O:16][Si:15]([CH3:30])([CH3:29])[CH3:11])=[CH2:18]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=Cc1cc(I)ccc1F
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: C=C(N=Cc1cc(I)ccc1F)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 190b, 2-fluoro-5-iodobenzaldehyde (2.62 g, 10.5 mmol) (Aldrich) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (2.14 mL, 10.5 mmol), n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol), trimethylsilyl chloride (1.33 mL, 10.5 mmol), triethylamine (1.9 mL, 13.6 mmol) and acetyl chloride (0.97 mL, 13.6 mmol) to give crude 1-(2-fluoro-5-iodophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:7]=[C:8]([CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24]Cl)=[CH:12][N:11]=1)([CH2:3][CH3:4])[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:29]([CH2:24][C:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[C:10]([CH2:9][C:8]2[CH:26]=[CH:27][CH:28]=[C:6]([O:5][CH:1]([CH2:3][CH3:4])[CH3:2])[CH:7]=2)=[N:11][CH:12]=1)=[N+:30]=[N-:31]
Reactant: CCC(C)Oc1cccc(Cc2ncc(CCl)c3cc(OC)c(OC)cc23)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCC(C)Oc1cccc(Cc2ncc(CN=[N+]=[N-])c3cc(OC)c(OC)cc23)c1
Temperature: 65 °C
Yield: 54.1 %

Procedure:
A solution of 1-(3-sec-butoxy-benzyl)-4-chloromethyl-6,7-dimethoxy-isoquinoline (1.0 g, 2.5 mmol) in dimethylsulfoxide (2 mL) was added to a solution of sodium azide (813 mg, 12.5 mmol) in dimethylsulfoxide (10 mL) prewarmed to 65° C. The solution was stirred at 65° C. for 1½ hrs. The reaction mixture was cooled and dissolved in ethyl acetate (100 mL). This ethyl acetate solution was washed with saturated aqueous sodium bicarbonate solution (2×20 mL), saturated aqueous sodium chloride solution (20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 4-azidomethyl-1-(3-sec-butoxy-benzyl)-6,7-dimethoxy-isoquinoline (550 mg, 54%) as a light yellow solid which was used without further purification: APCI-MS m/e calcd for C23H26N4O3 (M+H+) 407.5, found 406.9; 1H NMR (300 MHz) compatible.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[O-].[Na+].[C:31](OCC)(=[O:33])C>CO>[CH3:31][O:33][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOC(C)=O
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(C#N)c(F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1C#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
280 mg 2-Fluoro-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-ylmethoxy]-benzonitrile (intermediate example 1) were dissolved in 10 ml methanol. 390 mg sodium methoxide were added and the reaction mixture stirred at a temperature of 60° C. for two hours. The cooled reaction mixture was diluted by adding 200 ml ethyl acetate and washed three times with portions of 50 ml water. The organic layer was dried over MgSO4 and the solvent removed in vacuo to provide 140 mg 2-Methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-benzonitrile as pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=2)=[CH:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(Cl)Cl>N1C=CC=CC=1>[C:32]1([S:38]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:23])[CH2:12][C:13]3[CH:18]=[C:17]([Br:19])[C:16]([O:20][CH3:21])=[C:15]([Br:22])[CH:14]=3)=[CH:4][C:3]=2[O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1c(Br)cc(CC(=O)NCCc2ccc(N)c(OCc3ccccc3)c2)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(Br)cc(CC(=O)NCCc2ccc(NS(=O)(=O)c3ccccc3)c(OCc3ccccc3)c2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(4-amino-3-benzyloxy-phenyl)-ethyl]-2-(3,5-dibromo-4-methoxy-phenyl)-acetamide (0.995 g, 0.00181 mol) and phenylsulfonyl chloride (0.484 g, 0.00274 mol) 40 mL of methylene chloride was added 5 mL of pyridine. The reaction mixture was stirred overnight at room temperature, washed with 1N HCl and 1N NaOH, dried over Na2SO4 and concentrated. A crystallization from ethyl acetate-hexanes gave an oil. It was solidified under standing. Yield 1.043 g (83%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6][C:7]=1[Cl:8].[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[Cl:8][C:7]1[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[F:13]
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)n1
Yield: 92.5 %

Procedure:
Under an argon atmosphere, to a solution of methyl 5-bromo-6-chloropicolinate (12.0 g) in toluene (300 mL) were added 2-fluoro-5-methoxyphenylboronic acid (9.83 g), [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.00 g) and a solution of sodium carbonate (14.8 g) in water (60 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and diluted with water. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give the title compound (13.1 g) as pale-yellow crystals.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1.[H-].[Na+].F[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1>O>[CH3:38][C:34]1[N:33]=[C:32]([O:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]3)=[CH:27][CH:28]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(CCO)cc2)CC1
Reactant: Cc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(OCCc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)n1

Procedure:
To a DMF (10 mL) solution of tert-butyl 4-[4-(2-hydroxyethyl)benzyl]piperazine-1-carboxylate (1.000 g) was added NaH (112 mg, 60% in mineral oil) at 0° C., then the resultant mixture was stirred for 1 hour. To the mixture was added 2-fluoro-6-methylpyridine (0.419 mL), then the resultant mixture was stirred at 70° C. over night. The mixture was poured into water, and extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=4/1 to 1/1) to afford tert-butyl 4-(4-{2-[(6-methylpyridin-2-yl)oxy]ethyl}benzyl)piperazine-1-carboxylate as a pale yellow amorphous powder (350 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:6]#[N:7].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>>[Cl:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:2][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(Cl)c(CBr)c1
Agent: Cl
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(C#N)ccc1Cl

Procedure:
The title compound was prepared following general procedure 10, starting from 3-(bromomethyl)-4-chlorobenzonitrile and sarcosine tert-butyl ester hydrochloride. It was obtained as a colorless oil (1.9 g, 86%). LC/MS (Method B): 295.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[S:10][C:6]=2[CH:5]=1)([O-])=O.Cl[Sn]Cl.N.CO.C(Cl)Cl>C(O)C>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]2[N:8]=[C:9]([NH:11][CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[S:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2nc(NCCN3CCCC3)sc2c1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc2nc(NCCN3CCCC3)sc2c1
Yield: 65 %

Procedure:
A suspension of 6-nitro-2-(2-pyrrolidin-1-ylethylamino)benzothiazole (Example 11, 50 mg, 0.17 mmol) and SnCl2 (161 mg, 0.85 mmol) in 20 mL of ethanol (denatured) was heated at reflux for 4 hours. After cooling the mixture was partitioned between 50 mL of ethyl acetate and 20 mL of 1.0N aqueous NaOH. The organic layer was dried over sodium sulfate and concentrated to give a yellow residue which was subjected to silica gel column chromatography (5% 2M NH3/MeOH:95% CH2Cl2). Yield: 65%, 1H-NMR (CD3OD): δ 8.70 (d, 1H, J=8.3 Hz); 8.47 (d, 1H, J=2.0 Hz); 8.21 (dd, 1H, J=6.3, 1.9 Hz); 5.05 (t, 2H, J=6.3 Hz); 4.28 (t, 2H, J=6.8 Hz); 4.14 (m, 4H); 3.33 (m, 4H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]#[C:10][CH2:11][CH2:12][OH:13].C(N(CC)CC)C.O>CN(C=O)C.[Cu]I.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>[Br:8][C:4]1[CH:3]=[C:2]([C:9]#[C:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCO
Reactant: Brc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: OCCC#Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
A solution of 10.0 gm (35.3 mmol) of 3-iodo-bromobenzene in DMF was treated with 2.95 mL (88 mmol) of 4-butyne-1-ol, 0.2 gm (1.06 mmol) of copper (I) iodide, 1.23 gm of dichlorobis(triphenylphosphine)-palladium(II), and 49 mL (0.35 mol) of triethylamine, stirred at room temperature for 18 h, poured into water and extracted with EtOAc. The combined extracts were washed sequentially with water and brine, dried over Na2SO4 and concentrated at reduced pressure. Chromatography of the resultant concentrate on silica gel with a gradient of 5% to 30% EtOAc-hexanes afforded 4-(3-bromophenyl)but-3-yn-1-ol as an orange oil, 7.3 gm (92% yield); 1H NMR (400 MHz, CDCl3) δ: 1.79 (s, 1H), 2.67 (t, 2H, J=6.3 Hz), 3.80 (t, 2H, J=6.3 Hz), 7.14 (t, 1H, J=7.9 Hz), 7.30 (d, 1H, J=7.9 Hz), 7.41 (m, 1H), 7.54 (t, 1H, J=1.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:28])[CH2:25][CH2:26]Br)[C:3]=1[F:29].Cl.[CH3:31][NH:32][CH3:33].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([CH2:22][O:23][C:24](=[O:28])[CH2:25][CH2:26][N:32]([CH3:33])[CH3:31])[C:3]=1[F:29]
Reactant: CNC
Reactant: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(COC(=O)CCBr)c(F)c3o2)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
130 mg (0.276 mmol) of Compound 160 obtained in EXAMPLE 160 was dissolved in 5 mL of dimethylformamide, 112 mg (1.38 mmol) of dimethylamine hydrochloride and 0.24 mL (1.38 mmol) of diisopropylethylamine were added, and the mixture was stirred at 50° C. for 30 minutes. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1), to give 122 mg of Compound 162 (yield: 86%), which was converted to a hydrochloride according to the same manner as that in EXAMPLE 161.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([N:13]([CH3:20])C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32](CN)=[CH:31][CH:30]=1>CCO>[CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([NH:13][CH2:20][C:32]3[CH:31]=[CH:30][C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)=[CH:36][CH:35]=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:2])[CH3:3]
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Reactant: NCc1ccc(-c2ccccn2)cc1
Solvent: CCO
Product: CSc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Yield: 60 %

Procedure:
According to the same conditions resulting in the preparation of the compound IIa.1, the compound IIa.2 is prepared from 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine and from 4-(pyridin-2-yl)benzylamine. Yield=60%. Mp=136-138° C. (EtOH). 1H NMR (300 MHz, CDCl3): δ 8.71 (d, 1H, J=4.7 Hz, Harom), 8.00 (d, 2H, J=8.1 Hz, Harom), 7.82-7.72 (m, 3H, Harom), 7.49 (d, 2H, J=8.1 Hz, Harom), 7.26 (dd, 1H, J=4.7 Hz, 7.2 Hz, Harom), 6.76 (bs, 1H, NH), 4.86 (d 2H, J=6.0 Hz, CH2), 3.16 (hept, 1H, J=7.0 Hz, CH), 2.57 (s, 3H, CH3), 1.33 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 391 (MH+).