Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH:12]([CH2:14][CH3:15])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH:12]([CH2:14][CH3:15])[CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CCC(C)Sc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)Sc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-Amino-9-benzyl-2-(sec-butylthio)purine (60 mg, 0.19 inmol) and bromine (0.4 ml) were dissolved in 85 ml of methylene chloride and the solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (chloroform) to give the subject compound (53 mg, yield 71%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][C:28]1([CH3:36])[O:32][CH:31]([CH2:33][CH2:34]O)[CH2:30][O:29]1>C1COCC1.C(#N)C>[I:25][CH2:34][CH2:33][CH:31]1[CH2:30][O:29][C:28]([CH3:36])([CH3:27])[O:32]1
Reactant: CC1(C)OCC(CCO)O1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC1(C)OCC(CCI)O1
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
Triphenylphosphine (172 mmol, 45 g) and imidazole (172 mmol, 12 g) were dissolved in THF/acetonitrile (3:1, 300 ml). The mixture was cooled under an ice bath, and iodine (172 mmol, 44 g) was added in four portions with vigorous stirring over 20 minutes. The resulting slurry was warmed to 20° C. and then cooled to 0° C. (±)-2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (156 mmol, 25 g) was added dropwise to the reaction mixture over 15 minutes. The mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with 5% sodium bicarbonate solution and extracted with hexane. The combined organic layer was dried with MgSO4 and concentrated. Silica gel chromatography gave 4-(2-iodo-ethyl)-2,2-dimethyl-[1,3]dioxolane as a clear oil; 1H NMR (400 MHz, CDCl3): δ 4.18–4.12 (m, 1H), 4.06 (dd, 1H, J1=8.0 Hz, J2=6.1 Hz), 3.55 (dd, 1H, J1=8.0 Hz, J2=6.5 Hz), 3.28–3.17 (m, 2 H), 2.11–1.98 (m, 2H), 1.38 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[N:13]=[C:12]2[NH:14][CH:15]=[C:16]([CH:17]=O)[C:11]2=[CH:10][CH:9]=1>C1COCC1>[Br:7][C:8]1[N:13]=[C:12]2[NH:14][CH:15]=[C:16]([CH3:17])[C:11]2=[CH:10][CH:9]=1
Reactant: O=Cc1c[nH]c2nc(Br)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c[nH]c2nc(Br)ccc12

Procedure:
LAH (1.0M in THF, 4.45 mL, 4.45 mmol) was added dropwise to refluxing 6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (1000 mg, 4.45 mmol) in dry THF (16 mL). The mixture was refluxed for 1 h, allowed to attain room temperature, and quenched with water (0.34 mL), w/w 15% aq. NaOH (0.34 mL) and water (1 mL). The resulting precipitation was filtered off, the filtrate concentrated and the residue was partitioned between aqueous NaOH and DCM. The organic layers were combined, dried and concentrated to give title compound. LCMS-ESI+: calc'd for C8H7BrN2: 211.2 (M+H+); Found: 211.2 (M+H+).
Reaction SMILES: CCN(C1C=CC=CC=1)CC.O[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH2:22][CH3:23])[N:16]=[CH:15][N:14]=1.C(OCC)(=O)C.P(Cl)(Cl)[Cl:31]>>[Cl:31][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([CH2:22][CH3:23])[N:16]=[CH:15][N:14]=1
Reactant: ClP(Cl)Cl
Reactant: CCc1ncnc(O)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCc1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
18.7 g (0.125 mol) of diethylaniline are dissolved in 18 ml of phosphorus chloride, and then 8.46 g (0.05 mol) of 4-hydroxy-5-nitro-6-ethylpyrimidine are stirred in. During the addition, the temperature rises from 22° to 47° C. A solution is formed which is heated at 60° C. for 2 hours. It is then stirred with ice-water and ethyl acetate for 30 minutes for the purpose of hydrolysis. The organic phase is separated off and combined with the extracts obtained by extraction, and the mixture is washed with NaHCO3 solution. Removal of the solvent yields 9.1 g of crude product, which is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 20:80 parts). 6.76 g (72.1% of the theoretical yield) of pure product are obtained in the form of an oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(CCCCN=[N+]=[N-])(CCCc1cccnc1)C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCN)(CCCc1cccnc1)C(=O)OCC
Reaction time: 48 h

Procedure:
To a solution of 42.59 g (0.11 mole) of diethyl [4-azidobutyl][3-(3-pyridyl)propyl]malonate in 270 ml THF and 3.1 ml water is added 29 g (0.11 mole) of triphenyl phosphine and the solution is stirred well for 48 h. Solvent is evaporated and the residue subjected to flash chromatography to give diethyl [4-aminobutyl][3-(3-pyridyl)propyl]-malonate as an oil.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[C:14]1([CH:20]([CH3:24])[CH2:21][CH2:22][NH2:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][CH2:21][CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:24])[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: CC(CCN)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CCN1Cc2cccc(I)c2C1=O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.5 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.178 g, 0.5 mmol), 3-phenyl-butylamine (0.090 g, 0.6 mmol), and K2CO3 (0.166 g, 1.2 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-phenyl-butyl)-2,3-dihydro-isoindol-1-one (0.046 g, 23%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.32 (d, 3H), 1.96 (m, 2H), 2.78 (m, 1H), 3.54 (m, 2H) 4.16 (s, 2H), 7.14-7.38 (m, 7H), 7.88 (d, 1H). GC-MS: m/z 391 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:25][CH:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: CN1CCC(N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 86.7 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (510 mg, 1.64 mmol) was reacted with 1-methylpiperidin-4-amine (375 mg, 3.28 mmol) to afford the desired product (552 mg, 87%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 9.12 (s, 1H), 8.38 (d, J=2.0 Hz, 1H), 7.84 (dd, J=8.9, 2.1 Hz, 1H), 7.79-7.71 (m, 1H), 4.20-3.97 (m, 1H), 2.93-2.69 (m, 3H), 2.47-2.19 (m, 5H), 2.19-2.03 (m, 2H), 1.86-1.60 (m, 2H), 1.32-1.16 (m, 2H), 1.16-1.00 (m, 2H).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][S:4][C:3]1=[O:7].[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1)=[O:9].II>O1CCCC1.[Zn]>[OH:9][CH:8]([CH:2]1[CH2:6][CH2:5][S:4][C:3]1=[O:7])[C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: O=C1SCCC1Br
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C(O)C2CCSC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.6 %

Procedure:
3-Bromothiolan-2-one (315 mg) and ethyl 2-(4-formylphenyl)propionate (300 mg) were dissolved in tetrahydrofuran, and to the solution was added zinc (147 mg) and a catalytic amount of iodine, and the reaction mixture was heated until the mixture was refluxed. The reaction mixture was stirred overnight at room temperature, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (106 mg, 20%).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[S:70]1[CH:74]=[CH:73][N:72]=[C:71]1[NH2:75]>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[C:28]([CH3:36])=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:75][C:71]2[S:70][CH:74]=[CH:73][N:72]=2)=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3nccs3)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-2-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and 1,3-thiazol-2-amine (10.0 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 30%). LC-MS m/z 604 (M+H)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=O)[CH3:2].[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC>C(OCCO)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(=O)Oc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCO
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)=O)cc2)cc1
Yield: 75.8 %

Procedure:
4-Acetyloxy-4'-acetylbiphenyl (80.0 g, 0.315 mol) was suspended in ethylene glycol monoethyl ether (300 ml), followed by heating with stirring to obtain a uniform solution, pouring a 50% aqueous solution of KOH (70 g) therein, heating under reflux for 30 minutes, dropwise adding 1-bromo-n-octane (62.7 g, 0.325 mol), heating under reflux for 5 hours, cooling with air, pouring the solution on ice (1 l), extracting with toluene (2 l), washing the toluene layer with an acid, then with an alkali aqueous solution, further with water till the washing water became neutral, distilling off toluene for solidification, filtering on heating with toluene (1 l) and active carbon, and recrystallizing to obtain 4-n-octyloxy-4'-acetylbiphenyl (77.5 g). Yield: 75.71%. This product exhibited a smectic B liquid crystal phase (SB), and its C-SB point and SB-I point were 92.5° C. and 132.9° C., respectively.
Reaction SMILES: [CH3:1]N(C)C=O.O=P(Cl)(Cl)Cl.[NH:11](/[C:18](/[CH3:25])=[CH:19]\[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:25][C:18]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:1][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)/C=C(/C)Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccccc2nc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
A solution of 140 g of dimethylformamide (1.92 mole ) in 500 mL of methylene chloride is mechanically stirred under a condenser/scrubber in an ice bath while 295 g of POCl3 (1.92 mol) is added dropwise over a 40 minute period. The reaction is stirred for a further 3 hour period, during which time the bath temperature is allowed to warm to room temperature. The reaction is then diluted with 2 L of methylene chloride, cooled in an ice bath, and treated dropwise with 394 g of ethyl β-anilinocrotonate (1.92 mol) over a 1 hour period. After stirring at room temperature for 26 hours, the reaction is heated at reflux temperature for 48 hours, cooled in an ice bath, quenched with 500 mL ice water, and treated portionwise with concentrated NH4OH to pH 6. The phases are separated and the organic phase is concentrated in vacuo to give a solid residue which is redissolved in 1.5 L ethyl acetate, filtered, and the filtrate saturated with gaseous hydrogen chloride. The resultant solid precipitate is filtered off, washed thoroughly with ethyl acetate, dissolved in water and basified with concentrated NH4OH. The basic aqueous mixture is extracted with 1:1 hexanes-ethyl acetate; the organic phase is concentrated in vacuo to afford 240 g of the title product, mp 70°-72° C.
Reaction SMILES: [CH:1]([C:4]([CH3:6])=[O:5])([CH3:3])[CH3:2].Cl[CH:8]([Cl:16])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O>O1CCCC1>[Cl:16][C:8]1([O:5][C:4]1([CH:1]([CH3:3])[CH3:2])[CH3:6])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: CC(=O)C(C)C
Reactant: CC(C)(C)OC(=O)C(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1(C)OC1(Cl)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A solution of 122 g of potassium tert.-butylate in 720 ml of tetrahydrofuran was added with stirring under an inert atmosphere at -20°C to a mixture of 95 g of methyl isopropyl ketone and 185 g of tert.-butyl dichloroacetate and the mixture was allowed to return to room temperature and was stirred for 2 hours. The mixture was poured into iced water and stirred after which the organic phase was removed, washed with aqueous sodium chloride solution and dried over magnesium sulfate. After passing the solution through vegetable black, the solution was concentrated to dryness to obtain 230.4 g of tert.-butyl 2-chloro-2,3-epoxy-3-isopropyl-butanoate in the form of a colorless liquid soluble in the usual organic solvents and insoluble in water.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[N:28]1[C:32]([CH3:33])=[N:31][N:30]=[N:29]1)[C:22](O)=[O:23]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:27]([N:28]4[C:32]([CH3:33])=[N:31][N:30]=[N:29]4)=[C:19]([F:18])[CH:20]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Reactant: Cc1nnnn1-c1ccc(C(=O)O)cc1F
Product: Cc1nnnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1F

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 3-fluoro-4-(5-methyl-tetrazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=4.18 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1.Br[C:14]1[CH:15]=[C:16]([CH:30]=[CH:31][C:32]=1[CH3:33])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:18]>>[CH3:33][C:32]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:29])[F:28])[CH:21]=2)=[O:18])=[CH:30][C:31]=1[N:11]1[CH2:10][CH2:9][C:7]2[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[CH2:12]1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Br
Reactant: CSc1ncc2c(n1)CCNC2
Product: CSc1ncc2c(n1)CCN(c1cc(C(=O)Nc3cccc(C(F)(F)F)c3)ccc1C)C2

Procedure:
In a manner similar to that described for Example 138, 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine and 3-bromo-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide were converted to the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[CH:44][C:45]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([CH2:56][CH2:57][OH:58])[CH2:52][CH2:51]2)=[O:49])=[N:46][CH:47]=1.COC(=O)C1C=CC(Br)=CC=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([C:48]([N:50]6[CH2:51][CH2:52][N:53]([CH2:56][CH2:57][OH:58])[CH2:54][CH2:55]6)=[O:49])=[N:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: O=C(c1ccc(Br)cn1)N1CCN(CCO)CC1
Agent: COC(=O)c1ccc(Br)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(CCO)CC4)nc3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (5-bromo-pyridin-2-yl)-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone (70 mg) obtained in the same manner as Step A in Example 1-D-79 instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of [5-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone was obtained, and then the PMB groups were removed according to Deprotection method 1, to obtain the desired compound (D-117) as a yellow powder (23 mg, 23%).
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([N:10]=[N+:11]=[N-:12])[N:7]=[C:6]([NH:13][NH:14][C:15]2[N:20]=[C:19]([N:21]=[N+:22]=[N-:23])[N:18]=[C:17]([N:24]=[N+:25]=[N-:26])[N:16]=2)[N:5]=1)=[N+:2]=[N-:3].C(Cl)(Cl)Cl.ClCl>O>[N:1]([C:4]1[N:9]=[C:8]([N:10]=[N+:11]=[N-:12])[N:7]=[C:6]([N:13]=[N:14][C:15]2[N:20]=[C:19]([N:21]=[N+:22]=[N-:23])[N:18]=[C:17]([N:24]=[N+:25]=[N-:26])[N:16]=2)[N:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1nc(N=[N+]=[N-])nc(NNc2nc(N=[N+]=[N-])nc(N=[N+]=[N-])n2)n1
Agent: ClCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=Nc1nc(N=Nc2nc(N=[N+]=[N-])nc(N=[N+]=[N-])n2)nc(N=[N+]=[N-])n1

Procedure:
Briefly, 4,4′,6,6′-tetra(chloro)hydrazo-1,3,5-triazine (1) [9] reacts rapidly with an excess of hydrazine monohydrate in acetonitrile to give 4,4′,6,6′-tetra(hydrazino)-hydrazo-1,3,5-triazine (2). Compound (2) undergoes diazotization to yield 4,4′,6,6′-tetra(azido)hydrazo-1,3,5-triazine (3). A suspension of (3) in 1:2 (v/v) H2O:CHCl3 solution reacts with chlorine gas at room temperature to provide 4,4′,6,6′-tetra(azido)azo-1,3,5-triazine (4, TAAT).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[CH:4]=[C:5]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][C:7]2=[O:8].[CH3:22][O-].[Na+]>CO>[CH2:15]([O:14][CH2:13][C:5]1[NH:1][C:2]2[CH:12]=[CH:11][CH:10]=[C:9]([C:7]([O:6][CH3:22])=[O:8])[C:3]=2[CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccc2c(=O)oc(COCc3ccccc3)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(COCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5-amino-3-benzyloxymethylisocoumarin (800 mg) and sodium methylate in methanol (768 mg) was stirred at ambient temperature for 20 minutes. After removal of solvents, water (40 ml) was added to the residue and the whole was extacted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated to dryness to leave a crude product, which was purified by silica gel column chromatography with n-hexane:ethyl acetate (6:1) as an eluent to afford methyl 2-benzyloxymethylindole-4-carboxylate (660 mg).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1([C:7]([O-:9])=[O:8])[CH2:6][CH2:5]1.Cl.[C:13]1(C)[CH:18]=CC=C[CH:14]=1>>[CH:13]([CH:5]1[CH2:6][C:4]1([OH:3])[C:7]([OH:9])=[O:8])([CH3:18])[CH3:14]
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)OC1(C(=O)[O-])CC1
Agent: Cl
Product: CC(C)C1CC1(O)C(=O)O
Reaction time: 1 h

Procedure:
17.0 g (0.06 mole) of trimethylsilyl 2-isopropyl°-1-trimethylsiloxy-cyclopropanecarboxylate were stirred for 2 hours at 30° C. in 100 ml of toluene saturated with hydrogen chloride. Dry nitrogen was then passed through the solution for 1 hour and the precipitate was filtered off. Crystallization from xylene yielded 2-isopropyl-1-hydroxycyclopropanecarboxylic acid (6.1 g) with a melting point of 135° to 138° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[F:27])[CH2:13][C:12]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:11]1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([C:21]3[CH2:22][CH2:23][N:24]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:25][CH:26]=3)[CH:18]=[CH:17][C:16]=2[F:27])[CH2:13][C:12]([C:28]([F:33])([F:34])[C:29]([F:30])([F:32])[F:31])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(C3=CCNCC3)ccc2F)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-fluoro-5-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 148, triethylamine (41.0 uL, 0.30 mmol) and methanesulfonyl chloride (8.1 mg, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 3 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15 mg of the titled compound as a yellow liquid.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9]([CH3:13])=[CH:10][CH2:11]O>C(O)=O>[CH3:6][C:5]([CH2:7][CH2:11][CH:10]=[C:9]([CH3:13])[CH3:8])=[CH:4][C:2](=[O:1])[CH3:3]
Reactant: CC(C)=CCO
Reactant: CC(=O)C=C(C)C
Solvent: O=CO
Product: CC(=O)C=C(C)CCC=C(C)C
Yield: 78 %

Procedure:
800 parts of mesityl oxide, 200 parts of 3-methyl-2-buten-1-ol (prenol) and 2 parts of formic acid are heated at 250°C for 3 hours in a vibrated autoclave holding 2500 parts by volume at a pressure of 60 atmospheres. The reaction mixture is worked up by distillation and gives 190 parts of 4,8-dimethyl-3,7-nonadien-2-one having a boiling point of 60° to 62°C at 0.2 mm. The yield is 78% of theory at a conversion of 63% based on prenol.