Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[N:23]1([CH:29]2[CH2:35][CH2:34][C:33]3[CH:36]=[C:37]([NH2:40])[CH:38]=[CH:39][C:32]=3[CH2:31][CH2:30]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[CH3:14][NH:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[NH:8][C:6]1[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=[C:2]([NH:40][C:37]2[CH:38]=[CH:39][C:32]3[CH2:31][CH2:30][CH:29]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH2:35][CH2:34][C:33]=3[CH:36]=2)[N:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(N2CCOCC2)CC3)ncc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzamide and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine in an analogous manner to Example 195 (microwave: 120° C., 60 minutes) to afford an off-white solid (35 mg, 86%). Mp: 158-62° C. LCMS (m/e) 541 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.85 (s, 1H), 8.45 (d, J=9 Hz, 1H), 8.36 (s, 1H), 7.50 (d, J=7 Hz, 1H), 7.47-7.37 (m, 2H), 7.30 (m, 1H), 7.25 (m, 2H), 7.10 (m, 1H), 6.27 (br s, 1H), 3.90-3.70 (m, 4H), 3.04 (s, 3H), 2.90-2.50 (m, 7H), 2.17 (m, 2H), 1.80-1.35 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21]>>[CH3:21][O:20][N:19]([CH3:18])[C:10](=[O:11])[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(CC(=O)O)c1ccc(Br)cc1
Reactant: CNOC
Agent: Cl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)C(C)(C)C

Procedure:
In analogy to example 74, step 4, from 3-(4-bromo-phenyl)-4,4-dimethyl-pentanoic acid (CAS RN: [1017356-66-9]) and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a white solid, MS (ESI+): m/z=328.0895 ([M+H]+, 1Br).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[NH2:18][CH2:19][CH2:20][OH:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.CO.C(O)(=O)C>[OH:21][CH2:20][CH2:19][NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(OCc1ccccc1)N1CCC(NCCO)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 107.7 %

Procedure:
A solution of benzyl 4-oxopiperidin-1-carboxylate (7.0 g), 2-aminoethanol (2.8 g) and acetic acid (2.7 g) in 1,2-dichloroethane (150 mL)-methanol (10 mL) was stirred at room temperature for 3 hours, sodium triacetoxyborohydride (12.7 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. A 1N sodium hydroxide solution was added to the reaction mixture, pH of the aqueous layer was adjusted to about 12, and then the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (9.0 g, quantitative) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([Cl:17])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:17].[CH3:9][C:10]1[C:11]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]2[CH3:28])=[N:12][C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][C:15]=1[CH3:16]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 68.9 %

Procedure:
After 4-fluoroaniline(1.0 ml, 10 mmol) was added to a mixture solution of 5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine(1.4 g, 4.8 mmol) and dimethylformamide(10 ml), 1.32 g of the title compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:27]([C:29]1[CH:30]=[C:31]([NH:35][CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([OH:39])=[O:38])[CH:32]=[CH:33][CH:34]=1)[CH3:28].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:27][CH3:28])[CH:30]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCc1cccc(NC(C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.1 %

Procedure:
PS-DCC (1097 mg, 1.371 mmol, loading: 1.25 mmol/g) is suspended in THF (15 mL). HOBT (210 mg, 1.37 mmol), (3-ethyl-phenylamino)-phenyl-acetic acid hydrochloride (I42) (200 mg, 0.68 mmol), and (R)-quinuclidin-3-ol (262 mg, 2.06 mmol) are added and the suspension is shaken at RT for 16 hours. PS-DCC is filtered off and the filtrate is evaporated. The resulting residue is dissolved in EtOAc and washed with water, sat. NaHCO3, water and brine. The organic phase is dried over Na2SO4, filtered and evaporated. The crude is purified by flash chromatography (DCM/MeOH=95/5) to obtain the title compound as a colorless oil (72 mg, 30% yield, mixture of diastereoisomers).
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].[Br:16]NC(=O)CCC(N)=O>C1COCC1>[Br:16][C:7]1[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(Br)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 58.6 %

Procedure:
To a solution of 1-triisoproylsilyl-pyrrole (13.2 g,0.059 mol) in 250 ml of THF at -78° C. was added 10.45 g (0.0587 mol) of N-bromosuccinamide (NBS), the mixture was stirred at -78° C. for 3 h. The reaction mixture was warmed to room temperature and concentrated in vacuo, and the resulting residue in hexane was stirred overnight. The hexane solution was filtered through alumina eluting with hexane, the eluent was concentrated in vacuo, and the residue was distilled (b.p. 107°-108° C./0.2 mm) to afford 10.4 g (58.4%) of 3-bromo-1-triisopropylsilyl-pyrrole.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH2:15][C:16](O)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[C:9]1([CH2:15][C:16]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)OCc1ccccc1
Yield: 95 %

Procedure:
To a CH2Cl2 (2ml) solution of 2-chloro-1-ethyl-4-methoxypryridinium tetrafluoroborate (296 mg, 1.2 mmol) was added a mixture of benzyl alcohol (108 mg, 1.0 mmol), phenylacetic acid (136 mg, 1.0 mmol) and triethylamine (243 mg, 2.4 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and benzyl phenylacetate was isolated in 95% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9]Br)=[CH:4][CH:3]=1.[OH2:12].Br.CS(C)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH:9]([OH:16])[OH:12])=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Br
Product: O=C(c1ccc(Cl)cc1)C(O)O
Yield: 70 %

Procedure:
A solution of 4′-chloro-2-bromoacetophenone (25.0 g, 107 mmol), water (1.92 mL, 107 mmol) and 47% hydrobromic acid (0.20 mL) in dimethylsulfoxide (160 mL) was stirred at 80° C. for 5 h. After the reaction mixture was poured into water, the precipitate was filtered, washed with diethylether and dried, affording 4′-chloro-2,2-dihydroxyacetophenone (14.0 g, 70%). 1H NMR (300 MHz, CDCl3), δ 5.92(1H, s), 7.45-7.52(2H, m), 8.05-8.20(2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCO.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.O>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=2)[C:5]([OH:7])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Reactant: OB(O)c1cccc(F)c1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of 3-bromo-5-methylbenzoic acid (3.0 g, 13.95 mmol, 1.0 eq), 3-fluorophenylboronic acid (2.34 g, 16.74 mmol, 1.2 eq) and Na2CO3 (5.91 g, 55.8 mmol, 4.0 eq) in a mixture of EtOH (10 mL), DMF (40 mL) and H2O (10 mL) was added Pd(PPh3)4 (806 mg, 0.7 mmol, 0.05 eq). The mixture was stirred at 100° C. overnight. Water was added and the aqueous layer extracted with EtOAc. The organic extract was discarded and the aqueous layer was acidified to pH 4-5 by addition of 1M HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were filtered through silica gel and concentrated to give the title compound as a white solid (2.0 g, 62%)
Reaction SMILES: [Cl-].[CH3:2][C:3]([CH3:25])=[CH:4]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:26][O-].[Na+].[F:29][C:30]([F:35])([F:34])[C:31]([CH3:33])=O>C(Cl)Cl.CO>[CH3:4][C:3](=[CH:2][CH:33]=[C:31]([C:30]([F:35])([F:34])[F:29])[CH3:26])[CH3:25]
Reactant: CC(=O)C(F)(F)F
Reactant: C[O-]
Reactant: CC(C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)=CC=C(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A stirred solution of 144.3 g (0.39 mole) of (3-methyl-2-butenyl)triphenylphosphonium chloride in 300 ml of methylene chloride, under nitrogen atmosphere, was cooled to 0° C. To this cold solution a solution of 84.2 g (0.39 mole) of sodium methoxide 25% in methanol was added dropwise at a rate to keep the reaction mixture temperature below 4° C. Upon complete addition (40 minutes) a solution of 50.4 g (0.45 mole) of 1,1,1-trifluoroacetone in 5 ml of methylene chloride was added dropwise at a rate to keep the reaction mixture temperature below 6° C. Upon complete addition (40 minutes) the reaction mixture was allowed to warm to ambient temperature and was then stirred for 18 hours. The reaction mixture was washed twice with 150 ml portions of water, then dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated by distillation. Pentane was added to the pot residue to precipitate triphenylphosphine oxide. The mixture was filtered and the filtrate concentrated by distillation. Diglyme was added to the pot residue, and an additional amount of triphenylphosphene oxide was collected by filtration. The filtrate was fractionally distilled by a spinning band distilling system to give in sixteen fractions 14.2 g of 98% 2-methyl-5-trifluoromethyl-2,4-hexadiene; b.p. 122°-124° C. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH:22]1[CH:23]=[CH:24][N:25]2[CH2:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[NH:28][CH2:27][C:26]=12.C(N(CC)C(C)C)(C)C.Cl>C(Cl)Cl.CN(C)C=O>[CH:22]1[CH:23]=[CH:24][N:25]2[CH2:31][C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[N:28]([C:11]([C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=4)=[CH:15][CH:14]=3)=[O:13])[CH2:27][C:26]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(O)c1ccc(C2=CCCCC2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(C2=CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.7 %

Procedure:
4-Cyclohex-1-en-1-yl-benzoic acid of Step C (0.099 g, 0.489 mmol) and oxalyl chloride (0.065 g, 0.513 mmol) were dissolved in anhydrous methylene chloride (5 mL) and N,N-dimethylformamide (0.00114 mL, 0.0147 mmol) added. The resulting mixture was refluxed for 1 hour, then cooled to room temperature and solvent evaporated. The crude acid chloride thus prepared was combined with 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.090 g, 0.489 mmol) and N,N-diisopropyl ethylamine (0.103 mL, 0.589 mmol) in anhydrous dichloromethane (5 mL). After stirring at room temperature for 1.5 hours, 1 N hydrochloric acid (50 mL) was added and the resulting mixture extracted with diethyl ether (50 mL). The organic phase was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane. A slightly orange solid was isolated which was recrystallized from petroleum ether to afford the title compound (0.131 g) as white crystals, m.p. 156° C.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C.C1COCC1>[C:26]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:28][CH:29]=[C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])[N:19]=2)[CH:25]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1cccc(OC(C)(C)C(=O)O)c1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Under nitrogen, 2-{3-[2-(2-biphenyl-3-yl-5-methyloxazol-4-yl)ethoxy]phenoxy}-2-methylpropionic acid ethyl ester (0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to provide the desired product. mp 67-71° C.; Rf=0.09 in 60% ethyl acetate/hexanes; 1H NMR (400 MHz, CDCl3) δ8.22 (s, 1H), 7.91 (d,J=7.2 Hz, 1H), 7.65-7.63 (m, 3H), 7.51-7.41 (m, 3H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.38 (d, J=8.0 Hz, 1H), 6.53 (d, J=8.0 Hz), 4.19 (t, J=7.4 Hz, 2H), 2.92 (t, J=7.4 Hz, 2H), 2.36 (s, 3H), 1.58 (s, 6H); MS (EI) 479.9 (M+Na)+, 457.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[N:11]([CH3:19])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:41]C(/N=N/C(OCC)=O)=O.[CH2:51]1[CH2:55][O:54][CH2:53][CH2:52]1>[Cl-].[Na+].O>[CH3:55][O:54][C:53]([C@@H:52]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[N:11]([CH3:19])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:51])=[O:41]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: C1CCOC1
Reactant: Cn1c(C=Cc2ccccc2O)cc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC(=O)[C@H](C)Oc1ccccc1C=Cc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of 1.50 g (6.02 mmol) of 2-[2-(2-hydroxyphenyl)vinyl]-1-methylindole, 1.89 g (7.21 mmol) of triphenylphosphine and 0.69 ml (7.22 mmol) of R-(+)-methyl lactate in 15 ml of THF was added 1.14 ml (7.24 mmol) of diethylazodicarboxylate under an ice-cooled condition, followed by stirring at room temperature for 2 hours. Brine was added to the reaction mixture, followed by extraction with methylene chloride. The extract was dried over Na2SO4, and evaporated. CHCl3 -n-hexane was added to the residue and, after filtration, the organic layer was purified by silica gel column chromatography (CHCl3 /n-hexane/AcOEt=10/10/1) to give 1.82 g (90%) of (S)-2-{2[2-(1-methoxycarbonylethoxy)phenyl]vinyl}-1-methylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([CH2:7][C:8]#[N:9])=O.O.[NH2:15][NH2:16]>C(O)C>[NH2:9][C:8]1[CH:7]=[C:5]([C:4]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:2]([Cl:1])[CH:3]=2)[NH:16][N:15]=1
Reactant: NN
Reactant: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ccc(Cl)c(Cl)c2)[nH]n1

Procedure:
3,4-Dichlorobenzoylacetonitrile (3.0 g) was dissolved in ethanol (15 ml) to which was subsequently added hydrazine monohydrate (0.67 ml) while cooling with ice. The mixture was heatedunder reflux for 5 hours and allowed to cool. Then, the solvent was distilled away under a reduced pressure. The resulting residue was recrystallized from ethyl acetate-hexane to obtain the title compound (1.72 g) as colorless crystals (melting point: 169-170° C.).
Reaction SMILES: [OH:1][CH:2]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[H-].[Na+].Br[CH2:19][C:20]1[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1>O1CCCC1>[N:4]1([CH2:3][CH:2]([O:1][CH2:19][C:20]2[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=2)[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: CCCCCOCC(O)Cn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCOCC(Cn1ccnc1)OCc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-[2-hydroxy-3-(pentoxy)propyl]-1H-imidazole (Example 29b, 2.12 g, 0.010 mol) in anhydrous tetrahydrofuran (15 ml) was treated with sodium hydride, 0.44 g of a 60% dispersion in oil, 0.011 mol) and stirred at room temperature for 1 hour. Ethyl 4-(bromomethyl)benzoate (2.67 g, 0.011 mol) was then added and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated off under reduced pressure and the residue was dissolved in ethyl acetate, washed with water and dried (MgSO4). The solvent was evaporated off under reduced pressure and the crude product was purified by column chromatography (silica gel, chloroform) to give ethyl 4-[[1-(1H-imidazol-1-ylmethyl)-2-(pentoxy)ethoxy]methyl]benzoate as a yellow oil.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+]#N)=[CH:10][CH:9]=1.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:10][CH:9]=1
Reactant: C=Cc1ccccc1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: F[B-](F)(F)F
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2ccccc2)cc1
Reaction time: 22 h
Yield: 22.8 %

Procedure:
[BMIM][BF4] as Solvent: Palladium(II) acetate (0.5 mg, 0.002 mmol) was added to a solution of 1 (10.5 mg, 0.0330 mmol) and styrene (29.0 mg, 0.278 mmol) in 96.6 mg of [BMIM][BF4]. The mixture was stirred at room temp. for 22 h and was extracted with diethyl ether (0.5 mL×3). The solvent of the combined organic layer was evaporated to give a brown oil, which was purified by SiO2 column chromatography (9:1 hexane/CH2Cl2) to give 2a (2.3 mg, 23% yield) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.C(NCC)C>>[C:1]([C:5]1[N:6]=[C:7]([N:22]([CH2:27][CH3:26])[CH2:23][CH3:24])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: CCNCC
Product: CCN(CC)c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and diethylamine and isolated as colorless gum (11.5 mg, 65%). MS(m/e): 373.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH3:17])[CH:3]=1.CI.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:20][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of tert-butyl (4-hydroxy-2,5-dimethylphenyl)carbamate (1.25 g) and methyl iodide (1.12 g) in N,N-dimethylformamide (10.5 mL) was added potassium carbonate (1.46 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (1.32 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10][OH:11])[CH:7]=1.N1C=CC=CC=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10][O:11][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1cc(Br)ccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCc2cc(Br)ccc2F)cc1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a stirred solution of 3-(5-Bromo-2-fluoro-phenyl)-propan-1-ol (0.53 g, 2.3 mmol) in dry methylene chloride (10 mL) at 0° C. and under a nitrogen atmosphere was added pyridine (0.46 mL, 5.6 mmol) and tosyl chloride (0.47, 2.5 mmol). The cooling bath was removed and the mixture was warmed to room temperature for 12 h, and then quenched with 2 N HCl (6 mL). The mixture was partitioned between methylene chloride and H2O, and the aqueous layer was extracted with methylene chloride (2×10 mL). The organic layer was washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (10-20% Ethyl acetate/Petroleum Ether) to afford the titled compound (0.6 g, 69%) as a clear oil, identified by NMR and mass spectral analyses; MS (ES+): 403 (M+NH4+).