Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.CO[CH:22](N(C)C)[N:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)=[CH:22][N:23]([CH3:25])[CH3:24]
Reactant: COC(N(C)C)N(C)C
Reactant: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(=CN(C)C)c1ccc(OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
According to a modified literature procedure (Wasserman, H. H.; Ives, J. L. J. Org. Chem. 1985, 50, 3573–3580) a solution of 1.0 g (3.9 mmol) of (4-benzyloxy-phenyl)-acetic acid methyl ester in 4 mL of toluene was flushed with argon. To this solution was added 0.842 mL g (5.5 mmol) of methoxy bis(dimethylamino)methane, and the resulting mixture was stirred at 65° C. under argon overnight. The reaction mixture was concentrated to give 1.21 g of desired 2-(4-benzyloxy-phenyl)-3-dimethylamino-acrylic acid methyl ester as indicated by 1H NMR (containing traces of starting material). The product was used without any further purification in the next step.
Reaction SMILES: CC1CCCO1.[C:7](=[N:10][OH:11])([NH2:9])[CH3:8].C[O-].[Na+].[C:15]12([C:28](OCC)=O)[CH2:20][CH:19]1[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2>O>[CH3:8][C:7]1[N:9]=[C:28]([C:15]23[CH2:20][CH:19]2[CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]3)[O:11][N:10]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)C12CC1CN(C(=O)OC(C)(C)C)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1noc(C23CC2CN(C(=O)OC(C)(C)C)C3)n1
Yield: 53.6 %

Procedure:
2-Methyltetrahydrofuran (15 mL), acetamide oxime (2.54 g, 34.3 mmol) and sodium methoxide (3.70 g, 68.6 mmol) were added to 3-tert-butyl 1-ethyl 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylate (103) (3.5 g, 13.72 mmol) and the mixture was heated to reflux for 20 minutes. Upon cooling the suspension was treated with 60 mL of water and extracted with ethyl acetate (2×50 mL). The combined organics were washed with saturated sodium chloride and dried over magnesium sulfate. The mixture was concentrated and the residue was chromatographed over 20 g of silica gel with hexanes/ethyl acetate; obtained 1.95 g of 104 as a white solid. MS (ESI) m/z 304.0 [M+K]+. 1H NMR (CDCl3) δ: 1.17 (m, 1H), 1.46 (s, 9H), 1.74 (m, 1H), 2.18 (s, 2H), 2.22 (m, 1H), 2.36 (s, 3H), 3.50 (m, 1H), 3.70 (m, 1H).
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:13]=[C:14]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1.N([O-])=[O:29].[Na+]>O>[OH:29][C:7]1[CH:27]=[CH:26][C:10]([O:11][C:12]2[CH:13]=[C:14]([C:22]([O:24][CH3:25])=[O:23])[CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:9][CH:8]=1
Reactant: COC(=O)c1cc(Oc2ccc(N)cc2)cc(C(=O)OC)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(O)cc2)cc(C(=O)OC)c1
Temperature: 50 °C
Yield: 52 %

Procedure:
Into a 1 liter four-necked flask equipped with a thermometer, a stirrer and a dropping funnel, 450 ml of ion-exchanged water, 75 ml of a concentrated sulfuric acid and 45.20 g (0.15 moles) of dimethyl 5-(4-aminophenoxy)isophthalate obtained in accordance with the same procedures as those conducted in Example 5 were placed and the resultant mixture was stirred. The flask was cooled at a temperature of 50° C. or lower. Into the cooled flask, a solution prepared by dissolving 12.42 g (0.18 moles) of sodium nitrite into 25 ml of distilled water was added dropwise over 20 minutes. The resultant mixture was stirred at a temperature of 5° C. or lower for 40 minutes and at 100° C. for 2 hours. The formed precipitates were separated by filtration and, after a treatment with active carbon in methanol, recrystallized from methanol. The formed solid substance was separated by filtration and dried at 50° C. for 1 day under a reduced pressure and 23.58 g of a product was obtained (the yield: 52%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.[I:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1>>[Cl:13][C:10]1[S:9][C:8]([C:6]2[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=[C:2]([N:22]3[CH:23]=[C:19]([I:18])[N:20]=[CH:21]3)[N:7]=2)=[CH:12][CH:11]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example A.1) (1.2 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure Ia. Obtained as an off-white solid (1.78 g, 97%). MS (ISP) 457.0 [(M+H)+]; mp 251° C.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:39])C(=O)C1>CN(C=O)C>[Br:39][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a solution of undec-10-en-1-ol (0.86 g, 5.0 mmol) in DMF (15 mL) was added triphenylphosphine (1.46 g, 5.6 mmol). The solution was cooled to 0° C. and NBS (0.96 g, 5.4 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.5 mL). The solution was diluted with ether (80 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 11-bromo-undec-1-ene (0.96 g, 82%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.79 (1H, m), 4.93 (2H, m), 3.38 (2H, t, J=6.9 Hz), 2.02 (2H, m), 1.83 (2H, m), 1.20–1.55 (12H, m); 13C NMR (75 MHz, CDCl3) δ 139.36, 114.33, 34.27, 33.99, 33.01, 29.57×2, 29.27, 29.09, 28.94, 28.35.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.Cl.[NH2:19]O.C([O-])=O.[Na+]>C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:19]
Reactant: O=Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Yield: 76 %

Procedure:
A mixture of 22 g of 5-formyl-3-phenylindazole, 8 g of hydroxylamine hydrochloride and 12.5 g of sodium formate was added to 150 ml of formic acid, and after refluxing for 2 hours, the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated to give 16.5 g of 5-cyano-3-phenylindazole (m.p. 150°-151° C.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[NH2:10])=[N:7][CH:8]=1.[CH3:14][CH:15]([CH3:19])[C:16](=O)[CH3:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:13][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:11])[N:10]=[C:16]([CH:15]([CH3:19])[CH3:14])[CH3:17])=[N:7][CH:8]=1
Reactant: CC(=O)C(C)C
Reactant: CN(N)c1ccc(C(F)(F)F)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=NN(C)c1ccc(C(F)(F)F)cn1)C(C)C

Procedure:
A solution of 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazine (5.9 g; 0.031 mol), 3-methyl-2-butanone (5.6 g; 0.065 mol) and p-toluenesulphonic acid (0.1 g) in xylene (30 ml) was heated under reflux, with water removal (azeotrope), for 7 h. The solution was concentrated to yield an oil which was purified by distillation (70° C./72 mbar) to yield 3-methyl-2-butanone 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazone as a yellow oil (5.8 g; 72%). ##STR15##
Reaction SMILES: FC1C=CC(O)=CC=1.FC1C=CC(S)=CC=1.[OH:17][CH:18]([CH2:38][S:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH2:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[S:23]([CH3:26])(=[O:25])=[O:24]>>[OH:17][CH:18]([CH2:38][S:39][C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH2:19][CH2:20][CH2:21][N:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[S:23]([CH3:26])(=[O:24])=[O:25]
Reactant: CCOC(=O)CCCCCCN(CCCC(O)CSc1ccc(F)cc1)S(C)(=O)=O
Agent: Fc1ccc(S)cc1
Agent: Oc1ccc(F)cc1
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC(O)CSc1ccc(F)cc1

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step D, the p-fluorophenol is replaced by an equimolar amount of 4-fluorothiophenol. The product of Step D is thus ethyl 7-{N-[4-hydroxy-5-(4-fluorophenylthio)pentyl]methanesulfonamido}-heptanoate.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:22])([F:21])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C@@H:15]2[CH3:20])=[CH:10][CH:9]=1)([OH:7])[CH3:6].C(N(CC)CC)C.[O:30]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31]1>C(Cl)Cl>[F:22][C:4]([F:3])([F:21])[C:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:35]([C:32]3[CH:33]=[CH:34][O:30][CH:31]=3)(=[O:37])=[O:36])[CH2:16][C@@H:15]2[CH3:20])=[CH:12][CH:13]=1)([OH:7])[CH3:6]
Reactant: C[C@H]1CNCCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)c1ccoc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(S(=O)(=O)c2ccoc2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-methyl-1-piperazinyl)phenyl)-2-propanol dihydrochloride (100 mg, 0.277 mmol) and triethylamine (0.115 mL, 0.830 mmol) in CH2Cl2 (4.0 mL) was added 3-furansulfonyl chloride (55.3 mg, 0.332 mmol, Ryan Scientific, Inc., Mt. Pleasant, S.C.). After 30 min at room temperature, the reaction was concentrated and purified via column chromatography (12 g of silica, 0 to 70% EtOAc in hexanes) to yield 1,1,1-trifluoro-2-(4-((2S)-4-(3-furanylsulfonyl)-2-methyl-1-piperazinyl)phenyl)-2-propanol (25 mg) as a mixture of two isomers.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](OS(C2C=CC=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Li]>C(O)C.CO.O>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(OCc1ccccc1)N1CCC(OS(=O)(=O)c2ccccc2)CC1
Agent: [Li]
Agent: [Na]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(O)C(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
Sodium metal (3.2 g) was dissolved in ethanol (50 ml) under a nitrogen atmosphere at room temperature. A solution of diethyl malonate (56.4 ml) in ethanol (50 ml) was added dropwise, followed by a solution of 4-benzenesulfonyloxy-piperidine-1-carboxylic acid benzyl ester (31.88 g) in ethanol (50 ml), also added dropwise. The mixture was heated to reflux for 16 h then the solvent was removed under reduced pressure. The residue was partitioned between water (100 ml) and diethyl ether (100 ml) and the aqueous washed with further diethyl ether (60 ml). The combined organics were washed with 10% citric acid solution (50 ml), water (50 ml) and brine (50 ml). After drying (Na2SO4) and filtering the solvent was removed under reduced pressure to leave a yellow liquid. Half of this crude diester was taken and dissolved in methanol (150 ml) and water (50 ml). Lithium hydroxidemonohydrate (18.14 g) was added slowly and the reaction left to stir at room temperature for 16 h then the methanol was removed under reduced pressure. The aqueous was washed with diethyl ether (3×40 ml), acidified to pH=3 with citric acid and extracted with ethyl acetate (2×40 ml). The combined organics were washed with water (2×40 ml) and brine (40 ml), dried (Na2SO4), filtered and evaporated under reduced pressure to give the title compound (8.29 g, 56%) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:19])[C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22][CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[Cl:18][C:11]1[CH:12]=[C:13]([Cl:17])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][N:22]=2)[CH:7]=1)=[O:19]
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1ccncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Nc2ccncn2)c1)c1c(Cl)cc(Cl)cc1Cl
Temperature: 140 °C
Yield: 58.9 %

Procedure:
A mixture of N-(2-bromopyridin-4-yl)-2,4,6-trichlorobenzamide (76 mg, 0.20 mmol), pyrimidin-4-amine (38 mg, 0.40 mmol), Pd2(dba)3 (18.3 mg, 0.020 mmol), Xantphos (23.3 mg, 0.040 mmol), Cs2CO3 (131 mg, 0.40 mmol), and dioxane (1.2 mL) was heated at 140° C. for 1 hour in a microwave reactor under nitrogen atmosphere. The mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford the desired product (46.5 mg, yield: 59%). 1H NMR (500 MHz, MeOH-d4): δ 8.68 (s, 1H), 8.36 (d, J=6.0 Hz, 1H), 8.26 (d, J=6.0 Hz, 1H), 8.19 (s, 1H), 7.71 (d, J=6.0 Hz, 1H), 7.65 (s, 2H), 7.35 (m, 1H). LCMS (ESI) m/z: 394.0 [M+H+].
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][CH2:9][CH2:10][O:11][CH3:12]>>[CH2:10]1[O:11][CH2:12][C@@H:10]([OH:11])[C@H:9]([OH:8])[C@H:9]1[OH:8]
Reactant: COCCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O[C@H]1[C@H](O)COC[C@@H]1O

Procedure:
A stirred solution of 10.83 g of per-0-acetyl xylitol bromide in 30 ml of dry 1,2-dimethoxyethane was added dropwise to a stirred suspension of 13.0 g of lithium aluminum hydride in 200 ml of dry 1,2-dimethoxyethane kept under nitrogen at room temperature. After this processing, 3.34 g of 1,5-anhydroxylitol was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:4][CH:3]=1.Cl.[CH3:25][NH:26][O:27][CH3:28].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1.C(OCC)(=O)C>[CH3:28][O:27][N:26]([CH3:25])[C:13]([C:11]1[N:10]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:12]=1)=[O:15]
Reactant: CNOC
Reactant: O=C(O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cn(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid I-7d (1.31 g, 3.57 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.42 g, 1.2 equiv) in THF (14 ml) were added TEA (4.97 ml, 10 equiv) and 1-propane phosphonic acid cyclic anhydride (3.21 ml, 1.5 equiv). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with water, 10% citric acid, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous magnesium sulfate and concentrated to a foam which was purified by flash column chromatography (silica, 70:30 ethyl acetate/hexane grading to ethyl acetate) to give 1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-1H-imidazole-4-carboxylic acid methoxy-methyl-amide I-7e (485 mg, 33%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][C:13]12[CH2:20][CH2:19][C:16]([CH2:21][C:22]#[N:23])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2>O>[CH3:12][C:13]12[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][NH2:23])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2
Reactant: CC12CCC(CC#N)(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC12CCC(CCN)(CC1)CC2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.043 Mole of lithium aluminum hydride is dissolved in 100 ml. of anhydrous tetrahydrofuran, under nitrogen, at 0° C and then 0.043 mole of 4-methylbicyclo[2.2.2]oct-1-yl acetonitrile in 100 ml. of anhydrous tetrahydrofuran is added dropwise. The solution is allowed to warm to room temperature, then stirred for five minutes and then 5 ml. of water is added dropwise. The solution is then filtered and the filter cake is washed with ethyl ether, the washings combined with the filtrate, and the solution is then dried over potassium hydroxide pellets, and filtered. The filtrate is then distilled affording 2-(4-methylbicyclo[2.2.2]oct-1-yl)ethylamine as a residue.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)[CH2:3]1
Reactant: CN1CCOC(CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCOC(CN2CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-(4-methylmorpholin-2-ylmethyl)piperazine-1-carboxylate (5.00 g, 17.0 mmol) prepared according to Process Step 2 was dissolved in dichloromethane (60 mL), and the solution was mixed with trifluoroacetic acid (20 mL) added dropwise under ice-cooling. After stirring at room temperature for one hour, the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in dioxane (100 mL), and the solution was mixed with triethylamine (20 mL) to thereby yield 4-methyl-2-piperazin-1-ylmethylmorpholine.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:28]=[C:27](Br)[CH:26]=[CH:25][C:12]=1[O:13][CH2:14][CH:15]([OH:24])[CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:10])[CH3:9].C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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(O)C>[C:8]([C:11]1[CH:28]=[C:27]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:26]=[CH:25][C:12]=1[O:13][CH2:14][CH:15]([OH:24])[CH2:16][CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cc(Br)ccc1OCC(O)CCc1cccnc1
Reactant: Cc1ccccc1
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: OB(O)c1ccccc1
Solvent: CCO
Product: CC(=O)c1cc(-c2ccccc2)ccc1OCC(O)CCc1cccnc1

Procedure:
Prepared according to the method described in Example 33a) from toluene (7.5 ml), (±)-1-(2-acetyl-4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.134 g), benzeneboronic acid (0.07 g), aqueous sodium carbonate (2 M, 1 ml), ethanol (2.5 ml) and tetrakis(triphenylphosphine)palladium(0) (0.02 g) with heating at reflux for 3 hours. After work up the residue was purified by column chromatography over silica eluting with ethanol:dichloromethane (5:95) to give the title compound as an oil (0.070 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[C:17]=2[CH:25]=1)=[O:12].[F:27][C:28]([Si](C)(C)C)([F:30])[F:29]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:26])[C:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[N:18]([CH2:23][CH3:24])[C:17]=2[CH:25]=1)([OH:12])[C:28]([F:30])([F:29])[F:27]
Reactant: CCN1C(=O)COc2ccc(C(=O)C(C)c3ccc(OC)cc3Cl)cc21
Reactant: C[Si](C)(C)C(F)(F)F
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(OC)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 56, step 3, 6-[2-(2-chloro-4-methoxy-phenyl)-propionyl]-4-ethyl-4H-benzo[1,4]oxazin-3-one (1.58 g) was reacted with (trifluoromethyl)-trimethylsilane. The product was purified by flash chromatography (silica gel, heptane/AcOEt 2:1) to give the title compound (1.58 g) as a white solid. MS (m/e)=444.3 [M+H+]
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=1[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH2:16]1.[CH:39]1([C:42](Cl)=O)[CH2:41][CH2:40]1>>[CH:39]1([CH2:42][N:6]([CH2:5][C:4]2[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[C:2]([F:1])[CH:3]=2)[C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[CH2:16]2)[CH2:41][CH2:40]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(Cl)C1CC1
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N(Cc1ccc(OCCN3CCCCC3)c(F)c1)CC1CC1)C2

Procedure:
Synthesized from [3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (450 mg) and cyclopropanecarbonyl chloride (0.47 ml) according to an analogous synthetic method to Example 152, the title compound (430 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[C:19]([OH:21])[CH:20]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:6]([N:8]1[CH2:11][C:10]([CH2:12][O:21][C:19]2[CH:20]=[C:15]([Br:14])[CH:16]=[CH:17][C:18]=2[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)([OH:13])[CH2:9]1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: Oc1cc(Br)ccc1OCc1cccc(Cl)c1
Reactant: CC1(O)CN(C(=O)OC(C)(C)C)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(O)(COc2cc(Br)ccc2OCc2cccc(Cl)c2)C1
Temperature: 150 °C
Yield: 89.4 %

Procedure:
The mixture of the title compound of Example 215 Step B (2.3 mmol), 5-bromo-2-(3-chloro-benzyloxy)-phenol (1.3 mmol), and cyanomethylenetri-n-butylphosphorane (2 mmol) in toluene (5 mL) was heated at 150° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified by PTLC providing the title compound (580 mg). MS (ESI): mass calcd. for C22H25BrClNO5, 497.1; m/z found, 504.2 [M-OH+Na]+. 1H NMR (CDCl3): 7.52-7.23 (m, 4H), 6.99-6.68 (m, 3H), 5.70-5.10 (br S, 1H), 5.04 (s, 2H), 4.99-4.97 (m, 2H), 4.50-4.46 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Br.Br[CH2:45][C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:47]>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]([C:48]3[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:47])[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(CC(=O)c3cccnc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-bromo-1-(pyridin-3-yl)ethanone hydrobromide and isolated as light-yellow solid. MS (m/e): 402.3 (MH+).