Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([F:41])([F:40])[C:25]1[CH:29]=[C:28]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[O:27][N:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:31]([NH:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:41])([F:23])[F:40])[CH:29]=2)=[O:32])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1cc(C(F)(F)F)no1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)no4)c3)c2cc1OC
Yield: 6 %

Procedure:
According to the procedure described in Example 113C, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (104 mg, 0.35 mmol) and phenyl 3-(trifluoromethyl)isoxazol-5-ylcarbamate described in Example 229A (124 mg, 0.45 mmol) were reacted to give 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea (9.23 mg, 6%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.90 (bs, 1H), 9.30 (bs, 1H), 8.59 (bs, 1H), 7.8-7.20 (m, 5H), 7.06 (bs, 1H), 6.50 (s, 1H), 4.09 (s, 6H); LC-MS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.[F-].[Cs+]>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>[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=2)=[CH:40][CH:39]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(F)cc3)ccc2c1
Temperature: 85 °C

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.91 mmol), 4-fluorophenyl boronic acid (3.8 g., 3.8 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (266 mg, 0.38 mmol) and cesium fluoride (2.6 g, 17.1 mmol) in 125 mL degassed acetonitrile and heat at 85° C. for 8 hours. Cool and filter and purify on an SCX column and elute with 2 N ammonia/methanol. Evaporate to an oil and purify on a silica gel column eluting with a gradient of 0-10% methanol/methylene chloride: mass spectrum (ion spray) m/z=470 (M+H).
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4](Cl)[N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>CN(C=O)C.C(OCC)C.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>[Cl:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccnc-2[nH]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1nc(-c2ccco2)c2ccnc-2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
A solution of 2,4-dichloro-1H-pyrrolo[2,3-d]pyrimidine (4.1 g, 21.8 mmol) in DMF (20 mL) was treated with PdCl2(PPh3)2 (772 mg, 0.17 mmol) and 2-(tributylstannyl)-furan (6.9 mL, 21.8 mmol), stirred at room temperature for 16 h, diluted with diethyl ether and filtered to give the title compound (2.94 g, 61%) as a pale orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=[C:8]2[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:26][CH3:27].CN(C=O)C>CCOC(C)=O>[CH2:26]([O:18][C:8]1[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[CH:11]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:9]=1)[CH3:27]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c2cccc(OC)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC)c2cccc(OC)c2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To a 25 mL round bottom flask were added ethyl 8-methoxy-4-hydroxynaphthalene-2-carboxylate (0.25 g, 1.02 mmol), Cs2CO3 (0.33 g, 1.02 mmol), iodoethane (0.79 g, 5.1 mmol) and DMF (4 mL). The resulting reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified on a silica gel column eluting with a gradient of 10-20% EtOAc/hexanes to give the title intermediate (0.19 g) as a light yellow solid.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1.[ClH:34]>C(#N)C.CC(C)=O>[ClH:25].[ClH:34].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[CH:29][CH:28]=1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: Cc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: Cc1ccc(CN2CCN(c3cccc(-c4ccccc4)c3)CC2)cc1
Reaction time: 16 h

Procedure:
To a solution of 3-[1-piperazinyl]biphenyl (11.9 g) in aceonitrile (200 cc), there is added potassium carbonate (6.9 g) and then, in the course of 20 minutes, a solution of α-chloro-p-xylene (8 g) in acetonitrile (50 cc), at a temperature in the region of 20° C., and stirring is continued for 16 hours. The insoluble material which has formed is separated by filtration. The solution obtained is concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (30 cc) and the solution poured onto silica (1 kg) contained in a column 8 cm in diameter. Elution is performed with a mixture (3 liters) of methylene chloride and methanol (97.5:2.5 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetone (600 cc). The solution is cooled to a temperature in the region of 5° C., 2.5N ethereal hydrogen chloride (40 cc) is added and stirring is maintained for approximately 1 hour. The precipitate formed is separated by filtration and washed with acetone (2×40 cc). 3-[4-(4-Methylbenzyl)-1-piperzinyl]biphenyl dihydrochloride (17.3 g), m.p. 241° C., is thereby obtained.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH2:28])[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:21][N:20]=1)[CH3:14].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:13]([O:15][C:16](=[O:39])[CH2:17][S:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH2:27][NH:28][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=2)[C:22]([C:29](=[O:38])[NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[CH:21][N:20]=1)[CH3:14]
Reactant: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCN)n1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ncc(C(=O)Nc2ccc(F)cc2)c(NCCNC(=O)c2ccc(N=[N+]=[N-])cc2)n1
Reaction time: 8 h
Yield: 15.6 %

Procedure:
4-Azidobenzoyl chloride (67 mg, 0.37 mmol) was added to a solution of [4-(2-aminoethylamino)-5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylsulfanyl]acetic acid ethyl ester (145 mg, 0.37 mmol) in DMF (2.0 mL). DIPEA (100 μL, 0.55 mmol, 1.5 eq) was then added to the reaction mixture and the acylation was allowed to proceed overnight at ambient temperature. The reaction mixture was concentrated by rotary evaporation and purified using flash chromatography (4 g silica gel, 10 mL/min flow rate) to yield the titled product (31 mg, 16%) as a clear glass. 1H NMR: (d6-DMSO) δ 10.23 (s, 1H), 8.67 (m, 1H), 8.55 (s, 1H), 7.81 (d, 2H), 7.62 (m, 2H), 7.13 (m, 3H), 4.07 (q, 2H), 3.97 (s, 2H), 3.60 (m, 2H), 3.42 (m, 2H), 1.14 (t, 3H); HPLC: Rt=4.36 min; MS (ESI): m/z 537.31 (M−H)−; IR (KBr): 2126 cm−1.
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=[O:4].Cl[C:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>>[C:15]1([C:14]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:11][C:8]3[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][CH3:1])=[CH:6][C:7]=3[O:12]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Product: CCC(=O)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 170 °C

Procedure:
A mixture of 3,4-dihydroxypropiophenone (ICN Biomedicals, Inc., 3300 Hyland Ave., Costa Mesa, Calif., 92626, USA, 5.0 g, 30 mmol) and dichlorodiphenylmethane (10.0 mL, 52.1 mmol) was heated for 7 min at 170° C. The reaction was cooled and poured into 1 N sodium hydroxide. The mixture was extracted with ether (2×) and the combined extracts were washed with water and brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (2×5 inches packed in hexane) with elution proceeding as follows: 2% ether/hexane (500 mL), 0.84 g of a white solid tentatively identified as 2-chloro-1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one; 5% ether/hexane (250 mL), 1.9 g of an unidentified orange oil; 5% ether/hexane (250 mL), 2.18 g of recovered dichlorodiphenylmethane; 10% ether/hexane (500 mL), 4.82 g (48%) of 1-(2,2-diphenyl-benzo(1,3)dioxol-5-yl)-propan-1-one as an orange oil which solidified on standing. The product had: mp 69-70.5° C. Analysis calculated for C22H17CIO3: C, 79.98; H, 5.49. Found: C, 80.05; H, 5.34.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH:29]2[CH2:31][CH2:30]2)[N:24]=1>>[CH:29]1([C:25]2[N:26]=[C:27]([NH:1][C:2]3[S:3][C:4]([C:10]4[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=4[F:16])=[CH:5][C:6]=3[C:7]([NH2:9])=[O:8])[CH:28]=[CH:23][N:24]=2)[CH2:31][CH2:30]1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Clc1ccnc(C2CC2)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(C4CC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared by using the procedure listed in Example 1 with 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (0.10 g, 0.32 mmol) and 4-chloro-2-cyclopropylpyrimidine (0.05 g, 0.32 mmol) as the starting materials.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][C:5]=2[O:4]1.[CH:19](OCC)=[O:20]>O1CCCC1>[CH:19]([CH:13]([CH2:12][C:7]1[CH:8]=[CH:9][C:10]2[O:11][CH2:3][O:4][C:5]=2[CH:6]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:20]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C=O)Cc1ccc2c(c1)OCO2
Reaction time: 0.25 h

Procedure:
First, 42.4 g of 60% NaH was suspended in 500 ml of tetrahydrofuran (THF). 84.5 g (purity: 93.7% by weight) of ethyl 3-(3,4-methylenedioxyphenyl)-propionate was dissolved in 100 ml of THF and added dropwise to the suspension solution prepared above at room temperature. After the resultant suspension solution was raised in temperature to 40° C. and stirred for 15 minutes, 131 g of ethyl formate was added dropwise for 2.5 hours to the suspension solution and stirred for a further 3 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1>>[F:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([F:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCC(N)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(F)cncc2F)s1
Product: CN1CCC(NC(=O)c2cc([N+](=O)[O-])c(Sc3c(F)cncc3F)s2)CC1

Procedure:
Prepared according to the procedure described for example 70 from 5-((3,5-difluoropyridin-4-yl)thio)-4-nitrothiophene-2-carboxylic acid (200 mg, 0.63 mmol) from above and 1-methylpiperidin-4-amine (86.0 mg, 0.76 mmol). The title compound was obtained as a solid (50.0 mg, 19% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (2H, s), 8.64 (1H, m), 8.48 (1H, s), 3.57 (1H, m), 2.72 (2H, m), 2.14 (3H, s), 1.91 (2H, m), 1.73 (2H, m), 1.52 (2H, m). MS m/z: 415.13 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.[O-2].[Mn+4].[O-2]>[CH:15]([N:14]1[C:12](=[O:13])[C:11]2[C:2](=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=2)[N:1]=[C:22]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:17])[CH3:16]
Reactant: COC(=O)c1ccc(C(=O)NC(C)C)c(N)c1
Reactant: O=Cc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(=O)n(C(C)C)c(-c3ccccc3)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-amino-4-[(isopropylamino)carbonyl]benzoate (15 mg, 0.07 mmol) in ethanol (1.5 mL) was added acetic acid (32 μL, 0.56 mmol) and benzaldehyde (19.4 μL, 0.19 mmol). The reaction mixture was heated to 110° C. and stirred overnight. The mixture was then concentrated to dryness and taken up in chloroform (1 mL). To this solution was added manganese (IV) oxide (28 mg, 0.32 mmol) and the reaction mixture was heated to 110° C. and stirred for 2 d. The reaction mixture was then filtered through Celite, rinsed with chloroform and concentrated to dryness to afford methyl 3-isopropyl-4-oxo-2-phenyl-3,4-dihydroquinazoline-7-carboxylate. LC-MS: (FA) ES+ 323.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][F:13])[CH2:10][F:11].CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14][CH2:24][O:25][CH3:26])([CH2:10][F:11])[CH2:12][F:13]
Reactant: Cc1ccc(C(O)(CF)CF)c(Br)c1
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(CF)(CF)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 11 h
Yield: 79.2 %

Procedure:
To a stirring solution of 2-(2-bromo-4-methylphenyl)-1,3-difluoropropan-2-ol (1.3 g, 4.9 mmol) in DCM (10 mL) at rt were successively added DIPEA (3.4 mL, 19.6 mol) and MOMCl (0.6 mL, 7.4 mmol) over a 10 min period. The solution was stirred 11 h at rt followed by addition of a saturated aqueous NH4Cl solution (20 mL). The aqueous phase was segregated, and the organic one was washed with water (20 mL), brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(1,3-difluoro-2-(methoxymethoxy)propan-2-yl)-4-methylbenzene (1.2 g, yield 80%) 1H NMR (400 MHz, CDCl3): δ 7.50 (s, 1 H), 7.38 (d, 1 H), 7.15 (d, 1 H), 5.15-5.12 (m, 1 H), 5.03-5.00 (m, 2 H), 4.91-4.88 (m, 1 H), 4.62 (s, 2 H), 3.43 (s, 3 H), 2.32 (s, 3 H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:3]=1.[ClH:34].[N:35]1([CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:34].[CH3:17][C:14]1([CH3:16])[C:13]2[CH2:12][CH2:11][N:10]([CH2:18][C:19]([NH:21][C:22]([NH2:24])=[O:23])=[O:20])[CH2:9][C:8]=2[C:7]2[C:2]([O:1][C:44](=[O:45])[CH2:43][CH2:42][CH2:41][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:3][C:4]([CH:25]([CH3:33])[CH:26]([CH3:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:5][C:6]=2[O:15]1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Temperature: 6 °C
Reaction time: 8 h

Procedure:
A mixture of 1.14 g. (0.0025 mole) of {[10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridin-2-yl]acetyl}urea, 0.52 g. (0.0025 mole) of 4-piperidinobutyric acid hydrochloride, 0.54 g. (0.0026 mole) of dicyclohexylcarbodiimide, and 170 ml. of dried methylene chloride was stirred at room temperature for 26 hours. The reaction mixture was cooled at approximately 6° C. overnight and was filtered to remove dicyclohexylurea. The filtrate was evaporated in vacuo and the residue was dissolved in 3 ml. of methylene chloride and 12.5 ml. of cyclohexane. After standing overnight in the cold room (approximately 6° C.), the solid was filtered and recrystallized from methylene chloride-ether, giving 1.1 g. of the product, m.p. 167°-170°.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[N:10]=[N:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>C(#N)C>[N+:19]([C:4]1[CH:3]=[CH:2][C:1]([N:7]2[C:11](=[O:12])[N:10]=[N:9][NH:8]2)=[CH:6][CH:5]=1)([O-:20])=[O:18]
Reactant: O=c1nn[nH]n1-c1ccccc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: O=c1nn[nH]n1-c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A solution of 1-phenyl-5-tetrazolone (30 g) in acetonitrile (300 mL) was stirred under argon at 0° C. and nitronium tetrafluoroborate (36.9 g) was added over 30 minutes. After stirring at 0° C. for an additional 30 minutes the mixture was poured into water (900 mL). The precipitate was collected by filtration and dried under vacuum to give 23.1 g of the title compound as cream-colored solids. The filtrate was extracted with ethyl acetate, dried (MgSO4), filtered, and concentrated to give an additional 8.6 g of solids which was a 1:1 mixture of ortho- and para-substituted isomers. 1H NMR (acetone-d6) δ 13.62 (br s, 1H), 8.36 (ABq, JAB=9.2 Hz, 4H); MS (EI) m/z 207 (M+); Rf=0.2 (10% methanol/dichloromethane).
Reaction SMILES: [CH2:1]=[O:2].C([Al](CCCCCCCC)[CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])CCCCCCC>CCCCCC>[CH2:1]([OH:2])/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C=O
Reactant: CCCCCCCCC=C[Al](CCCCCCCC)CCCCCCCC
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CO
Yield: 27.2 %

Procedure:
Similarly to the procedure described in Example 1, a 25% slurry of 144 grams (4.80 moles) of paraformaldehyde in n-hexane was treated with 1083 grams (4.59 moles) of di-n-octyl decenyl aluminum (prepared from tri-n-octyl aluminum and acetylene). Distillation of the hydrolysis product was performed under 2 mm Hg. The product fraction was removed at 85°-95° C. There was obtained 210 grams (1.25 moles) of cis-2-undecen-1-ol (27.2% of theoretical yield), having a purity of 91%. Identity of the compound was confirmed by ir and nmr spectral analyses.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=1.C([Li])CCC.[F:26][C:27]([F:33])([F:32])[C:28](OC)=[O:29].[Cl-].[NH4+]>C1COCC1>[CH2:18]([S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:8]([CH3:20])[C:5]2=[N:6][CH:7]=[C:2]([C:28](=[O:29])[C:27]([F:33])([F:32])[F:26])[CH:3]=[C:4]2[N:10]=1)[CH3:19]
Reactant: COC(=O)C(F)(F)F
Reactant: CCSc1ccccc1-c1nc2cc(Br)cnc2n1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCSc1ccccc1-c1nc2cc(C(=O)C(F)(F)F)cnc2n1C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-bromo-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (1 g) and THF (20 ml), n-butyllithium (1.5 M in hexane, 2.1 ml) was added dropwise at −78° C. The mixture was stirred at −78° C. for 30 minutes, and then methyl trifluoroacetate (577 μl) was added dropwise. The mixture was heated to room temperature, and then saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give 778 mg of crude 1-[2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-2,2,2-trifluoro-ethanone (hereinafter referred to as Present Compound 91).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.[NH:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1)=[N:7][N:6]=[CH:5]2
Reactant: OC1CCNC1
Reactant: Clc1nncc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OC1CCN(c2nncc3cc(Br)ccc23)C1
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
The mixture of 6-bromo-1-chlorophthalazine (Example 1, 0.12 g, 0.5 mmol), pyrrolidin-3-ol (0.08 mL, 1.0 mmol) and potassium carbonate (0.07 g, 0.5 mmol) in 5 mL acetonitrile was added to a glass microwave reaction vessel. The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 180° C. for 20 min. After about 20 min., all starting material was converted to product (M+1=294, 296). The mixture was concentrated under vacuum and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 6% 2M ammonia in MeOH/DCM to give 0.13 1-(6-bromophthalazin-1-yl)pyrrolidin-3-ol as yellow solid. Found MS (ES+): 294, 296(M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15]2)=[N:12][CH:13]=1.C(N(CC)CC)C>ClCCl>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:18][CH2:17][C@@H:16]([NH:19][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:15]2)=[N:12][CH:13]=1
Reactant: N[C@@H]1CCN(c2ccc(Br)cn2)C1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N[C@@H]1CCN(c2ccc(Br)cn2)C1
Yield: 80.7 %

Procedure:
Add methoxyacetyl chloride (208 μL, 2.27 mmol) to a 0° C. solution of (R)-1-(5-bromo-pyridin-2-yl)-pyrrolidin-3-ylamine (0.5 g, 2.07 mmol) and triethylamine (317 μL, 2.27 mmol) in dichloromethane (10 mL). Remove the ice bath and stir the reaction overnight. Wash the reaction mixture with 10% aqueous NaHSO4 (20 mL). Separate the organic portion and extract the aqueous portion with dichloromethane (2×10 mL). Dry the combined organics over Na2SO4, filter, and concentrate to dryness. Purify using chromatography (0 to 5% MeOH/CH2Cl2) to afford 525 mg (81%) of the title compound. LC-MS/ES m/z (79Br) 314.0 [M+H]+.