Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:3]([O:5]CC)=[O:4].CC(C)([O-])C.[K+]>O1CCCC1.C(O)(C)(C)C>[F:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9]/[C:8]/2=[CH:2]\[C:3]([OH:5])=[O:4])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(Br)C1CCCc2ccc(F)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=C(O)/C=C1\CCCc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.4 %

Procedure:
A mixture of ethyl 2-bromo-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthyl)acetate (2.2 g, 7.0 mmol), 1N potassium tert-butoxide in tetrahydrofuran (14 mL, Aldrich) and tert-butanol (140 mL) was stirred for 5 h at room temperature. The resulting suspension was concentrated in vacuo, diluted with water (200 mL) and washed with diethyl ether. The aqueous layer was acidified by adding 1N hydrochloric acid (14 mL) and extracted with diethyl ether. The ether extract was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and chromatographed on Silica Gel 60 using ethyl acetate-hexane (1:1) as eluent. The fractions containing only (E)-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid were combined and concentrated in vacuo to give a white solid (0.8 g, 55%); NMR (DMSO-d6): d 12.22 (br s, 1H, COOH), 7.57 (d of d, Jm =2.6 Hz, Jo =11.0 Hz, 1H, Ar), 7.12-7.28 (m, 2H, Ar), 6.36 (s, 1H, =CH, E), 3.04 (t, 2H, ArCH2), 2.74 (t, 2H, CH2), 1.74 (m, 2H, CH2); steady-state nOe: irradiation at 6.36, observed 25% nOe at 7.57.
Reaction SMILES: COC(=O)NC(C(N1CCC(C2NC(C3C=CC([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:29][CH:28]=4)=CC=3)=CN=2)C1)=O)C(C)C.C(O[C:60]([N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[C:67]1[NH:68][C:69]([C:72]2[CH:77]=[CH:76][C:75]([O:78]C3C=CC=C(C4NC(C5CCCN5C(OC(C)(C)C)=O)=NC=4)C=3)=[CH:74][CH:73]=2)=[CH:70][N:71]=1)=[O:61])(C)(C)C>>[CH3:52][O:51][C:49](=[O:50])[NH:48][CH:44]([C:60]([N:62]1[CH2:66][CH2:65][CH2:64][CH:63]1[C:67]1[NH:68][C:69]([C:72]2[CH:77]=[CH:76][C:75]([O:78][C:28]3[CH:27]=[CH:32][CH:31]=[C:30]([C:33]4[NH:34][C:35]([CH:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:46])[CH3:47])=[N:36][CH:37]=4)[CH:29]=3)=[CH:74][CH:73]=2)=[CH:70][N:71]=1)=[O:61])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Oc3cccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)c3)cc2)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)cc3)[nH]2)C1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Oc3cccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)c3)cc2)[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound (1-{3-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, except that 2-[5-(4-{3-[2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl]-phenoxy}-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester was used instead of 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 7.80-7.10 (m, 10H), 5.30-5.15 (m, 2H), 4.30-4.20 (m, 2H), 4.18-4.05 (m, 2H), 3.95-3.80 (m, 2H), 3.70-3.60 (m, 6H), 2.65-2.45 (m, 2H), 2.40-2.00 (m, 8H), 1.05-0.85 (m, 12H); m/z 755.3 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:19])[C:4]([C:6]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[O:20]=[C:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH2:31][CH:32]=O>>[CH3:2][N:3]([CH3:19])[C:4]([C:6]1([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:32][CH2:31][N:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:29][CH2:30][C:21]2=[O:20])[CH2:10][CH2:11]1)=[O:5]
Reactant: CN(C)C(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=CCN1C(=O)CCc2ccccc21
Agent: Cl
Product: CN(C)C(=O)C1(c2ccc(Cl)cc2)CCN(CCN2C(=O)CCc3ccccc32)CC1

Procedure:
Compound 115 was prepared by the same method as Compound 86 with the exception that Compound 2-3 was used instead of Compound 1-9 and that Compound 1-8 was used instead of Compound 1-4. Compound 115 was isolated as a white solid (53%, mp 243-245° C.). 1H (300 MHz, CDCl3,) δ 7.44-7.01 (m, 8H), 4.55 (m, 2H), 3.62 (m, 2H), 3.31-2.40 (m, 18H); MS (ES+) m/z 440.0 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[N:4]1)[CH3:2].[B-](F)(F)(F)[F:14].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[CH2:1]([N:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([F:14])[CH:5]=[N:4]1)[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1ccnn1CC
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(F)cnn1CC
Temperature: 100 °C

Procedure:
A microwave vial was charged with ethyl 1-ethyl-1H-pyrazole-5-carboxylate (0.2 g) and Selectfluor™ (0.548 g) followed by acetonitrile (3 ml) and acetic acid (0.5 ml). The mixture was heated at 100° C. under microwave irradiation for 120 min. Selectfluor™ (0.548 g) was added and the mixture was heated was heated at 100° C. under microwave irradiation for 60 min. The solvent was removed in vacuo and the residue was partitioned between DCM (15 ml) and water (15 ml) and separated by hydrophobic frit. The aqueous layer was washed with dichloromethane (2×5 ml) and the combined organic layers concentrated in vacuo. Purification by chromatography on silica gel (20 g silica cartridge) eluting with a gradient of 0-50% DCM in cyclohexane over 20 min gave the title compound (67 mg) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20](Cl)=[O:21]>ClC1C=CC=CC=1>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[C:19]=1[C:20]([NH:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[NH:7]1)=[O:21]
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: CN1CCC(C(=O)c2cccc(N)n2)CC1
Solvent: Clc1ccccc1
Product: CN1CCC(C(=O)C2CCCC(NC(=O)c3c(F)cc(F)cc3F)N2)CC1

Procedure:
reacting (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone with 2,4,6-trifluorobenzoylchloride in the presence of chlorobenzene to yield 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-piperidin-2-yl]benzamide or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt produced in step 5 is the hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:36])[CH:30]=1)([CH3:28])[CH3:27]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
Using the procedure described in Example 113C 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (107 mg, 0.3 mmol) was reacted with phenyl 5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg, 0.45 mmol). The mixture was stirred at 50° C. overnight. Upon cooling to room temperature, the product precipitated out of the solution. The solid was filtered off and washed with diethyl ether to give 1-(5-isopropylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)phenyl)urea (72.22 mg, 47%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.02 (s, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.53-7.28 (m, 5H), 6.51 (s, 1H), 4.34 (bs, 2H), 4.00 (s, 3H), 3.76 (bs, 2H), 3.34 (s, 3H), 3.04-3.00 (m, 1H), 1.23 (s, 6H); LC-MS (ESI) m/z 510 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[O:12][CH:13]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:25])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOCC>[Br:25][C:13]1[O:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CSc1ccc(-c2coc3ccccc23)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(-c2c(Br)oc3ccccc23)cc1
Yield: 90.3 %

Procedure:
A solution of the product of Step 2 (100 mg), NBS (90 mg) and benzoyl peroxide in CCl4 (5 mL) was heated to reflux under a spotlight for 30 min. The mixture was cooled, diluted with Et2O (3 ml) and filtered. The filtrate was concentrated and the residue was purified by flash chromatography, eluted with 15:1 hexane/EtOAc to give the title compound (120 mg).
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:29])([F:28])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[NH:23][O:24][C:25](=[O:27])[N:26]=2)[CH:17]=1.[CH3:30][C:31]([CH3:37])([CH2:35][CH3:36])[C:32](Cl)=[O:33]>N1C=CC=CC=1>[CH3:30][C:31]([CH3:37])([CH2:35][CH3:36])[C:32]([N:26]1[C:25](=[O:27])[O:24][N:23]=[C:22]1[C:18]1[CH:17]=[C:16]([O:15][CH2:14][C:13]([F:12])([F:28])[F:29])[CH:21]=[CH:20][N:19]=1)=[O:33]
Reactant: O=c1nc(-c2cc(OCC(F)(F)F)ccn2)[nH]o1
Reactant: CCC(C)(C)C(=O)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CCC(C)(C)C(=O)n1c(-c2cc(OCC(F)(F)F)ccn2)noc1=O
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To 2 ml of pyridine were added 0.25 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.3 g of 3-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one, and 0.22 g of 2,2-dimethylbutanoyl chloride was added at room temperature. After stirring for 2 hours, the mixture was further stirred at 60° C. for 2 hours. The resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.13 g of 4-(2,2-dimethylbutanoyl)-3-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-1,2,4-oxadiazol-5-one (present compound (25)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5](CC)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH:25]([CH3:27])[CH3:26]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:25]([CH3:27])[CH3:26])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: CC(C)I
Reactant: CCOC(=O)C(CC)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC(C)C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 88.6 %

Procedure:
A mixture of ethyl (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (11.22 g, 53.4 mmol) and K2CO3 (22.13 g, 160 mmol) in DMF (100 ml) was heated at 60° C. 2-Iodopropane (9.06 ml, 91 mmol) was added and the mixture was vigorously stirred at 60° C. for 5 h. The reaction mixture was cooled to RT, diluted with AcOEt and washed with water. The aqueous phase was separated and further extracted with AcOEt. The combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/AcOEt 98:2→3:1) to yield the title compound (11.94 g, 47.3 mmol, 89%) as a colorless oil.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[NH:9][CH2:8]1.[Cl:19][CH2:20][CH2:21][CH2:22]Br.O>O1CCCC1>[Cl:19][CH2:20][CH2:21][CH2:22][N:9]1[CH2:8][C:7]([CH3:18])([CH3:6])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: ClCCCBr
Reactant: CC1(C)CNC(=O)c2ccccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CN(CCCCl)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
2-(3-Chloropropyl)-4,4-dimethyl-1,2,3,4-tetrahydro-1-isoquinolinone may be obtained in the following manner: 25.7 cm3 of n-butyllithium (1.6 M in hexane) are added to a solution of 6 g of 4,4-dimethyl-1,2,3,4-tetrahydro-1-isoquinolinone in 120 cm3 of tetrahydrofuran, at -76° C. under a nitrogen stream. The reaction mixture is left for three hours at 0° C. 13 g of 1-chloro-3-bromopropane are then added and the mixture is stirred for 18 hours at a temperature of about 25° C. The reaction mixture is treated with 240 cm3 of water and extracted with three times 100 cm3 ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness at 40° C. under reduced pressure (20 mm of mercury; 2.7 KPa). The residue is purified by flash chromatography on a silica column under a nitrogen stream at moderate pressure (0.5-1.5 bar) with a dichloromethane-methanol mixture (99.5-0.5 by volume) as eluent. 3.9 g of 2-(3-chloropropyl)-4,4-dimethyl-1,2,3,4-tetrahydro 1isoquinolinone are obtained; melting point =131° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=O)[CH:10]=2)=[C:4]([CH2:29][CH3:30])[N:3]=1.Cl.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][CH2:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:10]=2)=[C:4]([CH2:29][CH3:30])[N:3]=1
Reactant: CCCCCCCCCCC(=O)Nc1cc(-c2c(N)nc(N)nc2CC)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCNc1cc(-c2c(N)nc(N)nc2CC)ccc1Cl
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Under a nitrogen atmosphere, a stirred solution of 40 mL of 1M boranetetrahydrofuran complex was cooled to below 10° C., and a solution of 2.4 grams (0.006 mole) of 2,4-diamino-6-ethyl-5-(4-chloro-3-decylcarbonylaminophenyl)pyrimidine in 60 mL of tetrahydrofuran was added dropwise during about a 5 minute period. The reaction mixture temperature was maintained below 10° C. throughout the addition. Upon completion of addition, the reaction mixture was heated at 60° C. for about 18 hours. After this time, the reaction mixture was allowed to cool to ambient temperature, where it was stirred for about 24 hours. The reaction mixture was then made acidic with aqueous 2N hydrochloric acid, after which time it was stirred for about 15 minutes. The mixture was made basic with aqueous 10% sodium hydroxide, and then it was extracted with two 150 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 10:1 methylene chloride and methanol. The product-containing fractions were combined and concentrated under reduced pressure, yielding when dried, 0.7 gram of 2,4-diamino-6-ethyl-5-(4-chloro-3-undecylaminophenyl)pyrimidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=Cc1ccc(Oc2cccnc2)cc1
Yield: 44.1 %

Procedure:
A mixture of 25 g of 3-bromopyridine, 20 g of 4-hydroxybenzaldehyde, 60 g of potassium carbonate and 150 ml of hexamethylphosphoramide was heated at a temperature of 130° to 135° C. for 11 hours. After cooling, the mixture was poured into water and extracted with diethyl ether. The ether extract was washed with water and extracted with 10% hydrochloric acid. The aqueous layer was washed with diethyl ether, rendered alkaline with sodium hydroxide and extracted with diethyl ether. The ether extract was washed with water and dried over sodium sulfate. The solvent was distilled off and the resulting oily substance was purified by silica gel chromatography (eluted with diethyl ether) to obtain 13.9 g (45% yield) of 4-(3-pyridyloxy)benzaldehyde as a colorless oil having a boiling point of 135°-140° C./2-3 mmHg.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(O)C>[C:1]([N:9]1[CH2:14][CH2:13][C:12]([S:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:11]([C:16]([O:18][CH3:19])=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CS
Reactant: COC(=O)C1CN(C(=O)c2ccccc2)CCC1=O
Solvent: CCO
Product: CCOC(=O)CSC1=C(C(=O)OC)CN(C(=O)c2ccccc2)CC1
Reaction time: 5 h

Procedure:
A solution of 1-benzoyl-3-methoxycarbonyl-4-piperidone (12 g; 0.046 mole) in absolute ethanol (150 cc), cooled to -10° C, is saturated with dry hydrochloric gas. Ethyl mercapto-acetate (10.8 g; 0.092 mole) is added thereto and a slight stream of hydrochloric gas is further passed therethrough at -10° C during 5 hours. After leaving the reaction mixture aside at room temperature during 70 hours, it is evaporated to dryness and the residue is dissolved in ether. The organic phase is washed with a 5% sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting 1-benzoyl-4-ethoxycarbonylmethylthio-3-methoxycarbonyl-1,2,5,6-tetrahydro-pyridine is obtained as an oil (Yield: 100%) and used directly in the next step:
Reaction SMILES: [Br:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].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.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]2[CH:19]=[CH:18][C:17]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:22][CH:21]=2)=[N:4][CH:3]=1
Reactant: CCCCCCCCc1ccc(B(O)O)cc1
Reactant: Brc1cccnc1Br
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: Cc1ccccc1
Product: CCCCCCCCc1ccc(-c2ccc(Br)cn2)cc1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a 1000 mL round bottom flask equipped with a stirbar was added dibromopyridine 7C (22.506 g), boronic acid 7B (22.356 g), tetrakis(triphenylphosphine)palladium(0) (3.294 g), saturated sodium carbonate solution (238 mL), and toluene (190 mL). A reflux condenser was attached and the reaction was heated at 100° C. for 24 hours. The cooled reaction mixture was extracted with 1:1 hexane:ethyl acetate, and the combined organic layers were washed with brine and dried over magnesium sulfate and the solvent was removed in vacuo. The solid product was dissolved in dichloromethane, placed on silica gel, and silica gel filtered. The elution solvents were hexane, which removed a higher Rf side product, and 2.5% E/H, resulting in 31.251 g of solid. The product was recrystallized from acetonitrile to give 30.125 g of a white solid.
Reaction SMILES: Cl.[F:2][C:3]([F:15])([F:14])[C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1.[O:16]=[C:17]1[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:29][C:30](O)=[O:31].C(N=C=NCCCN(C)C)C>ClCCl>[O:31]=[C:30]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([C:3]([F:2])([F:14])[F:15])=[CH:5][CH:6]=2)[CH2:11]1)[CH2:29][N:18]1[CH2:19][CH2:20][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]1=[O:16]
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1
Reaction time: 39 h

Procedure:
To a solution of 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.056 g, 0.236 mmol) and 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (Example 91D, 0.050 g, 0.214 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.049 mL, 0.279 mmol), and the reaction was stirred for approximately 39 hours. The reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexane over 20 minutes (flow=30 mL/minute). The product was dissolved in a minimal amount of ethyl acetate, and hexanes were added which caused the product to precipitate. Concentration gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.48 (m, 8H), 4.80 (s, 1H), 4.71 (s, 1H), 4.48-4.57 (m, 1H), 4.09-4.23 (m, 1H), 3.78-3.99 (m, 1H), 3.68-3.79 (m, 2H), 3.54-3.67 (m, 1H), 3.40-3.54 (m, 1H), 2.90-3.03 (m, 2H), 2.13-2.30 (m, 1H), 1.93-2.11 (m, 2H), 1.76-1.96 (m, 1H); MS (ESI+) m/z 417 (M+H)+.
Reaction SMILES: [H-].[Na+].[O-]CC.[Na+].[CH2:7]([O:9][C:10](=[O:21])[CH:11]([NH:17][C:18](=[O:20])[CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:8].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>C(O)C>[CH2:15]([O:14][C:12](=[O:13])[C:11]([NH:17][C:18](=[O:20])[CH3:19])([CH2:23][C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10]([O:9][CH2:7][CH3:8])=[O:21])[CH3:16]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: O=C(CBr)c1ccccc1
Agent: CC[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CC(=O)c1ccccc1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (15 mmol) is added to anhydrous ethanol (50 mL) and to the resulting sodium ethoxide solution is added 2-acetylaminomalonic acid diethyl ester (15 mmol) in one portion. The resulting mixture is stirred at room temperature for 30 minutes. A solution of 2-bromoacetophenone (10 mmol) in ethanol (10 mL) is then added and the resulting mixture is stirred at room temperature for 12 hours. After concentrating under reduced pressure, the residue is dissolved in EtOAc and water. The organic phase is washed with brine and dried over Na2SO4. After removal of the solvent, the crude material is purified by column chromatography using EtOAc/hexane (1/3) giving 2-acetylamino-2-(2-oxo-2-phenyl-ethyl)-malonic acid diethyl ester as white solid; MS: (ES+): 336.1 (M+1)+.