Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8].[C:11]([OH:16])(=[O:15])[C:12]([CH3:14])=O>I.[PH2](O)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:12]([C:11]([OH:16])=[O:15])[CH3:14])=[C:5]([CH3:10])[C:6]=1[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)C(=O)O
Reactant: CC(=O)c1c(C)c[nH]c1C
Agent: I
Agent: O=[PH2]O
Product: CC(=O)c1c(C)[nH]c(C(C)C(=O)O)c1C
Reaction time: 0.17 h

Procedure:
A solution of 548 mg. of 2,4-dimethyl-3-acetyl-pyrrole in 10 ml of hydriodic acid and 2 ml of 50% hypophosphorous acid was treated with 0.4 ml of pyruvic acid and stirred for 10 min, when yellow crystals separated. After standing for 2 days at 0° C. the crystals were separated, dried and slurried with 5 ml of water. The resulting colourless product was separated, washed with water, dried and recrystallized from ether (thimble) as pale yellow plates (46%), m.p. 156°-158° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH:16]([CH3:17])[CH2:15][CH2:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:18]([CH:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:19])[CH:3]=1.[ClH:27].[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[ClH:27].[CH3:26][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:7]2[C:8]3[CH:16]([CH3:17])[CH2:15][CH2:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH3:19]
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CC1
Agent: Cl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2C(C)CC1

Procedure:
9-hydroxy-7-(3-methyl-2-octyl)-1,4,4-trimethyl-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran from Example 24 is reacted with γ-piperidinobutyric acid hydrochloride following the procedure of Example 2 to form 7-(3-methyl-2-octyl)-9[4-(piperidino)-butyryloxy]-1,4,4-trimethyl-1,2,3,4-tetrahydrocyclopenta[ c][1]benzopyran hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2].Br[C:27]1[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[C:13]=2[CH3:22])[C:6]=1[O:23][CH3:24])[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1OC
Reactant: Cn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1OC

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-methoxy-benzoic acid ethyl ester and 4-bromo-1-methylpyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N:25]([S:40]([CH3:39])(=[O:42])=[O:41])[S:40]([CH3:39])(=[O:42])=[O:41])=[CH:23][CH:24]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N)cc3)c2CC1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2c(-c3ccccc3)nn(Cc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3)c2CC1
Reaction time: 0.08 h

Procedure:
1-(4-Amino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 99, 0.05 mmol) was dissolved in 1 mL of DMF and treated with 1 equivalent of triethylamine. After 5 min, 1.5 equivalents of methanesulfonyl chloride were added and the mixture was stirred overnight. The reaction was quenched with water and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The resulting oil was purified by preparative TLC (50% EtOAc/hexanes) to provide 1-(4-dimethanesulfonylamino-benzyl)-3-phenyl-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The intermediate was then dissolved in 2 mL of 9:1 CH2Cl2/MeOH and treated with 3 mL of 1 N HCl in Et2O. After 6 h, the volatiles were removed in vacuo. The crude oil was purified by preparative TLC (9:1 CH2Cl2/2 M NH3 in MeOH) to afford 0.006 g of the title compound as an off-white solid. MS (ESI): exact mass calculated for C22H26N4O4S2, 474.14; found, m/z 475.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.50-7.47 (m, 2H), 7.44-7.40 (m, 2H), 7.37-7.35 (m, 1H), 7.22-7.20 (m, 2H), 7.13-7.11 (m, 2H), 5.34 (s, 2H), 2.97-2.94 (m, 4H), 2.92 (s, 6H), 2.89-2.87 (m, 2H), 2.82-2.80 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[C:1]1([CH:7]([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:19]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)NCCCNc2ccccn2)co1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(Cc1nc(C(=O)NCCCNc2ccccn2)co1)c1ccccc1
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a solution of ethyl (±)-3-phenyl-4-[4-[[[3-(pyridin-2-yl)amino-1-propyl]amino]carbonyl]-1,3-oxazol-2-yl]butanoate (131 mg, 0.30 mmole) in 1:1 THF/H2O (10 mL) was added 1N LiOH (0.36 mL, 0.36 mmole). After 18 hr, the mixture was concentrated under reduced pressure. The residue was dissolved in 20 mL H2O then acidified to pH 6 using 10% HCl. The resulting cloudy solution was extracted with CH2Cl2 (3×75 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was triturated with Et2O to give the title compound as a white solid (63 mg, 51%) which was collected by filtration. MS (ES) m/e 409 (M+H)+. Anal. Calcd for C22H24N4O4.0.75 H2O, 1.5 HCl: C, 55.44; H, 5.71; N, 11.75. Found: C, 55.49; H, 5.54; N, 11.63.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[C:3]([O:13][CH3:18])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Yield: 83.4 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (10 g, 38 mmol), dimethyl sulfate (4.3 mL, 46 mmol) and potassium carbonate (11 g, 76 mmol) in acetone (200 mL) was heated at reflux overnight. After evaporation to dryness, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to yield the desired product (8.8 g, 84%). LCMS calculated for C10H11BrClO2 (M+H)+: m/z=277.0. found: 277.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.[C:30]1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:31]=1.C([Sn](CCCC)(CCCC)C=C)CCC>CN1CCCC1=O.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.[Cu](I)I>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([CH:30]=[CH2:31])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Product: C=Cc1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 105 °C
Reaction time: 8 h
Yield: 153.4 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (1.0 g, 1.90 mmol) in N-methyl-2-pyrrolidinone (25 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol), triphenylarsine (60 mg, 0.2 mmol) and copper iodide (10 mg, 0.05 mmol) followed by tributyl(vinyl)tin (0.63 mL, 2.09 mmol). The reaction solution was heated to 105° C., stirred for 8 h, partitioned between dichloromethane and saturated aqueous sodium bicarbonate, and the layers separated. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with 10% 2 M ammonia/methanol solution in dichloromethane. The chromatography product was slurried in methanol and filtered to give 131 mg (16%) of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[C:5](/[CH:10]=[CH:11]/[C:12]([CH2:14][C:15](/[CH:17]=[CH:18]/[C:19]2[CH:27]=[C:24]([O:25][CH3:26])[C:22]([OH:23])=[CH:21][CH:20]=2)=[O:16])=[O:13])[CH:4]=1.[C:28](O)(=[O:50])/[CH:29]=[CH:30]\[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[C:28]([O:9][C:8]1[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][C:12](=[O:13])[CH2:14][C:15](=[O:16])[CH:17]=[CH:18][C:19]2[CH:20]=[CH:21][C:22]([OH:23])=[C:24]([O:25][CH3:26])[CH:27]=2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:50])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=[CH:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)O
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCC=CC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=CC(=O)CC(=O)C=Cc2ccc(O)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.5 %

Procedure:
To a solution of curcumin (300 mg, 0.81 mmol), cis-docosahexaenoic acid (275 mg, 0.83 mmol) and catalytic amount of 4-(dimethylamino)pyridine in DCM (10 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (252 mg, 1.2 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate mixture (90:10) as an eluent to give the product as oil (250 mg, 45%). IR (neat) νmax 3015, 2960, 2930, 1761, 1631, 1593, 1269, 1120, 1031, 972 cm−1; 1H NMR (CDCl3) δ 7.61 (1H, d, J=16.0 Hz, H-1), 7.60 (1H, d, J=15.6 Hz, H-7), 7.03-7.16 (5H, m, H-2′, 2″, 5′, 6′, 6″), 6.93 (1H, d, J=8.4 Hz, H-5″), 6.55 (1H, d, J=16 Hz, H-2), 6.49 (1H, d, J=16 Hz, H-6), 5.89 (1H, br s, Ar—OH), 5.83 (1H, s, H-4), 5.38-5.39 (12H, m, H-4′″, 5′″, 7′″, 8′″, 10′″, 11′″, 13′″, 14′″, 16′″, 17′″, 19′″, 20′″), 3.95 (3H, s, Ar—OCH3), 3.87 (3H, s, Ar—OCH3), 2.84-2.86 (10H, m, H-6′″, 9′″, 12′″, 15′″, 18′″), 2.58-2.66 (2H, m, H-2″), 2.22-2.23 (2H, m, H-21″), 2.05-2.09 (2H, m, H-3′″), 0.97 (3H, t, J=7.4 Hz, H-22′″); LCMS (ESI, negative ion mode): m/z 677 (M-H)−.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[C:5]=1[OH:11])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)[Cl:13].[OH-:17].[Na+]>O>[CH:1]([C:4]1[C:5]([O:11][CH2:15][CH:14]([OH:16])[CH2:12][Cl:13])=[C:6]([O:7][CH2:15][CH:14]([OH:17])[CH2:12][Cl:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(O)c1O
Reactant: ClCC1CO1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1cccc(OCC(O)CCl)c1OCC(O)CCl
Temperature: 40 °C
Reaction time: 504 h

Procedure:
22.9 g. of 3-isopropylcatechol, 56 g. of epichlorhydrin and 0.2 g. of sodium hydroxide, dissolved in a few drops of water, are stirred together for 21 days at 40° C under a nitrogen atmosphere. The excess of epichlorohydrin is distilled off under reduced pressure. The resulting oil is dissolved in chloroform, washed twice with water and purified by molecular distillation at 10-3 mm.Hg 32.55 g. of impure 1,1'-[(3-isopropyl-o-phenylene)dioxy]-bis-(3-chloropropan-2-ol) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21](I)=[CH:22][C:13]=12.[C:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)#[CH:25]>C1C=CC=CC=1.C(N(CC)CC)C.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.[Cu](I)I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:25]#[C:24][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][C:13]=12
Reactant: C#Cc1cccnc1
Reactant: COc1cc(Nc2c(C#N)cnc3sc(I)cc23)c(Cl)cc1Cl
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(Nc2c(C#N)cnc3sc(C#Cc4cccnc4)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 44.3 %

Procedure:
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[2,3-b]pyridine-5-carbonitrile (220 mg, 0.50 mmol), 3-ethynylpyridine (72 mg, 0.7 mmol), 20 mg of tetrakis(triphenylphosphine)palladium(0) and copper iodide (6 mg, 0.22 mmol) in 7 mL of benzene and 2 mL of triethylamine is heated at reflux for 5 hours. The reaction mixture is cooled to room temperature and a solid appears. The solid is triturated with hot ethyl acetate, filtered, washed with hexanes and dried under vacuum to provide 100 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(pyridin-3-ylethynyl)thieno[2,3-b]pyridine-5-carbonitrile as a tan solid, mp 191° C. (decomposition); 1H NMR (DMSO-d6+TFA) δ 3.88 (s, 3H), 7.37 (s, 1H), 7.43 (s, 1H), 7.78 (s, 1H), 7.85 (bs, 1H), 8.16 (s, 1H), 8.39 (bs, 1H), 8.54 (s, 1H), 10.02 (bs, 1H); MS 451.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: O=Cc1c(F)cccc1F
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2c(F)cccc2F)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2,6-difluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1(O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([O:1][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.7 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.00 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.70 mg, 23.6% yield) as a thick oil: 1H NMR δ 7.46 (s, 2H), 7.40–7.30 (m, 4H), 7.25 (m, 3H), 7.20 (m, 2H), 6.97 (apparent d, 1H, J=7.4 Hz), 6.89 (apparent tt, 1H, J=0.8, 7.6 Hz), 6.84 (apparent dt, 1H, J=0.8, 8.0 Hz), 5.20 (apparent dd, 1H, J=4.4, 8.5 Hz), 3.35 (m, 2H), 2.91 (m, 2H), 2.60 (m, 2H) 2.30–2.10 (m, 6H), 1.90 (m, 2H), 1.25 (d, 6H, J=7.9 Hz); ESMS m/e: 457.4 (M+H)+;
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].O>C1COCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:30][CH2:31][CH3:32]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CCCCCCCCCCCCc1ccsc1Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCc1ccsc1[Sn](CCCC)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To magnesium turnings (0.160 g, 6.6 mmol) in anhydrous THF (8.0 mL), heated to maintain a mild reflux, was added dropwise 2-bromo-3-dodecylthiophene (23; 2.00 g, 6.0 mmol). The reaction mixture was refluxed for 2 hours before being transferred to a solution of tributyltin chloride (1.80 mL, 6.41 mmol) in 10.0 mL of anhydrous THF at −78° C. The mixture was warmed to room temperature and stirred overnight before being poured into water. The aqueous layer was extracted with hexanes and the combined organic phase was washed with brine and dried over magnesium sulfate. After filtration, the solvent was removed in vacuo to yield 2-tributylstannyl-3-dodecylthiophene (24) as a yellow liquid (3.10 g, 95% yield). 1H NMR (CDCl3): δ 0.90-1.63 (m, 50H), 2.62 (t, 2H), 7.12 (d, 1H, J=4.5 Hz), 7.55 (d, 1H, J=4.5 Hz) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH:15]=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[OH:16][CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cnccc1C(=O)c1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccncc1C(O)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzoyl-pyridine-3-carbaldehyde (97 mg, ol) in THF (5 mL) at −78° C. was added 1.0 M phenylmagnesium bromide in THF (0.46 mL) and the reaction mixture stirred for 15 min. The reaction mixture was then quenched with aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by preparation TLC of silica gel with 10% methanol in dichloromethane to yield [3-(hydroxy-phenyl-methyl)-pyridin-4-yl]-phenyl-methanone as white crystals.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[C:5](N)[CH:6]=[CH:7][C:8]=1[F:9].C(O[N+]([O-])=O)(C)(C)C.[S:19](=[O:21])=[O:20]>C(Cl)Cl.CO.[Cu](Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([S:19]([Cl:1])(=[O:21])=[O:20])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=S=O
Reactant: Cl
Reactant: Nc1ccc(F)c(Br)c1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)O[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
Concentrated HCl (1.93 mL, 23.16 mmol) was added to a solution of 3-bromo-4-fluoro-phenylamine ((Example 265: part a) 2.2 g, 11.58 mmol) in 18 mL of 2:1 DCM/MeOH. A precipitate appeared and another 9 mL of 2:1 DCM/MeOH was added. The solution was cooled to −5° C. and tert-butylnitrate (2.71 mL, 23.16 mmol) was added dropwise over 8 min. After stirring for 15 min, sulfur dioxide (˜5 mL) was condensed into the reaction, followed by addition of copper (II) chloride (592 mg, 3.47 mmol) (gas evolution). The solvent was removed in vacuo and the residue was purified by SiO2 flash column chromatography to yield the title compound (1.9 g, 59%). 1H-NMR (CDCl3): δ 8.31 (dd, 1H, J=2.3, 5.8 Hz), 8.04 (ddd, 1H, J=2.6, 4.1, 8.8 Hz), 7.39 (dd, 1H, J=7.7, 8.8 Hz).
Reaction SMILES: [CH:1]([O:3][CH3:4])=[O:2].C[O-].[Na+].CO.[CH:10](=[O:13])[CH2:11][CH3:12].Br[CH2:15][CH2:16][CH3:17]>C1C=CC=CC=1>[CH3:12][CH:11]([CH:4]=[O:3])[CH:10]=[O:13].[CH3:12][C:11](=[CH:1][O:2][CH2:15][CH2:16][CH3:17])[CH:10]=[O:13]
Reactant: COC=O
Reactant: CCC=O
Reactant: CCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(C=O)C=O
Product: CCCOC=C(C)C=O
Temperature: 25 °C
Yield: 82 %

Procedure:
The sodium enolate of methylmalonaldehyde was prepared using methyl formate, sodium methoxide/methanol solution, and propionaldehyde exactly as described by the procedure of Example I. After addition of 5 mL of benzene to this mixture, excess methyl formate was removed by fractional distillation in accordance with Example II. Once the formate ester had been removed, 4.0 mL of N,N-dimethylformamide (spectrophotometric grade) was added to the mixture and distillative removal of methyl alcohol and most of the benzene was accomplished as outlined in the procedure of Example II. After allowing the mixture of the sodium enolate of methylmalonaldehyde in DMF to cool to room temperature, 1.00 mL (11.0 mmoles) of 1-bromopropane (purchased from Aldrich Chemical Co., Milwaukee, Wisc.) was added. This mixture was then stirred at 62° C. (oil bath temperature), while being maintained under a nitrogen atmosphere, for 18 hours. Isolation of the product as described in the procedure of Example II, followed by evaporative distillation, afforded 350 mg (82% yield) of 2-methyl-3-propoxypropenal: boiling point 60°-68° C. (bath temperature, 0.25 mm). The proton NMR spectrum of this vinylogous ester exhibited a singlet at δ9.15 (CHO), a quartet (J=1.5 Hz) at δ6.94 (vinyl H), a triplet (J=6.5 Hz) at δ4.1 (CH2O), a doublet (J=1.5 Hz) at δ1.72 (vinyl CH3), and a triplet (J=7 Hz) at δ1.02 (CH3CH2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[N:8]=[C:7]([O:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[C:5]2[C:18]([F:21])([F:20])[F:19]>CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([O:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[C:5]2[C:18]([F:21])([F:19])[F:20]
Reactant: COc1cc2nc(OC(C)C)cc(C(F)(F)F)c2cc1N
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(N)c(O)cc2n1

Procedure:
To a suspension of sodium hydride (60% mineral oil dispersion, 180 mg, 4.6 mmol, rinsed with hexanes) in 3.5 mL DMF was added thiophenol (550 mg, 5.0 mmol) at 0° C., whereupon a solution of 6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline (200 mg, 0.67 mmol) in 2 mL DMF was added. The mixture was heated at 110° C. for 6 h, then poured into ice, and the pH was adjusted to 5 by the addition of 2N NaHSO4. The mixture was extracted with EtOAc (2×30 mL), washed sequentially with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated. Flash chromatography (4:1 hexanes:EtOAc) afforded 147 mg (77%) of 6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline, a tan solid. Data for 6-amino-2-isopropyloxy-7-methoxy-4-(trifluoromethyl)quinoline: Rf 0.14 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.19 (broad s, 1H), 7.16 (s, 1H), 6.99 (s, 1H), 5.60 (v. broad s, 1H), 5.45 (hept, 1H, J=6.2), 4.00 (v. broad s, 2H), 1.38 (d, 6H, J=6.3).