Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=O)[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:57]([NH:59][CH2:60][CH3:61])[CH3:58]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C@H:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([C:22](=[O:24])[N:59]([CH2:60][CH3:61])[CH2:57][CH3:58])([CH3:25])[CH3:26])[CH:19]=2)[NH:14][C:13]=1[C:27]1[CH:28]=[C:29]([CH3:34])[CH:30]=[C:31]([CH3:33])[CH:32]=1)[CH3:11])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CNC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of (S)-2-[3-(2-tert-butoxycarbonylamino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid in dry methylene chloride at 0° C. is added 1-hydroxybenzotriazole followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the reagents allowed to mix for 1 hour. At this time diethylamine is added followed by 1.5 mL triehtylamine and the reaction stirred at room temperature. After completion, the mixture is concentrated in vacuo and purified by flash chromatography on silica gel to give the title compound.
Reaction SMILES: NC1C(C#N)=C(C2C=C(F)C=CC=2OC)C2C(=O)N(C)C(=O)N(C)C=2N=1.BrCCCC1C=CC=CC=1.[NH2:37][CH2:38][C:39]1[C:52]([NH:53][CH2:54][C:55]2C=C[C:62]3[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=3)[CH:56]=2)=[N:51][C:42]2[N:43]([CH3:50])[C:44](=[O:49])[N:45]([CH3:48])[C:46](=[O:47])[C:41]=2[C:40]=1[C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[CH:67][C:66]=1[O:72][CH3:73]>>[NH2:37][CH2:38][C:39]1[C:52]([NH:53][CH2:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=[N:51][C:42]2[N:43]([CH3:50])[C:44](=[O:49])[N:45]([CH3:48])[C:46](=[O:47])[C:41]=2[C:40]=1[C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[CH:67][C:66]=1[O:72][CH3:73]
Reactant: COc1ccc(F)cc1-c1c(CN)c(NCc2ccc3ccccc3c2)nc2c1c(=O)n(C)c(=O)n2C
Agent: BrCCCc1ccccc1
Agent: COc1ccc(F)cc1-c1c(C#N)c(N)nc2c1c(=O)n(C)c(=O)n2C
Product: COc1ccc(F)cc1-c1c(CN)c(NCCCc2ccccc2)nc2c1c(=O)n(C)c(=O)n2C

Procedure:
The synthesis of title compounds started from Compound 70a and (3-bromopropyl)benzene, according to procedures described in the synthesis of Compound 70. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.41-2.53 (m, 2H) 3.16 (m, 2H) 3.68 (s, 3H) 3.77-3.83 (m, 2H) 3.96 (s, 3H) 4.16 (s, 3H) 4.20 (d, J=14.4 Hz, 1H) 7.71 (d, J=5.6 Hz, 1H) 7.14-7.21 (m, 1H) 7.42-7.48 (dd J=8.8, 4.3 Hz 1H) 7.61-7.65 (m, 3H) 7.69-7.74 (m, 2H). MS [m+H] calc'd C26H29FN5O3 478; found 478.
Reaction SMILES: [F-].[NH4+].[CH3:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][O:10][C:11]([C@@H:13]2[C@@H:16]([CH2:17][CH:18]=[CH2:19])[C:15](=[O:20])[N:14]2[Si](C(C)(C)C)(C)C)=[O:12])=[CH:7][CH:6]=1.C(O)(=O)C>CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]([C@@H:13]2[C@@H:16]([CH2:17][CH:18]=[CH2:19])[C:15](=[O:20])[NH:14]2)=[O:12])=[CH:28][CH:29]=1
Reactant: C=CC[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)OCc1ccc(OC)cc1
Agent: [F-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6.2 mL of 0.5 M ammonium fluoride in methanol (3.1 mmol) was added to a mixture of compound 58 (1.0 g, 2.57 mmol), acetic acid (530 uL, 9.0 mmol) and methanol (25 mL). The mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was taken up in toluene (2˜3 mL) to assist removal of AcOH. After solvent was removed, the residue was taken up in DCM. The resulting white solids were filtered off. Concentration of the filtrate gave 0.70 g of the crude 59 with purity: 91.1%, 1HNMR (300 MHz, CDCl3): 2.60 (m, 2H), 3.38 (m, 1H), 3.87 (s, 3H), 3.98 (d, 1H), 5.22 (m, 4H), 5.83 (m, 1H), 6.15 (b, s, 1H), 6.90 (d, 2H), 7.35 (d, 2H). Anal. C15H17NO4, Mol. Wt.: 275.3. Found: ESI-MS: 275.8 (M+H)+.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[NH:19][CH3:20])=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[CH2:1]([S:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[N:19]([CH3:20])[C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCSc1ccccc1C(=O)Nc1cc(C(F)(F)F)ccc1NC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2n1C
Temperature: 150 °C
Yield: 89.9 %

Procedure:
A mixture of 2-ethylsulfanyl-N-(2-methylamino-5-trifluoromethylphenyl)-benzamide (1.64 g), p-toluenesulfonic acid monohydrate (1.76 g), and xylene (50 ml) was stirred under reflux at 150° C. for 1 hour. Into the reaction mixture cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.40 g of 2-(2-ethylsulfanylphenyl)-1-methyl-5-trifluoromethyl-1H-benzimidazole (hereinafter referred to as Present Compound 68).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:34])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29](O)=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:32])[C:17]=3[CH:33]=2)[C:3]1=[O:35].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].N1(C2CCCCCCCCCC2)CCCCCCCCCN1.Cl>O1CCCC1>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:34])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([NH:52][S:49]([CH3:48])(=[O:51])=[O:50])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:32])[C:17]=3[CH:33]=2)[C:3]1=[O:35]
Reactant: Cc1ccc(OCC(=O)O)cc1-c1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Reactant: CS(N)(=O)=O
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)NS(C)(=O)=O)cc1-c1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 25 °C
Yield: 92.7 %

Procedure:
A solution of {{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-6-fluoro-1,2-benzisoxazol-3-yl}-p-tolyl}oxy}acetic acid (1.54 g, 0.00312 mol) in tetrahydrofuran is added dropwise to a suspension of 1,1'-carbonyldiimidazole (1.06 g, 0.00655 mol) in tetrahydrofuran. The resultant mixture is stirred 1.5 hours and cooled to room temperature. A mixture of methanesulfonamide (0.594 g, 0.00624 mol), diazabicycloundecane (1.09 g, 0.00702 mol) and tetrahydrofuran is added dropwise. The resultant mixture is stirred overnight at room temperature and poured into 10% hydrochloric acid. The resultant white solid is filtered and dried to give the title compound (1.65 g, 91.6%, mp 123-125° C.) which is identified by NMR spectral analysis.
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2].[CH3:20]C(C)([O-])C.[K+].CI.C(OCC)(=O)C>CS(C)=O>[CH2:1]([C:3]1([CH3:20])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][CH:18]=[N:19][C:4]1=2)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCC1c2ncccc2C(=O)N(C)c2cccnc21
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCC1(C)c2ncccc2C(=O)N(C)c2cccnc21
Reaction time: 0.05 h

Procedure:
To a solution of 5,11-dihydro-11-ethyl-5-methyldipyrido[3,2-b:2',3'-e]azepine-6-one (0.10 g) in DMSO (1 mL) stirred under nitrogen was added potassium tert-butoxide (1M in tetrahydrofuran, 0.5 mL). After 3 minutes, methyl iodide (0.1 mL) was added, and the mixture was stirred for 10 minutes. Ethyl acetate was added, and the mixture was washed with water, dried, filtered, and evaporated. The residue was fractionated by preparative layer chromatography (developer chloroform/ethanol) to give 5,11-dihydro-11-ethyl-11-methyl-5-methyldipyrido[3,2-b:2',3 '-e]azepine-6-one (0.006 g).
Reaction SMILES: [BH4-:1].[Na+:2].[C:3]([OH:6])(=[O:5])[CH3:4]>C1C=CC=CC=1>[C:3]([O:6][BH-:1]([O:6][C:3](=[O:5])[CH3:4])[O:5][C:3](=[O:6])[CH3:4])(=[O:5])[CH3:4].[Na+:2]
Reactant: [BH4-]
Reactant: CC(=O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)O[BH-](OC(C)=O)OC(C)=O

Procedure:
A suspension of sodium borohydride (69.8 mg.) in benzene (15 ml.) is treated with acetic acid (92 mg.) and refluxed for 1 hour under nitrogen to afford a clear solution of sodium triacetoxyborohydride. To this solution is added a solution of 2S,3R,6R-6-(2-oxoethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane (158 mg.) in benzene (5 ml.) and the mixture refluxed for 5 hours under nitrogen. The solvent is removed in vacuo, the residue diluted with water and extracted with methylene chloride. Removal of the solvent from the dried organic phase affords a residue which is plate chromatographed on silica gel, using ethyl acetate:chloroform (4:1) as the developing solvent. The major band is eluted with ethyl acetate to afford 2S,3R-6-(2-hydroxyethyl)-2-methyl-2-(4,8-dimethyl-5-oxo-7-nonenyl)-3,6-oxidooxepane (121 mg.):
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](/[CH:19]=[CH:20]/[C:21](=[O:35])[N:22]([CH3:34])[CH2:23][C:24]3[O:25][C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]=3[CH3:29])[CH:17]=[N:18][C:12]=2[NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:34][N:22]([CH2:23][C:24]1[O:25][C:26]2[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=2[C:28]=1[CH3:29])[C:21](=[O:35])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[N:18][C:12]2[NH:11][CH2:10][CH2:9][NH:8][CH2:14][C:13]=2[CH:15]=1
Reactant: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C(=O)OC(C)(C)C)CCN3)oc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CNCCN3)oc2ccccc12
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A solution of (E)-7-{2-[methyl-(3-methylbenzofuran-2-ylmethyl)carbamoyl]vinyl}-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid tert-butyl ester (0.38 g, 0.80 mmol) in CH2Cl2 (4 mL) was cooled in an ice bath and then treated with TFA (4 mL). After stirring for 2 h, the mixture was concentrated under vacuum. The residue was treated with saturated NaHCO3 (25 mL) and extracted with CH2Cl2/MeOH (4×50 mL of a 98:2 mixture). The combined organic layers were dried over Na2SO4, filtered and concentrated to a light yellow solid. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 92:8) gave the title compound (0.21 g, 70%) as a white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 8.14 (br s, 1H), 7.68-7.63 (m, 1H), 7.50-7.40 (m, 3H), 7.26-7.20 (m, 2H), 7.04-6.72 (m, 1H), 5.10 (s, 1H), 4.83-4.72 (m, 2H), 3.89 (s, 2H), 3.30-3.26 (m, 2H), 3.22-3.04 (m, 5H), 2.31 (s, 3H), 1.70 (br s, 1H); MS (ESI) m/e 377 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1(O)[CH2:12][CH2:11][CH2:10]1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH:9]1[CH2:12][CH2:11][CH2:10]1
Reactant: OC1(c2cc(Br)ccc2Br)CCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(Br)c(C2CCC2)c1
Temperature: 25 °C

Procedure:
14.5 g (47.39 mmol) of 4 are dissolved in 50 ml of THF under nitrogen, and 35.72 ml (284.4 mmol) of boron trifluoride/diethyl ether complex are added dropwise at room temperature, and 12.54 g (189.6 mmol) of sodium cyanoborohydride are added dropwise in portions. The batch is heated under reflux overnight. The batch is allowed to cool to room temperature, sat. NaHCO3 solution is added, the mixture is extracted with methyl t-butyl ether, the organic phase is dried over sodium sulfate and filtered, the solvent is removed in vacuo, and the residue is filtered through silica gel with 1-chlorobutane, giving 5 as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]2[CH:20]([O:21]2)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Cl>CN(C=O)C.[K]>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:9]=[CH:8][C:7]([I:10])=[CH:6][C:3]=2[CH:4]=[O:5])[CH:20]([OH:21])[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1cc(I)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC2OC2C1
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(I)cc2C=O)C(O)C1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-hydroxy-5-iodo-benzaldehyde (Aldrich, 4.96 g, 20 mmol) in DMF (80 mL), potassium carbobate (10 g, 60 mmol) and 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (8 g, 40 mmol) were added and the mixture was stirred at 70° C. for three days and 80° C. for two days. The mixture was poured into 1N HCl and the mixture was extracted with EtOAc (3×50 mL). The extracts were combined and dried over sodium sulfate and concentrated to give an oil, which was chromatographied on an ISCO machine (10-30% EtOAc/Hexanes) to yield an oil, 3.4 g. MS (H+), 348.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]#[N:21].C(#N)C>O>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[O:1][CH2:19][C:20]#[N:21])=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C=O)c(OCC#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
The mixture of 2-hydroxy-4-methoxybenzaldehyde (9.50 g), potassium carbonate (17.3 g), bromoacetonitrile (11.2 g) and acetonitrile (100 ml) was stirred at room temperature for 12 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate), and then recrystallized from ethyl acetate-hexane to obtain the entitled compound (10.7 g).
Reaction SMILES: ClC1C=CC(N(CC)C([C@@H]2C3C(=CC=CC=3)N([C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[CH:24]=3)=[O:22])[C@@H](C)C2)=O)=CC=1.C1C=C2C=C(C(O)=O)SC2=CC=1.C(Cl)(=O)C([Cl:50])=O.CN(C)C=O>C(Cl)Cl>[S:27]1[C:23]([C:21]([Cl:50])=[O:22])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2cc3ccccc3s2)c2ccccc21)c1ccc(Cl)cc1
Agent: O=C(O)c1cc2ccccc2s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
(±)-trans-1-(Benzo[b]thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting benzo[b]thiophene-2-carbonyl chloride for 4-trifluoromethyl-benzoyl chlorided. Benzo[b]thiophene-2-carbonyl chloride was prepared by reaction of thianaphthene-2-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. The crude 1-(benzo[b]thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (1% methanol/methylene chloride) followed by purification via HPLC yielded (±)-trans-2-methyl-1-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (34%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.65-1.75 (m, 1H), 2.55-2.65 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 5.05-5.15 (m, 1H), 6.70 (d, 1H), 6.80-7.00 (m, 3H), 7.20-7.40 (m, 4H), 7.45 (s, 1H), 7.50 (d, 2H), 7.70 (d, 1H), 7.80 (d, 1H). MS m/z: 489/491 (M+1).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1OB(O)O>CCOC(C)=O>[Cl:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)Oc1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2ccc(Cl)cc2Cl)cn1

Procedure:
The product was prepared analogously to Example 48.1a from 1.74 g (10.0 mmol) of 5-bromopyrazin-2-ylamine and 1.91 g (10.0 mmol) of 2,4-dichlorophenylboric acid. Yield: 800 mg (33% of theoretical); C10H7Cl2N3 (M=240.088); calc.: molpeak (M+H)+240/242/244 (2 Cl); found: molpeak (M+H)+:240/242/244 (2 Cl); Rf value: 0.35 (silica gel, PE/EtOAc 7:3).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:18][CH:19]=1)C1C=CC=CC=1>CO.[Pd]>[CH2:20]([C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:19]=[CH:18][CH:17]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCC=Cc1cccc(CCCCCOCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CCCCCCc1cccc(CCCCCO)c1

Procedure:
A solution of 840 mgs of 3-(5-benzyloxypentyl)(1-hexenyl)benzene in 25 mls of methanol is hydrogenated over 5% palladium on carbon and then filtered through celite, concentrated, and chromatographed over silica gel (3:2 ether:hexane) to yield pure 5-(3-hexylphenyl)-pentanol.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH2:11][CH:12]=[CH2:13])[C:6](OCC)=[O:7])C.C[O-].[Na+].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23]>C(O)C>[CH2:11]([C:5]1[C:6](=[O:7])[NH:24][CH:22]=[N:23][C:4]=1[OH:3])[CH:12]=[CH2:13]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: C=CCc1c(O)nc[nH]c1=O
Reaction time: 0.17 h
Yield: 57 %

Procedure:
2-Allyl-malonic acid diethyl ester (Preparation 205, 100 g, 0.5 mol) was added dropwise to a mixture of sodium methoxide (27 g, 0.5 mol) in ethanol (1 L) at 0-5° C. and the mixture was stirred at this temperature for 10 min. Formamidine acetate (51.9 g, 0.5 mol) was added and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and aqueous hydrochloric acid (36.5%) and water were added to adjust the pH to approximately 3 at 0-20° C. The resulting mixture was filtered to afford the title compound as a colorless solid in 57% yield, 87.12 g.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]3[S:25][CH:24]=[N:23][C:22]=3[CH:26]=2)O1>>[S:25]1[C:21]2[CH:20]=[CH:19][C:18]([C:2]3[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=3)=[CH:26][C:22]=2[N:23]=[CH:24]1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: CNc1ccc(Br)cc1
Product: CNc1ccc(-c2ccc3scnc3c2)cc1

Procedure:
Compound 4-(benzo[d]thiazol-5-yl)-N-methylaniline (W189) was prepared using the general procedure for Suzuki coupling reaction between 4-bromo-N-methylaniline (56 mg, 0.3 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (78 mg, 0.3 mmol), as a white solid (20 mg, 28%). 1H NMR (400 MHz, acetone-d6) δ 9.22 (s, 1 H), 8.22 (d, J=1.6 Hz, 1 H), 8.08 (d, J=8.4 Hz, 1 H), 7.71 (dd, J=8.4, 1.6 Hz, 1 H), 7.56 (m, 2 H), 6.72 (m, 2 H), 5.14 (brs, 1 H), 2.83 (s, 0.5 H), 2.82 (s, 0.5 H); MS (ESI) m/z 241 (M+H+).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].C1(C)C=CC=CC=1.[CH3:14][C:15]1([CH3:21])[CH2:20][CH2:19][O:18][CH2:17][NH:16]1.C(N(CC)CC)C>O.C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([N:16]1[C:15]([CH3:21])([CH3:14])[CH2:20][CH2:19][O:18][CH2:17]1)=[O:4]
Reactant: CC1(C)CCOCN1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCOCN1C(=O)C(Cl)Cl
Temperature: -10 °C

Procedure:
At -10° C. and while stirring, 23.2 parts by weight of dichloroacetyl chloride in 100 parts by volume of toluene is dripped into 23.0 parts by weight of 4,4-dimethyltetrahydro-1,3-oxazine and 20.7 parts by weight of triethylamine in 100 parts by volume of toluene. After the mixture has been stirred for 2 hours at room temperature, there are added 150 parts by volume of methylene chloride and enough water for 2 clear phases to be formed. The organic phase is separated and washed twice, each time with 50 parts by volume of water. After drying and evaporation of the solvents under reduced pressure, there is isolated 41 parts by weight of N-dichloroacetyl-4,4-dimethyltetrahydro-1,3-oxazine of melting point 105°-106° C., which melts, after recrystallization from methanol, at 106°-107° C.
Reaction SMILES: [C:1]1(C2C=CC=CC=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:8]([O:14][CH3:15])[O:9][CH:10]([O:12][CH3:13])[CH:11]=2)=[CH:3][CH:2]=1.C1(C2C=COC=2)C=CC=CC=1>>[CH3:15][O:14][CH:8]1[C:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]([O:12][CH3:13])[O:9]1
Reactant: COC1C=C(c2ccc(-c3ccccc3)cc2)C(OC)O1
Agent: c1ccc(-c2ccoc2)cc1
Product: COC1C=C(c2ccccc2)C(OC)O1
Yield: 82 %

Procedure:
According to the procedure described in Example 1(a) for the preparation of 3-biphenyl-4-yl-2,5-dihydro-2,5-dimethoxyfuran, 3-phenylfuran (see Pridgen, L. N.; Jones, S. S. J. Org. Chem. 1982, 47, 1590-1592 and Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 32, 9583-9608; 848 mg, 5.89 mmol) provided 1.00 g (82%) of 2,5-dihydro-2,5-dimethoxy-3-phenylfuran as a yellow oil, which was an approximately 80:20 mixture of diastereomers by 1H NMR and used without further purification. 1H NMR (CDCl3): δ 7.64-7.52 (m, 2H), 7.44-7.30 (m, 3H), 6.36-6.30 (m, 0.9H, major+minor isomer), 6.28 (dd, 0.1 H, minor isomer, J=1.2, 3.7 Hz), 6.04-6.00 (m, 0.9H, major+minor isomer), 5.70 (d, 0.8H, major isomer, J=1.2 Hz), 3.52 (s, 2.2H, major isomer), 3.46 (s, 0.60H, minor isomer), 3.43 (s, 2.2H, major isomer), 3.40 (s, 0.60H, minor isomer); Anal. Calculated for C12H14O3•0.04 Br2: C, 67.78; H, 6.64. Found: C, 67.79; H, 6.45.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N[C@H](C(O)=O)CCC(=O)N.O(C/C=C(/CC/C=C(\C)/CC/C=C(/CCC=C(C)C)\C)\C)P(OP([O-])([O-])=O)(=O)[O-].[CH3:52][CH:53]([C:55]1[CH:60]=[C:59]2[CH2:61][CH2:62][C@H:63]3[C@@:68]([C:70](O)=[O:71])([CH3:69])[CH2:67][CH2:66][CH2:65][C@:64]3([CH3:73])[C@H:58]2[CH2:57][CH:56]=1)[CH3:54].[Cr](Cl)(Cl)(=O)=O.[NH+]1C=CC=CC=1>>[CH3:54][CH:53]([C:55]1[CH:60]=[C:59]2[CH2:61][CH2:62][C@H:63]3[C@@:68]([CH2:70][OH:71])([CH3:69])[CH2:67][CH2:66][CH2:65][C@:64]3([CH3:73])[C@H:58]2[CH2:57][CH:56]=1)[CH3:52]
Reactant: CC(C)C1=CC[C@H]2C(=C1)CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(=O)O
Agent: O=[Cr](=O)(Cl)Cl
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COP(=O)([O-])OP(=O)([O-])[O-]
Agent: NC(=O)CC[C@H](N)C(=O)O
Product: CC(C)C1=CC[C@H]2C(=C1)CC[C@H]1[C@](C)(CO)CCC[C@]21C

Procedure:
Ginkgo biloba “white nut” seeds were purchased from Dynasty Supermarket (Houston, Tex.). The seeds were stored at 4° C. for several days before sowing. Embryos were cultivated under aseptic conditions in an agar medium supplemented with D-glucose, L-glutamine, and Heller's salts at room temperature in the dark for four to six weeks (Schwarz, 1994). Synthesis of geranylgeranyl was performed as indicated in Ruan (1999) and Coates et al. (1978). Synthesis of geranylgeranyl diphosphate was performed as indicated by Corey et al. (1972), Davisson et al. (1985), and Davisson et al. (1986). Levopimarol was synthesized from levopimaric acid (Helix Biotech; New Westminster, British Columbia, Canada) according to procedures of Abad et al. (1985), Gigante et al. (1999), and Ayer and Talamas (1988). (6E,10E)-Geranyllinalool and pyridinium dichlorochromate were obtained from Fluka. All other reagents were obtained from either Sigma/Aldrich or Fisher Scientific, unless otherwise noted. Dichloromethane, dimethylformamide, methansulfonyl chloride, triethylamine, and toluene were freshly distilled over calcium hydride; tetrahydrofuran was freshly distilled over Na/benzophenone. Ammonium molybdate, ascorbic acid, tetrabutylammonium hydroxide, and citric acid were from ACROS. HP 20 polyaromatic dianion resin (250-850 μm) was purchased from Supelco.