Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.COCCOC.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1>O>[Cl:18][C:19]1[CH:24]=[C:23]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[N:22]=[CH:21][N:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1cccc(F)c1F
Solvent: COCCOC
Solvent: O
Product: Fc1cccc(-c2cc(Cl)ncn2)c1F
Temperature: 80 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
A reaction vessel was charged with 2.03 g of tetrakistriphenylphosphine palladium, 5.55 g of 2,3-difluorophenylboronic acid, and 14.9 g of tripotassium phosphate n-hydrate, to which 120 ml of 1,2-dimethoxyethane, 30 ml of water, and 5.20 g of 4,6-dichloropyrimidine were added, followed by stirring at 80° C. under an atmosphere of a nitrogen gas for 12 hours. The reaction mixture was then left for cooling to room temperature, and water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 3.32 g of 4-chloro-6-(2,3-difluorophenyl)pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc(F)c(F)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution (20 mL) of 2-chloro-4,5-difluorobenzoic acid (1.0 g) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.15 g) and N-hydroxysuccinimide (717 mg) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 28% aqueous ammonia solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2-chloro-4,5-difluorobenzamide as a colorless solid (yield: 760 mg, yield: 76%). To a solution (5 mL) of 2-chloro-4,5-difluorobenzamide (300 mg) in N,N-dimethylformamide was added pyridine (0.253 mL), and oxalyl chloride (0.20 mL) was added dropwise thereto under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, water was added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a colorless solid (yield: 250 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:10]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O.[C:28](=O)([O-])[O-:29].[Na+].[Na+]>CN(C=O)C.O>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[S:7][C:8]([CH:28]=[O:29])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCN(CCCC)c1nc(-c2cccc(OC)c2)cs1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1nc(-c2cccc(OC)c2)c(C=O)s1
Reaction time: 8 h

Procedure:
To a solution of 100.8 g (316.5 mmol) of crude 2-di-n-butylamino-4-(3-methoxyphenyl)thiazole (compound 2-12) and 630 ml of DMF was added, over about 30 mins, a solution of 55.81 g (364 mmol) of phosphorus oxychloride in 188 ml of DMF. The mixture was stirred overnight and poured into a solution of 158.1 g of sodium carbonate in 3.5 l of water. The oily precipitate was extracted with methylene chloride, and the extract was washed with water, dried over magnesium sulfate, and concentrated. The yield of brown oil was 88.77 g and was used without further purification. Anal. Calcd. For C19H26N2O2S: C, 65.9; H, 7.6; N, 8.1; S, 9.3. Found: C, 66.20; H, 7.85; N, 8.60; S, 7.93.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[CH2:6][C:7]1[C:8]([CH3:25])=[N:9][N:10]([C:18]2[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[Cl:24][C:21]1[N:20]=[N:19][C:18]([N:10]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:7]([CH2:6][C:5]([OH:26])=[O:4])[C:8]([CH3:25])=[N:9]2)=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1c(C)nn(-c2ccc(Cl)nn2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(-c2ccc(Cl)nn2)c(-c2ccccc2)c1CC(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.058 g (1.444 mmol) of 2-molar aqueous sodium hydroxide solution was added to 0.099 g (0.289 mmol) of methyl[1-(6-chloropyridazin-3-yl)-3-methyl-5-phenyl-1H-pyrazol-4-yl]acetate in 5.00 ml of methanol, and the mixture was stirred at 20° C. for 1 h. The methanol was removed under reduced pressure and the residue was poured into a mixture of 10 ml of water and 15 ml of dichloromethane. The aqueous phase was extracted with 15 ml of dichloromethane, acidified with concentrated hydrochloric acid (pH=3) and extracted three times with in each case 15 ml of dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure gave 0.052 g (54.7% of theory) of a brown wax-like solid.
Reaction SMILES: Cl.N[C@@H](C)C([C:6]1[C:7]([CH:15]([CH3:17])[CH3:16])=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=O.Cl>>[CH:15]([C:7]1[CH:6]=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1nn2ccccc2c1C(=O)[C@H](C)N
Agent: Cl
Product: CC(C)c1cc2ccccn2n1

Procedure:
(S)-2-Amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one hydrochloride (also referred to herein as S-AV1013.HCl) was prepared on a preparative scale using two different routes to obtain the intermediate isopropylpyrazolo[1,5-a]pyridine (IPPP). In the first approach (method 1), ibudilast was employed as the starting material to obtain IPPP; an alternate synthetic approach (method 2) employed ibudilast acid as the starting material.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26][CH:27]([C:39]2[CH:44]=[CH:43][C:42]3[O:45][CH2:46][O:47][C:41]=3[CH:40]=2)[C:28](N2[C@@H](C(C)C)COC2=O)=[O:29])[N:23]=[C:22]1[CH2:48][CH2:49][CH2:50][CH3:51])=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26][CH:27]([C:39]2[CH:44]=[CH:43][C:42]3[O:45][CH2:46][O:47][C:41]=3[CH:40]=2)[C:28]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[N:23]=[C:22]1[CH2:48][CH2:49][CH2:50][CH3:51])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: OCc1ccccc1
Reactant: CCCCc1nc(CC(C(=O)N2C(=O)OC[C@@H]2C(C)C)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1nc(CC(C(=O)OCc2ccccc2)c2ccc3c(c2)OCO3)cn1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
To a solution of benzyl alcohol (1.29 g) in tetrahydrofuran (60 ml) was added dropwise n-butyl lithium (6.6 ml, 1.6M n-hexane solution) at 2-8° C. and the mixture was stirred for 20 minutes. A solution of (4S)-3-[3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-4-isopropyloxazolidin-2-one (4.86 g) was added dropwise to the mixture and the resulting solution was stirred at 2° C. for 2 hours. The reaction was quenched with saturated ammonium chloride aqueous solution, and then the solution was extracted with ethyl acetate. The organic layer was washed successively with saturated sodium bicarbonate aqueous solution and brine. Drying, filtering and removal of the solvents afforded a crude product. The crude product was purified by a silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1) to give benzyl 3-(1-tert-butoxycarbonyl-2-n-butylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionate (2R:2S=1:4) (3.67 g) as a slightly yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH:9]=2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3ccccc3F)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3F)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
7-(2-Fluoro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.23 mmol) and CuCN (41 mg, 0.46 mmol) were suspended in DMF (1.0 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 75 mg. 1H NMR (CDCl3, 200 MHz): δ=12.27 (s, 1H), 8.45 (d, 1H, J=9.0 Hz), 7.63-7.57 (m, 1H), 7.50-7.48 (m, 1H), 7.29-7.20 (m, 4H), 4.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:2].[OH-].[K+:12]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O-:10])=[CH:6][CH:5]=1)[CH3:2].[K+:12]
Reactant: CCOc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: CCOc1ccc([O-])cc1

Procedure:
In a 50-ml flask at ambient temperature 4-ethoxy-phenol (Aldrich) (1492 mg, 10.8 mmoles) was stirred with 2.0M aqueous KOH (5.50 ml) to form potassium 4-ethoxy-phenolate. Methyl 4-chloro-3,5-dinitrobenzoate (Ullmann, 1909, Annalen der Chemie 366:92-93; commercial source: Spectrum Chemical Company, Gardena, Calif.; 2606 mg, 10.0 mmoles) was added, the mixture heated to reflux for 1 hour and chilled in an ice-bath, whereupon a rubbery mass of product deposited. Cold aqueous 1.0M KOH (20 ml) was added, and upon continued chilling the product solidified. The yellow-orange solid was broken-up, collected on a suction filter, rinsed with water and dried. The material (3.08 g) was crystallized from hot 95% ethanol (50 ml) to give 2.56 g (70.6% yield) of methyl 3,5-dinitro-4-(4'-ethoxyphenoxy)benzoate. Melting point: 101°-103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[H-].[Na+].Br[CH:19]([CH3:21])[CH3:20].C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:20][CH:19]([CH3:21])[CH:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]#[N:15]
Reactant: COc1cc(CC#N)cc(OC)c1OC
Reactant: CC(C)Br
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C#N)C(C)C)cc(OC)c1OC
Yield: 54.2 %

Procedure:
With stirring under ice cooling, 20.25 g (97.7 mmols) of 3,4,5-trimethoxyphenylacetonitrile was added by small portions to 50 ml of a solution of 2.45 g (102.1 mmols) of sodium hydride in dimethylformamide. The solution was dropwise added to 100 ml of a solution of 12.45 g (101.2 mmols) of 2-bromopropane in dimethylformamide with stirring under ice cooling. The mixture was stirred under ice cooling for further 3 hours. After the reaction, an aqueous saturated sodium bicarbonate solution was added to the mixture followed by extraction of the solution with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate =4/1) to afford 13.2 g (yield: 54%) of 3-methyl-2-(3,4,5-trimethoxyphenyl)butyronitrile.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH:7]([CH3:10])[C:6]1=[O:11])=[O:4].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][CH2:8][C:7]([CH2:17][C:16]([Cl:19])=[CH2:15])([CH3:10])[C:6]1=[O:11])=[O:4]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XII), R1=CH3, R2=CH3) (4.0 g, 14.2 mmol) was dissolved in DMF (20 ml), sodium hydride (0.63 g (ca. 60% in mineral oil), 15.8 mmol) was added, and the solution was heated to about 60 degrees C., and then cooled with ice. 2,3-Cichloropropene (1.89 g, 17.0 mmol) was added, the ice bath was removed, stirring was conducted at room temperature for 5 hours, and then stirring was conducted at about 60 degrees C. for 1 hour. To the reaction solution, water (50 ml) was added, extraction with ethyl acetate (80 ml×2) was conducted, and then the organic layer was washed with saturated brine (50 ml), and then dried over anhydrous sodium sulfate, and concentrated. A silica gel column (eluent; hexane:ethyl acetate=10:1) was employed for purification to obtain the desired substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:11]2[C@H:16]([NH2:17])[CH2:15][CH:14]=[CH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:26](Cl)=[O:27])[CH2:20][CH2:19]1>ClCCl>[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=2[O:32][CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:26]([NH:17][C@H:16]2[C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12][CH:13]=[CH:14][CH2:15]2)=[O:27])[CH2:19][CH2:20]1
Reactant: O=C(Cl)c1ccc(OCC2CC2)c(OCC2CC2)c1
Reactant: COc1ccc([C@H]2CC=CC[C@H]2N)cc1OC
Solvent: ClCCl
Product: COc1ccc([C@H]2CC=CC[C@H]2NC(=O)c2ccc(OCC3CC3)c(OCC3CC3)c2)cc1OC
Yield: 93.5 %

Procedure:
20 g of (±)-cis-6-(3,4-dimethoxyphenyl)-cyclohex-3-enylamine (compound G1) are dissolved in 125 ml of dichloromethane and treated with a solution of 24.1 g of 3,4-bis-cyclopropylmethoxybenzoyl chloride in 125 ml of dichloromethane at room temperature. After 1 h the reaction mixture is extracted with 2 N hydrochloric acid and water, the organic phase is dried using sodium sulfate and concentrated. 38.3 g of the title compound of m.p. 152-153.5° C. are obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:24]O>>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:24])=[O:15])=[CH:17][CH:18]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Yield: 84 %

Procedure:
4-(morpholinosulfonyl)benzoic acid (150 mg, 0.553 mmol) was refluxed in the presence of con. Sulfuric acid (3.57 mg, 0.028 mmol) in methanol at 70° C. for overnight. Reaction was monitored by TLC. After completion of the reaction, solvent was removed by vacuum and then compound was purified by flash chromatography afforded the methyl 4-(morpholinosulfonyl)benzoate (135 mg, 0.464 mmol, 84% yield). 1H NMR (CDCl3, 400 MHz): δ 8.21 (m, 2H), 7.82 (m, 2H), 3.97 (s, 3H), 3.4 (m, 4H), 3.02 (m, 4H). Mass [M+H]+: 286.0
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29][CH3:30])[CH2:22][CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:35]([BH3-])#N.[Na+].Br>CC(O)C.CO>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]([CH3:35])[CH:16]2[C:19]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29][CH3:30])[CH2:20][CH2:21][CH2:22]2)=[CH:11][C:10]=1[O:31][CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)NCC2
Reactant: [BH3-]C#N
Agent: Br
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(C)O
Product: COc1cc2c(cc1OCc1ccccc1)C(C1(c3ccccc3SC)CCC1)N(C)CC2

Procedure:
A mixture of 7-benzyloxy-6-methoxy-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline. (1.89 g), 37% aqueous formaldehyde solution (3 ml), methanol (30 ml) and sodium cyanoborohydride (0.5 g) was stirred at ambient temperature for 24 hours. The mixture was poured onto water (100 ml) and extracted with dichloromethane (300 ml). The extract was washed with dilute aqueous ammonia solution to yield a residue which was dissolved in propan-2-ol and treated with 48% aqueous hydrobromic acid. The solvent was removed by evaporation to yield 7-benzyloxy-6-methoxy-2-methyl-1-[1-(2-methylthiophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinoline which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH2:19])[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2].C(O)(=O)C.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19][CH2:30][C:29]2[CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=[C:27]([C:26]([F:25])([F:39])[F:40])[CH:28]=2)[CH2:8][C@@H:7]1[CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](N)C[C@@H]1C)CCC3
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1c2cc3c(cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C)CCC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
To a solution of cis-4-amino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 3) (0.35 g, 1.28 mmol) in anhydrous 1,2-dichloroethane (50 mL) was added acetic acid (0.73 mL, 1.28 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (0.21 mL, 1.28 mmol) and sodium triacetoxyborohydride (0.406 g, 1.92 mmol). The reaction was stirred at room temperature for 18 h. The reaction mixture was then diluted with chloroform and washed with 1 N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 10% ethyl acetate/hexanes as eluent afforded the title compound (approximately 300 mg). 1H NMR (CDCl3) δ1.1 (d, 3H), 1.3 (t, 3H), 2.6 (m, 1H), 3.6 (dd, 1H), 4.5 (m, 1H), 7.30 (s, 1H), 7.35 (s, 1H), 7.8 (s, 1H), 8.0 (s, 2H).
Reaction SMILES: [Mg].BrBr.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][CH:13]([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=1.[CH:20](=[O:26])[C:21]1[O:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>CCOCC.O>[O:25]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:20]([OH:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[O:12][CH:13]([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=1
Reactant: O=Cc1ccco1
Reactant: CC1CC(C)(C)N=C(CCCCCCBr)O1
Agent: BrBr
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC1CC(C)(C)N=C(CCCCCCC(O)c2ccco2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.61g (25 mg. atom) of magnesium in 30 ml of ether is added 1.76g (11 mmol) of bromine dropwise during 20 min. at 15°-20° C. After 15 min. the mixture is treated dropwise with a solution of 2.90g (10 mmol) of 2-(6-bromohexyl)-4,4,6-trimethyl-5,6-dihydro-1,3-oxazine [J. Org. Chem., 38, 36(1973)] in 5 ml of ether. The resulting mixture is stirred at ambient temperature for 3 hr. and at reflux temperature for 30 min. The mixture is cooled to 0° and treated during 20 min. with a solution of 1.15g (12 mmol) of furfural. The stirred mixture is brought to reflux temperature during 20 min., maintained at that temperature for 20 min., cooled and treated with 2.5 ml of saturated ammonium chloride. The mixture is diluted with ether and water and filtered. The organic phase is separated, washed with brine, dried over potassium carbonate, and concentrated.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[OH:23][C:24]1[C:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCc1cccc(B(O)O)c1O
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: CCCCCCc1cccc(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1O
Yield: 68 %

Procedure:
6-(2-Hydroxy-3-hexylphenyl)-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-3-hexylphenylboronic acid in 68% yield using method F; δH [2H6]-DMSO 13.23,(1H, s), 8.35,(2H, t), 8.27,(2H, m), 8.17,(1H, d), 8.10,(1H, d), 7.97,(1H, d), 7.72,(1H, d), 7.26,(1H, d), 7.09,(1H, d), 6.93,(2H, m), 3.84,(3H, s), 2.68,(2H, t), 1.62,(2H, m), 1.42-1.25(6H, m), 0.88(3H, t); MS 455 (MH)+; HPLC retention time (system 1) 4.94 minutes.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15]Cl)=[O:11])=[CH:4][CH:3]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(C(C)=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][N:27]2[CH2:28][CH2:29][N:24]([CH:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:26]2)=[O:11])=[CH:4][CH:3]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: Cc1ccc(C=CC(=O)NCCCCl)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(C=CC(=O)NCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)cn1
Reaction time: 6 h
Yield: 36.1 %

Procedure:
A mixture of 1.0 g of N-[3-(6-methyl-3-pyridyl)acryloyl]-3-amino-1-chloropropane, 1.0 g of 1-diphenylmethylpiperazine, 0.55 g of potassium carbonate, 0.55 g of sodium iodide, and 30 ml of methyl ethyl ketone is refluxed with stirring for 6 hours. The reaction mixture is concentrated, and 20 ml of water is added. The mixture is extracted with three 30-ml portions of chloroform. The combined extracts are dried over magnesium sulfate, and the chloroform is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give 0.65 g of the title compound. The product is converted into the fumarate in a usual manner to give the trifumarate 3/4 hydrate of the title compound. m.p. 196°-200° C. (recrystallized from ethanol)
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH2:13]1[C:18](=O)[N:17](Br)[C:15](=[O:16])[CH2:14]1.COC(=O)C1C=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1C.N>C(Cl)(Cl)(Cl)Cl>[N+:30]([C:27]1[CH:28]=[C:13]2[C:14](=[CH:25][CH:26]=1)[C:15](=[O:16])[NH:17][CH2:18]2)([O-:32])=[O:31]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1NCc2cc([N+](=O)[O-])ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
AIBN (58.6 mg, 0.357 mmol), NBS (785 mg, 4.46 mmol), and 2-methyl-4-nitrobenzoic acid methyl ester (696 mg, 3.57 mmol) were suspended in CCl4 (35 mL) in a sealed tube. The above mixture was flushed with N2 for 5 min and heated at 80° C. for 22 h. After cooling, the solid was filtered off and the filtrate was concentrated to dryness to obtain a crude light-brown solid. To above solid was added NH3 (7 N in MeOH, 5 mL), and the mixture was stirred at rt for 2 h and concentrated in vacuo to obtain a yellow solid. This crude solid was triturated with EtOAc (15 mL) and was then cooled at −20° C. The mixture was filtered to obtain the title compound as yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ=4.51 (s, 2H), 7.13 (brs, 2H), 7.91 (d, 1H, J=8.4 Hz), 8.25 (dd, 1H, J=2.0 & 8.4 Hz), 8.48 (d, 1H, J=2.0 Hz), 9.04 (brs, 1H). MS (ES+): m/z 179.22 (100) [MH+]. HPLC: tR32 2.14 min (ZQ2000, polar—5 min).