Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24](=[O:27])[CH2:25]Br)=[CH:22][CH:21]=1>CC(C)=O>[CH3:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([C:25]2[O:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([OH:11])[C:4]=3[C:2]=2[CH3:1])=[O:27])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(=O)c2oc3cccc(O)c3c2C)cc1
Yield: 65.8 %

Procedure:
A mixture of 2,6-dihydroxyacetophenone (5.35 gm; 35.0 mmoles), potassium carbonate (4.83 gm; 35.0 mmoles), and p-methoxyphenacylbromide (8.05 gm; 35.0 mmoles) in acetone (150 mL) was refluxed for a period of 22 hours. The reaction mixture was cooled, filtered through Celite, and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with 1N sodium hydroxide. The aqueous phase was then acidified with 20% citric acid. The solid was filtered, washed with water, and air-dried to yield 6.5 gm (65%) of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxybenzofuran, mp. 192°-195° C.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)(=[O:25])[CH3:24]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:29][CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])[C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OCCCBr
Reactant: CCCCCCCCOc1c(O)c2c(O)cccc2oc1=O
Product: CCCCCCCCOc1c(O)c2c(OCCCOC(C)=O)cccc2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-octyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-octyloxy-4-hydroxy-5-(3-acetoxypropoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: F[C:2]1(F)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([F:14])([F:13])[C:5]([F:16])([F:15])[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.Cl.C(O)(=[O:25])C>>[F:16][C:5]1([F:15])[C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[C:2](=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]1([F:14])[F:13]
Reactant: CC(=O)O
Reactant: FC1(F)c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Agent: Cl
Product: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A solution of 989 mg. (0.00328 mole) of 10,11-dihydro-5,5,10,10,11,11-hexafluoro-5H-dibenzo[a,d]cycloheptene in 13.2 ml. of glacial acetic acid - 3.5 ml. of 6 N hydrochloric acid is held at room temperature for approximately 20 hours, heated in a 65° C. bath for 3 hours, again held at room temperature for about 20 hours, and finally heated in a 65° C. bath for 3 hours. The solution is concentrated under reduced pressure and the residue partitioned between benzene and water. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Sublimation of the residue at 80° C. and 0.1 mm. yields the crude product as an oily solid. Purification is effected by column chromatography on silica gel, the product being eluted with carbon tetrachloride. The fractions that show one spot of Rf 0.1 on a silica thin layer plate developed with carbon tetrachloride are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, m.p. 76°-78° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>ClCCl>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23](=[O:24])[N:9]([CH:10]3[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[C:3]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)ccc2N)CC1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccc(Cl)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chlorophenyl)amino]-1-piperidinecarboxylate (D28) (5.8 g) was dissolved in 100 ml of dichloromethane at 0° C. and phosgene (20% in toluene, 10 ml) and triethylamine (5.6 ml) were added and the mixture was stirred at 0° C. for 1 h, then washed with aqueous citric acid, dried over MgSO4, filtered and evaporated The product was crystallised from diethyl ether to yield the title compound, 5.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:20][C:21]([O:23]CC)=O)[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:26]([N:28]([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:29][CH3:30])[CH3:27]>>[CH2:26]([N:28]([CH2:29][CH3:30])[CH2:31][CH2:32][CH2:33][NH:34][C:21](=[O:23])[CH2:20][N:12]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=[N:11]1)[CH3:27]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc(OC)cc2)c1-c1ccccc1

Procedure:
A solution of 7.5 g (0.022 mol) of ethyl 4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetate of example 4 in 35 mL of diethylaminopropylamine was stirred on a steam bath under nitrogen for 14 hours. The diethylaminopropylamine was removed in vacuo and the residue taken up in 200 mL of ethyl acetate. The ethyl acetate solution was washed twice with water, once with brine, and dried over sodium sulfate. The solvent was removed in vacuo and the residue was distilled in a Kugelrohr at 250° C./0.1 mm to yield 6.39 g of N-[3-(diethylamino)propyl]-4-(4-methoxyphenyl)-5-phenyl-1H-pyrazole-1-acetamide as a clear viscous amber oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)=O)C.[Cl-].[NH4+:13].[Cl-].[Na+].Cl>N.O1CCCC1>[C:4]([C:6]1[N:7]=[C:8]([SH:11])[S:9][CH:10]=1)(=[O:3])[NH2:13]
Reactant: [NH4+]
Reactant: CCOC(=O)c1csc(S)n1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Product: NC(=O)c1csc(S)n1
Reaction time: 8 h
Yield: 556.4 %

Procedure:
To a mixture of 4-ethoxycarbonyl-2-mercaptothiazole (150 mg) in ammonia solution (25%) (0.8 ml) was added ammonium chloride (4.2 mg) at room temperature. After stirring at the same temperature for 8 hours, the solution was poured into a mixture of tetrahydrofuran and saturated sodium chloride solution, and adjusted to pH 3.0 with 1N-hydrochloric acid. The separated tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: chloroform/methanol) to give 4-carbamoyl-2-mercaptothiazole (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([O-:11])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[Na+].[NH:19]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[NH2:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.[Cl-].[Na+].O.O>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:20][NH:19][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:11])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: NNC(=O)OCc1ccccc1
Reactant: COc1nc(C(=O)[O-])ccc1-n1cnc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a mixture of sodium 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (12.7 g), benzyl hydrazinecarboxylate (9.10 g) and HOBt (7.4 g) in DMF (250 mL) was added WSC (8.50 g) at 0° C., and the mixture was stirred at 0° C. for 1 hr. Saturated aqueous sodium hydrogen carbonate solution (200 mL), water (400 mL) and saturated brine solution (200 mL) were added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous' magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate and dried to give the title compound (14.6 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:13]1([NH:1][C:2]2[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cccc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2CCCC2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a stirred solution of methyl 3-amino-2-methylbenzoate (2 g, 12.1 mmol) and cyclopentanone (5 g, 60.6 mmol) in methanol (20 mL) was added acetic acid (0.72 g, 12.12 mmol) and the reaction stirred at room temperature for 3 h. Sodium cyanoborohydride (1.13 g, 18.2 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and the product was purified by column chromatography to afford methyl 3-(cyclopentylamino)-2-methylbenzoate (2.2 g, 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:30])[C:11](Br)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[S:47]1[CH:51]=[CH:50][N:49]=[C:48]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:1]([O:8][C:9]1[C:10](=[O:30])[C:11]([C:48]2[S:47][CH:51]=[CH:50][N:49]=2)=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:15](=[O:28])[C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C1c2c(OCc3ccccc3)c(=O)c(-c3nccs3)cn2CCN1Cc1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of 9-benzyloxy-7-bromo-2-(3,4-dichlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (150 mg) in dioxane (5 ml) were added tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (63 mg), tri-2-furylphosphine (57 mg) and (2-thiazolyl)tributyltin (0.285 ml) under an argon stream and a microwave at 80 W was irradiated under sealing for 1 hr. The obtained reaction mixture was concentrated, and then purified by silica gel column chromatography (chloroform:methanol=40:1) to give 9-benzyloxy-2-(3,4-dichlorobenzyl)-7-(thiazol-2-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (95 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:12]([C:14]1[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CCc1ccnc(C#N)c1
Reactant: O=C(O)c1ccc(Cl)cc1S
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1ccnc(-c2nc(=O)c3ccc(Cl)cc3s2)c1
Yield: 53.8 %

Procedure:
4-Chlorothiosalicylic acid (2.3 g, 12.2 mmol) and tert-butyl 3-(2-cyano-4-pyridyl)propanoate (1.4 g, 6.0 mmol) were dissolved in pyridine (20 ml), and the mixture was refluxed for 16 hrs. The solvent was evaporated and the residue was subjected to a silica gel column chromatography. The fraction eluted with hexane-ethyl acetate (2:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.3 g, 52%) as white crystals.
Reaction SMILES: [NH:1]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][C@@H:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]([NH:33][C@H:34]([C:43]([NH:45][C@@H:46]([C:54]([O:56]CC1C=CC=CC=1)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)=[O:32])=[O:27])[CH3:25])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CO.[Pd]>[NH:1]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][C@@H:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]([NH:33][C@H:34]([C:43]([NH:45][C@@H:46]([C:54]([OH:56])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)=[O:32])=[O:27])[CH3:25])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](C)C(=O)NCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](C)C(=O)NCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)O
Yield: 93.8 %

Procedure:
Boc-Leu-(D)Trp-(D)Ala-βAla-Tyr-(D)Phe-OBzl (0.2 g) was dissolved in methanol (50 ml) and then catalytically reduced in a hydrogen stream in the presence of palladium black catalyst. After the catalyst was filtered out and the solvent was distilled off, the residue was dissolved in a 50% aqueous solution of acetic acid (3 ml) and applied to a column (2×95 cm) of Sephadex G-25, packed with 50% aqueous acetic acid, and developed with the same solvent. The major fractions were collected and lyophilized to yield a white powder of Boc-Leu-(D)Trp-(D)Ala-βAla-Tyr-(D)Phe-OH (170 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][C:19]=4[F:27])=[C:11]3[C:10]([I:28])=[N:9]2)=[CH:5][CH:4]=1>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:27])=[C:11]3[C:10]([I:28])=[N:9]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Solvent: CCO
Product: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 65 °C

Procedure:
A stirred mixture of 1-(4-methoxybenzyl)-4-(2-fluoro-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine (10.4 g, 20.0 mmol), stannous chloride-dihydrate (22.6 g, 100.0 mmol), and absolute EtOH (200 mL) was heated to 65° C. for 1.5 hours under N2. After cooling to room temperature, the reaction was concentrated in vacuo, and then diluted with DCM (100 mL) and water (100 mL). Aqueous 2N NaOH was added until the pH of the aqueous phase was in the 11-12 range. The biphasic suspension was filtered through a pad of celite, rinsing with DCM (3×100 mL). The filtered biphase was separated, and the aqueous phase was re-extracted with DCM (3×75 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated. Yield: 7.90 g, 78%. The product was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=6 Hz, 1H), 7.35 (d, J=9 Hz, 2H), 7.03 (t, J=9 Hz, 1H), 6.83 (d, J=9 Hz, 2H), 6.53 (m, 2H), 6.24 (m, 1H), 5.61 (s, 2H), 3.81 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Clc1nccc2ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(-c2nccc3ccccc23)c1
Temperature: 25 °C

Procedure:
1-chloroisoquinoline (7 g, 42.8 mmol), (3-methoxyphenyl)boronic acid (8.78 g, 57.8 mmol), Tris(dibenzylideneacetone)palladium(0) (0.783 g, 0.856 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (1.403 g, 3.42 mmol) were charged into the reaction vessel with 250 mL of toluene. Lastly, potassium phosphate tribasic monohydrate (29.5 g, 128 mmol) was dissolved in 60 mL of water and was charged into the reaction mixture. The reaction was degassed with nitrogen gas then was heated to reflux for 18 h. The reaction mixture was cooled to room temperature and the toluene layer was separated and dried over magnesium sulfate. The organics were filtered and stripped under vacuum. The crude residue was purified by silica gel chromatography using 25-35% ethyl acetate/hexanes yielding 9.4 g (93%) of 1-(3-methoxyphenyl)isoquinoline as a viscous yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:27]=[CH:28][C:29]=2[CH3:30])=[N:8][C:7]=1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCc1ccc(C)c(O)c1
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCc1ccc(C)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Yield: 88.4 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (350 mg) in acetonitrile (30 ml) were added ethyl 3-(3-hydroxy-4-methylphenyl)propanoate (191 mg) and cesium carbonate (597 mg), and the mixture was heated under reflux for 15 hr. The reaction mixture was concentrated, and water was added to the residue. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow oil.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=2)=[CH:39][CH:38]=1>C(#N)CC.O>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSCC12
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc2N2CCSCC12
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.7 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (100 mg, 0.36 mmol) was suspended in propionitrile (1 mL) and (cyanomethyl)trimethylphosphonium iodide (123.0 mg, 0.51 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (180 ul, 1.03 mmol). To the stirred mixture was then added 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (104.5 mg, 0.45 mmol). The reaction was heated to 90° C. with stirring for 2 h. The reaction was then cooled to room temperature and diluted with water (3 mL) and filtered. The solids were collected and refluxed in ethanol (5 mL) for 1 h. The suspension was cooled back to room temperature and filtered. The solids were collected to afford the title compound (79.5 mg, 19%) as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.66 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.41-7.47 (m, 2H), 7.33-7.40 (m, 2H), 7.02 (d, J=2.0 Hz, 1H), 6.18 (br. s., 1H), 4.88 (dt, J=13.6, 2.7 Hz, 1H), 4.27 (dd, J=10.6, 3.0 Hz, 1H), 3.43 (d, J=3.5 Hz, 2H), 2.98-3.07 (m, 3H), 2.66-2.83 (m, 3H), 2.58-2.65 (m, 2H), 2.39-2.48 (m, 3H). [M+H] calc'd for C22H23ClN4OS, 427; found, 427.
Reaction SMILES: [CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][C:5]1[C:10]([CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:8]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)=[C:7]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)[CH:6]=1)[CH3:2].B(F)(F)F.CCOCC.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CO>[CH2:1]([CH:3]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:4][C:5]1[CH:6]=[C:7]2[C:24]3[CH:28]=[CH:27][S:26][C:25]=3[C:20]3[S:21][CH:22]=[CH:23][C:19]=3[C:8]2=[CH:9][C:10]=1[CH2:11][CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCCCC(CC)Cc1cc(-c2ccsc2)c(-c2ccsc2)cc1CC(CC)CCCC
Agent: FB(F)F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: CCOCC
Product: CCCCC(CC)Cc1cc2c(cc1CC(CC)CCCC)c1ccsc1c1sccc21
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A dry 500 mL 3-neck flask, flushed with dry nitrogen, was charged with 5 g (10.7 mmol) of 3,3′-(4,5-bis(2-ethylhexyl)-1,2-phenylene)dithiophene. The flask was evacuated and backfilled with nitrogen 3 times. Dry CH2Cl2 (214 mL, 0.05 M) was added to the flask via cannula. The solution was bubbled with nitrogen for 15 min. The solution was then cooled to 5° C. and BF3.Et2O (1.61 mL, 12.9 mmol) was added. DDQ (2.43 g, 10.7 mmol) was added in 0.5 g increments over 30 min. The reaction was monitored by TLC using C18 silica plates in methanol. After DDQ addition was completed, continued to monitor the reaction. At 15 min after DDQ addition, added another 0.1 g of DDQ followed by another 0.1 g addition at 18 min after first DDQ addition. At 30 min after initial DDQ addition, 0.3 mL of BF3.Et2O was added followed by another 1 mL of BF3.Et2O at 40 min. At 1 h after initial DDQ addition was complete, no starting material was noticed by TLC and the reaction was quenched by the adding 3 g of Zn powder followed by stirring of the reaction for 2 h. The mixture was diluted with 200 mL of methanol and stirred for another hour. The mixture was diluted with water and extracted with chloroform (3×500 mL). The organic fractions were dried over MgSO4 and then concentrated. The product was purified by column chromatography using hexane as the eluent to yield the product as pale yellow oil that crystallized upon standing (3.2 g, 64%). 1H NMR (300 MHz, CDCl3): δH 7.90 (d, 2H), 7.37 (d, 2H), 2.77 (m, 4H), 1.72 (m, 16H), 0.89 (m, 12H).
Reaction SMILES: O[C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[C-]#[N:14].[Na+].C(O)(=O)C.S(=O)(=O)(O)O>O.CCOCC.[OH-].[Na+]>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([NH2:14])([CH3:12])[CH2:3][C:4]([CH3:11])([CH3:10])[CH2:5]1
Reactant: CC1(C)CC(C)(C)CC(C)(O)C1
Reactant: [C-]#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1(C)CC(C)(C)CC(C)(N)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 66.2 %

Procedure:
To a vigorously stirred solution of 1-hydroxy-1,3,3,5,5-pentamethylcyclohexane (3.4 g; 20 mmol) and sodium cyanide (1.96 g; 40 mmol; 2 eq.) and 5 ml acetic acid, 95% sulfuric acid (5.3 ml; 100 mmol; 5.15 eq) are added during 1 hour keeping the temperature at 10° C. for 30 min, and then allowing the mixture to reach ambient temperature. After stirring at ambient temperature for 17 hours, the mixture is diluted with 20 ml ice water. Subsequently, the mixture is refluxed with stirring for 10 hours, cooled to ambient temperature, diluted with 40 ml water and 20 ml ether and neutralized with 20% aqueous sodium hydroxide until a pH of 10. The organic phase is separated and dried. Dry hydrogen chloride is passed through the solution until the ether becomes acidic. Solvent is removed and the residue is washed with ether to give 2.24 g Neramexane in the form of its hydrochloride.