Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])[CH2:11][CH2:12][CH3:13].C(OCCOCCO)CCC>>[CH2:1]([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCOCCOCCOCCO
Reactant: CCCCCCCCBr
Solvent: CCCCOCCOCCO
Product: CCCCCCCCOCCOCCOCCOCCCC

Procedure:
The procedure followed that of Reference Example 4, except for use of n-octyl bromide and triethylene glycol n-butyl ether instead of butyl bromide and diethylene glycol butyl ether, respectively. Triethylene glycol n-butyl n-octyl ether (abbreviated as “TEG-BO” hereafter) was obtained by distillation (b.p.: 140-145° C. at 70 Pa). TEG-BO has a corresponding boiling point of about 350° C. under normal pressure. The solubility of glycolide in this compound at 25° C. was 2.0%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>O>[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][C@H:16]2[O:18][CH2:17]2)=[CH:7][CH:6]=1)(=[O:10])[NH2:11]
Reactant: NC(=O)Cc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)Cc1ccc(OC[C@@H]2CO2)cc1
Temperature: 5 °C
Yield: 96.7 %

Procedure:
p-Hydroxyphenyl acetamide (30.02 g) was dissolved in 106.5 g of water containing sodium hydroxide (9.6 g) and the solution was cooled to 5° C. Epichlorohydrin (18.5 g, 98.9% e.e.) was dropped in the solution over a period of 10 minutes under stirring at the same temperature and the solution was stirred for 24 hours. Sodium hydroxide (2.4 g) was added thereto and the mixture was stirred for 5 hours. Resulting crystals were filtrated by suction, washed with water and dried in vacuo to give crude (S)-1-[p-(carbamoylmethyl)phenoxy]-2,3-epoxypropane (39.8 g). The optical purity of it was 91.2% e.e. by measurement of Chiral column OD (Daisel Chemical Industries Ltd.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(=O)[N:10]([CH2:14][C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[CH:17][CH:16]=3)[CH:9]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[CH:9]([NH:10][CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC(c2ccc(F)cc2)C(Cc2ccc(C(F)(F)F)cc2)N1Cc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OC(c1ccc(F)cc1)C(Cc1ccc(C(F)(F)F)cc1)NCc1cccc2ccccc12
Yield: 31.1 %

Procedure:
To a solution of (4RS,5SR)-5-(4-fluorophenyl)-3-(1-naphthalenylmethyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (100 mg, 0.21 mmol) in ethanol (2 ml) was added 8N aqueous sodium hydroxide solution (130 ml) and the mixture was heated under reflux for 4 hrs. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from diisopropyl ether-hexane gave (1RS,2SR)-1-(4-fluorophenyl)-2-((1-naphthalenylmethyl)amino)-3-(4-(trifluoromethyl)phenyl)-1-propanol (29.6 mg, 31%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH:15](=[O:17])[CH3:16].Cl>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:15]([CH3:16])[OH:17]
Reactant: COc1cccc(F)c1
Reactant: CC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(C)O
Reaction time: 1 h

Procedure:
n-Butyl lithium (3.9 mls of 1.14M in hexane) was added dropwise to a solution of 3-fluoroanisole (0.45 mls) in dry tetrahydrofuran (10 mls) at -75° under nitrogen. The solution was kept at -75° for 1 hour, and then acetaldehyde (0.68 mls) was added dropwise and the mixture allowed to warm up. 2M Hydrochloric acid (20 mls) was added, the mixture was extracted with ether, the organic solution was dried (MgSO4) and the solvent was evaporated. The product was distilled to give the title compound as an oil (0.4 g). NMR (CDCl3) δ 7.17 (1H, d of t, 4-H), 6.75-6.6(2H, m, 3-H, 5-H), 5.24(1H, m, CHO--), 3.89(3H, s, OCH3), 3.27 (1H, d OH), 1.56(3H, d, CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[C@@H:28]([CH3:39])[CH2:27]3)=[O:25])=[C:16]2[N:15]=1.[ClH:40]>>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24]([N:26]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH3:39])[CH2:27]3)=[O:25])=[C:16]2[N:15]=1.[ClH:40]
Reactant: C[C@H]1CN(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Product: C[C@H]1CN(C(=O)Nc2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (S)-tert-butyl 4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)-2-methylpiperazine-1-carboxylate (Example 30; 47 mg, 0.087 mmol), was added 1 mL 4 N HCl (dioxane) solution and stirred at ambient temperature for 1 hour. The reaction was concentrated, treated with ether, and filtered, giving the final product HCl salt as a fine yellowish powder. MS (apci) m/z=442.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([F:14])[CH:12]=2)[CH2:7][C:6]=1[CH3:16].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.O>N1C=CC=CC=1>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[F:15])[C:7](=[CH:23][C:22]1[CH:21]=[C:20]([O:19][CH3:18])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=1)[C:6]([CH3:16])=[C:5]2[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(=O)CC1=C(C)Cc2cc(F)c(F)cc21
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C=C2C(C)=C(CC(=O)O)c3cc(F)c(F)cc32)cc(OC)c1OC
Reaction time: 8 h

Procedure:
1.19 g (5.0 mmol) of 5,6-difluoro-2-methylindene-3-acetic acid methyl ester is dissolved in 10 ml of dry pyridine followed by 0.98 g (5.0 mmol) of 3,4,5-trimethoxy-benzaldehyde. The flask is placed under nitrogen, and 5.0 g (5.1 mol) of Triton B is added. The deeply colored solution is allowed to stand overnight, and then water (2 ml) is added. After standing for 15 minutes, it is poured into an excess of water. The organics are extracted with ether (2×50 ml). The aqueous phase is added to 10% HCl-ice. The orange, gummy solid that precipitates is extracted into methylene chloride and dried (MgSO4). The solvent is removed to leave an orange solid. The solid is filtered to give a crude product which is recrystallized to give 5,6-difluoro-2-methyl-1-(3,4,5-trimethoxy-benzylidene)indene-3-acetic acid. When 2,4,6-trimethoxybenzaldehyde or 2,4,5-trimethoxybenzdehyde is utilized in the above procedure, instead of 3,4,5--trimethoxy-benzaldehyde, the corresponding indene acetic acid is obtained. (R and R1 =H, R2 and R3 =F, R4 =H, R5, R6 and R7 =OCH3, R8 =CH3, o=1, M=OH)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21]Br>CN(C)C=O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:21][CH2:20][NH:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(O)c(N)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)NCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A solution of 3-amino-4-hydroxy-benzoic acid methyl ester (4.2 g, 25.4 mmol) in dimethylformamide (85 mL) was treated with K2CO3 (14.2 g, 102.9 mmol, 4 equiv.) and 1,2-dibromoethane (19.3 g, 102.9 mmol, 4 equiv.). The mixture was stirred at 70° C. overnight, then filtered to remove the solids. The filtrate was removed under vacuo, and the residue was purified by flash chromatography (heptane/ethyl acetate gradient) to yield 3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, 3.65 g (73%) as a light yellow solid, MS (ISP): m/e=235.1 (M+CH3CN+.); δH (300 MHz; CDCl3) 7.36 (1H, dd, J=8.5, 2.0), 7.30 (1H, d, J=2.0), 6.78 (1H, d, J=8.5), 4.30 (2H, m); 3.85 (3H, s), 3.43 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:15]([O:14][C:12](=[O:13])[CH:17]=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=Cc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4-nitrobenzaldehyde (53, 10.00 g, 66.23 mmol) and (carbethoxymethylene)triphenylphosphorane (27.92 g, 72.85 mmol, 1.1 equiv) was refluxed in CH2Cl2 (74 mL) for 24 h. The solvent was removed at reduced pressure. The oily residue was chromatographed (silica, hexanes/diethyl ether, 1:1) to give a pale yellow solid, which was shown by 1H NMR and TLC analysis to contain triphenylphosphine oxide. This sample was further purified by short-path Kugelrohr distillation (0.05 mmHg, up to 180° C.) to yield a pale yellow solid (3.74 g, 26%, mixture of E and Z isomers): 1H NMR δ 1.33 (t, J=7.5 Hz, 3H), 4.27 (q, J=7.5 Hz, 2H), 6.54 (d, J=15.6 Hz, 1H), 7.62-7.71 (m, 3H), 8.17-8.24 (m, 2H); 13C NMR δ 14.48, 61.22, 122.81, 123.54, 124.38, 130.43, 132.24, 140.76, 141.82, 166.24.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]1[CH:27]=[C:28]([CH:45]=[C:46]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:47]=1)[O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][OH:44])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:71]([O:75][C:76](=[O:79])[CH2:77]Br)([CH3:74])([CH3:73])[CH3:72]>C1COCC1.CN(C=O)C.C1COCC1>[C:71]([O:75][C:76](=[O:79])[CH2:77][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][C:28]1[CH:27]=[C:26]([O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:47]=[C:46]([O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[CH:45]=1)([CH3:74])([CH3:73])[CH3:72]
Reactant: OCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCOCc2ccccc2)cc(OCCOCCOCCOCCOCCOCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCOCc2ccccc2)cc(OCCOCCOCCOCCOCCOCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To an ice-cooled suspension of sodium hydride (175 mg, 4.4 mmol; 60% in mineral oil) in THF/DMF (4/1 mixed fluid 5 ml), a solution of Compound 47 (1.05 g, 1.09 mmol) in THF (5 ml) was gradually added, and this was followed by stirring for 30 minutes. A solution of bromoacetic acid tert-butyl ester (847 mg, 4.3 mmol) in THF (6 ml) was added thereto. After the ice bath was removed, stirring was further conducted at room temperature for 2 hours. Water was carefully added to stop the reaction, and this was followed by extraction from ethyl acetate, and the combined organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. Filtration and concentration under reduced pressure were conducted, after which the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (ethyl acetate-ethyl acetate solution containing 5% methanol)) to yield Compound 48 (light-yellow oil 530 mg, 45%).
Reaction SMILES: C([N:4]1[CH2:8][C@H:7]([O:9][CH2:10][CH3:11])[C@H:6]([NH:12][C:13]2[C:18]([CH2:19][CH3:20])=[N:17][C:16]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:15]([CH2:29][CH3:30])[N:14]=2)[CH2:5]1)(=O)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[N:17]=[C:18]([CH2:19][CH3:20])[C:13]([NH:12][C@H:6]2[C@@H:7]([O:9][CH2:10][CH3:11])[CH2:8][N:4]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:5]2)=[N:14][C:15]=1[CH2:29][CH3:30]
Reactant: CS(=O)(=O)Cl
Reactant: CCO[C@H]1CN(C(C)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting methanesulfonyl chloride and making non-critical variations provided the title compound as an oil:
Reaction SMILES: O[C:2]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:24]>>[ClH:24].[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:2]2[CH2:8][CH2:7][CH2:6][CH2:5][NH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(C2(O)CCCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Product: COc1ccc(C2=CNCCCC2)cc1
Yield: 96.3 %

Procedure:
A solution of tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate (0.25 g, 0.78 mmol) in HCl (4M solution in dioxane) (3 mL, 12 mmol) was stirred at room temperature for 5 h. The reaction mixture was concentrated and the residue was titurated with diethyl ether to yield 6-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepine hydrochloride (0.18 g, 62%) as a black gum. LCMS: R.T. 0.60 min. LCMS (ES-API), m/z 204 (M+1).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([OH:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C([O-])([O-])=O.[K+].[K+].Cl>O.C1COCC1>[NH:4]([C:1]([CH3:2])=[O:3])[C@H:5]([C:14]([OH:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:9][CH:8]=1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccc(OC(=O)OCc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 75 %

Procedure:
To a solution of (−) tyrosine xxvii (2.50 g, 13.8 mmol) in NaOH (aq) (2 N, 7.59 mL, 15.2 mmol) was added H2O (6 mL). This vigorously stirred solution was cooled to 0° C., and acetic anhydride (3.25 mL, 3.52 g, 34.5 mmol) was added via syringe pump over 30 min. During this addition, excess NaOH (aq) (2 N, 34.5 mL, 69.0 mmol) was added in 10 portions. After the addition was complete, the reaction was warmed to room temperature and stirred for 45 min. The colorless solution was then carefully acidified to pH 2 with 6 N HCl (aq). After concentrating under reduced pressure, the resulting solid was extracted with 15% H2O in acetone (4×). The filtrate was concentrated under reduced pressure to afford a slightly yellow oil. The addition of H2O (1.5 mL) afforded N-acetyl tyrosine as a white precipitate (670 mg, 3.00 mmol, 22%) that was washed with H2O (3×). The washings were saved for later precipitations. To a solution of N-acetyl tyrosine (72 mg, 0.32 mmol) in 1:1 THF:H2O (1 mL) was added NaOH (aq) (1 N, 0.32 mL, 0.32 mmol). Benzyl chloroformate (49 μL, 58 mg, 0.34 mmol) was added followed by the dropwise addition of K2CO3 (aq) (2 N, 0.16 mL, 0.32 mmol). After stirring for 7 h at rt, the reaction was poured over H2O (10 mL) and carefully acidified to pH 2 with 6 N HCl (aq). The product was extracted from the water layer with EtOAc (3×), and the combined organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product xxix as a white solid (81 mg, 0.24 mmol, 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:30](/B(O)O)=[CH:31]/[CH3:32].C1(C)C=CC=CC=1>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.[Cl-].[Cl-].[Pd+2].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:30]=[CH:31][CH3:32])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C/C=C\B(O)O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 100.5 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.7 g), bis(tricyclohexylphosphine)palladium (II) dichloride (148 mg), tripotassium phosphate (13 g) and cis-1-propene-1-boronic acid (2.6 g) were added toluene (60 mL) and water (3 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-[3-methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propenylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in ethanol (40 mL), 5% palladium carbon-ethylenediamine complex (1.2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. After celite filtration, the solvent in the filtrate was evaporated to give 4-[3-methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g). 4-[3-Methyl-5-propylpyridin-2-yl]piperazine-1-carboxylic acid tert-butyl ester (6 g) was dissolved in chloroform (10 mL), 4N hydrogen chloride/ethyl acetate (10 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (40 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (2.9 g).
Reaction SMILES: C(Cl)(=O)C(C)C.C(Cl)C=C.[CH3:11][CH:12]([CH3:19])[C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[O:17].[CH:20]1[CH2:24][CH:23]=[CH:22][CH:21]=1.CC([O-])(C)C.[K+]>>[CH3:11][CH:12]([CH3:19])[C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[O:17].[CH:12]([C:13]1[CH:22]=[CH:21][CH:20]=[C:24]2[C:14]=1[CH:15]=[CH:16][CH2:23]2)([CH3:19])[CH3:11]
Reactant: C1=CCC=C1
Agent: CC(C)(C)[O-]
Agent: CC(C)C(=O)CCC=O
Agent: CC(C)C(=O)Cl
Solvent: C=CCCl
Product: CC(C)c1cccc2c1C=CC2
Yield: 35 %

Procedure:
5-Methyl-4-oxocaproaldehyde (b1) was prepared analogously to a1 by reaction of iso-butyryl chloride and allyl chloride (see I.1.). 45.6 g (356 mmol) of b1 were reacted with cyclopentadiene and potassium tert-butylate and the mixture was worked up, analogously to instructions I.1. Column chromatography gave 19.6 g (35%) of indene b2 as a yellow oil (2 double bond isomers).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]([CH:16]2[CH2:19][CH2:18][CH2:17]2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.N>C(#N)C>[CH:16]1([C:14]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3)[CH2:11][CH2:12][N:13]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(CCNC(=O)C2CCC2)cc1OC
Agent: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)C(C1CCC1)=NCC2
Reaction time: 16 h

Procedure:
A mixture of N-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (44 g, prepared in a similar manner to that described in Example E46), phosphorus oxychloride (150 ml) and acetonitrile (900 ml) was heated under reflux for 2.5 hours. The cooled solution was poured onto dilute aqueous ammonia solution and the product was extracted into ethyl acetate. The extracts were washed with brine, dried and the solvent removed in vacuo. The resulting oil solidified on standing for 16 hours. The solid was recrystallised from petroleum ether (b.p. 60°-80° C.) to give 1-cyclobutyl-3,4-dihydro-6,7-dimethoxyisoquinoline (20 g).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5][C:6]1[NH:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[N:7]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([C:6]1[NH:7][C:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=2[N:10]=1)=[O:27]
Reactant: Nc1ccccc1CSc1nc2c([nH]1)CCCC2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ccccc1CS(=O)c1nc2c([nH]1)CCCC2
Temperature: 0 °C
Yield: 45.4 %

Procedure:
To a solution of 1.3 g (5.0 mmol) of 2-(2-aminobenzylthio)-4,5,6,7-tetrahydro-1H-benzimidazole in 13 ml of chloroform was added under stirring and chilling with ice (5°-10° C.) 1.08 g (5.0 mmol) of 80% m-chloroperbenzoic acid for approx. 15 min. The mixture was further stirred for 15 min., and to the mixture was added saturated aqueous sodium hydrogencarbonate solution. Thus precipitated solid was collected by filtration and washed with two portions of water and one portion of acetonitrile. There was obtained 590 mg of a crude product. The chloroform portion of the mother liquor was taken out and subjected to extraction using 10 ml of 0.2N aqueous NaOH. The aqueous alkaline solution was made ammonia alkaline by addition of 20% aqueous NH4Cl to precipitate a crystalline product. The crystalline product was collected and washed successively with two portions of water and one portion of acetonitrile to give 130 mg of a crude product. The crude products were combined and dissolved in 30 ml of 0.5N aqueous NaOH. The aqueous solution was washed with three portions of chloroform and then made ammonia-alkaline by addition of 20% aqueous NH4Cl to precipitate a crystalline product. The obtained product was washed successively with two portions of water, one portion of acetonitrile and one portion of diethyl ether and then dried under reduced pressure at 35° C. for 8 hrs. to 624 mg of the desired compound as a white crystalline product, yield 45.4%.