Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][CH3:3].[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[OH:16].C(=O)([O-])[O-].[K+].[K+]>>[CH3:4][O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:2][CH3:3]
Reactant: CCI
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(C(C)=O)cc1C(=O)OC
Yield: 43.5 %

Procedure:
Iodoethane (16.4 g, 0.105 mol) was added to a stirred mixture of 5-acetyl-2-hydroxybenzoic acid methyl ester (10 g, 51.5 mol) and anhydrous potassium carbonate (14.4 g, 0.104 mol) in 2-butane (200 ml) and the resulting mixture heated under reflux for 3 days. The solvent was removed by evaporation under vacuum and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was removed and extracted with further ethyl acetate (4×100 ml). The organic solutions were combined, dried (Na2SO4) and evaporated under vacuum. The residue was chromatographed on silica gel (130 g), using a methanol in dichloromethane elution gradient (0-1% methanol), to give the title compound as colourless crystals (10.15 g, 89%), m.p. 50°-55° C. Found: C,64.88; H,6.38. C12H14O4 requires C,64.85; H,6.35%.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:22](=[O:24])=[O:23].[OH-].[Na+]>CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.C(OCC)C.O.O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:22]([OH:24])=[O:23])[N:4]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:3]=1
Reactant: O=C=O
Reactant: Clc1cccnc1-n1ccc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 9.2 g of 2-(3-bromo-1H-pyrazol-1-yl)-3-chloropyridine and 80 ml of tetrahydrofuran was added dropwise 21.3 ml of a 2.0M lithium diisopropylamide solution in heptane/tetrahydrofuran/ethylbenzene at −78° C. The resulting mixture was stirred at −78° C. for 15 minutes, poured to a mixture of dry ice and 50 ml of tetrahydrofuran, and stirred for 1 hour with allowing it to rise to around room temperature. After water and diethyl ether were poured into the reaction mixture, the aqueous layer was adjusted to pH 10-12 by an addition of a 2N aqueous sodium hydroxide solution and layers were separated. The resulting aqueous layer was washed with diethyl ether two times, adjusted to around pH 3 by an addition of 2N hydrochloric acid, and extracted with methyl tert-butyl ether three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 7.96 g of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid of the formula:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: COCCN
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 4-iodophenylsulphonyl chloride (3.64 g, 12 mmol) in DCM (30 ml) was added dropwise to a solution of 2-methoxyethylamine (1.3 ml, 15 mmol) and triethylamine (2 ml, 15 mmol) in DCM (60 ml) cooled by an ice bath to 0° C. The mixture was then allowed to warm to ambient temperature and stirred for 1 hour. The solvent was removed by evaporation and the resulting oil dissolved EtOAc (100 ml) and washed with 0.33 M aqueous citric acid solution (2×100 ml), brine (100 ml) and dried. The volatiles were removed by evaporation to give the title compound (4.1 g, 100%) as a clear oil. NMR 3.12 (2H, q), 3.28 (3H, s), 3.44 (2H, t), 4.90 (1H, t), 7.57 (2H, d), 7.81 (2H, d); m/z: 342.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:20][NH:21][O:22][CH3:23]>C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:21]([O:22][CH3:23])[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A solution of 4-bromobenzoyl chloride (4.67 g, 21.3 mmol), diisopropylethylamine (3.78 mL, 46.8 mmol), and N,O-dimethylhydroxylamine (2.18 g, 22.3 mmol) in ethyl acetate (100 mL) was heated to 45° C. After 1 h, the reaction mixture was diluted with ethyl acetate (100 mL). The resulting solution was washed sequentially with water and saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (hexanes→ethyl acetate in hexanes) provided producted as a tan solid (4.12 g, 79%). LCMS (ESI) m/z: 244.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8]C(=O)[C:5]2=[CH:11][C:12]=1[F:13].CCCCCCCCCCCCC>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:11][C:12]=1[F:13])[C:9]([OH:10])=[O:8]
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Agent: CCCCCCCCCCCCC
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(F)c(F)c1
Reaction time: 3 h
Yield: 85 %

Procedure:
4,5-difluorophthalic anhydride (0.5 grams, 2.7 mmole) was added to a slurry of cupric oxide (5% by weight of starting material) in 5 ml. of N-methyl-2-pyrrolidone. n-tridecane (0.25 grams) was added as an internal standard. The mixture was heated to l90° C. for 3 hours, at which time GC analysis indicated complete consumption of the starting material and conversion to 3,4-difluorobenzoic acid in an 85% yield, based upon the internal standard, corrected for response factors.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]([F:16])([F:15])[F:14])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[F:14][C:13]([F:16])([F:15])[O:12][C:5]1[CH:4]=[CH:3][C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:7][C:6]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1cc(Br)ccc1OC(F)(F)F
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(=O)Nc1cc(N2CCN(C)CC2)ccc1OC(F)(F)F
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Pd2(dba)3 (157 mg, 0.17 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (134.7 mg, 0.34 mmol), N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide (5.05 g, 17 mmol)) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. LiN(TMS)2 solution (1M in THF, 37.6 mL) and N-methylpiperazine (2.3 mL, 20.5 mmol) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 4.78 g (88% yield) of the N-[2-trifluoromethoxy-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2>[Cl-].[Zn+2].[Cl-]>[N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]2[CH2:4][CH2:3][CH2:2][C:1]2=[O:6])[CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCCO1
Reactant: Nc1cccc2cccnc12
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C1CCCN1c1cccc2cccnc12

Procedure:
A mixture of γ-butyrolactone (4.3 g), 8-aminoquinoline (7.2 g) and zinc chloride (0.7 g) was heated at 225° for 20 hours in an autoclave. The cooled reaction mixture was partitioned between chloroform and 0.2 N hydrochloric acid. The aqueous layer was basified with sodium hydroxide then extracted with methylene chloride. Following treatment of the methylene chloride extract with FILTROL No. 1 (Trade Name) the solvent was vacuum-stripped to give 1-(8-quinolyl)-2-pyrrolidinone, identical by tlc with the product of Example 1.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>O>[CH3:19][CH2:18][O:17][C:12]([C:13]1([CH3:15])[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]1)=[O:16]
Reactant: CCOC(=O)C(C)=O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(C)NC(C(=O)O)CS1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
L-Cysteine hydrochloride monohydrate (100 g, 569 mmol) was dissolved in water (200 ml), and the pH of the solution was adjusted to 5.03 with 6N aqueous sodium hydroxide. The reaction mixture was heated to 40° C., ethyl pyruvate (76 ml, 684 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 3.5 hr to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 55:45). After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. To the obtained ethyl acetate solution was added triethylamine (159 ml, 1141 mmol) under argon, and acetyl chloride (61 ml, 858 mmol) was slowly added dropwise thereto. The reaction mixture was heated under reflux for 4 hr to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by the area ratio of an HPLC chart to find about 95:5). After completion of the reaction, water (300 ml) was added thereto, and the pH of the mixture was adjusted to 1.0 with HCl. The aqueous layer was separated, and the organic layer was washed with water (300 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated until a weight of 500 g, to the residue was added heptane to allow recrystallization of the residue, and the crystals were washed with heptane/ethyl acetate=2/1, and dried at 50° C. under reduced pressure to give the trans form (mixture of (2R,4S)-form, (2S,4R)-form) of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester as crystals (81 g, yield 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Cl)c1
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Cl)c1

Procedure:
It is furthermore known from J. Pharm. Sci. 67(1) 1978, 81, to prepare the chloro-substituted indanonecarboxylic acid ester 5-chloro-2-methoxycarbonyl-1-indanone starting from 3-chlorobenzaldehyde. Here, 3-chlorobenzaldehyde is initially reacted in pyridine with malonic acid to give 3-chlorocinnamic acid. Following hydrogenation of the ethylenic double bond and cyclization to the 5-chloro-1-indanone, the latter is then reacted with dimethyl carbonate in the presence of sodium hydride and benzene as solvent to give 5-chloro-2-methoxycarbonyl-1-indanone. This synthesis method has the disadvantage of the multistep mechanism which considerably increases the likelihood of the formation of various by-products, which is reflected in only a low yield of 48%. Additionally, the total reaction requires the repeated use of substances such as sodium hydride and benzene, which are expensive, problematic with respect to safety or hazardous to health.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[C:7]1(=[O:16])[N:6]([CH2:5][CH:4]=[O:3])[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.5 %

Procedure:
A solution of 50.0 g (190 mmol) of 2-(phthalimido)acetaldehyde diethyl acetal in 300 mL of toluene was treated with 150 mL of 50% aqueous trifluoroacetic acid and the mixture was stirred vigorously at ambient temperature for 72 h. The solution was concentrated in vacuo and 100 mL of ethyl acetate was added. The white precipitate was filtered off and washed with ice-cold ethyl acetate (100 mL) to give 30.0 g (78%) of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1([CH3:22])[C:16]2[C:11](=[CH:12][C:13]([NH2:20])=[C:14]([N+:17]([O-])=O)[CH:15]=2)[C:10](=[O:21])[NH:9][CH2:8]1>[N+]([O-])(O)=O>[CH3:6][C:7]1([CH3:22])[C:16]2[CH:15]=[C:14]3[NH:17][C:15]([C:16]4[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=4)=[N:20][C:13]3=[CH:12][C:11]=2[C:10](=[O:21])[NH:9][CH2:8]1
Reactant: CC1(C)CNC(=O)c2cc(N)c([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: CC1(C)CNC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
45 g. (186 mmole) of the above compound were nitrated in 300 ml. concentrated sulphuric acid at 0° C. by dropping in nitration acid (8.5 ml. 96% nitric acid +30 ml. concentrated sulphuric acid). After completion of the addition, the reaction mixture was further stirred for 3 hours at 25° C., poured on to ice, filtered off with suction and recrystallized from 400 ml. glacial acetic acid. The crystallizate contained the false isomer (24 g.). The filtrate was evaporated and the residue boiled with 200 ml. ethanol and 40 ml. concentrated hydrochloric acid for 20 hours, evaporated, mixed with water, neutralized, extracted with methylene chloride, dried and evaporated. The residue was purified by column chromatography (silica gel, elution agent: ethyl acetate/methylene chloride; 1:10 v/v to 1:1 v/v) to give 11 g. (25% of theory) 4,4-dimethyl-6-nitro-7-amino-1,2,3,4-tetrahydroisoquinolin-1-one; m.p. 231°-234° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Add a solution of methyl 2-nitro-4-trifluoromethylbenzoate (106 g, 425 mmol) in ethyl acetate (2.2 L) to a slurry of 10% palladium on carbon (11.0 g) in ethyl acetate (200 mL) and stir the suspension at room temperature under an atmosphere of hydrogen at 60 psi for 3 h. Filter the suspension through a pad of Celite® and wash the pad with additional ethyl acetate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with isohexane/ethyl acetate (9:1), to provide the title compound as a white crystalline solid (84 g, 95%). 1H NMR (300 MHz, CD3OD) δ 7.93 (d, J=8.48 Hz, 1H), 7.06 (s, 1H), 6.78 (s, 1H), 4.86 (s, 3H), 3.89 (s, 3H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][OH:40])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.C(Cl)(Cl)Cl.O>[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH:39]=[O:40])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 3 h
Yield: 66 %

Procedure:
Dess-Martin reagent (17 g, 39.6 mmol) was added portion-wise to a solution of 4-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester from Example E33.1 (8.33 g, 33 mmol) in dichloromethane (100 ml) at room temperature. The mixture was stirred for 3 h under an inert atmosphere then diluted with chloroform and water and the layers were partitioned. The organic layer was washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% EtOAc:60% hexane) to yield the title compound (5.5 g, 66%).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][C@H:8]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]([CH3:17])([CH3:16])[O:9]1)(C)(C)C.CO.[OH-].[Na+].Cl>C(OCC)(=O)C.CCCCCC.O>[OH:15][CH2:14][C@H:12]1[O:11][C:10]([CH3:16])([CH3:17])[O:9][C@@H:8]([CH2:7][C:6]([OH:18])=[O:5])[CH2:13]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCCCCC
Product: CC1(C)O[C@H](CO)C[C@H](CC(=O)O)O1
Reaction time: 8 h
Yield: 102 %

Procedure:
tert-Butyl-2-[(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]acetate (100.0 g), methanol (700.0 mL), water (100.0 mL), and sodium hydroxide (30.7 g) were added to a reactor. The reaction mixture was stirred at 40˜50° C. for over 8 hours. The reaction was monitored with thin layer chromatography (ethyl acetate/n-hexane=1:1). The reaction mixture was cooled to 15˜20° C. and then the pH of the reaction mixture was adjusted to 4.0˜4.2 using 6N hydrochloric acid solution. The reaction mixture was concentrated under reduced pressure to remove the solvent. Ethyl acetate (800.0 mL) and sodium sulfate (100.0 g) were added to the resulting residue, which was then stirred for over 1 hour. The resulting suspension was filtered under reduced pressure. The filtrate was washed with ethyl acetate (200.0 mL) and then concentrated under reduced pressure to obtain [(4R,6S)-6-hydroxymethyl-2,2-dimethyl-[1,3]dioxan-4-yl]-acetic acid (80.0 g, yield 102%) as a gel form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]#[N:28]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]#[N:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (32.5 g, 0.1 mol) in MeCN (325 mL), NaH (12 g, 0.3 mol) was added at 0° C. The mixture was stirred for 1 hr at rt. The mixture was cooled to −40° C., then bromoacetonitrile (35.7 g, 0.3 mol) was added in portions. The mixture was stirred for 0.5 hr at −20° C. After the reaction was complete it was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated. Crude (R)-tert-butyl 3-((R)-(3-chlorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](Cl)[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.[Cl-].[NH4+].O1CCC[CH2:23]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH3:23])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2cc3ccccc3c(Cl)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Product: COc1ccc(-c2cc3ccccc3c(C)n2)cc1
Yield: 100 %

Procedure:
3-(4-Methoxyphenyl)-1-chloroisoquinoline (3.25 g) was dissolved in tetrahydrofuran (30 ml), followed by the addition of 3.0M ethylmagnesium bromide diethyl ether solution (12 ml) and NiCl2-(dppp) (50 mg) at 0° C. After the mixture was reacted overnight at room temperature, the resulting reaction solution was poured into an aqueous solution of saturated ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, dried and evaporated, to give 3-(4-methoxyphenyl)-1-methylisoquinoline as an oil (3.3 g, yield; 100%).
Reaction SMILES: [O-]CC.[Na+].[Na].C([S:9][CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)(=O)C.[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18]>C(O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][S:9][CH:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1)[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: CC(=O)SC1C=CCCCC1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(CSC1C=CCCCC1)OCC
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A solution of fresh sodium ethoxide prepared from 7.6 g (0.330 gram-atom metallic sodium) in 200 ml of absolute ethanol was treated dropwise with 56.18 g (0.330 mole) of 3-acetylmercaptocycloheptene in 10 ml of absolute ethanol. The reaction was heated under reflux for 15 minutes and then cooled to room temperature. A solution of 49.69 ml (0.330 mole) of bromoacetaldehyde diethylacetal in 30 ml of absolute ethanol was added dropwise. The reaction mixture was heated under reflux for 2.0 hours and cooled. The precipitated sodium bromide was filtered and washed well with absolute ethanol. The filtrate was concentrated and the residue partitioned between ether/brine. The aqueous phase was further extracted with ether. The organic extracts were pooled, dried over magnesium sulfate, and evaporated to afford 80.1 g (0.328 mole, 99%) of pure 3-[(2,2-diethoxyethyl)thio]-1-cycloheptene, as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:24]3[NH:28][N:27]=[N:26][N:25]=3)[CH:22]=2)[O:17][C:4]2([CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.[ClH:29]>CO>[ClH:29].[NH:28]1[C:24]([C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[O:17][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][C:2]3=[O:1])=[N:25][N:26]=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(-c3nnn[nH]3)ccc1O2
Agent: Cl
Solvent: CO
Product: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21

Procedure:
A mixture of 5-bromo-2-hydroxyacetophenone (104.35 g, 485.26 mmol), N-Boc-piperidin-4-one (98.62 g, 494.96 mmol), 20 mL of pyrrolidine (17.26 g, 242.63 mmol) and 261 mL of MeOH was heated under reflux until the reaction was complete. The mixture was cooled, then 87 mL of H2O were added, and the mixture was filtered and dried to give tert-butyl 6-bromo-4-oxospiro-[chroman-2,4′-piperidine]-1′-carboxylate. Alternatively, 10 mL of pyrrolidine (121.31 mmol) may be used in this procedure. To a solution of tert-butyl 6-bromo-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (6593 g, 16.6 mol) and DMF (33 L) was added Zn(CN)2 (1947 g, 16.6 mol) and Pd(PPh3)4 (192 g, 0.17 mol). The slurry was heated to 90° C. for 3 hours, then cooled to room temperature and filtered. Water (16 L) was added to the filtrate. The resulting slurry was cooled to 5° C., stirred for 1 hour and filtered. The solid was washed with DMF/water (2:1) and dried under vacuum to give tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 23 g of tert-butyl 6-cyano-4-oxospiro[chroman-2,4′-piperidine]-1′-carboxylate (67.17 mmol), 13.10 g sodium azide (201.52 mmol), 27.74 g of triethylamine hydrochloride (201.52 mmol), and 460 mL of dry DMF was stirred under a nitrogen atmosphere at 100° C. for 12 hours. After cooling to room temperature, 506 mL of EtOAc were added, followed by 322 mL of 1M HCl (322 mmol). Alternatively, 0.5M HCl maybe added until pH=3. The resulting layers were separated, the organic layer was washed with water/methanol (115 ml/46 mL), and then concentrated to give tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate. A solution of 5.08 g of tert-butyl 4-oxo-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-1′-carboxylate (13.18 mmol), 8.8 mL of 12 M HCl (105.44 mmol) and 8 mL of methanol was heated to 50° C. until the reaction was complete. The resulting slurry was filtered, washed with 25 mL of methanol at room temperature, and dried to give 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidine]-4-one hydrochloride salt.