Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(Cl)C=[C:7](Cl)[C:3]=1[C:4](Cl)=O.[C:13]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CC(O)(C)C>CN(C1C=CN=CC=1)C.C1C=CC=CC=1.C1COCC1>[C:13]([CH2:21][CH2:22][C:23]([O:25][C:3]([CH3:7])([CH3:4])[CH3:2])=[O:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: O=C(O)CCC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CCC(=O)c1ccccc1
Reaction time: 6 h
Yield: 64.6 %

Procedure:
To a 500 mL round bottom flask was added 10.40 g (0.0426 mol) of 2,4,6-trichlorobenzoyl chloride. To this was added 300 mL of THF followed by 7.65 g (0.0429 mol) of 3-benzoylpropionic acid (I). Once the 3-benzoylpropionic acid had dissolved, then 6.1 mL (0.0830 mol) of triethylamine was added. The solution was stirred for 6 hours, after which the THF solution was filtered to remove the triethylamine hydrochloride. The filtrate was rotoevaporated to yield a light beige solid. To this solid was added 200 mL of benzene followed by 6.0 mL (0.104 mol) of 2-methyl-2-propanol and the mixture was stirred with heating to dissolve all of the solid. After complete dissolution, 5.40 g (0.0442 mol) of DMAP was added to the solution. The solution immediately turned dark red and was stirred at room temperature for 36 hours. The solution was washed with 10% aqueous HCl solution, followed by 2×5% aq. NaOH solution and finally with water. The organic layer was then dried (MgSO4), filtered and concentrated. The resultant oil was purified twice by column chromatography (silica gel, Eluent: 20% ethyl acetate: hexanes) and the resultant oil obtained was distilled under reduced pressure to yield 6.45 g (64%) of t-butyl 3-benzoylpropionate as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[CH2:19][C:20]([O:22]C)=[O:21].[OH-].[Na+]>O1CCOCC1.C(OCC)C>[OH:1][CH:2]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][CH:25]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C@@H:6]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: COC(=O)C[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4cccs4)C[C@@H]3CC(=O)O)c2c1
Temperature: 60 °C
Yield: 65.2 %

Procedure:
A solution of 3 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-acetate in 50 cm3 of dioxane to which had been added 5 cm3 of 5N aqueous sodium hydroxide solution was heated for 17 hours, with stirring and under an inert atmosphere, at a temperature in the region of 60° C. After cooling to approximately 20° C., the mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then the residue was taken up in 100 cm3 of dichloromethane and 5 cm3 of water. The mixture was acidified with an amount of citric acid sufficient to obtain a pH in the region of 4-5 and then dried over magnesium sulfate, filtered, and concentrated as above. The residual water was entrained by azeotroping in chloroform. After concentrating as above, the residue obtained was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 3.5 cm; silica volume 200 cm3), elution was carried out with a chloroform/methanol/28% aqueous ammonia (12/2/0.5 by volume) mixture, and approximately 60-cm3 fractions were collected. The fractions comprising the expected product were combined and then concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in 40 cm3 of diethyl ether, filtered off, washed with 2 times 5 cm3 of ether, and dried under reduced pressure (5 kPa) at a temperature in the region of 20° C. and then in an oven under reduced pressure (10 Pa) at a temperature in the region of 40° C. 1.9 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-acetic acid were obtained in the form of a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7]C)=O.Cl.[CH2:11]([O:13][C:14](=[NH:16])[NH2:15])[CH3:12].[OH-].[Na+]>O>[CH2:11]([O:13][C:14]1[N:16]=[C:3]([CH2:2][Cl:1])[CH:4]=[C:5]([OH:7])[N:15]=1)[CH3:12]
Reactant: CCOC(=N)N
Reactant: COC(=O)CC(=O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1nc(O)cc(CCl)n1

Procedure:
An emulsion of 20.9 g (0.135 mol) of methyl 4-chloroacetoacetate and 23.5 g (0.189 mol) of O-ethylisourea hydrochloride is treated with a solution of 41.3 g (0.31 mol) of sodium hydroxide in 40 ml of water at -20° C. to -10° C. during 5 minutes while stirring well. After stirring at room temperature for 2 hours the resulting crystalline product is filtered off and dried. The crystals, m.p. 156°-158° C., are washed well with diethyl ether. There is obtained 2-ethoxy-4-chloromethyl-6-hydroxy-pyrimidine, m.p. 161°-163° C.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)(=O)=O)=CC=1.[Cl:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[NH:25][N:24]=[N:23]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[Cl:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[N:25]([CH2:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[N:24]=[N:23]1
Reactant: O=c1[nH]nnn1CCCl
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccs2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCCl)nnn1CCc1cccs1
Temperature: 70 °C
Yield: 46.5 %

Procedure:
A mixture of 19.6 parts of [2-(2-thienyl)ethyl] 4-methylbenzenesulfonate, 10 parts of 1-(2-chloroethyl)-1,4-dihydro-5H-tetrazol-5-one, 10 parts of sodium carbonate and 90 parts of N,N-dimethylformamide is stirred and heated overnight at 70° C. The reaction mixture is cooled, 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and petroleumether (70:30 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (46.5%) of 1-(2-chloroethyl)-1,4-dihydro-4-[2-(2-thienyl)ethyl]-5H-tetrazol-5-one as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]([C:21]([NH:23][C:24]1[S:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=1)=[S:22])[NH2:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[S:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
From 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (40.0 mg, 0.14 mmol) and 5-hydrazinocabonothioylamino-2-thiophenecarboxylic acid (33.9 mg, 0.14 mmol), the desired product was obtained in the same manner as in Synthetic Example 114 as a pale yellow solid (62.2 mg, yield 92%).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[I:7][C:8]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:9]=2)=[O:12])=[C:8]([I:7])[CH:16]=1
Reactant: O=C(O)c1ccc(Cl)cc1I
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(c1ccccc1)c1ccc(Cl)cc1I
Temperature: 0 °C
Reaction time: 1 h
Yield: 164.9 %

Procedure:
A solution of 1.47 g of PCl5 (7.08 mmol, 1 eq.) in 35 mL of 1,2-dichloroethane was cooled to 0° under N2, then 2.00 g of 2-iodo-4-chlorobenzoic acid (7.08 mmol), 1 eq.) was added neat, at once. The bath was removed, the reaction allowed to warm to 25° and maintained there for 3 hr. The volatiles were removed in vacuo, the residue dissolved in 35 mL of fresh 1,2-chloroethane and again evaporated. The residual oil was dissolved in 70 mL of benzene, cooled to 0° and treated with 0.94g of AlCl3 (7.08 mmol, 1 eq.). After 1 hr at 0°, the reaction was allowed to warm to 25° and maintained there overnight. The mixture was poured onto 200 mL of ice, warmed and extracted with Et2O (3×100 mL). The combined Et2O layers were washed with saturated NaHCO3 (2×200 mL), saturated NaCl (1×300 mL), dried (MgSO4), and the solvents removed in vacuo to yield 2.00 g (82%) of 4-chloro-2-iodobenzophenone as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1cc2ccccc2cc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 76.7 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:11]([C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[N+]([O-])=O)#[N:12]>CS(C)=O>[C:11]([C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1[O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)#[N:12]
Reactant: N#Cc1ccc([N+](=O)[O-])c(C#N)c1
Reactant: N#Cc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C#N)cc2C#N)cc1

Procedure:
The sodium salt of p-hydroxybenzonitrile (1 ml) was heated with 2,4-dicyanonitrobenzene (1 mole) in dry dimethyl sulphoxide for 18 hours at 105° to form 4-(2,4-dicyanophenoxy) benzonitrile m.p. 222°-223°, which was recovered by dilution with water, and purified by crystallisation from acetic acid. This compound was hydrolysed with 60% w/w aqueous sulphuric acid (25 pts.) mixed with glacial acetic acid (10 parts), refluxing the mixture for 24 hours; on cooling, diphenyl ether 2,4,4'-tricarboxylic acid separated. The tricarboxylic acid was cyclized either (a) by heating to 300° for 5 minutes, or (b) dissolving in concentrated sulphuric acid, heating at 100° for 3 hours and subsequently diluting with water. The solid resulting from (a) or from (b) was recrystallised from dimethyl formamide to give xanthone-2,7-dicarboxylic acid identical with that prepared by Methods (i) and (ii).
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[Br:11][CH2:12][CH2:13][CH2:14][Cl:15]>C(#N)C>[Br-:11].[Cl:15][CH2:14][CH2:13][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: CNCCC[N+](C)(C)C
Reactant: ClCCCBr
Agent: [Br-]
Solvent: CC#N
Product: CN(CCCCl)CCC[N+](C)(C)C

Procedure:
To a stirred solution of 3.02 g. (14.3 mmoles) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.25 g. (14.3 mmoles) of 3-bromo-1-chloropropane and the mixture is stirred at room temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is extracted with chloroform. The chloroform extract is evaporated and dried to give 2.05 g. (100%) of oily product; NMR δ: 2.2 (3H, S, --NCH3); 3.43 (9H, S, --N+ (CH3)3).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.C[N:31]1CCOCC1.[OH-].[NH4+]>C1COCC1.[Cl-].[Na+].O>[NH2:31][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
A stirred solution of racemic (2S)-2-(((benzyloxy)carbonyl)amino)-3-tert-butoxypropanoic acid (1.01 g, 3.43 mmol) in THF (10 mL) at −15° C. was treated with isobutyl chloroformate (0.440 mL, 3.43 mmol) followed by N-methylmorpholine (0.380 mL, 3.43 mmol). After 15 minutes, the milky white reaction mixture was treated dropwise with ammonium hydroxide (2.8 mL of 30% reagent, 5.0 mmol). The reaction flask was warmed to −15° C. and stirred for 45 minutes. The clear homogeneous mixture was treated with brine (20 mL) and extracted with ethyl acetate (2×40 mL). The organic portions were combined and washed with saturated aqueous NaHCO3 solution (15 mL) and brine (15 mL), and dried (MgSO4). Filtration and removal of solvent provided 928 mg of the desired product a white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:34][CH2:35][CH2:36][CH3:37])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:22]=2[C:23](O)=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:62]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][C@@H:64]([CH2:72][OH:73])[NH:63]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:34]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:22]=2[C:23]([N:63]2[C@H:64]([CH2:72][OH:73])[CH2:65][C:66]3[C:71](=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:62]2)=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:35][CH2:36][CH3:37]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a solution of 2-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (130 mg, 0.25 mmol) in DMF (5 mL) was added HATU (293 mg, 0.77 mmol), (S)-1,2,3,4-tetrahydroisoquinoline-3-yl-methanol (84 mg, 0.51 mmol) and diisopropylethylamine (269 μL, 1.54 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated to give crude product. The crude material was purified by flash chromatography (gradient from 0% to 50% EtOAc/hexanes) to provide the title compound (113 mg, 61%) as a light yellow oil. 1H NMR (DMSO-d6, 1:1 mixture amide rotamers) δ 8.14-8.01 (m, 2H), 7.64 (s, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.26-7.21 (m, 3H), 7.17-7.03 (m, 5.5H), 6.98 (d, J=6.8 Hz, 0.5H), 5.03 (d, J=18.4 Hz, 0.5H), 4.91 (br s, 1H), 4.39 (br s, 0.5H), 4.24 (d, J=18.4 Hz, 0.5H), 4.16-4.07 (m, 2.5H), 3.91 (s, 3H), 3.88-3.85 (m, 0.5H), 3.76-3.73 (m, 0.5H), 3.65-3.55 (m, 1H), 3.39-3.34 (m, 2H), 3.24-3.00 (m, 2H), 2.96-2.85 (m, 3H), 2.70-2.65 (m, 2H), 1.50-1.11 (m, 8H), 0.88-0.76 (m, 6H); MS(ESI+) m/z 651.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][CH2:24]C[CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].C1(B(O)O)CCCC=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: OB(O)C1=CCCC1
Product: Cc1cc2ccccc2c(C2=CCCC2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(1-cyclopentenyl-3-methylnaphthalen-2-yl)acetic acid (12) was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6, except that cyclopentenylboronic acid was used instead of cyclohexenylboronic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.78 (m, 1H), 7.53 (s,1H), 7.40 (m, 2H), 6.10-5.54 (m, 3H), 2.90 (m,1H), 2.65 (m, 5H), 2.57 (s, 3H), 1.18 (s, 9H). LCMS-ESI− (m/z): [M−H]-calcd for C22H25O3: 337.44. found: 337.1.
Reaction SMILES: C(OC(=O)[NH:7][N:8]1[C:17]([CH3:18])=[C:16]([C:19](=[O:29])[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([I:28])[CH:23]=2)[C:15]2[C:10](=[C:11]([F:30])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:31])(C)(C)C>C(#N)C>[I:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:19]([C:16]1[C:15]2[C:10](=[C:11]([F:30])[CH:12]=[CH:13][CH:14]=2)[C:9](=[O:31])[N:8]([NH2:7])[C:17]=1[CH3:18])=[O:29]
Reactant: Cc1c(C(=O)NCc2cccc(I)c2)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Solvent: CC#N
Product: Cc1c(C(=O)NCc2cccc(I)c2)c2cccc(F)c2c(=O)n1N

Procedure:
[8-Fluoro-4-(3-iodo-benzylcarbamoyl)-3-methyl-1-oxo-1H-isoquinolin-2-yl]-carbamic acid tert-butyl ester in acetonitrile (prepared as described in example 8) was heated to remove the tert-butoxy carbonyl group as described in the synthesis of 2-amino-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide to give the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[C:3]([C:16](O)=[O:17])[CH:2]=1.B#B>O1CCCC1.O>[OH:17][CH2:16][C:3]1[CH:2]=[CH:1][C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Agent: B#B
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)Sc1ccccc1CC2

Procedure:
Dissolve 7.5 gm. of 10,11-dihydrodibenzo[b,f]-thiepin-3-carboxylic acid in 140 ml. of tetrahydrofuran. With stirring, add 90 ml. of 1 N diborane in tetrahydrofuran. Stir at room temperature for 2 hours and dilute the reaction mixture with water. Extract into ether, and evaporate the ether extract to dryness. Stir the residue with hexane and filter to obtain the title product (m.p., 82°-84° C.).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O.[OH-].[Na+]>O>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([C:14]([C:9]3[CH:8]=[C:7]4[C:12](=[CH:11][CH:10]=3)[N:3]([CH3:2])[CH2:4][CH2:5][CH2:6]4)([CH3:16])[C:13]([OH:18])=[O:17])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)C(=O)O
Reactant: CN1CCCc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1CCCc2cc(C(C)(C(=O)O)c3ccc4c(c3)CCCN4C)ccc21
Yield: 76.9 %

Procedure:
Into 6.0 ml of 6N--HCl solution was dissolved 4.2 g of 1-methyl-1,2,3,4-tetrahydroquinoline. To the solution was added 3 g of pyruvic acid and the mixture was heated with reflux for 20 hours. The reaction mixture was, after cooled, diluted with 100 ml of water and adjusted to pH 6 with addition of 20% aqueous solution of sodium hydroxide. The precipitated crystal was collected by filtration which was 4.0 g (yield 77%) of 2,2-bis(1-methyl-1,2,3,4-tetrahydroquinoline-6-yl)propionic acid as light brown crystal, having a melting point of 155°~157° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:10]([C:12]2[C:16]([NH:17][C:18]([C:20]3[C:25]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)=[CH:24][CH:23]=[C:22]([CH:33]4[CH2:35][CH2:34]4)[N:21]=3)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=2)=[O:9])[CH2:4]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: COC1CCNC1
Product: COC1CCN(C(=O)c2nn(C)cc2NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)C1
Yield: 23 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3-methoxypyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (23%) as amorphous yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=O.[Li]C>C1COCC1.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([C:3]1[CH:4]=[CH:5][CH:9]=[CH:10][CH:11]=1)=[O:8]
Reactant: COc1cc(C(=O)O)ccc1C
Agent: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-methoxy-4-methyl benzoic acid (3.32 g, 20 mmol) in anhydrous THF (100 mL) was cooled to −78° C. A solution of MeLi (25 mL of a 1.6M solution in diethyl ether, 40 mmol) was added slowly to the reaction flask via syringe over 10 min. The cooling bath was removed, and the reaction mixture was allowed to warm to rt, and was stirred for 1 h at rt. The reaction mixture was quenched with 1N HCl (50 mL) and extracted with diethyl ether (3×50 mL). The organic extracts were combined, washed with brine (50 mL), dried (MgSO4), and concentrated to afford 3-methoxy-4-methyl benzophenone as a colorless oil.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.C(Cl)C=C.C[Si](Cl)(C)C.[C:17]1(=[O:23])[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18]1>C1COCC1>[CH:2]1([CH:19]2[CH2:20][CH2:21][CH2:22][C:17](=[O:23])[CH2:18]2)[CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: O=C1C=CCCC1
Reactant: ClC1C=CCCC1
Agent: C[Si](C)(C)Cl
Solvent: C=CCCl
Solvent: C1CCOC1
Product: O=C1CCCC(C2C=CCCC2)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
In an effort to diminish homocoupling, 3-chlorocyclohexene (3.20 mmol) was weighed in a large vial and capped with a septum. Once under an argon atmosphere, THF (10 ml) was added to the vial. To a stirring active coppersolution (8.23 mmol in 23 ml of THF) at -95° C., the allyl chloride is delivered dropwise from a cannula, over 30 minutes. After 5 minutes, TMSCl (2.84 mmol) is injected neat prior to the neat, dropwise injection of 2-cyclohexenone (0.82 mmol). The reaction flask is placed in a -78° C. bath and allowed to gradually warm to room temperature. Thereaction mixture is quenched with NH4Cl (sat'd) (50 ml) and Et2O (25 ml) is added prior to further extraction of the organic layer with 0.5M HCl (50 ml), water (50 ml), and brine (50 ml). The combined aqueous layers are back extracted with Et2O (30 ml). The combined organic layers are dried with MgSO4 and reduced in volume for column chromatography. 3-(2-cyclohexenyl)cyclohexanone (0.43 mmol) was isolated in 52% yield (not shown in Table III). Rf =0.31 in 9:1 (v/v) hexane and ethyl acetate, respectively. 1H NMR (300 MHz) 5.73-5.67 (m, 1H),5.53-5.50 (m, 1H), 2.37-1.16 (m, 16H). 13C NMR (75 MHz) 212.50, 212.47, 129.1, 128.8, 128.7, 128.5, 45.2, 45.0, 43.6, 41.4, 40.0, 39.9, 28.4, 28.1, 25.52, 25.46, 25.41, 25.3, 25.2, 25.1, 21.8, 21.7.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[CH3:3].[CH:10](=[O:12])[CH3:11].B(F)(F)F.CCOCC>ClCCCl>[CH3:3][C:2]1=[CH:4][CH2:8][CH2:7][CH2:6][C:5](=[O:9])[O:12][CH:10]([CH3:11])[CH2:1]1
Reactant: C=C(C)C1CCCC1=O
Reactant: CC=O
Agent: C/C1=C/CCCC(=O)OC(C)C1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCCl
Product: CC1=CCCCC(=O)OC(C)C1

Procedure:
Following the general procedure as described in Example 1, 2-(prop-1-en-2-yl)cyclopentanone (1.24 g, 10 mmol), acetaldehyde (0.53 g, 12 mmol) and boron trifluoride etherate (0.14 g, 1.0 mmol) in 1,2-dichloroethane (10 mL) were reacted to give the title product as a colorless liquid (0.59 g, 35% yield). Single Z-isomer.