Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(Br)c(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-bromo-5-methyl benzoic acid (1.0 g, 0.00465 mole) in dry dichloromethane (10 mL) was added oxalylchloride (1.22 mL, 0.013 mole) dropwise at 0° C. followed by 1-2 drops of N,N-dimethyl formamide. The reaction mixture was then stirred for 2 hours at room temperature and the solvents were evaporated and the product dried under vacuum to yield 2-bromo-5-methylbenzoyl chloride which was used for the next step. To a precooled solution of 2-bromo-5-methyl benzoyl chloride in toluene (5 mL) was slowly added a pre-cooled solution of triethylphosphite (1.05 mL, 0.00604 mole) in toluene. The reaction was then left at room temperature for overnight. The solvents were then evaporated on a rotovap. The resultant product was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (NaHCO3, 25 mL), and then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided 1.1 g of product. Flash chromatography on silica gel using 0%-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.900 g of (2-bromo-5-methylbenzoyl)phosphonic acid diethyl ester. B. The material from A above was used to prepare [2-bromo-5-methylbenzoyl)difluoromethyl]phosphonic acid diethyl ester following a procedure similar to Example 80C. This material was used to prepare Compound 82 following a procedure similar to Example 40. 1H NMR: (DMSO-d6, 400 MHz) δ 7.56 (d, 1H, J=8.4 Hz), 7.40 (s, 1H), 7.19 (d, 1H, J=8.0 Hz), 2.28 (s, 3H). MS (ion spray): m/z 300.15/301.05 (M−H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C:18]2[S:22][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:20][CH:19]=2)[CH:9]=1.[OH-:27].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:18]2[S:22][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:20][CH:19]=2)[N:11]=[C:12]([OH:27])[N:13]=1
Reactant: [OH-]
Reactant: CC(C)Nc1ncc(-c2cc(-c3ccccc3Cl)nc(S(C)(=O)=O)n2)s1
Agent: [Na+]
Product: CC(C)Nc1ncc(-c2cc(-c3ccccc3Cl)nc(O)n2)s1

Procedure:
Example 318 was prepared from 5-(6-(2-chlorophenyl)-2-(methylsulfonyl)pyrimidin-4-yl)-N-isopropylthiazol-2-amine utilizing a similar procedure as described in Example 50 by substituting 1-methylpiperazine with 1N NaOH aqueous solution. Yellow solid. HPLC Ret. time: 2.55 min. LCMS MH+ (m/z) 347.20. 1H NMR: (d6-DMSO, 500 MHz) δ 11.58 (br, 1H), 8.41 (d, 1H), 8.12 (s, 1H), 7.60 (m, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 6.86 (br. s, 1H), 3.86 (m, 1H), 1.18 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH2:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 79.3 %

Procedure:
2-tert-Butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoronitrobenzene (5.7 ml, 54 mmol), and sodium bicarbonate (8.25 g, 98 mmol) was taken into 130 ml of dimethylformamide and heated at 80° C. for 18 hours. The reaction was evaporated in vacuo to give a viscous orange residue that was dissolved in 300 ml of water and extracted with diethyl ether (3×150 ml). The aqueous solution was acidified to pH 5 with 10% sodium hydrogen sulfate and extracted with ethyl acetate (3×250 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to give 12.64 g (83%) of the title compound as an orange amorphous solid. 1H NMR (CD3OD) δ 8.15-8.10 (1H,d), 7.54-7.48 (1H,t), 7.13-7.08 (1H, d), 6.73-6.65 (1H, t), 4.45-4.35 (1H, m), 3.9-3.8 (1H, dd), 3.65-3.55 (1H, dd), 1.45 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=3)[CH2:26][CH2:25]2)=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)CC1
Yield: 98.4 %

Procedure:
A solution of 4,6-dichloropyrimidine (8.60 g), 1-[1-(tert-butoxycarbonyl)-piperazin-4-ylcarbonyl]piperazine 15.64 g) and triethylamine (21.95 ml) in ethanol (300 ml) was stirred at room temperature for 30 minutes. Solvent was evaporated and the residue dissolved in dichloromethane and washed with water, saturated aqueous sodium chloride solution, dried (Na2SO4) and evaporated to give, as a pale yellow solid 1-[1-(tert-butoxycarbonyl)-piperazin-4-ylcarbonyl]-4-(6-chloro-pyrimidin-4-yl) piperazine (21.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1F
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution 4-chloro-2-fluorobenzoic acid (1 eq) in CH2Cl2 (1.6 M) was added N,O-dimethylhydroxylamine hydrochloride (1.5 eq), EDCI (1.5 eq) and triethylamine (4 eq). The reaction mixture was stirred at rt for 16 hrs, concentrated and 0.5M aqueous citric acid was added. The mixture was extracted with 1:1 EtOAc:Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give 4-chloro-2-fluoro-N-methoxy-N-methylbenzamide, which was used as such for the next step.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[CH3:16]CCCC=C>>[CH3:16][N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C=CCCCC
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: C=O
Product: CN(C1CCCCC1)C1CCCCC1
Yield: 195 %

Procedure:
In a similar manner to Example 1, 204.0 g (1.13 mol) of dicyclohexylamine and 185.5 g (1.80 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.4 MPa is established at a temperature of 160° C. After the end of the reaction, 50 g of hexene-1 are added and the organic phase is removed from the aqueous phase. The remaining organic phase is subsequently distilled. 226.3 g of N-methyldicyclohexylamine having a purity of 93.7% are isolated, corresponding to a yield of 96.1% of theory.
Reaction SMILES: C[Si](CCOC[N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH:11]=[CH:10]1)(C)C.FC(F)(F)S(O[CH:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])(=O)=O>C(Cl)Cl>[N:9]1[CH:10]=[CH:11][C:12]([O:15][CH:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[CH:13][CH:14]=1
Reactant: CC(OS(=O)(=O)C(F)(F)F)C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc(=O)cc1
Solvent: ClCCl
Product: CC(Oc1ccncc1)C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of benzyl lactate (6.0 g, 33 mmol) and N-methyl morpholine (2.7 mL, 33 mmol) in 100 mL anhydrous CH2Cl2 at −20° C. was added trifluoromethanesulfonyl anhydride (5.6 mL, 33 mmol). After stirring at −20° C. for 1 h, the reaction mixture was diluted with 100 mL hexane and washed with dilue aqueous sodium hydrogen sulfate and brine/saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 10% ether in hexane to give benzyl 2-trifluoromethanesulfonyloxypropionate (6.4 g), which was used immediately for the ensuing reaction. Thus, a mixture of N-trimethylsilylethoxymethyl-4-pyridone (Step A, 3.4 g, 15 mmol) and benzyl 2-trifluromethanesulfonyloxypropionate (4.7 g, 15 mmol) was heated at 60° C. overnight. After cooling to room temperature, the reaction mixture was dissolved in CH2Cl2 and loaded onto a silica gel column, which was eluted with 5% MeOH in CH2Cl2 to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.57 (d, 2H), 7.42 (d, 2H), 7.4-7.3 (m, 5H), 5.44 (q, 1H), 5.24 (ABq, 2H), 1.72 (d, 3H). LC-MS: m/e 258 (M+H)+ (1.8 min).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].[CH:6]1([N:12]=[C:13]=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>O1CCCC1>[CH:6]1([NH:12][C:13]([N:4]([CH2:3][CH2:2][OH:1])[NH2:5])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C=NC1CCCCC1
Reactant: NNCCO
Solvent: C1CCOC1
Product: NN(CCO)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxyethylhydrazine (7.15 g, 0.09 moles) in 125 mL tetrahydrofuran was added dropwise with stirring 11.76 g (0.09 moles) cyclohexyl isocyanate in 70 mL tetrahydrofuran. The solution was stirred overnight at room temperature, and the solvent was evaporated to yield quantitatively a pale viscous oil which slowly crystallizes.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:56]1[C:64]2[C:59](=[C:60]([CH2:65][NH2:66])[CH:61]=[CH:62][CH:63]=2)[CH:58]=[N:57]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:66][CH2:65][C:60]2[CH:61]=[CH:62][CH:63]=[C:64]3[C:59]=2[CH:58]=[N:57][NH:56]3)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCc1cc(C(=O)O)sc1C(=O)OC
Reactant: NCc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
To a solution of 3-Ethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (130 mg, 0.61 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.26 mL, 1.83 mmol), HBTU (0.35 g, 0.92 mmol), HOBT (0.099 g, 0.73 mmol), and C-(1H-Indazol-4-yl)-methylamine (100 mg, 0.67 mmol). The mixture was stirred at room temperature 2 d, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-80% EtOAc in hexane to afford the desired product (0.095 g, 46% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][P:13]([CH2:22][CH2:23][CH2:24][NH2:25])([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[O:14])[CH3:11].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:10]([O:12][P:13]([CH2:22][CH2:23][CH2:24][NH:25][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])=[O:14])[CH3:11]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(OCC)P(=O)(CCCN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(CCCNCc1ccc(Cl)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.41 g of p-chlorobenzaldehyde are added to a solution of 2.53 g of 3-aminopropyl(diethoxymethyl)phosphinic acid ethyl ester in 10 ml of anhydrous methanol, and the resulting clear solution is stirred at room temperature for 30 minutes. There are then added first 0.6 g of glacial acetic acid and then, dropwise, 0.21 g of sodium cyanoborohydride in solution in 5 ml of methanol. An exothermic reaction begins. The mixture is stirred at 20° for 3 hours and adjusted to pH 8, and the solvent is removed. The residue is dissolved in dichloromethane and washed with water. The organic phase is separated off, dried over sodium sulfate and concentrated to dryness by evaporation. The oil that remains is purified by chromatography on silica gel, yielding 3-(p-chlorobenzylamino)propyl(diethoxymethyl)phosphinic acid ethyl ester in the form of a yellowish oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CC(O)C>[N:11]1([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCCN3CCCC3)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: c1cc(NCCN2CCCC2)cc(N2CCNCC2)c1
Reaction time: 18 h
Yield: 137.3 %

Procedure:
To a solution of 4-[3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (338 mg, 0.90 mmol) in MeOH (10 mL) was added a solution of HCl in IPA (5M, 1.8 mL). The mixture was stirred for 18 h then concentrated to provide the title compound (339 mg, 99%). m/z (M+1) 275.49 (free base).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[OH:28]O>C(O)(=O)C.O.N>[CH3:1][C:2]1([CH3:27])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:28])=[CH:19][C:18]=4[O:25][CH3:26])[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: OO
Reactant: COc1cc(SC)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(S(C)=O)ccc1C1=NC2=C3C=NC(C)(C)C(=O)C3CC(=O)C2=N1
Reaction time: 50 h

Procedure:
5.1 gm of 7,7-dimethyl-2-(2-methoxy-4-methylmercapto-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione were reacted in 100 ml of 70% acetic acid with 1.7 gm of 30% hydrogen peroxide, and the mixture was allowed to stand for 50 hours at room temperature (the first 3 hours while stirring). After 18 and again after 26 hours 1.3 gm of 30% hydrogen peroxide were added. The reaction mixture was then diluted with water, and ammonia was added until alkaline reaction. The precipitate was suction-filtered off and the filtrate was extracted twice with chloroform. The combined chloroform phases were evaporated, and the evaporation residue was combined with the precipitate. The thus obtained product was purified on a silicagel column (eluant: chloroform/acetone 19:1).
Reaction SMILES: C([Mg]Cl)C(C)C.[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[CH2:23](/[C:8](=[CH:7]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:19][CH2:20][CH3:21]
Reactant: C1CCOC1
Reactant: CCOC(=O)C#CC(=O)OCC
Agent: CC(C)C[Mg]Cl
Product: CCCC/C(=C/C(=O)OCC)C(=O)OCC
Temperature: -40 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mechanically stirred suspension of copper(I) bromide-dimethylsulfide complex (20.4 g, 99.0 mmol) in 500 mL of THF was cooled to −40° C. and treated dropwise with 2.0 M solution of i-butylmagnesium chloride in THF (49.5 mL, 99.0 mmol) under an atmosphere of dry nitrogen. After stirring at −40° C. for 2 h, the reaction mixture was cooled to −78° C. and then treated dropwise with a solution of diethyl acetylenedicarboxylate (13.2 mL, 82.5 mmol) in 160 mL of THF. Upon completion of the addition, the mixture was stirred at −78° C. for 1 h, quenched with saturated NH4Cl aq., then allowed to slowly warm up to room temperature, and stirred at this temperature for additional 30 min. The organic phase was separated and the water phase was thoroughly extracted with ether. The combined organic extracts were washed with saturated NH4Cl aq., then with brine, dried over Na2SO4, and distilled in vacuum to give 14.8 g (79% yield, bp 74–75° C./1 mm Hg) of diethyl 2-1-butylmaleate as a colorless oil.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>C(O)C>[C:1]([N:6]1[CH2:11][CH2:10][N:9]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 1-carboethoxypiperazine (25 g; 0.157 mole), 4-chlorobenzyl chloride (26 g; 0.162 mole) and ethanol (250 ml) was gently refluxed for 5 hours and the solvent removed in vacuo. The resulting oil crystallised on cooling to give the hydrochloride of the title compound. Recrystallisation from ethanol gave 29 g (58%) of material of m.p. 208°-210°. (Found; C, 52.70; H, 6.41; N, 8.62; Cl, 21.51; C14H19ClN2O2HCl requires; C, 52.67; H, 6.31; N, 8.78; Cl, 22.20%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1.O.[OH-].[Na+]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1
Reactant: CCOC(=O)c1cc2c(nc1NCc1ccco1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc2c(nc1NCc1ccco1)CCCC2
Temperature: 80 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
To a solution of ethyl 2-[(furan-2-ylmethyl)amino]-5,6,7,8-tetrahydroquinoline-3-carboxylate (600 mg) in ethanol (4 ml)-water (4 ml) was added 8 M aqueous sodium hydroxide solution (1.25 ml), and the mixture was stirred at 80° C. for 10 hr. The reaction mixture was concentrated under reduced pressure to about 1/3 volume, and neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object compound (522 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:13][C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:19][C:13]1[C:12](=[O:14])[NH:11][C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[S:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2SC(c2ccccc2)=C1Cl
Reaction time: 5 h

Procedure:
2,3-Dihydro-2-phenyl-1,5-benzothiazepin-4(5H)-one (25.5 grams, 0.1 mole) is stirred in 250 ml of dimethylformamide. To the stirred solution is added a solution of N-chlorosuccinimide (27 grams, 0.2 mole) in 100 ml of dimethylformamide. The mixture is stirred at 105°-110°C for 5 hours, followed by cooling. The cooled solution is poured into 1.8 liters of cold water and a solid precipitates. The crude product (28 grams) has a melting point of 238°-240°C. The crude product is crystallized from a mixture of 30 ml hot dimethylformamide and 90 ml acetonitrile yielding 26.2 grams of the title compound, melting point 241°-243°C.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.[OH-].[Na+].[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.[BH4-].[Na+]>C(O)C.C(OCC)C>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][N:1]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]1[C:8]([OH:10])=[O:9]
Reactant: CC(C)(C)C=O
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)CN1C(=O)CC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
L-glutamic acid (1.47 g, 10 mmol) was dissolved in 2N aqueous sodium hydroxide (10 ml, 20 mmol) and treated with a solution of trimethylacetaldehyde (1.09 ml, 10 mmol) in ethanol (5 ml) and then stirred at room temperature for 30 minutes. The mixture was cooled to 0° C. and treated with sodium borohydride (0.130 g). The mixture was allowed to warm to room temperature with stirring over 4 hrs and then acidified to neutral pH. Concentration in vacuo was followed by slurrying in ethanol and azeotroping three times with more ethanol. Finally the remaining material was suspended in ethanol (50 ml) and heated at reflux for 48 hrs. The mixture was then cooled to room temperature, salts were filtered off and the solvent was evaporated in vacuo to give a gum. Trituration with diethyl ether followed by drying afforded pure solid 1-(2,2-dimethylpropyl)-5-oxoproline (1.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33]O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: O=C1c2ccccc2C(=O)N1CCOc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCO
Product: CC(C)(C)[Si](C)(C)OCCCCOc1cccc(OCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 24 with 4-(tert-butyldimethylsilanyloxy)butan-1-ol gave 2-(2-(3-(4-(tert-butyldimethylsilyloxy)butoxy)phenoxy)ethyl)isoindoline-1,3-dione as yellow oil. Yield (1.3 g, 78%): 1H NMR (400 MHz, CDCl3) δ 7.84-7.87 (m, 2H), 7.70-7.74 (m, 2H), 7.10-7.14 (m, 1H), 6.42-6.49 (m, 3H), 4.20 (t, J=5.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 3.92 (t, J=6.6 Hz, 2H), 3.66 (t, J=5.6 Hz, 2H), 1.78-1.86 (m, 2H), 1.61-1.69 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[C:11]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])=[O:38])=[N:35][CH:36]=2)[CH:12]=[C:13]([C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH:14]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[C:11]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:38])=[N:35][CH:36]=2)[CH:12]=[C:13]([C:15](=[O:30])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)cc(C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)c2)cn1
Temperature: 25 °C

Procedure:
A 1M aqueous solution of NaOH (2.0 mL, 2.0 mmol) was added to a THF (1 mL) and MeOH (5 mL) solution of ethyl 3-(5-(3-chloro-5-((4′-chloro-[1,1′-biphenyl]-4-yl)carbamoyl)phenyl)picolinamido)propanoate (40 mg, 0.07 mmol) and the resulting mixture was stirred at room temperature. After 16 h the mixture was acidified with 2 M HCl and the aqueous phase was extracted with EtOAc. The combined organics were washed with water, dried (Na2SO4), and concentrated to yield the title compound.