Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:5]=1[C:6](=[O:15])[NH:7][S:8]2(=[O:10])=[O:9])(C)C.ClCS[C:19]1[CH:24]=CC=C[CH:20]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:19]([N:7]1[C:6](=[O:15])[C:5]2[C:11](=[CH:12][CH:13]=[CH:14][CH:4]=2)[S:8]1(=[O:9])=[O:10])([CH3:24])[CH3:20]
Reactant: ClCSc1ccccc1
Reactant: CC(C)c1cccc2c1C(=O)NS2(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)c2ccccc2S1(=O)=O
Yield: 141.2 %

Procedure:
A mixture of 4-isopropylsaccharin (37.9 g), phenyl chloromethyl sulfide (33.3 g), tetrabutylammonium bromide (5.4 g) and toluene (200 mL) was heated under reflux for 24 hours, then stripped of volatiles. Column chromatography of the residue on silica gel (485 g) and elution first with hexane, then hexane-dichloromethane (1:1), then dichloromethane gave in the hexane-dichloromethane eluate 2-phenylthiomethyl-4,-isopropylsaccharin as a pale yellow oil (53.5 g, 92% yield).
Reaction SMILES: [OH:1][C@@H:2]([C:24]([CH3:30])([CH3:29])[CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[N:18]=1.[OH-].[Na+].Cl>CO>[OH:1][C@@H:2]([C:24]([CH3:29])([CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])/[CH:3]=[CH:4]/[C@H:5]1[CH2:9][O:8][C:7](=[O:10])[N:6]1[CH2:11][CH2:12][S:13][C:14]1[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=1
Reactant: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the compound 7 (84.0 mg) in methanol (1.00 mL) was added an aqueous solution of 2N sodium hydroxide (0.19 mL) at 0° C. and the solution was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous solution of 2N hydrochloric acid (0.30 mL). The solution was extracted with ethyl acetate and washed with water and brine. The reaction solution was dried over anhydrous sodium sulfate and concentrated to give the title compound (78.8 mg) having the following physical data.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1/[CH:11]=[CH:12]\[S:13][C:14]1[C@H:15]([CH3:28])[C@@H:16]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])(=[O:3])[CH3:2].[Na+].[CH:30]1([O:36][C:37]([O:39][CH:40](I)[CH3:41])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[C:1]([O:4][CH2:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1/[CH:11]=[CH:12]\[S:13][C:14]1[C@H:15]([CH3:28])[C@@H:16]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]2[C:18]=1[C:19]([O:21][CH:40]([O:39][C:37]([O:36][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:38])[CH3:41])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1ncsc1/C=C\SC1=C(C(=O)[O-])N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reactant: CC(I)OC(=O)OC1CCCCC1
Agent: [Na+]
Product: CC(=O)OCc1ncsc1/C=C\SC1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Yield: 91.8 %

Procedure:
In the same manner as in Example 81, 159 mg of the title compound was prepared from 130 mg of sodium (1R,5S,6S)-2-[[(Z)-2-(4-acetoxymethylthiazol-5-yl)ethen-1-yl]thio]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 79 and 104 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([O:10][CH2:11][CH2:12]O)[CH:8]=[CH2:9].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]([O:6][CH2:12][CH2:11][O:10][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=CCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOCCOC(=O)C(=C)C
Temperature: 120 °C
Yield: 72.5 %

Procedure:
To a three-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a Dean-Stark apparatus were added methacrylic acid (137.7 g, 1.6 moles), ethyleneglycol monoallylether (80.7 g, 0.8 moles), p-toluenesulfonic acid (0.76 g, 4.0 mmole) and toluene (650 mL). The mixture was heated to 120° C. for 5 hours with exclusion of water. Another portion of p-toluenesulfonic acid (0.12 g) and the mixture was heated to 120° C. for 6 hours. The other portion of p-toluenesulfonic acid (0.1 g) was added and the mixture was heated to 120° C. for 9 hours. During the reaction, the consumption of methacrylic acid and ethyleneglycol monoallylether were monitored by liquid chromatography and the conversion reached 98%. The mixture was neutralized by addition of aq. NaHCO3 and the layers were separated. The aqueous layer was extracted with toluene and the combined organic layers were dried over CaCl2 and concentrated under reduced pressure. Distillation of the crude material (60° C. at 2 mmng) yielded 2-allyloxyethyl methacrylate (98.7 g, 73%) shown below.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][CH2:9][CH:7]([OH:8])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CCN)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CCNCC(O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
Phenyl glyoxal (0.8 g) and 2-(4-carbomethoxyphenyl)ethanamine (1.1 g) were heated in refluxing benzene (100 ml) under a Dean and stark head until the theoretical amount of water had been collected. The solvent was replaced with methanol and sodium borohydride (2.0 g) was added portionwise with ice cooling. The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The dried organic extract was evaporated and crystallised from benzene/hexane, mp 105°-106°. (CDCl3) 6.80-7.60 (8H, m), 6.18 (3H, s), 5.34 (1H, m), 2.94 (2H, d, J=8 Hz), 2.77 (5H, m), 2.09 (2H, d, J=8 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]=[C:21]1[C:19]([N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C@H:12]1[CH2:11][C@@H:10]([C:36]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[O:37])[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13]1)=[O:20]
Reactant: C1COCCN1
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 80.8 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (10 g) and morpholine (1.6 g) were dissolved in DMF (100 ml), WSC.HCL (4.8 g) and HOBt (3.1 g) were added, and the mixture was stirred at 50° C. for 12 hr. The reaction mixture was poured into 10% aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:1-1:0) was concentrated under reduced pressure to give the object product (8.9 g).
Reaction SMILES: [CH3:1][C@@:2]([S:25]([CH3:28])(=[O:27])=[O:26])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[N:11]1)[C:3]([O:5]CC)=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C@@:2]([S:25]([CH3:28])(=[O:27])=[O:26])([CH2:8][CH2:9][N:10]1[CH:14]=[C:13]([C:15]2[CH:24]=[N:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH:12]=[N:11]1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@](C)(CCn1cc(-c2cnc3ccccc3n2)cn1)S(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@](CCn1cc(-c2cnc3ccccc3n2)cn1)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
To a solution of ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanoate (0.078 g, 0.19 mmol) in THF-H2O (20 mL:10 mL) was added LiOH (0.047 g, 1.94 mmol, 10 eq). The mixture was allowed to stir at room temperature overnight. The mixture was acidified with 1M HCl and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanoic acid (0.072 g, 99% yield) as a white solid. LC-MS M+H+375.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][NH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C(=O)NC=1.S(Cl)([Cl:34])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:34])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(cc1OCc1ccccc1)N=CNC2
Agent: O=c1[nH]cnc2ccccc12
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1

Procedure:
After repetition of the reaction so described, a mixture of 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-3,4-dihydroquinazolin-4-one (20.3 g), thionyl chloride (440 ml) and DMF (1.75 ml) was heated to reflux for 4 hours. The thionyl chloride was evaporated under vacuum and the residue was azeotroped with toluene three times to give 7-benzyloxy-4-chloro-6-methoxyquinazoline.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:37])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=4)[CH:20]([C:29]([OH:31])=O)[NH:19][CH:18]3[CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:62][C:63]1[CH:72]=[CH:71][C:66]([C:67]([O:69][CH3:70])=[O:68])=[CH:65][C:64]=1[O:73][CH3:74]>>[CH3:70][O:69][C:67](=[O:68])[C:66]1[CH:71]=[CH:72][C:63]([NH:62][C:29]([C@@H:20]2[NH:19][C@@H:18]([CH2:32][C:33]([CH3:36])([CH3:34])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:37])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[O:31])=[C:64]([O:73][CH3:74])[CH:65]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2)c(OC)c1

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 63 (0.28 g, 0.5 mmol), was reacted with diisopropylethylamine (0.38 mL, 2.25 mmol), diphenylphosphinic chloride (0.36 mL, 1.9 mmol), then reacted with methyl 4-amino-3-methoxy-benzoate (Ark Pharm) (0.09 g, 0.5 mmol) to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield, 102 mg, 33%). MS (H+), 610.
Reaction SMILES: C(O[C:4](=[O:14])[CH:5]([S:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH3:6])C.C[O-].[Na+].Cl>CO>[CH3:6][CH:5]1[S:7][CH2:8][CH:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]1=[O:14]
Reactant: CCOC(=O)C(C)SCCC(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CSC(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a solution of methyl 3-(2-ethoxy-1-methyl-2-oxo-ethyl)sulfanylpropanoate (2.2 g, 10 mmol) in methanol (15 mL) at 0° C. was added sodium methoxide (886 mg, 16.4 mmol). The reaction was warmed to rt and stirred for 3 h. The mixture was acidified with 1 N HCl to pH 2 and extracted with DCM. The organic phase was washed with water and brine, dried (Na2SO4), concentrated and purified by column chromatography, eluting with EtOAc in petroleum (3%-10%) to give methyl tetrahydro-5-methyl-4-oxothiophene-3-carboxylate as a colourless oil (0.85 g, 50% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:12][C@@H:13]([NH:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([C@H:30]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:31][CH2:32][CH2:33][NH:34][C:35](=[O:38])[O:36][CH3:37])[CH2:25]1)=[O:23])[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)C(OCC[Si](C)(C)C)=O.CCN(CC)CC.C(O)=O>CC#N>[CH3:1][NH:2][CH2:12][C@@H:13]([NH:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([C@H:30]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:31][CH2:32][CH2:33][NH:34][C:35](=[O:38])[O:36][CH3:37])[CH2:25]1)=[O:23])[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: COC(=O)NCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCOCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CC#N
Product: CNC[C@H](CC1CCOCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2ccccc2)C1
Yield: 42.4 %

Procedure:
In a round bottom flask methyl 2-((R)—((R)-1-((S)-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate (20 mg, 0.03 mmol) and TEAF (15 mg, 0.07 mmol) was dissolved in a 15 mL of in MeCN. The solution was allowed to stir at reflux for 1 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give methyl 2-((R)—((R)-1-((S)-1-(methylamino)-3-(tetrahydro-2H-pyran-4-yl)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate (6.24 mg, 42%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1.[Cu][C:17]#[N:18].ClCCl>CN(C=O)C>[C:17]([C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][CH2:14][CH2:15][CH:5]3[C:4]=2[CH:3]=1)#[N:18]
Reactant: N#C[Cu]
Reactant: O=C1Nc2ccc(Br)cc2C2CCCC12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)C1CCCC1C(=O)N2
Yield: 38.3 %

Procedure:
A solution of 8-bromo-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (230 mg, 0.86 mmol) in DMF (20 ml) is mixed with copper(I) cyanide (77 mg, 0.86 mmol) and refluxed for 16 hours. The batch is diluted dichloromethane, washed with saturated NH4Cl, dried (Na2SO4) and concentrated by evaporation in a vacuum. Purification on silica gel with ethyl acetate-hexane yields 70 mg (38%) of product.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[CH2:19]([NH:26][CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:19]([N:26]([CH2:1][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH2:27][CH2:28][OH:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1[nH]cnc1C=O
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1[nH]cnc1CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a stirred suspension of Intermediate 1C (3.20 g, 20.76 mmol) in dry THF (180 mL) was added anhydrous Na2SO4 (14.48 g, 192 mmol) and N-benzylethanolamine (3.70 g, 24.47 mmol). The resulting mixture was stirred at room temperature under nitrogen for 1 hour. Sodium triacetoxyborohydride (6.37 g, 28.5 mmol) was added portion-wise and the resulting mixture was stirred under nitrogen for 48 hours. The resulting mixture was quenched with water and neutralized with saturated NaHCO3 solution. The mixture was extracted with DCM and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The crude mixture was purified using normal phase chromatography eluting with a 10-30% methanol/DCM gradient to provide Intermediate 1D as a white solid (5.80 g, 98%).
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[CH3:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[OH:26].[OH-].[Na+]>C(#N)C.O.[Cl-].[Na+].O>[CH2:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][C@@H:6]([O:26][C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[C:19]=2[CH3:18])[C@H:1]([OH:7])[CH2:2]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC2OC2C1
Reactant: Cc1cccc(O)c1C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: Cc1cccc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2O)c1C
Temperature: 25 °C
Yield: 51.4 %

Procedure:
Benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (21.0 g, 92.0 mmol) was added to a stirred solution of 2,3-dimethylphenol (23.0 g, 188 mmol) and aqueous sodium hydroxide (100 ml, 2N, 200 mmol) in acetonitrile (400 ml). The reaction mixture was heated at reflux for 14 h. On cooling to room temperature, the reaction mixture was concentrated in vacuo before dilution with water (500 ml). Extraction with dichloromethane (4×100 ml) was followed by washing of the combined organics with aqueous sodium hydroxide (100 ml, 3N, 300 mmol), water (100 ml) and brine (100 ml). The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to furnish a crude product. Purification was carried out by silica gel chromatography using a gradient eluent system of iso-hexanes and ethyl acetate (100% iso-hexanes to 80:20 iso-hexanes:ethyl acetate) to furnish trans-benzyl-4-(2,3-dimethylphenoxy)-3-hydroxypiperidine-1-carboxylate as a pale yellow syrup (16.8 g, 50%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[C:7]2=[O:16])[CH2:3][CH2:2]1.C(N1C2C(=CC=CC=2)C(=O)C1=O)CCCC.O1C2C=CC(O)=CC=2OC1.[F:43][C:44]1[CH:45]=[C:46]([OH:51])[CH:47]=[CH:48][C:49]=1[F:50]>>[F:43][C:44]1[C:49]([F:50])=[CH:48][C:47]([C:8]2([OH:15])[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:5][CH2:4][CH2:1][CH2:3][CH3:2])[C:7]2=[O:16])=[C:46]([OH:51])[CH:45]=1
Reactant: O=C1C(=O)N(CCC2CC2)c2ccccc21
Reactant: Oc1ccc(F)c(F)c1
Agent: CCCCCN1C(=O)C(=O)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCCCCN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-pentyl-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 3,4-difluorophenol, the title compound was obtained (31%): 1H NMR (300 MHz, CDCl3) δ 9.69-9.65 (br, 1H), 7.51-7.41 (m, 2H), 7.26-7.21 (m, 1H), 6.99-6.57 (m, 3H), 4.18-4.14 (br, 1H), 3.78-3.58 (m, 2H), 1.76-1.62 (m, 2H), 1.40-1.28 (m, 4H), 0.87 (t, 3H); MS (ES+) m/z 330 (M−17), 370 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: BrCCc1ccncc1
Product: O=C1OC2(CCN(C(=O)c3cn(CCc4ccncc4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with commercially available 4-(2-bromo-ethyl)-pyridine gave the title compound. ES-MS m/e (%): 504.2 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1>C1COCC1.O.CCCCCC>[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]1[CH:32]([OH:33])[C:31]1[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCNC(=O)C1C(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of diisopropylamine (3.1 ml, 22 mmole) and dry THF (5 ml) at 0° C. under argon is added dropwise a hexane solution of n-butyllithium (13.8 ml, 22 mmole). After 3/4 hour, a solution of 2 (2.0 g, 10 mmole) in 75 ml of dry THF is added dropwise and stirred at 0° C. for 3 hours and 4-fluoro-benzaldehyde (13.6 g, 11 mmole) added dropwise. The reaction mixture was stirred at room temperature for 68 hours, poured into water, and extracted into ether. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure, and the residue recrystallized from ethanol to give 35. M.p. 219° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18](O)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[ClH:33]>C(O)(C)C>[ClH:33].[C:25]1([C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][CH:9]=[CH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:17][CH2:16]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: Fc1ccc(C=CCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
A mixture of 15 g (0.034 mole) of α-(p-fluorophenyl)-4-(α-hydroxy-α-phenylbenzyl)-1-piperidinebutanol, 400 ml of concentrated HCl and 1500 ml of isopropyl alcohol was heated on a steam bath for 16 hours. The isopropyl alcohol was then concentrated by heating, and the remaining solution was cooled to room temperature. A precipitate formed which was collected on a filter and recrystallized from isopropyl alcohol and ethyl acetate to give the desired product, M.P. 166°-168.5° C.