Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1)[CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=1)[CH2:9][NH:10][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CN)Cc1ccc(O)c(C(C)(C)C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)Cc1ccc(O)c(C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
To a solution of 1.53 g (4.75 mmol) of [2-amino-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]carbamic acid tert-butyl ester in methylene chloride (20 ml), 0.725 ml (5.23 mmol) of triethylamine and 0.746 ml (5.23 mmol) of benzyl chloroformate were added and the resulting mixture was stirred for 15 minutes. Under cooling with ice, saturated aqueous NaHCO3 was added and the mixture was extracted with methylene chloride and washed with saturated brine. The organic layer was dried with magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate:n-hexane=1:1) to give [2-(benzoxycarbonylamino)-1-[(3-tert-butyl-4-hydroxyphenyl)methyl]ethyl]carbamic acid tert-butyl ester in the amount of 1.78 g (82%).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:39])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[CH:18][C:17]=1[Cl:38])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:39])=[C:17]([Cl:38])[CH:18]=1)([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)COc1ccc(OCC(=O)N2CCC[C@@H]2C(=O)O)c(Cl)c1
Reaction time: 8 h

Procedure:
A solution of 140 mg (0.25 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-2-chloro-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 1.5 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 126 mg (quantitative) of the title compound as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:12][CH2:13][C:14]([OH:16])=[O:15]>[OH-].[Na+].C1COCC1.O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][S:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)CS
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CSCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
4-Nitrobenzyl chloride (2.5 g, 15 mmol) was added to a solution of mercaptoacetic acid (80% in H2O, 1 mL,~12 mmol) in aqueous sodium hydroxide (2.75N, 10 mL) and THF (10 mL) with stirring at 50° C. After 1 hour, the reaction was cooled to ambient temperature, diluted with water (30 mL) and extracted with Et2O to remove excess halide. The aqueous layer was distributed between EtOAc and 5% citric acid and the organic extract then washed with H2O, dried (MgSO4) and evaporated to give the title compound as a pale yellow solid, m.p. 101-104° C. [lit. m.p. 114° C⟧ 1H NMR (CDCl3); δ3.10 (s, 2H), 3.94 (s, 2H), 5.37 (d, 2H, J =8.7 Hz), 8.21 (d, 2H, J=8.7 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C:56]1([CH2:62][C@H:63]([C:65]2[O:66][C:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)=[N:68][N:69]=2)[NH2:64])[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37](=[O:38])[NH:64][C@@H:63]([C:65]1[O:66][C:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)=[N:68][N:69]=1)[CH2:62][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
First, N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was synthesized by analogy with the synthesis of intermediate 17 by reacting 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 7) with 12.2 mg (32 μmol) (1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanamine trifluoroacetic acid salt (intermediate 15).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.Br[C:10]1[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:12](=[O:18])[C:11]=1[C:19]#[N:20]>C(O)C>[C:19]([C:11]1[C:12](=[O:18])[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:10]=1[NH:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)#[N:20]
Reactant: NCc1ccncc1
Reactant: CCn1ncc(Br)c(C#N)c1=O
Solvent: CCO
Product: CCn1ncc(NCc2ccncc2)c(C#N)c1=O
Yield: 62.5 %

Procedure:
Into 5 ml of an absolute ethanol solution of 0.16 g of 4-picolylamine, 5 ml of an absolute ethanol suspension of 0.11 g of 5-bromo-4-cyano-2-ethylpyridazin-3-(2H)-one, was dropwise added under cooling with ice over a period of 20 minutes. After completion of the dropwise addition, the mixture was reacted at room temperature for one hour. Then, ethanol was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed once with water and dried over anhydrous sodium sulfate and then concentrated. To the residue, n-hexane and ethyl ether were added in a small amount for crystallization. The crystals were collected by filtration and dried to obtain 77 mg of the desired product (Compound No. 47) having a melting point of from 193° to 195° C.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH2:9]([O:16][CH2:17][CH:18]=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:20]([CH:23]([CH3:25])[CH3:24])([O-:22])=[O:21]>C1COCC1>[CH2:9]([O:16][CH2:17][CH:18]([OH:19])[C:23]([CH3:25])([N+:20]([O-:22])=[O:21])[CH3:24])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[N+](=O)[O-]
Reactant: O=CCOCc1ccccc1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C(O)COCc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Yield: 87.1 %

Procedure:
1,1,3,3-Tetramethylguanidine (620 μL, 5 mmol) was added slowly to a cold, 0° C., stirring solution of benzyloxy acetaldehyde (4.6 g, 31 mmol) and 2-nitropropane (30 mL, 333 mmol) in 100 mL of anhydrous THF. The reaction was stirred at 0° C. for ten minutes then allowed to warm to room temperature and stirred for 18 hours. The reaction was concentrated under reduced pressure and the product purified by column chromatography (5 to 50% ethyl acetate in hexanes) to give the title compound as a clear liquid (6.4 g, 27 mmol, 84%). 1H NMR (CDCl3, 400 MHz) δ 1.58 (s, 3H), 1.63 (s, 2H), 2.87-2.89 (d, J=5.0 Hz, 1H), 3.48-3.53 (dd, 6.8, 9.8 Hz, 1H), 3.60-3.63 (dd, J=4.5, 9.8 Hz, 1H) 4.29-4.33 (m, 1H), 4.57 (s, 2H), 7.32-7.39 (m, 5H). LRMS (ESI/APCI) m/z 238 [M−H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([F:21])=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)ccc1F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Temperature: 80 °C

Procedure:
A 50 mL Schlenk tube was charged with (3-fluorophenyl)boronic acid (140 mg, 1.0 mmol), 5-bromo-2-fluorobenzoic acid (263 mg, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0) (58 mg, 0.05 mmol) and cesium carbonate (1.3 g, 4.0 mmol). Ethanol (5 mL) and toluene (5 mL) were added and the tube was sealed and heated at 80° C. for 3 h. The cooled mixture was transferred to a flask, washing with ethanol, and concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with EtOAc (2×10 mL). The aqueous phase was acidified with 1.0 N aqueous HCl (10 mL) and extracted with EtOAc (3×10 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo. 1H-NMR showed the desired product, 3′,4-difluoro-[1,1′-biphenyl]-3-carboxylic acid, was slightly contaminated with 2-fluorobenzoic acid. The impure product (215 mg, ˜92%) was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].[OH-].[Na+].Br[CH2:10][CH2:11][CH2:12][Cl:13]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][OH:6]
Reactant: ClCCCBr
Reactant: CCNCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCN(CCO)CCCCl
Yield: 38.8 %

Procedure:
2-Ethylamino ethanol (6.2 g, 70 mmol), acetone (18 ml, 3 vol), 5M NaOH solution (16.8 ml, 1.2 eq.) and 1-bromo-3-chloropropane (16.5 g, 105 mmol, 1.5 eq.) were reacted together according to general procedure A to give the title compound (4.5 g, 39%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Cl)[CH:17]=1)[C:5]2([CH3:21])[CH3:20].[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)[CH:17]=1)[C:5]2([CH3:21])[CH3:20]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CCl)c1
Product: Cn1cc(Cc2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)cn1

Procedure:
In analogy to the procedure described for the preparation of example 204, 5-chloro-2-(5-chloromethyl-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12-1) and 1-methylpyrazole-4-boronic acid pinacol ester were used to yield the title compound as a light yellowish solid (yield 15%). MS: 367.2 (M+H+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[O:11].[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH2:8][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:13][CH:14]=1
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccc(F)cc3)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 3-chloro-1-(4-fluorophenyl)-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 397.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[N:8][C:4]=2[CH:3]=1.[OH-:23].[NH4+].OO>CO>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:7]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]([NH2:12])=[O:23])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2ccccc2C#N)nc2cc(Br)ccc21
Reactant: [OH-]
Agent: OO
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)n1c(-c2ccccc2C(N)=O)nc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a round bottom flask is added 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzonitrile (1800 mg, 5.08 mmol) in MeOH (40 mL), followed by the addition of ammonium hydroxide (20 mL) and hydrogen peroxide (10 mL) (30% in water). The reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water then brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-4% MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 2-(5-bromo-1-tert-butyl-1H-benzimidazol-2-yl)-benzamide (1590 mg, 84%) as a light brown solid. LCMS (ESMS): m/z 372.46, 374.35 (M++1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[C:10](=[CH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[O:23][C:22]([CH3:25])=[CH:21][C:20]3=[O:26])[C:11](=O)[CH3:12])=[CH:5][CH:4]=1.[NH2:28]/[C:29](/[CH3:36])=[CH:30]\[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[O:23][C:22]([CH3:25])=[CH:21][C:20]4=[O:26])[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([CH3:36])[NH:28][C:11]=2[CH3:12])=[O:27])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: COc1ccc(C(=O)C(=Cc2cccc3c(=O)cc(C)oc23)C(C)=O)cc1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(OC)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
230 mg (0.63 mmol) of 1-(4-methoxyphenyl)-2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-butane-1,3-dione are heated with 81.9 mg (0.63 mmol) of ethyl 3-aminocrotonate in 5 ml of 2-propanol under reflux overnight. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 50 mg (16% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:39]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:40])[CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N1CCOCC1)N1CCCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)C1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.20 mmol) (from Example 25a supra) in tetrahydrofuran (3 mL) was added triethylamine (32 mg, 0.3 mmol), followed by the addition of morpholine-4-carbonyl chloride (38 mg, 0.24 mmol) (Aldrich). The mixture was stirred at 45° C. for 3 hours, then cooled to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue were triturated with dichloromethane-hexanes to give rac-6-chloro-3-(3-chloro-benzyl)-3-[1-(morpholine-4-carbonyl)-piperidin-3-yl]-1,3-dihydro-indol-2-one as a white solid. (Yield 60 mg, 60%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]>CN(C=O)C.CCOC(C)=O>[CH3:5][O:6][C:7](=[O:23])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:1]=[N+:2]=[N-:3])=[CH:10][C:9]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture at 0° C. under N2 of sodium azide (1.47 g, 22.6 mmol) in anhydrous DMF (30 mL) was added a solution of 4-bromomethyl-2-(2-methylphenyl)benzoic acid methyl ester (6.00 g, 18.8 mmol), prepared as in Example 1178A-D, in anhydrous DMF (10 mL). Reaction stirred overnight at room temperature. Reaction diluted with EtOAc and washed with water and brine. Organic layer dried with Na2SO4, filtered, and concentrated in vacuo.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Br[CH:27]([CH:33]1[CH2:35][CH2:34]1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:27]([CH:33]2[CH2:35][CH2:34]2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(Br)C1CC1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(C(=O)OCC)C2CC2)C1=O

Procedure:
Coupling of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) and ethyl 2-bromo-2-cyclopropylacetate (Example 249, Step A) using the procedure as described in Example 9, step A afforded the title compound as a mixture of two diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[CH2:22][OH:23])[N:14]=2)[C:9](=[O:24])[C:8]([C:25]([O:27]CC)=[O:26])=[CH:7]1.[OH-].[Li+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:22][OH:23])[N:14]=2)[C:9](=[O:24])[C:8]([C:25]([OH:27])=[O:26])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCCCC3CO)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccc(N4CCCC[C@@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 5A (2.3 g) and 0.1M lithium hydroxide (90 mL) in ethanol (110 mL) was stirred for 16 hours, adjusted to pH 3 with 1M hydrochloric acid, treated with water, and extracted with dichloromethane. The extract was concentrated, and the concentrate was recrystallized from ethyl acetate/hexanes.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]([CH3:33])([CH3:32])[CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[N+:29]([O-:31])=[O:30]>ClCCl>[CH2:22]([O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([NH:10][CH2:9][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])([CH3:33])[CH3:32])=[C:12]([N+:29]([O-:31])=[O:30])[CH:13]=[N:14]2)=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)N=C=O
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Solvent: ClCCl
Product: CC(C)NC(=O)NC(C)(C)CNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Isopropyl isocyanate (2.05 mL, 20.9 mmol) was added to a stirred suspension of (2-amino-2-methylpropyl)(7-benzyloxy-3-nitroquinolin-4-yl)amine (prepared as described in Part A of Example 45, 6.95 g, 19.0 mmol) in dichloromethane (200 mL) at 0° C. After approximately 30 minutes, the reaction mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure to afford 8.49 g of N-(2-{[7-(benzyloxy)-3-nitroquinolin-4-yl]amino}-1,1-dimethylethyl)-N′-isopropylurea.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])(=[O:3])[CH3:2].[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:17][CH:16]=[CH2:15])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(C)=O)cc1C(=O)O

Procedure:
The reaction of methyl 5-acetyl-2-hydroxyl-benzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 5-Acetyl-2-allyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.94 (s, —CO2H); 8.21 (m, 1 arom. H); 8.06 (m, 1 arom. H); 7.20 (m, 1 arom. H); 6.02 (m, —CH═CH2); 5.50, 5.28 (2 d-like, CH═CH2); 4.73 (d-like, CH2—CH═CH2); 2.53 (s, CH3C═O). 13C-NMR (100 MHz, d6-DMSO): 195.91 (CH3C═O); 166.71 (C(OH)═O); 160.44; 133.22; 132.76; 131.12; 129.11; 121.46; 117.30; 113.35; 69.81; 26.42.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][S:11]([NH2:14])(=[O:12])=[O:13])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CS(N)(=O)=O)cc1
Reaction time: 8 h

Procedure:
step 2—To a solution of (4-nitro-phenyl)-methanesulfonamide (1.18 g, 5.41 mmol) in EtOH (120 mL) was added Pd/C (10%, 118 mg). The mixture was stirred overnight under H2 (balloon pressure), the catalyst was filtered off on a CELITE® pad and the filter cake was washed with EtOH. The filtrate was concentrated in vacuo to afford (4-amino-phenyl)-methanesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@H:15]2[C@H:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:13][C@@H:14]2O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:32])=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]2[C@@H:15]([C@@H:14]([Cl:32])[CH2:13][CH2:12][C:11]2([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Product: CC(C)(C)OC(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2Cl

Procedure:
A solution of 1 g of (3aR,4S,7aR)-2-tert-butyloxycarbonyl-7,7-diphenyl-4-perhydroisoindolol in 10 cm3 of thionyl chloride is stirred for 3 hours at 80° C. The reaction mixture is then concentrated to dryness under reduced pressure (2.7 kPa). 1.03 g of (3aR,7S,7aR)-2-tert-butyloxycarbonyl-7-chloro-4,4-diphenylperhydroisoindole are obtained in the form of a solid which is used in the crude state in the next test.