Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[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.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[C:66]([Cl:74])[CH:65]=1>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[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:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]=1[Cl:74]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)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)c2F)cc1Cl
Yield: 32.3 %

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-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with methyl 4-amino-2-chlorobenzoate (0.099 g, 0.53 mmol) to give rac-2-chloro-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-benzoic acid methyl ester as a white solid (Yield 0.09 g, 32%).
Reaction SMILES: F[C:2]1[C:11]([B:12]([OH:14])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][OH:16]>Cl>[CH3:15][O:16][C:2]1[C:11]([B:12]([OH:14])[OH:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CO
Reactant: OB(O)c1cc2ccccc2nc1F
Agent: Cl
Product: COc1nc2ccccc2cc1B(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2-Fluoroquinolin-3-yl)boronic acid was dissolved in 1.25M HCl in MeOH and stirred for 1 hr at RT. The mixture was quenched with sat. aq. NaHCO3 solution and the mixture was extracted with DCM (3×). The organics were dried (Na2SO4) and concentrated under reduced pressure to yield the crude product as a pale yellow solid which was used in the next step without further purification. MS (ES) C10H10BNO3 requires: 203, found: 204 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][OH:18])[CH2:15][OH:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:15][O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:17][O:18][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:10][CH:9]=1)=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(CO)CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccc(C(COS(C)(=O)=O)COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of [4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-carbamic acid tert-butyl ester (267 mg, 1.00 mmol, as prepared in the previous step) in DCM (10 mL) and Et3N (0.35 mL, 2.5 mmol), methanesulfonyl chloride (MsCl) (0.15 mL, 2.0 mmol) was added dropwise at 0° C. The resulting mixture was stirred at RT for 30 min, diluted with DCM (10 mL) and washed with satd NaHCO3 (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated to afford methanesulfonic acid 2-(4-tert-butoxycarbonylamino-phenyl)-3-methanesulfonyloxy-propyl ester, which was dried in vacuo and directly used in next step: Mass spectrum, (ESI, m/z): Calcd. for C16H25NO8S2, 446.1 (M+Na). found 446.0.
Reaction SMILES: O.[N-:2]=[N+:3]=[N-:4].[Na+].CS(O[CH2:11][C:12]1[O:13][CH2:14][CH2:15][CH2:16][CH:17]=1)(=O)=O>CN(C)C=O>[N:2]([CH2:11][C:12]1[O:13][CH2:14][CH2:15][CH2:16][CH:17]=1)=[N+:3]=[N-:4]
Reactant: CS(=O)(=O)OCC1=CCCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1=CCCCO1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Water (35 mL) and sodium azide (15.1 g, 232 mmol) were added to a solution of the crude (5,6-dihydro-4H-pyran-2-yl)methyl methanesulfonate (about 193 mmol) in N,N-dimethylformamide (350 mL), and the mixture was stirred at room temperature for 20 hours. Water (300 mL) was added to the reaction solution, followed by extraction with ethyl acetate (1.5 L). The resulting organic layer was washed with water (3×200 mL) and brine (200 mL). The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to about 300 mL. The resulting crude title compound solution was used for the next reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][N:19]=3)=[O:17])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:29](Br)[CH:30]=[CH2:31]>>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][NH:15][C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:31][CH:30]=[CH2:29])[N:19]=3)=[O:17])[CH2:11][CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C(NCCN1CCN(Cc2ccc(F)cc2)CC1)c1n[nH]c2ccccc12
Reactant: C=CCBr
Product: C=CCn1nc(C(=O)NCCN2CCN(Cc3ccc(F)cc3)CC2)c2ccccc21

Procedure:
The title compound was synthesized by using N-[2-(4-p-fluorobenzyl-1-piperazinyl)ethyl]-1H-indazole-3-carboxamide obtained in Example 11 and allyl bromide according to the same process as in Example 12.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].Cl[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[S:10][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(O)c(S)c(=O)o1
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2cccc3ccccc23)c(=O)o1

Procedure:
A solution of 15.8 g. (0.100 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone in 100 ml. of pyridine was cooled in an ice bath to about 15°C., and 17.7 g. (0.100 mole) of 1-chloromethylnaphthalene was added in one portion. The flask was then heated at 90°-95°C. on the steam plate for four hours. The reaction mixture was cooled and poured into 200 ml. of concentrated hydrochloric acid and about 400 g. of ice. A gummy solid was formed and was extracted with methylene chloride. The wet extract was treated with Darco and dried over anhydrous sodium sulfate. The solvent was removed by evaporation in vacuo, leaving a brown gum, which was crystallized (Darco) from ethanol to give 9.8 g. (33 percent) of tan crystals m.p. 155.5°-157.5°C. Recrystallization from ethanol gave the pure 4-hydroxy-6-methyl-3-(1-naphthylmethylthio)-2-pyrone as cream colored crystals, m.p. 169.5°-170.5°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N=C=NC(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.[C:27]([C:30]1[CH:60]=[CH:59][C:33]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=3)[CH2:37][CH2:36]2)=[CH:32][CH:31]=1)(O)=[O:28]>CN(C=O)C>[N:1]1([C:27]([C:30]2[CH:60]=[CH:59][C:33]([CH2:34][N:35]3[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:43](=[O:58])[CH2:44][NH:45][C:46](=[O:57])[C:47]4[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:54])([F:56])[F:55])[CH:48]=4)[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)O)cc2)CC1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(C(=O)N3CCCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Piperidine (0.04 mmol), diisopropylcarbodiimide (0.45 mmol) in DMF (0.15 mL), 1-hydroxybenzotriazole hydrate (0.45 mmol) in DMF (0.15 mL) were added to a solution of 1-(4-carboxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (0.040 mmol) in DMF (1.0 mL). The reaction mixture was stirred at room temperature for 17 h, loaded onto Varian™ SCX column, and washed with CHCl3/CH3OH 1:1 (5 mL) and CH3OH (5 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 1{-4-(piperidinocarbonyl)benzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1572) (14.3 mg, 66%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 545 (M++H, C29H35F3N4O3).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:16])[C:6](=[CH:10][C:11]=1[C:12](=[O:15])[CH2:13][CH3:14])C(O)=O)[CH3:2].C>C(O)C>[CH2:1]([C:3]1[NH:4][C:5](=[O:16])[CH:6]=[CH:10][C:11]=1[C:12](=[O:15])[CH2:13][CH3:14])[CH3:2]
Reactant: CCC(=O)c1cc(C(=O)O)c(=O)[nH]c1CC
Solvent: CCO
Product: CCC(=O)c1ccc(=O)[nH]c1CC

Procedure:
A 15 g portion of 6-ethyl-1,2-dihydro-2-oxo-5-(n-propanoyl)-nicotinic acid was heated in an oil bath at 235°-240° C. for 5 hours, cooled and the reaction mixture dissolved in hot ethanol, treated with decolorizing charcoal and filtered. The filtrate was evaporated in dryness and the residue recrystallized from isopropyl alcohol to yield 8.2 g of 6-ethyl-5-(n-propanoyl)-2(1H)-pyridinone, m.p. 138°-140° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH:17]=[C:16]4[C:31]([O:33]C)=[O:32])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:35])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH:17]=[C:16]4[C:31]([OH:33])=[O:32])[CH:12]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cn(Cc2ccncc2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccncc3)cc(C(=O)O)c2c1
Temperature: 50 °C

Procedure:
To a mixture of the product of step ii) (0.7 g) in methanol (15 mL) was added a 5M aqueous solution of sodium hydroxide (1.8 mL) and the reaction heated at 50° C. for 6 hours. The reaction mixture was allowed to cool to room temperature and then treated with water (20 mL). The precipitate was collected by filtration, washed with water and dried to give the sub-title compound (0.52 g).
Reaction SMILES: [C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].[Ca+2].[C:17]([O-])(=O)[CH2:18][CH2:19]NC(=O)[C@@H](C(CO)(C)C)O.F[C:33](F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.COC(OC)(C)C>[CH3:33][O:14][C:1](=[O:15])[CH2:2][CH2:3][NH:4][C:5]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH2:11][O:12][C:18]([CH3:19])([CH3:17])[O:7]1)=[O:13]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: COC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Reaction time: 8 h

Procedure:
A 5.0 g portion of calcium pantothenate was slurred in 100 ml of acetone:2,2-dimethoxypropane (1:1). Trifluoroacetic acid (3.0 ml) was added until solution was complete and stirring was continued overnight. A 10 g portion of potassium carbonate was added, this mixture stirred vigorously for 10 minutes and then concentrated to a gummy solid. A 100 ml portion of acetonitrile and 10 ml of methyl iodide were added to the solid. This mixture was stirred for 1 day, then poured into water and extracted twice with ethyl acetate. The extracts were combined, dried and concentrated, giving 4.8 g of the desired compound as a yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].[O:42]1[CH:47]=[CH:46][CH2:45][CH2:44][CH2:43]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.C(OCC)(=O)C>[O:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH:43]1[O:1][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(COC1CCCCO1)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1

Procedure:
A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (106 mg) and dihydropyran (25 mg) in dry dichloromethane (1 ml) was treated with p-toluenesulfonic acid (1 mg) at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by thin-layer chromatography (SiO2) to yield (3S,4S)-4-(1-tetrahydropyranyloxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone.
Reaction SMILES: [F:1][C:2]1[C:3]([N:40]=[C:41]=[O:42])=[C:4]([CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:16]3=[N:17][CH:18]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[OH:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.C(N(CC)C(C)C)(C)C>ClCCl>[N:46]1([CH2:45][CH2:44][O:43][C:41](=[O:42])[NH:40][C:3]2[C:2]([F:1])=[CH:12][C:11]([C:13]3[CH:14]=[C:15]4[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]5[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=5)(=[O:32])=[O:31])[C:16]4=[N:17][CH:18]=3)=[CH:10][C:4]=2[C:5](=[O:6])[N:7]([CH3:9])[CH3:8])[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1
Reactant: OCCN1CCOCC1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N=C=O)c(C(=O)N(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NC(=O)OCCN4CCOCC4)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
75 mg (0.13 mmol) of 3-fluoro-2-isocyanato-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide was dissolved in 1.0 mL dichloromethane and combined with 31 μL (0.26 mmol) of 4-(2-hydroxyethyl)-morpholine (which was dried over molecular sieves) and 22 μL (0.13 mmol) of N,N-diisopropylethylamine. The reaction was stirred for 16 hours at room temperature. 31 μL (0.26 mmol) of 4-(2-hydroxyethyl)morpholine was added and the reaction was continued to stir for 24 hours at room temperature. The reaction was concentrated and purified by flash chromatography on silica gel using a gradient of ethyl acetate (containing 10% methanol) and hexanes. The clean fractions were concentrated. MS: m/z 715.3 (M+H+).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>CCOCC.C1COCC1>[OH:4][C:5]1[N:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:3])=[O:8]
Reactant: Cc1ccc(C(=O)O)c(O)n1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C)nc1O
Reaction time: 2 h

Procedure:
Excess diazomethane in ether was added portionwise over 15 mins to 9.58 g (~60 mmoles) of 2-hydroxy-6-methyl nicotinic acid in 900 mL of THF at 0°. After stirring 2 hours, excess diazomethane was removed in vacuo. The resulting white solid was filtered and washed with hexane and dried. This fluffy solid was the required methyl ester. The filtrate was concentrated. The resulting solid was redissolved in a minimum amount of THF and hexane was added until no further precipitation was observed. Solid was filtered and washed with hexane and dried to provide more of the desired compound.
Reaction SMILES: [OH-].[Na+].[N+](C1C=CC(C([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C@@H:19]([CH2:27][N+:28]([O-:30])=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=O)=CC=1)([O-])=O.C(O)(=O)C>C(O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:19]([C@@H:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]2[OH:12])[CH2:27][N+:28]([O-:30])=[O:29])=[CH:21][CH:22]=1
Reactant: O=C(O[C@@H]1CCCC[C@H]1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])C[C@@H](c1ccc(Cl)cc1)[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 490 ml (12.1 mmol) of sodium hydroxide in 40 ml of ethanol is added dropwise to a solution of 3.5 g (8.09 mmol) of rac-(1R*)-trans-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexyl p-nitrobenzoate in 80 ml of ethanol. The mixture is stirred at room temperature for 16 hours, treated with 1 ml of acetic acid and the solvent is distilled off in a water-jet vacuum. The residue is treated with water, whereupon the mixture is extracted twice with 100 ml of ether each time. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The residue is chromatographed on a 30-fold amount of silica gel and there is obtained rac-(1R*)-trans-2-[(R*)-4-chloro-α-(nitromethyl)benzyl]cyclohexanol in the form of a yellowish oil.
Reaction SMILES: [H-].NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][S:12][C:13]2[O:14][CH:15]=[CH:16][N:17]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][S:12][C:13]1[O:14][CH:15]=[CH:16][N:17]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ncco1
Agent: NN
Agent: [H-]
Solvent: CCO
Product: NCCCSc1ncco1

Procedure:
Hydrazine hydride (5.3 g) was added carefully to a solution of 2-(3-phthalimidopropylthio)oxazole (10 g) in ethanol (173 ml) with stirring. The solution was then heated under reflux for 25 minutes. After cooling, and filtration from phthalhydrazide, the filtrate was concentrated under reduced pressure and the residue was re-evaporated with ethanol to yield crude 2-(3-aminopropylthio)oxazole.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:8][C:9]#[N:10].[CH3:11][C:12]1([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1>>[C:9]([CH2:8][C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[NH:1][CH:27]1[CH2:26][CH2:25][N:24]([C:12]2([CH3:11])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)[CH2:29][CH2:28]1)#[N:10]
Reactant: N#CC[C@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(=O)CC2)C1
Product: CC(C)(C)OC(=O)N1CCC(C)(N2CCC(N[C@H]3CCCC[C@@H]3CC#N)CC2)C1
Yield: 9 %

Procedure:
Following the procedure used in step D of the example 14 and starting with 2-[(1R,2S)-2-aminocyclohexyl]acetonitrile (0.342 g, 2.47 mmol) and tert-butyl 3-methyl-3-(4-oxo-1-piperidyl)pyrrolidine-1-carboxylate (0.699 g, 2.47 mmol), the title compound (0.090 g, 8.99%) was obtained after purification by preparative LC/MS (High pH). MS (M+1): 405.23.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[C:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]1=[O:24])[O:10][CH2:9]2.[H][H]>[Pd].CO>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[C:15]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]1=[O:24])[O:10][CH2:9]2
Reactant: CN(C)CC#Cc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Yield: 23 %

Procedure:
A mixture of 3-[5-(3-dimethylamino-prop-1-ynyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one (300 mg, 0.91 mmol) and 10% palladium on carbon (60 mg) in MeOH (20 ml) was shaken under 43 psi of hydrogen for 4 hours. The catalyst was removed by filtration through celite and rinsed with MeOH. The combined filtrates were evaporated to give a crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of MeOH in CHCl3, to give 3-[5-(3-dimethylamino-propyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (70 mg, 23%).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:20][C:21]([OH:23])=[O:22])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1.Cl[Si](C)(C)[CH3:26]>CO>[CH3:26][O:23][C:21](=[O:22])[CH2:20][N:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=[C:9]1[C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Solvent: CO
Product: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
To [2-(4-methoxy-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid (3.4 g, 11.0 mmol) dissolved in anhydrous MeOH (200 mL) and cooled to 0° C. is added chlorotrimethylsilane (1.40 mL, 11.0 mmol). The mixture is refluxed for ˜12 h. The contents are concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (10% hexanes/ethyl acetate) to give-(2,5-Diphenyl-pyrrol-1-yl)-acetic acid methyl ester as a yellow solid (2.68 g), characterized by LCMS (Obs: 322.56, Cal: 321.14) and 1H NMR.
Reaction SMILES: O.O.C1(C)C=CC=CC=1NC1NC2C=C(CC([NH:22][C:23]3[CH:28]=[CH:27][C:26]([C@H:29]([CH3:34])[CH2:30][C:31]([OH:33])=[O:32])=[CH:25][CH:24]=3)=O)C=CC=2N=1.C([O-])=O.[NH4+].[CH2:40](O)[CH3:41]>[Pd]>[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([C@H:29]([CH3:34])[CH2:30][C:31]([O:33][CH2:40][CH3:41])=[O:32])=[CH:27][CH:28]=1
Reactant: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc([C@H](C)CC(=O)O)cc3)cc2[nH]1
Reactant: CCO
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Temperature: 50 °C

Procedure:
A solution of ethyl 3(R)-(4-nitrophenyl)butanoate (4.0 g, Reference Example 2) in ethanol (100 mL) was treated with ammonium formate (about 15 g). The reaction mixture was immersed in an oil-bath in a single neck flask, the solution was heated to 50° C., then treated with palladium on charcoal (about 1 g, 5%) to give an immediate visible effervescence. The mixture was kept at 50° C. with stirring for about an hour, then filtered through filter-aid. The filtrate was evaporated and the residue was partitioned between tert-butyl methyl ether and water. The organic phase was dried then evaporated to give the title compound (2.8 g) as a light brown gum.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=O)[C:10]=1[F:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[CH:15]=[N:7]/[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[C:10]=1[F:17]
Reactant: O=Cc1nccc(Cl)c1F
Reactant: CC(C)(C)[S@](N)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1nccc(Cl)c1F
Yield: 106.5 %

Procedure:
A solution of (R)-2-methylpropane-2-sulfinamide (0.540 g, 4.32 mmol), 4-chloro-3-fluoropicolinaldehyde (0.627 g, 3.93 mmol) and Cs2CO3 (1.921 g, 5.89 mmol) in DCM (20 mL) was stirred for 1 h at rt. The reaction mixture was diluted with EtOAc and washed with brine (3×20 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to provide the desired product (1.1 g, 100%). MS (ESI) m/z: 263.0 (M+H)+.