Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=O)[C:6]=2[CH:17]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[S-2].[K+].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH:10]([CH2:12][CH2:13][Cl:14])[CH2:9][N:8]([CH3:15])[C:7](=[S:19])[C:6]=2[CH:17]=1
Reactant: CN1CC(CCCl)Oc2ccc(Br)cc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [K+]
Agent: [S-2]
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(Br)cc2C1=S
Yield: 72.6 %

Procedure:
To a solution of 11.0 g (0.035 mole) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-benzoxazepin-5(4H)-one in 150 ml of dry toluene was added a mixture of 13.4 g (0.07 mole) of phosphorus pentasulfide and 13.4 g of potassium sulfide which had been ground together. The reaction mixture was heated at reflux for 5 hr under a nitrogen atmosphere. The mixture was filtered hot and the filtrate concentrated under reduced pressure. The residue was dissolved in chloroform. The chloroform solution was washed twice with dilute aqueous sodium hydroxide, dried over magnesium sulfate and concentrated under reduced pressure to give 8.5 g (72%) of yellow solid. The solid was recrystallized from ethanol, m.p. 118°-120° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]([O-:16])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13].[H][H]>[Ni].C(OC(=O)C)C>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH:13][CH:12]([CH3:14])[CH2:11][C:10]([O-:16])=[O:15]
Reactant: CC(=O)CC(=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CC1(C)OCC(CO)O1
Solvent: CCOC(C)=O
Product: CC(O)CC(=O)[O-]
Temperature: 60 °C
Reaction time: 7 h
Yield: 91.8 %

Procedure:
A Zipperclave Autoclave (Autoclave Engineers) was charged with ethylacetate (2.4 L), solketal acetoacetate from Example 1 (609.5 g, 2.82 mole) and Raney Nickel (25 g, W-2 grade, PM-77, water wet) under an inert atmosphere of nitrogen. The nitrogen was displaced with hydrogen to a pressure of approximately 1100 psi. The reaction mixture was then heated with vigorous stirring (1500 rpm) at 60° C. for approximately seven hours. A small (ca. 5 ml) sample of the reaction mixture was removed from the reactor, filtered through celite and concentrated in vacuo. Proton NMR analysis revealed that roughly 2 mole % of unreduced acetoacetate remained. The crude reaction mixture was then heated at 60° C. and 1000 psi hydrogen with vigorous stirring for an additional 5 hours. The autoclave was cooled to room temperature and the hydrogen atmosphere was displaced with nitrogen. The crude reaction mixture was filtered through celite. The resulting solution was extracted in a separatory funnel with saturated aqueous sodium chloride. The organic phase was isolated, filtered through magnesium sulfate and sodium sulfate. The resulting filtrate was concentrated in vacuo to provide an oil (565.11 g, 2.59 mole, approximately 92%). This oil was not purified further but was shown by NMR to be of high purity. Small amounts, <15 total mole %, of ethyl acetate and acetone were also detected.
Reaction SMILES: [F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[O:21][C:20]([CH3:28])([CH3:27])[CH:19]=[C:18]2[CH:29]([CH3:31])[CH3:30])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.C1COCC1>[F:1]/[C:2](=[C:13](/[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[O:21][C:20]([CH3:28])([CH3:27])[CH:19]=[C:18]2[CH:29]([CH3:31])[CH3:30])\[CH3:14])/[CH:3]=[CH:4]/[C:5](/[CH3:12])=[CH:6]/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl (2E,4E,6E)-6-fluoro-7-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-3-methyl-octa-2,4,6-trienoate (Compound 108, 116 mg, 2.71 mmol) in ethanol and THF was hydrolyzed with NaOH to yield a yellow oil after purification by column chromatography (silica gel, 100% hexane to 5% to 50% ethyl acetate in hexanesethyl). The resulting oil was recrystallized from acetonitrile to produce the title compound as a yellow solid.
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])(=[O:6])[CH3:5].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CO>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[O:6])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
Part A. Sodium methoxide (25% in MeOH, 1.5 mL, 6.8 mmol) was added dropwise to a solution of 3-acetylbenzonitrile (987 gm, 6.8 mmol) and 4-nitrobenzaldehyde (1 gm, 6.8 mmol) in dry methanol. Within 5 minutes, a precipitate begins to appear. The mixture was stirred at room temperature for 4 hours and diluted with methanol. The solids were filtered off, washed with cold methanol and dried to give 3-[3-(4-nitrophenyl)-1-oxo-2-propenyl]benzonitrile as a white solid 1.7 gm (97%) MS: 279(M+H)+ ; 1H NMR (CDCl3): 7.60 (d, 1H), 7.70 (t, 1H), 7.85 (m, 4H), 8.25 (m, 4H)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.C(N(CC)CC)C.Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[Cl-].[Na+]>ClCCl>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)=[CH:29][CH:30]=1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of 1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H), 4′-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethane (100 ml) and 4-(chloromethyl)anisole (1.95 g) was allowed to stand overnight at ambient temperature, under nitrogen, with stirring. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The layers were separated, and the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was flash chromatographed (silica gel), eluting with 7.5% acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.5 g (40%) of product, mp 39-40° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[Cl:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[N:1]\[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[OH:9])=[CH:13][CH:12]=1
Reactant: NCc1ccccc1O
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Product: Oc1ccccc1C/N=C\c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred suspension of 2-(aminomethyl)phenol, (4.0 g, 32.5 mmol) in ethanol (65 mL) was added 4-chlorobenzaldehyde (3.86 mL, 32.8 mmol). The resulting reaction mixture was stirred at rt for 3 h. The solvent was removed and 100 ml of toluene was added and concentrated in vacuum twice. The resulting imine was dried under vacuum overnight and used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:21])[CH:27]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: Cc1cccc(B(O)O)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cccc(C)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@:4]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:6])[NH2:5].[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[O:35][C:36](Cl)=[O:37])[CH2:32]2.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[C@:4]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:20]([CH3:23])(=[O:22])=[O:21])[C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:6])[NH:5][C:36]([O:35][CH:26]1[CH:25]2[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]1[CH2:28]3)[CH2:32]2)=[O:37]
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)[C@](C)(N)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@](C)(NC(=O)OC1C2CC3CC(C2)CC1C3)c1cc2c3ccccc3n(S(C)(=O)=O)c2cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methylester (0.5 g, 1.4 mmol) in THF (10 mL) was added 2-adamantyloxycarbonyl chloride (345 rag, 1.7 mmol) and the solution was treated with diisopropyl ethylamine (219 mg, 1.7 mmol) in THF (5 mL). The reaction mixture was stirred for 4 hours at room temperature, evaporated in vacuum and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated,washed successively with 7.5% citric acid solution (50 mL), 8% NaHCO3 solution (50 mL) and then dried over Na2SO4. The solvent was evaporated in vacuum and N-(2-adamantyloxy-carbonyl)-2-[9-(methylsulfonyl)-β-carbolin-3-yl]-alanine methylester was isolated as a yellow oil which solidified upon drying(0.73 g, 97.7%).
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2.Br[CH2:32][C:33]([NH2:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:32][C:33]([NH2:35])=[O:34])[N:14]=[CH:13][CH:12]=[C:11]2[O:19][C:20]1[C:21]([CH3:30])=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
N,N-Dimethylformamide (1.5 ml) was added to 6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-ol (compound 352) (50 mg), bromoacetamide (62 mg), and potassium carbonate (62 mg), and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (49 mg, yield 83%).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C@H:30]1[CH2:35][CH2:34][C@H:33]([CH2:36][CH2:37][C@H:38]2[CH2:43][CH2:42][C@H:41]([CH:44]=O)[CH2:40][CH2:39]2)[CH2:32][CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:44][C@H:41]1[CH2:42][CH2:43][C@H:38]([CH2:37][CH2:36][C@H:33]2[CH2:32][CH2:31][C@H:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:39][CH2:40]1
Reactant: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=O)CC2)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CC[C@H]2CC[C@H](C=C(Br)Br)CC2)CC1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A solution of 4.4 g of tetrabromomethane in 80 ml of methylene chloride was placed at -15° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 7.0 g of triphenylphosphine in 20 ml of methylene chloride. The clear deep orange solution was stirred at -5° C. for a further 10 minutes and then a solution of 1.95 g of the trans-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise within 10 minutes. The mixture was stirred at 0° C. for a further 30 minutes, then poured into 600 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 300 ml of hexane, left to stand at 0° C. for 30 minutes, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.0 g) on silica gel with hexane gave 2.68 g (89.2%) of trans-1-(2,2-dibromovinyl)-4-[2-(trans-4-pentylcyclohexyl)ethyl]cyclohexane which contained about 10% of the corresponding epimeric cis compound in accordance with NMR spectroscopic analysis and which was used without additional purification.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30]Br.[H-].[Na+]>>[CH:1]1([N:6]([CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([OH:32])=[O:22])[C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(C)c1ccc(-c2csc(NC3CCCC3)n2)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)c1ccc(-c2csc(N(Cc3ccccc3C(=O)O)C3CCCC3)n2)cc1
Yield: 16.1 %

Procedure:
2-({Cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-methyl)-benzoic acid (19 mg) was prepared following general method S2 using cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amine (80 mg, 0.28 mmol), 2-bromomethyl-benzoic acid methyl ester (68 mg, 0.33 mmol) and NaH (34 mg, 60%, 0.84 mmol). Purification (Silica gel, ethyl acetate/hexane 5:95) provided the ester, which was hydrolyzed following general procedure T. Sodium 2-({cyclopentyl-[4-(4-isopropyl-phenyl)-thiazol-2-yl]-amino}-methyl)-benzoate was prepared following procedure J. LCMS m/z: 422 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=1.[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:16][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([NH:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:6]=1)=[O:28])[CH3:15]
Reactant: Nc1nnn(Cc2ccccc2)n1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)Nc1nnn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
5-Amino-2-benzyltetrazole (1.55 g, 8.84 mmol) was dissolved in 20 mL methylene chloride after which 2,6-diisopropylphenyl isocyanate (2.25 mL, 10.6 mmol) and 1.5 mL triethylamine was added. The mixture was stirred at room temperature for 4 days then quenched with 5 mL 2N sulfuric acid and extracted with 50 mL ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium carbonate, dried over magnesium sulfate, filtered, and evaporated, leaving a white solid which was recrystallized from ethyl acetate/ether to give the title compound, m.p. 180-181° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:51])([CH3:52])[CH3:50])=[O:47])[NH:26][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCC(C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At 0° C. triethylamine (0.31 mL, 2.2 mmol) and 4-methylbenzenesulfonyl chloride (0.141 g, 0.74 mmol) were added to a solution of di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.239 g, 0.427 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0° C. for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-{3-{[(4-methylphenyl)sulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.255 mg, 67%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak AD-H 5 μm 250×20 mm, hexane/2-propanol 9:1, 25 mL/min):
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCc2ccc(OCCCCBr)cc2N1
Yield: 73.8 %

Procedure:
7-hydroxy-3,4-dihydroquinolin-2(1H)-one (163 mg, 1.0 mmol), 1,4-dibromobutane (0.36 mL, 3.0 mmol) and anhydrous K2CO3 (138 mg, 1.0 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 4) (220 mg, 74%) as a white solid. mp: 106-109° C.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O>N1CCCCC1.C(O)C>[O:16]=[C:12]1[C:11](=[CH:17][C:19]2[NH:20][C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:27]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cc(-c4ccccc4)ccc32)[nH]c2c1CCCC2
Reaction time: 4 h
Yield: 33.3 %

Procedure:
A mixture of 90 mg 6-phenyl-2-oxindole, 95 mg 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was held in a sealed tube at 90° C. for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. The precipitate was collected by filtration and washed with water and hexane to give 59 mg of 3-[2-(2-oxo-6-phenyl-1,2-dihydro-indol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid as a brown solid (31% yield).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([NH2:31])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([O:27]CC)=[O:26])=[O:8])C.Cl>O1CCCC1.O>[NH2:31][C@@:9]1([C:7]([OH:8])=[O:6])[C@H:14]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:13][C@@H:12]2[C@H:10]1[C@@:11]2([F:30])[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@H]1SCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
12 mg of lithium hydroxide hydrate was added to 41 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 0.8 mL of tetrahydrofuran and 0.4 mL of water, and the mixture was stirred for 5.5 days at room temperature. The mixture was adjusted to pH=3 with 1N hydrochloric acid in an ice bath. 30 mL of water was added thereto, and after the mixture was stirred for 1 hour at room temperature and then purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent: water, a 40% aqueous solution of tetrahydrofuran and a 10% aqueous solution of pyridine), the obtained solids were further washed with tetrahydrofuran, thereby yielding 26 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23]N1C(=O)CCC1=O>CN(C=O)C>[Br:23][C:4]1[CH:3]=[CH:2][C:1]([N:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:11][CH2:12]2)=[CH:6][CH:5]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccccc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Benzyl 4-phenylpiperazine-1-carboxylate (2.1 g) was dissolved in DMF (80 ml), and N-bromosuccinimide (1.4 g) was added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and subjected to liquid separation by the addition of CHCl3 and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and dried over Na2SO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain benzyl 4-(4-bromophenyl)piperazine-1-carboxylate (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.O=S(Cl)[Cl:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)cc1
Product: O=C(Cl)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
A mixture of 4-bromobenzoic acid (8 g, 39.8 mmoL) in SOCl2 (80 mL) was stirred at 80° C. for 4 hours and then concentrated under reduce pressure. The resulting white solid was used directly for next step without further purification (8.5 g, yield 97.3%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4](S(C)=O)[N:3]=1.[CH2:20]([OH:22])[CH3:21].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:15]#[N:16])=[C:4]([O:22][CH2:20][CH3:21])[N:3]=1
Reactant: CS(=O)c1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reactant: CCO
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CCOc1nc(N)c(C#N)c(-c2ccco2)c1C#N
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a stirred suspension of 300 mg (1.10 mmol) 2-amino-4-furan-2-yl-6-methanesulfinyl-pyridine-3,5-dicarbonitrile in 15 ml dry DME were added 0.23 ml (3.86 mmol) ethanol and 0.25 ml (1.65 mmol) DBU and stirring continued for 2 hours at room temperature. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 1/4) followed by trituration in ether/hexane afforded 21 mg (8%) 2-amino-6-ethoxy-4-furan-2-yl-pyridine-3,5-dicarbonitrile as a light yellow crystalline solid. EI-MS m/e (%): 254 (M+, 90), 226 (100), 198 (44), 143 (26).