Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([OH:8])=O.[C:18]([O-])(=[O:20])[CH3:19].[Na+]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([O:8][C:18](=[O:20])[CH3:19])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[CH:9]=1)=[O:17]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C(=Cc1ccc(F)cc1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(OC(C)=O)c2cc(F)ccc2c1
Yield: 49.9 %

Procedure:
To a stirred solution of 2-(4-fluoro-benzylidene)-succinic acid 1-methyl ester (2 g, 8.4 mmol) in acetic anhydride (10 mL) was added sodium acetate (0.83 g, 10.1 mmol). After being heated at reflux for 6 hours, the mixture was concentrated in vacuo. The residue was dissolved in 1 N hydrochloric acid (20 mL). The aqueous solution was extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 10-20% ethyl acetate in petroleum ether) to afford 4-acetoxy-6-fluoro-naphthalene-2-carboxylic acid methyl ester (1.1 g, 50%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.52 (s, 1H), 8.00 (dd, J=9.09, 5.56 Hz, 1H), 7.89 (s, 1H), 7.50 (dd, J=9.85, 2.53 Hz, 1H), 7.37 (td, J=8.59, 2.53 Hz, 1H), 3.99 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH2:26]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](Cl)=[O:32])[CH3:27]>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=2[O:28][CH2:26][CH3:27])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccccc1C(=O)N[C@@H]1CCc2cccc(N3CCN(C)CC3)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (10 mg, 0.43 mmol) and triethylamine (90 μL, 0.65 mmol) in methylene chloride (15 mL) was added dropwise 2-ethoxybenzoyl chloride (84 mg, 0.45 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 110 mg (64%) of the title compound as white solid: [α]21D -36° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 393 (15, M+). The hydrochloride salt was precipitated out of diethyl ether and 110 mg (59% yield) of white crystals were isolated; mp sinters at 176° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:15]([Cl:21])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH3:22][NH2:23].[BH4-].[Na+].N>CCO.CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[Br:20][C:18]1[CH:19]=[C:14]([NH:13][S:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:1]([NH:23][CH3:22])[CH3:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[C:15]([Cl:21])=[N:16][CH:17]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: CN
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: N
Solvent: O
Solvent: CO
Solvent: CCO
Product: CNC(C)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4-Acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide (540.2 mg, 1.386 mmol) was suspended in EtOH (5.0 mL) and titanium (IV) isopropoxide (0.82 mL, 2.8 mmol) and methylamine (4.2 mL, 8.4 mmol, 2.0 M in THF) were added. The reaction was stirred at room temperature overnight. Then, sodium borohydride (95.7 mg, 2.53 mmol) was added, and the reaction was stirred at room temperature for 30 minutes, and then water (10 mL) and ca. 7 N ammonia in MeOH (2.9 mL) were added simultaneously via syringe, causing precipitation. The reaction was stirred at room temperature, and after 45 minutes, the reaction contents were filtered. The solid was washed with EtOAc and MeOH, and the filtrate was concentrated and purified using silica gel with 20:1 DCM/MeOH to 3:1 DCM/2 N ammonia in MeOH to afford N-(5-bromo-2-chloropyridin-3-yl)-4-(1-(methylamino)ethyl)benzenesulfonamide (488 mg, 87% yield). MS (ESI positive ion) m/z: 404 (M+1, 79Br), 406 (M+1, 81Br). Calcd. for C14H15BrClN3O2S: 403 (79Br), 405 (81Br).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:19])[C:3]=1[CH:4]=[O:5].O.[BH4-].[Na+].Cl>C(O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:7]=[C:6]([F:19])[C:3]=1[CH2:4][OH:5]
Reactant: CCCc1ccc(-c2cc(F)c(C=O)c(F)c2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCc1ccc(-c2cc(F)c(CO)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
Then, 50.01 g of 2,6-difluoro-4-(4-propylphenyl)benzaldehyde and 7 mL g of water were dissolved in 35 mL of ethanol, the resultant solution was cooled with ice, and 2.18 g of sodium tetrahydroborate was slowly added to the solution. After stirring at room temperature for 2 hours, 10% hydrochloric acid was added until the reaction system became acidic, followed by stirring for 1 hour. Then, toluene was added to separate an organic layer, an aqueous layer was subjected to extraction with toluene, and the toluene extract was combined with the organic layer. The resultant mixture was washed with saturated brine and dried by adding sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to yield 48.02 g of 2,6-difluoro-4-(4-propylphenyl)benzyl alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.C([Li])CCC.[C:13](=[O:15])=[O:14].Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COc1ccsc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccsc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at −78° C., butyllithium (17 mL, 47.6 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hour, then it was warmed to 0° C. for 3 hours. After to recooling −78° C. the reaction mixture was poured into a beaker filled with crushed dry ice (14.5 g) and allowed to stand until the excess dry ice had completely sublimed. Then the reaction mixture was poured into a mixture of ice (10 g) to which conc. HCl (24 mL) had been added. The product was purified by precipitation from ether and filtering (6.42 g, 96 %). EI-MS m/z 159 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[OH:17])([O-:3])=[O:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:7][C:6]=2[N+:14]([O-:16])=[O:15])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])cc(C(C)(C)C)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-dinitro-4-t-butyl-phenol (80 mmol; 10) and tosyl chloride (80 mmol) were dissolved in 300 ml CH2Cl2. Diisopropylethylamine (DIEA, 80 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solution was washed with 10% citric acid, saturated aqueous NaCl (sat. NaCl), and dried with MgSO4. The solvent was removed under reduced pressure, and the product was obtained as a bright yellow solid in quantitative yield. 1H NMR (500 MHz, CDCl3): δ=8.12 (s, 2H), 7.80 (d, 2H), 7.40 (d, 2H), 2.51(s, 3H), 1.41 (s, 9H). ESI-MS: m/z: 417.2 (M+Na+).
Reaction SMILES: Br.[NH2:2][C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=[CH:5][N:4]=1.Cl.N[NH:16][C:17]([NH2:19])=[O:18].C([O-])(=O)C.[K+].C(=O)(O)[O-].[Na+]>O.CO>[NH:2]([C:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=[CH:5][N:4]=1)[NH:16][C:17]([NH2:19])=[O:18]
Reactant: NNC(N)=O
Reactant: NC1=NC=Cc2ccccc2C1
Agent: Br
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)NNC1=NC=Cc2ccccc2C1

Procedure:
A solution of 24 parts of 2-amino-1H-3-benzazepine hydrobromide, 33 parts of semicarbazide hydrochloride, and 40 parts of potassium acetate in 500 volume parts of methanol is stirred at room temperature overnight. After dilution with water the reaction mixture is neutralized with an aqueous solution of sodium bicarbonate and, then, extracted with chloroform. The chloroform layer is dried over sodium sulfate. Evaporation of the solvent gives 2-semicarbazido-1H-3-benzazepine as crystals. Recrystallization from methanol gives colorless prisms, melting at 188° - 189° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][C:9]1([CH3:27])[CH2:14][C:13](=O)[CH2:12][CH2:11][CH:10]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:8][C:9]1([CH3:27])[CH2:14][CH:13]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH2:12][CH2:11][CH:10]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)CC(=O)CCC1NC(=O)OCc1ccccc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C2CCC(NC(=O)OCc3ccccc3)C(C)(C)C2)CC1
Reaction time: 2 h
Yield: 44 %

Procedure:
N-Methylpiperazine (0.620 ml, 5.6 mmol, 2 eq) was added at 0° C. to a solution of benzyl 2,2-dimethyl-4-oxocyclohexylcarbamate (770 mg, 2.8 mmol, 1 eq) in dichloromethane (15 ml), and stirring was carried out for 2 h at RT. Na(OAc)3BH (1.78 g, 8.4 mmol, 3 eq) was added in portions at 0° C., and stirring was carried out for 18 h at RT. The reaction solution was diluted with dichloromethane (60 ml), washed with water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (Alox neutral, 1% MeOH in dichloromethane), a white solid was obtained. Yield: 44% (440 mg, 1.225 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH2:8])=[N:3]1.CC(C)([O-])C.[Na+].[CH3:15][S:16][C:17]1[N:22]=[C:21](SC)[C:20]2=[N:25][CH:26]=[C:27]([C:28]#[N:29])[N:19]2[N:18]=1>C1COCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[N:5][C:4]([NH:8][C:21]2[C:20]3=[N:25][CH:26]=[C:27]([C:28]#[N:29])[N:19]3[N:18]=[C:17]([S:16][CH3:15])[N:22]=2)=[N:3]1
Reactant: Cc1nc(N)nn1C
Reactant: CSc1nc(SC)c2ncc(C#N)n2n1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nc(Nc2nc(C)n(C)n2)c2ncc(C#N)n2n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,5-dimethyl-1H-1,2,4-triazol-3-amine (170 mg, 1.517 mmol) was taken up in 6 ml of anhydrous THF and cooled to 0° C. Sodium tert-butoxide (243 mg, 2.53 mmol) was added and the reaction was stirred at 0° C. for 5 min. Next, a solution of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Intermediate (300 mg, 1.264 mmol) in 8 ml of THF was added, and the reaction was brought to rt. The reaction was stirred at rt for 1 h. The solvent was removed in vacuo and the material was dissolved in EtOAc. The organic layer was washed once with water, and the aqueous layer was reextracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give 4-((1,5-dimethyl-1H-1,2,4-triazol-3-yl)amino)-2-(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (157 mg) as a yellow solid. The crude material was taken onto the next step without further purification.
Reaction SMILES: [CH2:1]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1>C(O)(=O)C>[C:22]([C:21]1[CH:25]=[CH:26][C:18]([N:17]2[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]=3[CH:1]=[C:2]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:19][CH:20]=1)([OH:24])=[O:23]
Reactant: O=C(CC1CCCCC1=O)c1ccccc1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1

Procedure:
A solution of 10.8 g. (0.05 mole) of 2-phenacylcyclohexanone, 6.85 g. (0.05 mole) of p-aminobenzoic acid and 30 ml. of glacial acetic acid was heated under reflux for 5 hours and cooled. The solid which separated was collected and recrystallized from ethanol to provide 5.85 g. (37%) of pale yellow crystals, m.p. 244°-246°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[C:5](O)=[O:6].O.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CO)cc1Cl
Temperature: 76 °C
Yield: 91.8 %

Procedure:
To a solution of 3-chloro-4-(methoxycarbonyl)benzoic acid (400 mg, 1.9 mmol) in anhydrous THF (15 mL) was added Borane methyl sulfide complex (10 M, 0.56 mL, 5.6 mmol). The resulting solution was heated at 76° C. for 6 hours. After being cooled, the mixture was slowly poured into water (40 mL) at −10° C., then followed a standard aqueous/EtOAc workup procedure to give crude product (350 mg, yield 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CC(C)=O>[CH2:24]([O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH:23]=[CH2:22]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OC)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
A stirred suspension of dimethyl 5-hydroxyisophthlate (5.0 g, 23.8 mmol) and potassium carbonate (7.5 g, 54.5 mmol) in acetone (120 mL) was treated with allyl bromide (4.6 mL, 53.0 mmol). The mixture was stirred at room temperature for 3 days. The mixture was then filtered and concentrated. The residue was dissolved in ethyl acetate and washed with water and brine. The remaining organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. Trituration with hexane afforded 5.0 g (84%) of dimethyl 5-allyloxy-isophthalate
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=2)[NH:14][C@@H:13]([CH2:25][CH3:26])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].[OH-].[K+]>ClCCl>[CH2:38]([O:37][C:35]([N:14]1[C:15]2[C:20](=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[C@H:11]([NH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:27])[CH2:12][C@@H:13]1[CH2:25][CH3:26])=[O:36])[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: CC[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of cis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (Example 7B) (37.0 g, 97.9 mmol) and pyridine (23.2 g, 293.7 mmol) in dichloromethane (1 L) was cooled in an ice/water bath as ethyl chloroformate (37.2 g, 342.6 mmol) was added slowly. After stirring at room temperature overnight, the mixture was cooled with an ice/water bath as a 1M potassium hydroxide solution was added to quench the reaction. The organic phase was washed twice with a 2M hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product which was purified by silica gel chromatography using 10-15% ethyl acetate/hexanes as eluent to afford 40 g of the title product. 1H NMR (CDCl3) δ 0.83 (t, 3H), 1.28 (t, 3H), 1.4-1.6 (m, 3H), 2.53 (m, 1H), 4.23 (m, 2H), 4.47 (m, 1H), 4.80 (m, 1H), 4.94 (m, 1H), 5.18 (s, 2H), 7.3-7.6 (m 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH:14]=[CH:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C=CC1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd]
Product: COC(=O)CCC1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1
Reaction time: 17 h
Yield: 90 %

Procedure:
A methanolic solution of the compound of Example 201, Step A was hydrogenated (40 psi) in a Parr shaker over 10% Pd-C (35 mg). After 17 hours, the reaction was filtered through a pad of Celite® and then concentrated to give yellowish solid of the compound of the compound of Example 201, Step B (153 mg, 90%) which was a 1:2 mixture of ester and lactam: +APcI MS (M+1, ester)+363, (M+1, lactam)+331; 1H NMR (400 MHz, CDCl3) δ: 7.25-7.05 (arom, series of m, 5H), 3.54 (ester Me, s, 1H), 1.44 (lactam BOC, s, 6H), 1.37 (ester BOC, s, 3H).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][C:12]([N:20]([CH3:22])[CH3:21])([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.CCOC(C)=O.CCCCCC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[CH3:21][N:20]([CH3:22])[C:12]1([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CN(C)C1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)C1(c2cccs2)CCNCC1
Yield: 88.6 %

Procedure:
HCl gas was passed through a solution of 10 g (1 eq) tert-butyloxycarbonyl-4-(dimethyl-amino)-4-(thiophen-2-yl)piperidine in chloroform at 0° C. for ˜1 h. The reaction course was monitored by thin-layer chromatography (75% EtOAc/hexane). Once the conversion was complete, 200 ml water were added to the reaction mixture, it was adjusted to a pH of ˜8 with Na2CO3 and then extracted with 15% IPA/CHCl3. The combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 6 g (89%) of product were obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=O.[CH3:15][C:16]([S:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.C([O-])C.C([O-])C.C([O-])C.C([O-])C.[Ti+4]>[Br:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][C:6]1([CH2:8][CH2:7]1)[C:5]2=[N:21][S:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20]
Reactant: O=C1c2cc(Br)ccc2OCC12CC2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2OCC12CC2
Temperature: 80 °C
Reaction time: 48 h
Yield: 57 %

Procedure:
The mixture of 6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-one (8.0 g, 32 mmol), 2-methylpropane-2-sulfinamide (12 g, 99 mmol), and titanium(IV) tetraethanolate (22 g, 95 mmol) in THF (160 ml) was stirred for 48 hours at 80° C. To the mixture was added H2O (20 ml), filtered through Celite and washed by EtOAc (50 ml). The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc=100:0-0:100) to give N-(6-bromo-4H-spiro[chromene-3,1′-cyclopropan]-4-ylidene)-2-methylpropane-2-sulfinamide (6.5 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:16][CH2:15][CH2:14][NH:13]2)=[CH:8][CH:7]=1.Br[CH2:19][CH2:20][C:21]1[C:22]([CH3:27])=[N:23][NH:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH2:19][CH2:20][C:21]2[C:22]([CH3:27])=[N:23][NH:24][C:25]=2[CH3:26])=[CH:8][CH:7]=1
Reactant: Cc1n[nH]c(C)c1CCBr
Reactant: COC(=O)/C=C/c1ccc([C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc([C@H]2CCCN2CCc2c(C)n[nH]c2C)cc1
Temperature: 85 °C

Procedure:
(E)-3-((R)-4-Pyrrolidin-2-yl-phenyl)-acrylic acid methyl ester (697 mg, 3 mmol) and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (734 mg, 3.62 mmol) were dissolved in acetonitrile, potassium carbonate (833 mg, 6 mmol) was added, and the reaction mixture heated under nitrogen at 85° C. for 14 h. Cooled to room temperature, diluted with DCM (20 mL) and filtered through a plug of celite. Wash plug with DCM (30 mL). Filtrate was concentrated to 110 mL and columned on silica with EtOAc/hexane. Product elutes with neat EtOAc, and after concentrating gave (E)-3-(4-{(R)-1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl]-pyrrolidin-2-yl}-phenyl)-acrylic acid methyl ester as a tacky, pale yellow solid (804 mg, 2.275 mmol, 75%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH2:15]I)[N:14]=2)=[CH:6][CH:5]=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([O:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:28]=2[C:29]([O:31][CH3:32])=[O:30])[CH2:20]1.C(OC)(C)(C)C>CN(C)C=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:17])=[C:13]([CH2:15][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH:21]([O:25][CH2:26][C:27]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:28]=4[C:29]([O:31][CH3:32])=[O:30])[CH2:20]3)[N:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)c1c(C)cccc1COC1CCCC(OCc2nc(-c3ccc(Br)cc3)oc2C)C1
Reaction time: 1 h

Procedure:
At room temperature, 50 mg of a 60% sodium hydride suspension and then 408 mg of 2-(4-bromophenyl)-4-iodomethyl-5-methyloxazole were added to a solution of 200 mg of methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate in 5 ml of dimethylformamide. After one hour, methyl tert-butyl ether was added, and the mixture was extracted with water. The organic phase was dried over magnesium sulfate, the solvents were removed under reduced pressure and the residue was purified by RP-HPLC. This gave 49 as a light-yellow oil. C27H30BrNO5 (528.45), MS(ESI): 528.2, 530.2 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH:21]1[CH:26]=[C:25]2[C:27]([CH2:30][C:31](O)=[O:32])=[CH:28][NH:29][C:24]2=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.C(Cl)CCl>[NH:29]1[C:24]2[C:25](=[CH:26][CH:21]=[CH:22][CH:23]=2)[C:27]([CH2:30][C:31]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:32])=[CH:28]1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)Cc1c[nH]c3ccccc13)C2
Reaction time: 8 h
Yield: 57.4 %

Procedure:
200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 140 mg Indolyl-3-acetic acid, 98 mg HOBT and 0.6 ml Et3N are dissolved in 8 ml DMF. To this mixture are added 278 mg EDC and the mixture is stirred overnight. The reaction mixture is evaporated and the crude product is purified by silica gel flash chromatography. 180 mg of the title compound are obtained in 57% yield.