Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.NCC(OCC1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+].N1C=CC=CC=1.Cl[C:38]([O:40][CH:41]([Cl:43])[CH3:42])=[O:39]>C(Cl)Cl.O>[Cl:43][CH:41]([O:40][C:38]([NH:1][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:39])[CH3:42]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(Cl)OC(=O)NCC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
Benzyl 2-aminoacetate was generated from a treatment of benzyl 2-aminoacetate hydrochloride (Aldrich) in methylene chloride with aqueous sodium bicarbonate solution followed by water wash. To a cooled solution of benzyl 2-aminoacetate (1.837 g, 11.1 mmol) and pyridine (1.1 g, 1.1 mL, 13.9 mmol) in methylene chloride (17 mL) at −78° C., was added slowly 1-chloroethyl chloroformate (Aldrich, 1.67 g, 11.7 mmol) over ˜10 min. The reaction mixture was allowed to stir at −78° C. for 3 h, giving a white precipitate. This cold reaction mixture was filtered to remove the solid and the filtrate was concentrated to dryness, giving the crude benzyl 2-((1-chloroethoxy)carbonylamino)acetate which was used for the next step without further purification.
Reaction SMILES: [C:1]([O:6]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][N:9]([CH3:11])[CH3:10]>CO>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:8][N+:9]([CH3:1])([CH3:11])[CH3:10]
Reactant: CN(C)C
Reactant: C=C(C)C(=O)OC
Solvent: CO
Product: C=C(C)C(=O)[O-]
Product: C[N+](C)(C)C
Reaction time: 3 h

Procedure:
In a 100 milliliter (hereinafter abbreviated to "mL") autoclave were placed 27.2 g of methyl methacrylate, 15.3 g of trimethylamine and 40 g of methanol under heating and shaking. After the temperature inside the autoclave reached 170° C., the reaction was continued at 170° C. for 3 hours. Upon completion of the reaction, the content in the autoclave was cooled, brought back to atmospheric pressure and analyzed. As a result, tetramethylammonium methacrylate was obtained in a yield of 76 mol % (based on trimethylamine).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:18]=[O:19]
Reactant: COC(OC)c1ccsc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccsc1C=O
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a solution of 3-dimethoxymethylthiophene (14 g) in tetrahydrofuran (80 ml) was slowly added n-butyllithium (1.6M in n-hexane, 47.8 ml) at -10° C. with stirring. The reaction mixture was further stirred at same temperature for 1 hour. N,N-Dimethyl-formamide (11.9 g) in tetrahydrofuran (40 ml) was then added. The reaction mixture was warmed to room temperature and stirred for overnight. Ice water was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give brownish oily product (13 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][C:29]#[C:30][CH3:31])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OC)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
To a solution of product from step 2 (500 mg, 1.11 mmol) in methylene chloride (10 ml) was added 4M HCl (2 ml) and the resulting mixture was stirred for 2 hours at room temperature. The solid was filtered, washed with ether to obtain 410 mg (95%) of the product as a solid. 1H NMR (300 MHz, CDCl3): δ1.86 (m, 3H), 2.52 (m, 4H), 2.89 (m, 2H), 3.52 (m, 2H), 3.74 (s, 3H), 4.74 (m, 2H), 7.10 (d, 2H, J=8.7 Hz), 7.69 (d, 2H, J=8.7 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]([NH2:17])=O)=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2].[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.C(OCC)(=O)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:17])=[C:13]([CH3:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[CH:20]=3)[C:11](=[O:29])[NH:10]2)=[C:5]([N+:30]([O-:32])=[O:31])[CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2[N+](=O)[O-])NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction was carried out under argon. (4R)-4-(4-Cyano-2-nitrophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxamide (5.0 g, 10.1 mmol; purity 90%) was initially charged in dry THF (135 ml), methoxycarbonylsulfamoyltriethylammonium hydroxide (Burgess reagent; 3.85 g, 16.17 mmol; 1.6 eq.) was added and the mixture was then stirred at RT for 2 h. Ethyl acetate (300 ml) was then added to the reaction mixture. The organic phase was washed twice with water and once with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallized from cyclohexane/ethyl acetate. The crystals obtained were dried under high vacuum. The title compound was obtained as a solid (2.8 g, 65% of theory).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:24]=[CH:23][C:12]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[N:14][S:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:12]3[CH:23]=[CH:24][C:9]([O:8][CH2:7][C:6]([OH:25])=[O:5])=[CH:10][C:11]=3[S:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
3.89 g (9.3 mmol) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid tert-butyl ester in 35 ml CH2Cl2 were added 17 ml TFA at 0° C. The solution was stirred at RT for 2 h, concentrated and titurated with ether to yield 3 g (89%) [3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-acetic acid as white solid, MS: 362(M−H, 1Br).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[CH:8][S:9](Cl)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C(OC([N:20]1[C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=[C:21]1[CH2:29][N:30]1[CH2:34][CH2:33][C@H:32]([NH2:35])[C:31]1=[O:36])=O)(C)(C)C>>[O:36]=[C:31]1[C@@H:32]([NH:35][S:9]([CH:8]=[CH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:11])=[O:10])[CH2:33][CH2:34][N:30]1[CH2:29][C:21]1[NH:20][C:28]2[CH:27]=[CH:26][N:25]=[CH:24][C:23]=2[CH:22]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2cnccc21
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Product: O=C1[C@@H](NS(=O)(=O)C=Cc2ccc(Cl)s2)CCN1Cc1cc2cnccc2[nH]1

Procedure:
The title compound is prepared as described in EXAMPLE 56. Part A using 2-(5-chlorothiophen-2-yl)-ethenesulfonyl chloride and 2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester as starting material. The crude product can be purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid or used in the subsequent step after an aqueous work-up without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].O.O.[Cl:15][Sn]Cl>Cl>[ClH:15].[Br:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: O=N[O-]
Reactant: Cl[Sn]Cl
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 3-bromoaniline (17 g, 0.1 mol) in conc. HCl (200 mL) was added an aqueous solution (20 mL) of NaNO2 (7 g, 0.1 mol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (45 g, 0.2 mmol) in conc. HCl (500 mL) was then added at 0° C. The reaction solution was stirred for 2 h at RT. The precipitate was filtered and washed with EtOH and ether to yield (3-bromophenyl)hydrazine hydrochloride as a white solid, which was used for the next reaction without further purification
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[ClH:9].[CH3:10][O:11][NH2:12].CO.C(=O)([O-])[O-].[K+].[K+]>O>[ClH:9].[CH3:10][O:11][N:12]=[C:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CON
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.3 %

Procedure:
1-Methyl-4 piperidone (5 g, 44.2 mmol) and methoxyamine hydrochloride (3.69 g, 44.2 mmol) were taken into 25 mL of methanol and stirred at room temperature for 2 days. The reaction mixture was evaporated in vacuo to afford a solid residue. The residue was dissolved in water, made basic with solid potassium carbonate, and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated to give a clear, yellow liquid that was purified on silica gel, eluting with dichloromethane-methanol (95:5) to afford 2.55 g of the desired product. Treatment with ethereal hydrogen chloride gave the hydrochloride salt, 2.99 g, m.p. 145°-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1B(O)O.[F-].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:37][C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Temperature: 75 °C
Yield: 46.2 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.0 g, 1.91 mmol) and add 20 mL degassed acetonitrile. To this solution add 2,5-difluorophenyl boronic acid (0.6 g, 3.82 mmol), transdichlorobis(triphenylphosphine) palladium II, (270 mg, 0.38 mmol) and cesium fluoride (2.61 g, 17.2 mmol). Sonicate the mixture briefly and heat to 75° C. After 3 hours add an additional small amount of the acid, the catalyst and the cesium fluoride and heat overnight. In the morning filter the mixture and run through and SCX column eluting with 2N ammonia in methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. Concentrate to give 430 mg (46%) of the title compound: 1H-NMR (CDCl3, 300 MHz) δ7.85 (d, J=9.3 Hz, 1H); 7.73 (d, J=8.7 Hz, 1H); 7.33 (d, J=8.4 Hz, 1H); 7.18 (d, J=2.7 Hz, 1H); 7.11-6.89 (m, 4H); 6.86-6.82 (m, 2H); 6.73-6.69 (m, 2H); 4.34-4.19 (d, H); 4.04-3.99 (t, 2H); 3.93 (s, 3H); 2.72 (t, J=6.3 Hz, 2H); 2.47 (t, J=5.1 Hz, 4H); 1.58 (qui, J=5.4 Hz, 4H); 1.46-1.41 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11](Cl)[N:10]=1>O1CCOCC1.ClCCl.CCOCC>[Cl:8][C:9]1[CH:14]=[N:13][CH:12]=[C:11]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:10]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCC1CCCC1
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Clc1cncc(OCC2CCCC2)n1
Reaction time: 2.5 h
Yield: 61 %

Procedure:
K-t-BuO (1.65 g, 14.7 mmol) was added portionwise to a stirred mixture of cyclopentanemethanol (2.99 g, 29.9 mmol) and 2,6-dichloropyrazine (1.90 g, 12.8 mmol) in dioxane (6 mL) at 0° C. (ice-bath). The reaction mixture was then stirred for 2.5 h, while the temperature was allowed to reach room temperature. The reaction mixture was diluted with dichloromethane/ether (1:1), filtered, and concentated in vacuo. The beige liquid was purified by column chromatography on silica gel (18×4 cm) using n-hexane/ethyl acetate (94:6) as eluent. Two chromatographic runs afforded 1.66 g (61%) of the title compound as a colorless oil. HRMS m/z calcd for C10H13ClN2O (M)+212.0716, found 212.0723. Anal. (C10H13ClN2O) C, H, N.
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH:14](C)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[C:24]1(C)C=CC=CC=1>>[C:8]([C:2]([CH3:24])([CH2:1][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:9])[CH3:10]
Reactant: Cc1ccccc1
Reactant: CCOC(=O)CCCC(C)Br
Reactant: CCOC(=O)C(C)C(C)=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCCC(C)(C(C)=O)C(=O)OCC

Procedure:
Ethyl 2-methylacetoacetate (7.9 g, 60 mmol) was added to a stirred solution of 1.44 g of sodium hydride (60 mmol) in 80 mL of toluene over a 30 minutes period. The resulting solution was heated under reflux for two hours, cooled slightly and treated with ethyl 5-bromohexanoate over a 30 minutes period. The resulting mixture was then heated at reflux for twelve hours, cooled, and the solvent evaporated under reduced pressure. The residue, a yellow oil was used as such in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][CH2:11][OH:12].[H-].[Na+].C(OCC)C>C1COCC1>[CH2:10]1[CH2:11][O:12][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=2[O:9]1
Reactant: Cc1nccc(Cl)c1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nccc2c1OCCO2
Yield: 58.9 %

Procedure:
A mixture of 4-chloro-3-hydroxyethoxy-2-methylpyridine (1.03g, 0.0055 mol) and NaH (55% in oil, 599 mg, 0.0138 mol) in 600 ml THF was refluxed for 15 h. Excess NaH was destroyed with 3 ml of H2O. The solvent was evaporated and the residue partitioned between 100 ml 1M HCl and 100 ml CH2Cl2. The aqueous layer was collected, washed once more with 100 ml CH2Cl2 and then treated with Na2CO3 until the pH was ≈10. The aqueous layer was extracted with 150+100 ml CH2Cl2. The two latter organic layers were combined, dried over MgSO4, and evaporated leaving 720 mg enriched product. Chromatography (silica gel, diethyl ether) furnished 0.49 g (59%) pure product.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)/[C:9]1=[O:26])=O)(C)(C)C.C([Si](C)(C)[O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([O:39][C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[CH:47]=[N:48][C:49]([O:51][Si](C)(C)C)=[CH2:50])[CH2:35][CH2:34]1)(C)(C)C>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:26])[C:10]3([CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH2:51][C:49](=[O:50])[NH:48][CH:47]3[C:41]3[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=3[O:39][C@H:36]3[CH2:35][CH2:34][C@@H:33]([OH:32])[CH2:38][CH2:37]3)[C:11]2=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1cc(Cl)ccc1O[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(Cl)ccc2O[C@H]2CC[C@@H](O)CC2)N1

Procedure:
In a manner similar to the method described in example 1e, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 1b (0.47 g, 1.2 mmol) was reacted 1-[2-[trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyloxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene (3 mmol) in toluene to give racemic(2′R, 3R, 4′S)-6-chloro-2′-[5-chloro-2-(cis-4-hydroxy-cyclohexyloxy)-phenyl]-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a pale yellow solid (Yield 0.3 g, 42%)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9](F)(F)C(O)=O.[CH2:15]=[C:16]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19][C:18]2[CH:27]=[CH:28][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:30][C:17]1=2>ClCC(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH:15]=[C:16]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:20][O:19][C:18]3[CH:27]=[CH:28][C:29]([C:31]([O:33][CH3:34])=[O:32])=[CH:30][C:17]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: C=C1c2ccccc2COc2ccc(C(=O)OC)cc21
Reactant: O=C(O)C(F)(F)F
Agent: ClCC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(c1)C(=CCN1CCN(C)CC1)c1ccccc1CO2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In this example, 1.5 ml of 4-methylpiperazine and 0.37 g of p-formaldehyde are dissolved in 100 ml of tetrachloroethane. To the solution is dropwise added 5 ml of trifluoroacetic acid. After stirring the mixture at 60° C. for 2 hours, a solution obtained by dissolving 1.8 g of methyl 11-methylene-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate in 30 ml of tetrachloroethane is dropwise added thereto and the mixture is stirred at 90° C. for 3 hours.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH3:18])[CH3:17])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:18][N:16]([CH3:17])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:38]([C:37]4[C:41]([N:45]5[N:49]=[CH:48][CH:47]=[N:46]5)=[CH:42][CH:43]=[CH:44][C:36]=4[F:35])=[O:39])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(N(C)C)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)nc(N(C)C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-methyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate L) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H25FN8O, 436.492; m/z found 437.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.19-7.72 (m, 2M), 7.55-7.29 (m, 2H), 7.21-6.81 (m, 1H), 5.52-5.08 (m, 1H), 4.70-4.26 (m, 1H), 4.13-3.44 (m, 5H), 3.23-3.03 (m, 2H), 2.95-2.70 (m, 5H), 2.30-1.68 (m, 6H).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:17][C:18]1[O:22][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:20][C:19]=1[CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C1COCC1.O>[CH3:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:7]([NH:6][S:37]([C:34]2[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:19]3[N:20]=[C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:22][C:18]=3[CH3:17])=[CH:32][CH:33]=2)(=[O:38])=[O:39])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(NS(=O)(=O)c2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1C(=O)O
Temperature: 60 °C

Procedure:
Sodium bicarbonate (159 mg, 1.89 mmol) and 2-amino-6-methylbenzoic acid (95.5 mg, 0.63 mmol) are dissolved in a mixture of 1 mL of THF and 1.5 mL of water and heated to 60° C. A solution of the title C compound, 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonyl chloride (200 mg, 0.55 mmol) in 1 mL of THF is then added dropwise. The mixture is heated for an additional 2 h at 60° C., after which most of the THF is removed by passing a stream of nitrogen gas over the solution. The residue is partitioned between EtOAc and 1 N aqueous HCl. The organic phase is dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give crude product which is purified by chromatography on silica gel with an EtOAc (15%)-hexane (85%) mixture (containing 0.5% formic acid) as the eluent to give 2-methyl-6-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzenesulfonylamino]-benzoic acid as a white solid: m.p. 167-170° C.; ESI-MS 479 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.C(N(CC)CC)C.[NH2:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([NH:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC1Cc2ccccc2C1
Reactant: COC(=O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(NC1Cc2ccccc2C1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 200 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of triethylamine and 8.8 g (66.0 mmol) of 2-aminoindan. The reaction mixture was refluxed for four hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using chloroform as eluent and was concentrated to dryness to give a quantitative yield of the desired mixture of isomers as a tan, viscous oil. MS (ion spray) 282.2 (M+).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(N([CH2:17][CH3:18])CC)C.[C:19](#N)C>[Cu]I>[N+:9]([C:6]1[CH:7]=[CH:8][C:2]([C:19]#[C:17][CH3:18])=[C:3]([NH2:4])[CH:5]=1)([O-:11])=[O:10]
Reactant: CC#N
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: CCN(CC)CC
Agent: [Cu]I
Product: CC#Cc1ccc([N+](=O)[O-])cc1N

Procedure:
Stir a mixture of 2-bromo-5-nitroaniline 16 (2.81 g, 12.95 mmol), dichlorobis(triphenylphospine) palladium (II) (0.45 g, 0.65 mmol), and copper (I) iodide (0.12 g, 0.65 mmol) in anhydrous acetonitrile (10 mL) under inert atmosphere. Saturate the mixture with propyne gas, then add triethyl amine (3.6 mL, 25.90 mmol), seal the vessel, and stir at ambient temperature 14 hours. Concentrate the mixture in vacuo, suspend in 100 mL diethylether, add celite, and filter. Concentrate the filtrate in vacuo and chromatograph the residue over silica gel, eluting with hexanes/ethyl acetate (9:1 v/v) to afford the title compound, 1.75 g (76%). LRMS (API ES+)=177.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(Cl)nn1
Temperature: 80 °C

Procedure:
To a solution of 3,6-dichloropyridazine (250 mg, 1.68 mmol) and 2-methylbut-3-yn-2-ol (282 mg, 3.36 mmol) in DMF (4 mL) were added CuI (64 mg, 0.33 mmol), triethylamine (0.47 mL, 3.36 mmol), and palladium tetrakis triphenylphosphine (194, 0.168 mmol). The solution was degassed and heated to 80° C. overnight. The residue was worked up with EtOAc and water, dried with MgSO4, filtered, and concentrated. Column chromatography on silica gel 100% Hex to 100% EtOAc provided the title compound.