Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:25][C:26]([Cl:33])([Cl:32])[C:27]([N:29]=[C:30]=[O:31])=[O:28]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:30]([NH:29][C:27](=[O:28])[C:26]([Cl:33])([Cl:32])[Cl:25])=[O:31])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](COC(=O)NC(=O)C(Cl)(Cl)Cl)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (100 mg) was dissolved in 3 ml of dry ethyl acetate. To the solution was added 0.05 ml of trichloroacetyl isocyanate under ice-cooling in a nitrogen stream, followed by stirring at the same temperature for 1 hour. The mixture was diluted with ethyl acetate, washed successively with a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-trichloroacetylaminocarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:17]=[CH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:24])=[O:3]
Reactant: CCOC(=O)CCCCOc1ccccc1C=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)CCCCOc1ccccc1C=Cc1ccccn1
Yield: 40.7 %

Procedure:
A mixture of 32.5 g (0.1 mol) of compound of Example 6, 450 ml 50 percent ethanol and 27 g potassium carbonate is heated under reflux for 2 h, evaporated, the residue taken up in water, washed with ether, the aqueous phase adjusted to pH 6.5 and the precipitate filtered off. After trituration with ether, one isolates 12.1 g of title compound (41% of theory) of the m.p. 90°-93° C.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5].P([O-])([O-])([O-])=O>O>[OH:2][CH:3]1[O:22][C@H:21]([CH2:23][OH:24])[C@@H:8]([O:9][C@@H:10]2[O:18][C@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@H:13]([OH:14])[C@H:11]2[OH:12])[C@H:6]([OH:7])[C@H:4]1[OH:5]
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O

Procedure:
A solution of 0.2 mg of bovine pancreatic insulin (Wako Pure Chemical Industries, Itd.) in 1 mL of a 2 mmol/L aqueous solution of hydrochloric acid, a solution of 320 mg of anhydrous β-lactose (Nacalai Tesque, Inc.) in 2 mL of distilled water, and 1 mL of a 200 mmol/L phosphate buffer (pH 8.4) were mixed in a test tube to give a mixture having a pH of about 8.1. The test tube was put into a constant temperature water bath at 40° C. to cause reaction. The reaction mixture was sampled after 0, 5 and 24 hours, and analyzed for products obtained by the reaction of insulin with lactose by high performance liquid chromatography (HPLC) under the following conditions.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20](O)=[O:21])=[CH:14]3)=[O:10])[CH2:4]1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:21])=[CH:14]3)=[O:10])[CH2:4]1
Reactant: CN(C)C1CCCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)C1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CN(C)C1CCCN(C(=O)c2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)C1

Procedure:
The title compound was synthesized in analogy to Example 1, from 5-(3-dimethylamino-piperidine-1-carbonyl)-1H-indole-2-carboxylic acid, morpholine and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, to afford the product as an off-white solid (37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17]>>[NH2:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])=[O:20]
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Reactant: N#CCC(N)=O
Product: COc1cc(/C=C/C=C(\C#N)C(N)=O)cc(OC)c1O

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.1 g, 0.48 mmol) to 2-cyanoacetamide (0.04 g, 0.48 mmol). After refluxing for 3 h and recrystallization from ethanol an orange solid was obtained (0.083 g, 63%). The product gave the following analytical data:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]=[O:40])[N:36]([CH3:38])[N:37]=1>O1CCCC1>[Cl:27][C:28]1[CH:29]=[C:30]([CH:41]=[CH:42][CH:43]=1)[CH2:31][NH:32][C:33]1[CH:34]=[C:35]([CH:39]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=2)[OH:40])[N:36]([CH3:38])[N:37]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(F)cnc21
Reactant: Cn1nc(NCc2cccc(Cl)c2)cc1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cc(NCc3cccc(Cl)c3)nn2C)c2cc(F)cnc21
Temperature: -20 °C

Procedure:
5-Fluoro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (146, 0.33 g, 0.79 mmol) and 1.5 mL of tetrahydrofuran were combined in a round bottom flask and cooled to −20° C. Isopropylmagnesium chloride (400 μL, 2.0 M in tetrahydrofuran, 0.8 mmol) was added dropwise and the reaction stirred and brought to −5° C. The reaction was cooled to −20° C. and 5-(3-chloro-benzylamino)-2-methyl-2H-pyrazole-3-carbaldehyde (145, 0.090 g, 0.36 mmol) in tetrahydrofuran was added and the reaction stirred and brought to 0° C. The reaction was concentrated under vacuum, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, then brine. The organic layer was separated and dried over sodium sulfate, filtered and the filtrate purified by silica gel flash column chromatography eluting with a gradient of 5-80% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=542.7, 543.95.
Reaction SMILES: [H-].[Na+].C1COCC1.C(O[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C.[C:20](#[N:22])[CH3:21]>CCOCC>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([CH2:21][C:20]#[N:22])=[O:19])=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: CCOC(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 50% oil dispersion of NaH (24 grams) was placed in a 2 l. 3-necked flask and covered with 250 ml. THF. After heating to reflux, a solution composed of 55 ml. THF, ethyl-4-chlorobenzoate (57 grams), and acetonitrile (20.5 grams) was added in dropwise fashion. The reaction mixture started to solidify after the reactants were added so an additional 200 ml. of THF was added. The mixture was then heated to reflux for 21/2 hours, cooled to room temperature, treated with 1 l. ether, and allowed to stand for 72 hours.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18](Br)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]([C:16]2[O:17][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccc(-c2ccccc2)o1
Temperature: 80 °C
Yield: 75 %

Procedure:
5-Bromo-furan-2-carboxylic acid (2-piperidin-1-yl-phenyl)-amide (1.0 mmol), phenylboronic acid (1.2 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) [“Pd(dppf)2Cl2”] (Aldrich) (0.05 mmol) and Na2CO3 (3.0 mmol) were dissolved in a solution of THF/H2O (4:1, 5 mL; saturated with argon) and heated to 80° C. for 5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography to afford the pure product. Yield: 75%. MS: 347 (M+1). 1H NMR (CDCl3, 300 MHz): δ 9.90 (br s, 1H), 8.50 (d, 1H), 7.82 (d, 2H), 7.50-7.28 (m, 4H), 7.24-7.05 (m, 3H), 6.82 (d, 1H), 3.00-2.80 (m, 4H), 1.95-1.80 (m, 4H), 1.75-1.60 (m, 2H).
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:8]([C:11]1[N:16]2[N:17]=[C:18]([CH3:28])[C:19]([C:20]3[S:24][C:23]([CH2:25][O:26][CH3:27])=[N:22][CH:21]=3)=[C:15]2[N:14]=[C:13]([CH3:29])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[Cl:30]N1C(=O)CCC1=O.[Cl-].[NH4+]>C1COCC1>[Cl:30][C:21]1[N:22]=[C:23]([CH2:25][O:26][CH3:27])[S:24][C:20]=1[C:19]1[C:18]([CH3:28])=[N:17][N:16]2[C:11]([CH:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[CH:12][C:13]([CH3:29])=[N:14][C:15]=12
Reactant: CCC(CC)c1cc(C)nc2c(-c3cnc(COC)s3)c(C)nn12
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nc2c(-c3sc(COC)nc3Cl)c(C)nn12
Reaction time: 0.5 h
Yield: 4.3 %

Procedure:
Add n-butyl lithium (2.5 M in hexanes, 174 mL, 0.43 mmol) to a stirred solution of 7-(1-ethyl-propyl)-3-(2-methoxymethyl-thiazol-5-yl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (150 mg, 0.43 mmol) in THF (3 mL) at −78° C. Stir for 30 min and add N-chlorosuccinimide (87 mg, 0.653 mmol). Stir 30 min and then warm the reaction slowly to room temperature allowing the reaction to continue overnight. Quench the reaction by adding saturated ammonium chloride solution, extract with ethyl acetate, dry over sodium sulfate, filter, and concentrate to a residue. Purify by flash chromatography, eluting with hexanes/ethyl acetate (10/2) to give the title compound (7 mg). MS (APCI) m/z (35Cl) 379.3 (M+1)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.I[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1>>[CH2:14]([O:13][C:11](=[O:12])[C:10]1[CH:16]=[CH:17][C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:8][CH:9]=1)[CH3:15]
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CCOC(=O)c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with ethyl 4-iodobenzoate (336 μL, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=80/20) to provide 400 mg (93% isolated yield) of the desired product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:13])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O.N>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([O:6][CH2:7][CH2:8][O:9][CH3:20])=[C:10]([CH3:12])[CH:11]=1
Reactant: Cc1cc(Br)cc(C)c1OCCO
Reactant: COS(=O)(=O)OC
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COCCOc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2-(4-bromo-2,6-dimethylphenoxy)ethanol (15 g) in methylene chloride (100 ml) was added to a stirred solution of sodium hydroxide (50 g) in water (50 ml) at 5° C. Dimethyl sulphate (8.6 ml) was added dropwise to the stirred solution at 5° C. over 30 minutes. The mixture was stirred at ambient temperature for 12 hours. Dimethylsulphate (5 ml) was added at ambient temperature and the mixture stirred for a further 2 hours. The mixture was cooled to 0° C. and a solution of ammonia (10 ml, density=0.88 g/cm3) was added. The mixture was stirred for 20 minutes, diluted with iced water (500 ml). The methylene chloride phase was removed and the aqueous phase extracted with methylene chloride (2×150 ml). The organic extracts were combined, washed with water (2×100 ml), saturated brine (100 ml) and evaporated. The residue was distilled using a short path distillation apparatus (furnace temperature 120° C./0.08 bar) to give 1-(4-bromo-2,6-dimethylphenoxy)-2-methoxyethane (11.6 g); NMR(CDCl3): 2.34(6H,s), 3.52(3H,s), 3.78(2H,m), 3.96(2H,m) and 7.2(2H,s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C2CCCCO2)=[CH:14][CH:13]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH:6]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: COC(=O)CC(c1ccc(OC2CCCCO2)cc1)c1ncco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CC(c1ccc(O)cc1)c1ncco1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of M11.4 (2.1 mmol), p-toluenesulfonic acid monohydrate (0.57 mmol) in MeOH (15 mL) was stirred at room temperature for 1.5 hours. After it was quenched with NaHCO3 (aqueous) solution, MeOH was removed by rotary evaporator. The residue was extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered through short plug of silica gel. After removing solvent, compound M11 was obtained. MS ESI (pos.) m/e 248.1 (M+H). 1H NMR (500 MHz) (DMSO-d6) δ 9.04 (s, 1H); 7.99 (s, 1H); 7.14 (s, 1H); 7.05 (m, 2H); 6.72 (m, 2H); 4.49-4.52 (m, 1H); 3.57 (s, 1H); 3.22-3.27 (m, 1H); 2.89-2.94 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[O:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]=2[CH:8]=[CH:9]1
Reactant: Oc1cccc2occc12
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCOc1cccc2occc12

Procedure:
4-Hydroxybenzofuran (1.0 g., 0.00746 M), ethyl 4-bromobutanoate (1.46 g, 0.00746 M), anhydrous potassium carbonate (1.13 g), sodium iodide (50 mg) and 95% ethanol (20 ml) were reacted together to give ethyl 4-(4-benzofuranyloxy)butanoate which was subsequently hydrolysed, as previously described for the preparation of 5-(4-benzofuranyloxy)pentanoic acid, to give 4-(4-benzofuranyloxy)butanoic acid, m.p. 91°-93° C. (Found: C, 65.50; H, 5.40. C12H12O4 requires C, 65.45; H, 5.45%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2.[N+](=[CH2:22])=[N-]>O1CCOCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:22])=[O:14])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]1=2
Reactant: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1
Reactant: C=[N+]=[N-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
5.0 G. of 5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid (as prepared above) is suspended in 50 ml. of dioxane, added to excess ethereal diazomethane, and stirred until dissolution is complete. The solution is then evaporated to dryness to yield methyl (5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)carboxylate (m.p. 115°-116° C).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].N1CCCCC1.C(O)(=O)C>CO.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:13]/[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1c[nH]c2ccccc12)c1ccccc1

Procedure:
In a dried, 25 mL round bottom flask under argon, indole-3-carboxaldehyde (300 mg, 2.07 mmol) was dissolved in anhydrous methanol (8 mL). Acetophenone (240 μL, 2.07 mmol) and piperidine (100 μL, 1.00 mmol) was added. The reaction was stirred under reflux for 18 hours. 10% Acetic acid was added (10 mL), precipitating 248 mg of a crude yellow solid. This was recrystallized in 100% EtOH, filtered, and dried under vacuum, yielding a pure, yellow solid (198 mg, 39%, 247.29 MW). 1H NMR (600 MHz, d6-DMSO): δ 8.133-8.114 (m, 3H, phenyl-2,6H, indole-2H), 8.095-8.081 (m, 1H, indole-4H), 8.075-8.049 (d, J=15.6, 1H, C═CH), 7.668-7.642 (d, J=15.6, 1H, C═CH), 7.655-7.629 (m, 1H, phenyl-4H), 7.581-7.556 (t, J=1.5, 2H, phenyl-3,5H), 7.504-7.490 (m, 1H, indole-7H), 7.254-7.231 (m, 2H, indole-5,6H). 13C NMR (150 MHz, d6-DMSO): δ 188.8, 139.1, 138.5, 137.5, 133.4, 132.4, 128.7, 128.2, 125.1, 122.8, 121.2, 120.4, 115.3, 112.8, 112.5. Melting point: 167-170° C. TLC (in 2:1 ethyl acetate:hexanes) Rf=0.48. Elemental analysis calculated for C17H13NO: C, 82.57; H, 5.30; N, 5.66. found: C, 82.19; H, 5.35; N, 5.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH:10]=O)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH2:22])=[CH:15][CH:14]=1>>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][CH2:10][CH:8]([OH:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:15][CH:14]=1
Reactant: O=CC(=O)c1cccc(Cl)c1
Reactant: Cc1ccc(CCCN)cc1
Product: Cc1ccc(CCCNCC(O)c2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 9 using 3-chlorophenylglyoxal and 3-(4-methylphenyl)propanamine. Recrystallisation of the chromatographed material from ether gave the title compound, mp 115°-117.5°.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)=[C:6]([CH3:16])[CH:5]=[N:4]1)[CH3:2].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:64]/[C:65](/[C:69](/[C:72]([F:75])([F:74])[F:73])=[CH:70]\[CH3:71])=[CH:66]/[CH:67]=C)[CH2:52][N:53]1[C:61](=[O:62])[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]1=[O:63]>>[O:63]=[C:54]1[C:55]2[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:61](=[O:62])[N:53]1[CH2:52][C@@H:51]([NH:50][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=2[CH3:16])[CH:9]=1)=[O:15])[CH2:64][C:65]1[CH:66]=[CH:67][CH:71]=[CH:70][C:69]=1[C:72]([F:74])([F:75])[F:73]
Reactant: C=C/C=C(C[C@H](N)CN1C(=O)c2ccccc2C1=O)\C(=C/C)C(F)(F)F
Reactant: CCn1ncc(C)c1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCn1ncc(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.17 h
Yield: 63.2 %

Procedure:
To a mixture of 4-(1-ethyl-4-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (240 mg, 1.02 mmol) and bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (Pybrop) (568 mg, 1.22 mmol) was added DIPEA (1.77 ml, 10.16 mmol). After 10 min, 2-{(2S,4Z)-2-amino-4-[(1E)-1-(trifluoromethyl)-1-propen-1-yl]-4,6-heptadiene-1-yl}-1H-isoindole-1,3(2H)-dione (425 mg, 1.22 mmol) was added. After 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (365 mg, 63%) as a white solid: LC-MS (ES) m/z 567 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=2)=O.O>O1CCCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:12]2[C:13]3[C:18](=[CH:17][C:16]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:15][CH:14]=3)[CH:19]=[C:11]2[CH2:9][OH:8])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)ccc2n1Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)cc(CO)n2Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of lithium aluminum hydride (366 mg) in tetrahydrofuran (20 ml), a solution of 1-(4-fluorobenzyl)-5-methanesulfonylindole-2-carboxylic acid methyl ester obtained in Example 27 (3) (1.86 g) in tetrahydrofuran (20 ml) was added dropwise at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was poured into water, filtered through Celite and extracted with chloroform. The organic layer was washed with water and dried. The solvent was distilled off under reduced pressure to obtain (1-(4-fluorobenzyl)-5-methanesulfonylindol-2-yl)-methanol (1.8° g). To a solution of the resulting alcohol (1.8 g) in dichloromethane (100 ml) was added manganese dioxide (15.3 g) at 15 to 30° C. and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was filtered through Celite. The solvent was distilled off under reduced pressure to obtain 1.5 g (88.4%) of the desired product as a yellow powder.
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].[CH3:9][N:10]=[C:11]=[O:12]>>[CH3:9][NH:10][C:11]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:12]
Reactant: CSC(C)(C)C=NO
Reactant: CN=C=O
Product: CNC(=O)ON=CC(C)(C)SC

Procedure:
The process of this invention can be carried out by contacting 2-methyl-2-(methylthio) propionaldehyde oxime with methyl isocyanate in the presence of an aqueous medium for a period sufficient to form 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime as a solid in an aqueous slurry which is then filtered to give a water-wet cake.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[C:13]2[N:14]([C:19]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[F:31])=[O:23])=[CH:20][N:21]=2)[N:15]=[C:16]([Cl:18])[CH:17]=1>C1COCC1.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:12]2[C:13]3[N:14]([C:19]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][C:26]=4[F:31])=[O:23])=[CH:20][N:21]=3)[N:15]=[C:16]([Cl:18])[CH:17]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Reactant: Nc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(Br)n3)cc(Cl)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 6-bromopyridin-2-amine (1.24 g, 7.17 mmol) in THF (10.00 mL) was added 60% NaH (294 mg, 7.35 mmol). The mixture was stirred for 30 min until cessation H2 evolution. The resulting dark green solution was added by syringe to a suspension of 8A (800 mg, 2.453 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight, and then added to ice water. The brown solid was collected by filtration and dried under vacuum to give 17A (1.125 g, 89%) MS (m+1)=462. HPLC Peak Rt=3.696 minutes (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).