Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([CH:14]=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2].CC(C)=[O:18].OS(O)(=O)=O.O=[Cr](=O)=O>>[CH2:1]([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([C:14]([OH:18])=[O:15])[CH2:8][CH2:7]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C12CCC(C=O)C(CC1)C2
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)C12CCC(C1)C(C(=O)O)CC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To an ice-cold solution of 4-formyl-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (3.85 mmol, 0.81 g) was added slowly Jones reagent (2.7 M, 1.43 mL). The reaction was stirred at ice temperature 20 min. then quenched by addition of iPrOH. diluted with H2O and extracted with Et2O (3×). The combined organic extracts were washed with H2O (2×). brine (1×), and dried (MgSO4). Filtration and evaporation provided the viscous oily bicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethyl ester (0.76 g, 87%) as a mixture of axial and equatorial acids. 13CNMR (100 MHz, CDCl3): 14.16 (q), 19.86 (t), 21.07 (t), 25.98 (t), 29.20 (t), 31.52 (t), 31.87 (t), 32.27 (t). 33.39 (t), 37.80 (d), 38.07 (t), 38.10 (d), 42.06 (t). 44.80 (d), 45.78 (d), 49.38 (s), 49.60 (s), 60.31 (t), 60.36 (t), 177.08 (s), 180.0.1 (s).
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][C:6]([CH3:10])(O)[C:5]1=[CH2:11])([CH3:3])=[CH2:2].[CH:12]([O:15]CC)=[CH:13][CH3:14]>P(=O)(O)(O)O>[CH:12]([CH:13]([CH3:14])[CH2:11][C:5]1[CH:4]([C:1]([CH3:3])=[CH2:2])[CH2:8][CH2:7][C:6]=1[CH3:10])=[O:15]
Reactant: CC=COCC
Reactant: C=C(C)C1CCC(C)(O)C1=C
Agent: O=P(O)(O)O
Product: C=C(C)C1CCC(C)=C1CC(C)C=O
Yield: 66.7 %

Procedure:
15 drops of 85% phosphoric acid were added to a mixture, cooled to -30° C in a laboratory autoclave, of 76 g of 3-isopropenyl-1-methyl-2-methylene-cyclopentan-1-ol and 130 g of ethyl 1-propenyl ether. After gassing with nitrogen, the autoclave was brought, in an oil bath of 180° C, to an internal temperature of 150° C (this took about 15 minutes) and held at this temperature until a distinct drop in pressure occurred (about 75 minutes). The reaction mixture was then quenched, taken up in ether, washed with aqueous bicarbonate solution and water, the solution dried over anhydrous magnesium sulphate and concentrated under reduced pressure. The crude product (135 g), obtained as a yellow oil, was fractionated and yielded 64 g (67%) of pure 2-(2-formylpropyl)-3-isopropenyl-1-methyl-cyclopent-1-ene having woody, earthy, musty fragrance; boiling point 0.005 = 51° C; nD20 = 1.4825; IRfilm : νmax = 3090, 2730, 1735, 1645, 1460, 1380 and 898 cm-1.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:13]2[S:12][CH2:11][C@H:10]([NH:14]C(=O)OC(C)(C)C)[C:9](=[O:22])[NH:8][C:7]=2[CH:6]=[C:5]([C:23]([F:26])([F:25])[F:24])[CH:4]=1>O1CCOCC1>[ClH:2].[NH2:14][C@@H:10]1[C:9](=[O:22])[NH:8][C:7]2[CH:6]=[C:5]([C:23]([F:26])([F:25])[F:24])[CH:4]=[C:3]([Cl:2])[C:13]=2[S:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CSc2c(Cl)cc(C(F)(F)F)cc2NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CSc2c(Cl)cc(C(F)(F)F)cc2NC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 183.8 %

Procedure:
11 mL of a solution of hydrogen chloride in dioxane (4 M) are added to a 25 mL round-bottomed flask containing 582 mg of 15 (1.47 mmol). The mixture is stirred for 4 hours at room temperature under argon. A white precipitate forms, which is filtered off by suction and washed with 3 mL of dioxane and then 5 mL of isopropyl ether. 450 mg of amine 16 are thus obtained in the form of the hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20].O>CS(C)=O>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:17]=1[O:16][CH3:15])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(Cl)ccc2nc1Cl
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc3ccc(Cl)cc3nc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 78.3 %

Procedure:
To 2,6-dichloro-3-methoxyquinoxaline (4.00 g, 17.5 mmol) dissolved in dimethyl-sulfoxide (40 ml), 2,4-dimethoxybenzylamine (14.6 g, 87.3 mmol) was added at room temperature. The mixture was stirred at room temperature for 36 hours and then water was added thereto. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (30:1) mixture and concentration gave 4.93 g of the titled compound (yield, 78%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[Cl-].[NH4+]>C(O)C>[CH3:14][CH2:13][O:12][C:5]([C:6]([CH2:1][C:2]([CH3:4])=[O:3])=[O:8])=[O:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(C)=O

Procedure:
Ethyl acetopyruvate was prepared from acetone and diethyl oxalate as described in Org. Synthesis, Coll. Vol. 1, 238 (1958). Further reaction with triethylorthofcrmate and ammonium chloride in ethanol. afforded the known enol ether 1. See L. Claisen, Chem. Ber., 40, 3903 (1907).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl(trans)-4-aminocyclohexylcarbamate (1.500 g) and triethylamine (2.93 mL, 2.125 g) were added to dichloromethane and stirred until the tert-butyl(trans)-4-aminocyclohexylcarbamate had dissolved completely. Acetyl chloride (0.577 g) was added slowly, and the solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue taken up in ethyl acetate, washed with pH 4 buffer, washed with brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH2:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C=O>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:15]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
43.2 g of Z-D-Lys(Boc)-OH, prepared analogously to the L-compound, are dissolved in 400 ml of dimethylformamide. 24.5 g of H-Phe-OMe.HCl, 15.33 g of HOBt, 14.53 ml of NEM and, with stirring, 25 g of DCC are added, and the mixture is left to stand overnight at room temperature. After the urea has been filtered off, the solvent is distilled off in vacuo and the oily residue is recrystallized from 200 ml of 80% strength ethanol.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([CH2:14][C:15]#[N:16])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.Cl.Br[CH2:19][CH2:20]Cl>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:3][C:4]1[C:5]([C:14]2([C:15]#[N:16])[CH2:20][CH2:19]2)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: ClCCBr
Reactant: N#CCc1ncc(C(F)(F)F)cc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: N#CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: 0 °C

Procedure:
2.90 g of Sodium hydroxide was dissolved in 10 ml of water and 1.94 g of benzyltriethylammonium chloride was added at ambient temperature. The solution was stirred and a solution of 2.00 g of (3-chloro-5-trifluoromethyl-pyridin-2-yl)-acetonitrile in 2.8 ml of 1-bromo-2-chloroethane was added dropwise. The reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was then cooled to 0° C. and acidified to pH1 with concentrated aqueous hydrochloric acid (36%). The reaction mixture was extracted twice with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Thus, 2.09 g of crude 1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropanecarbonitrile was obtained as a brown oil, which was used for the next step without further purification. 1H-NMR (CDCl3): 8.68 ppm (s, 1H), 8.00 ppm (s, 1H), 1.80 ppm (m, 2H), 1.70 ppm (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[CH3:13][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]=1[OH:1]
Reactant: CO
Reactant: O=C(O)c1cc(O)ccc1O
Agent: Cl
Product: COC(=O)c1cc(O)ccc1O

Procedure:
2,5-Dihydroxybenzoic acid (30 g) was added to methanol (100 ml) which had been acidified with hydrogen chloride gas. The solution was refluxed for 12 hours when the solvent was removed. The resulting solid was taken up in diethyl ether (200 ml) and washed with water (2×100 ml). The organic layer was dried over magnesium sulphate and the solvent removed under vacuum. The resulting solid (30 g) (m.p. 83°-84° C.) was identified as the desired methyl ester.
Reaction SMILES: Cl.C1(OC(=O)[C@H](CCCCN)N[C:16](=[O:38])[C@H:17]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:18][C:19](=[O:33])[C@H:20]([CH:30]([CH3:32])[CH3:31])[NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C2C(=CC=CC=2)C=CC=1.[OH-:45].[Na+]>CO>[C:22]([NH:21][C@H:20]([C:19]([NH:18][C@H:17]([C:16]([OH:38])=[O:45])[CH2:34][CH:35]([CH3:36])[CH3:37])=[O:33])[CH:30]([CH3:31])[CH3:32])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)N[C@@H](CCCCN)C(=O)Oc1cccc2ccccc12
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
In 150 ml of methanol was dissolved 5.0 g of the above ester, and 20 ml of 1N sodium hydroxide solution was added to the solution. The mixture was stirred at room temperature for 8 hrs. The reaction mixture was concentrated at a low temperature, after which ethyl acetate and distilled water were added to the residue. The resulting mixture was shaken, and the aqueous layer was separated and made weakly acidic with 10% hydrochloric acid solution. The oily substance thus precipitated was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate, and thereafter evaporated under reduced pressure to remove the solvent, thereby obtaining 3.0 g (yield 65%) of a colorless oily substance of N-benzoyl-L-valyl-L-leucine.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[S:30][C:29]([C:31]([OH:33])=O)=[CH:28][CH:27]=1.[CH:34]([N:47]1[CH2:50][C:49]2([CH2:55][NH:54][CH2:53][CH2:52][O:51]2)[CH2:48]1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>CN(C=O)C>[CH:34]([N:47]1[CH2:50][C:49]2([CH2:55][N:54]([C:31]([C:29]3[S:30][C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:33])[CH2:53][CH2:52][O:51]2)[CH2:48]1)([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: c1ccc(C(c2ccccc2)N2CC3(CNCCO3)C2)cc1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCOC3(C2)CN(C(c2ccccc2)c2ccccc2)C3)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (2.267 g) was added in one portion to a solution of 5-methylthiophene-2-carboxylic acid (0.652 g) and 2-benzhydryl-5-oxa-2,8-diazaspiro[3.5]nonane (example 33, step f) (1.35 g) and triethylamine (1.917 mL) in DMF (20 mL) at 0° C. The cooling bath was removed and the mixture stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine before being dried over sodium sulphate, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0.4 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 1.5 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9](Br)[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH:15]1(B(O)O)[CH2:17][CH2:16]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([CH:15]2[CH2:17][CH2:16]2)[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13]
Reactant: COC(=O)Cc1cc(Br)c(C)cc1C
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1cc(C2CC2)c(C)cc1C
Reaction time: 0.08 h
Yield: 49.1 %

Procedure:
To a solution of 6.0 g of (5-bromo-2,4-dimethyl-phenyl)-acetic acid methyl ester (WO99/48869) in 100 ml of toluene is added 2.2 g of cyclopropylboronic acid and 20 g of potassium phosphate tribasic trihydrate at room temperature. The reaction mixture is stirred for 5 minutes under nitrogen atmosphere, followed by further addition of 1.2 g of tetrakis(triphenylphosphine)palladium(0). After heating and stirring for 16 hours at 110° C., the reaction mixture is filtered, the solvent removed in vacuo and the residue is subjected to silica gel chromatography (isohexane/diethyl ether 2:1) to yield 2.5 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N:12]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:29]([O-])=O)[CH:3]=1.[BH4-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:29][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[C:5]=1[N:12]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=1)[C:13](=[O:17])[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)N(Cc1cccc(C(F)(F)F)c1)c1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: CCOC(=O)N(Cc1cccc(C(F)(F)F)c1)c1c(N)cc(Br)cc1C(F)(F)F
Reaction time: 0.17 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenyl[3-(trifluoromethyl)benzyl]carbamate (225.7 mg) and nickel(II) chloride hexahydrate (211.9 mg) in methanol (5 ml) was added sodium borohydride (71.7 mg) in an ice bath. After the mixture was stirred for 10 minutes, 1N hydrochloric acid was added. The mixture was basified with saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (213.4 mg, quantitative yield).
Reaction SMILES: C(O[N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[C:15]([OH:17])=O)C1C=CC=CC=1.Cl.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[C:15]([CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][NH:9]1)=[O:17]
Reactant: CNC
Reactant: O=C(O)C1CCCCN1OCc1ccccc1
Agent: Cl
Product: CN(C)C(=O)C1CCCCN1

Procedure:
The general procedure of Referential Example 131 was repeated through use of N-benzyloxypiperidine-2-carboxylic acid (6.4 g) and dimethylamine hydrochloride (2 g), to thereby give the title compound as an oily product (3.8 g, quantitative amount).
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=C)=[O:12])([CH3:9])([CH3:8])[CH3:7].O=O.S(C)C>C(Cl)Cl>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=[O:4])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C=C[C@H](OC(C)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Ozone/oxygen was bubbled at -70° C. into a solution of (3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene (2.55 g, 8.0 mmol) [prepared by the method of Hanson et al., J. Org. Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deep blue color persisted. Oxygen was introduced until the blue color completely faded, then 3.0 mL of Me2S was added and the solution was allowed to warm to 0°-5° C. and stand overnight. The solvent was removed at 0° C. under vacuum yielding the title compound as a thick yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 48.8 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.038 g (49%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]1[N:19]([CH3:22])[CH2:20][CH2:21][C:12]21[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si]([N-][Si](C)(C)C)(C)C.[Li+].COS(OC)(=O)=O.O>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]1[N:19]([CH3:22])[CH2:20][CH2:21][C:12]21[CH3:23])[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCC2(C)c3cc(NC(=O)OC(C)(C)C)ccc3N(C)C12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc2c(c1)C1(C)CCN(C)C1N2C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
5-(t-Butyloxycarbonylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (1.7 g) was dissolved in dry THF (15 ml) under nitrogen and cooled to -78° C. in a dry ice/acetone bath. A 1M solution of lithium bis(trimethylsilyl)amide (7.2 ml) in THF was added via a syringe. The solution was stirred at -78° C. for 15 minutes, warmed to room temperature and again cooled to -78° C. before the addition of dimethylsulfate (0.74 g) in THF (5 ml) via syringe. The mixture was stirred for 1 hour and allowed to warm to ambient temperature and water was added in order to quench the reaction. Ethyl acetate (100 ml) was added and the mixture was washed with brine (20 ml), dried (Na2SO4), concentrated and purified by flash chromatography (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 5-(t-butoxycarbonyl-N-methylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo[2,3-b]indole (0.42 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13]N1C(=O)CCC1=O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Nc1ccc2c(c1)CCCC2=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1ccc2c(c1Br)CCCC2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a flask was added 6-amino-3,4-dihydro-1(2H)-naphthalenone (5.30 g, 32.9 mmol) and DCM (329 mL) and the mixture was cooled to 0° C. N-bromosuccinimide (5.85 g, 32.9 mmol) was added portionwise over 1 hour. The mixture then was stirred at 0° C. for 3 hours. The reaction was quenched with aqueous sodium bicarbonate (100 mL) and then extracted with DCM (3×100 mL). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The product was purified by silica gel chromatography using a gradient solvent system of 0-65% EtOAc/Hexanes. Concentration of the product-containing fractions yielded 6-amino-5-bromo-3,4-dihydronaphthalen-1(2H)-one (7.8 g, 87%) as a light tan solid. MS ESI calcd for C10H10BrNO 240 [M+H]+. found 240.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Nc1cccc(Cl)c1
Product: Cc1cc(Nc2cc3ccccc3c(Nc3cccc(Cl)c3)n2)n[nH]1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-chloro-phenylamine to give N1-(3-chloro-phenyl)-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 350(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]=[C:4]2[NH:9][N:10]=[C:11]([OH:12])[C:3]=12.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:6]1[N:5]=[C:4]2[NH:9][N:10]=[C:11]([OH:12])[C:3]2=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(O)nc2[nH]nc(O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc(Cl)nc2[nH]nc(O)c12
Temperature: 115 °C
Reaction time: 5 h

Procedure:
2.5 g (15.14 mmol) of 4-methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diol and 4.75 ml (39.2 mmol) of N,N-dimethylaniline were cautiously added to 60 ml of phosphorus oxychloride and the mixture was stirred at 115° C. for 5 h. The reaction mixture was concentrated and hydrolyzed with 30 g of ice. The product crystallized after some time. It was filtered off with suction and dried. Yield: 1.77 g (64%), M+H+: 184.1.