Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][C@H:30]([C:39](OC)=[O:40])[CH2:31][S:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:25]([N+:43]([O-:45])=[O:44])[CH:24]=3)(=[O:22])=[O:21])=[O:18])=[CH:13][CH:12]=2)=[C:7]([O:46][CH3:47])[CH:6]=1.[Li+].[BH4-]>C1COCC1>[OH:40][CH2:39][C@@H:30]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][C:7]=3[O:46][CH3:47])=[CH:12][CH:13]=2)=[O:18])(=[O:22])=[O:21])=[CH:24][C:25]=1[N+:43]([O-:45])=[O:44])[CH2:31][S:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(-c3ccc(CCCO)cc3OC)cc2)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CCCO)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CO)CSc3ccccc3)c([N+](=O)[O-])c2)cc1
Reaction time: 2 h

Procedure:
A solution of Example 133D (300 mg, 0.38 mmol) in THF (4 mL) at room temperature was treated with 2M LiBH4 in THF (470 μL, 2.5 eq), stirred for 2 hours, quenched with a drop of water, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 100% ethyl acetate to provide the desired product. MS (ESI(−)) m/e 650 (M−H)−, 1H NMR (300 MHz, DMSO-d6) δ 1.75 (m, 2H), 2.65 (t, 2H), 3.32 (m, 4H), 3.43 (t, 2H), 3.61 (dd, 11), 3.72 (dd, 1H1), 3.77 (s, 31), 4.06 (m, 1H), 6.88 (d, 1H), 6.96 (s, 1H), 7.11 (m, 2H), 7.22 (m, 2H), 7.31 (m, 2H), 7.59 (m, 2H), 7.88 (m, 3H), 8.10 (d, 1H), 8.12 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[C:20]([CH3:27])[CH:19]=1.Cl>C(OC)(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:25][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:13][CH:17]=[CH:16][CH:15]=2)=[CH:19][C:20]=1[CH3:27])=[O:26]
Reactant: CC(=O)c1ccc(-c2ccco2)cc1C
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: Cc1cc(-c2ccco2)ccc1C(=O)CC(=O)C(F)(F)F
Reaction time: 20 h
Yield: 104.7 %

Procedure:
To a stirred solution of ethyl trifluoroacetate (9.90 g, 6.31 mmol) in t-butylmethylether (3 ml) was added sodium methoxide (28 wt. % solution in methanol, 1.5 ml, 6.23 mmol) over 2 min. A solution of 1-[4-(2-furyl)-2-methylphenyl]ethanone (1.15 g. 5.74 mmol) in t-butylmethylether (4 ml) was added dropwise over 5 min. and the mixture was stirred for 20 hours. 2N HCl (10 ml) was added, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give 1.78 g of brown oil. The compound was used for next reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20](=O)[CH2:21][C:22](OCC)=[O:23])=[CH:17][CH:18]=2)[CH:13]=[N:12]1)(=[O:10])[CH3:9].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:8]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[NH:7][C:5]4[N:4]([N:3]=[C:2]([CH3:1])[N:6]=4)[C:22](=[O:23])[CH:21]=3)=[CH:17][CH:18]=2)[CH:13]=[N:12]1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Reactant: Cc1n[nH]c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(C)nc4[nH]3)ccc21
Temperature: 170 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methyl-1H-1,2,4-triazol-5-amine (150 mg, 1.52 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (710 mg, 2.59 mmol), TsOH (11 mg, 0.06 mmol), and the mixture was stirred for 1 h at 170° C. The resulting solution was diluted with petroleum ether (8 ml), and solids were collected by filtration and washed with ethyl ether (3 ml) to afford 5-(1-acetyl-1H-indazol-5-yl)-2-methyl-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a crude brown solid (100 mg, crude).
Reaction SMILES: [N:1]12[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19][N:10]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]2.[C:27](Cl)(=[O:30])[O:28][CH3:29]>>[C:27]([N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:28][CH3:29])=[O:30])[CH2:20][CH2:19][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:1]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9]2)[CH2:26][CH2:25]1)([O:28][CH3:29])=[O:30]
Reactant: C1CNCCN2CCOCCOCCN(CCN1)CCOCCOCC2
Reactant: COC(=O)Cl
Product: COC(=O)N1CCN2CCOCCOCCN(CCOCCOCC2)CCN(C(=O)OC)CC1

Procedure:
In a manner similar to that described in Example 7, treat 4,7,13,16-tetraoxa-1,10,21,24-tetraazabicyclo[8,8,8]-hexacosane (compound of Example 68B) with methyl chlorocarbonate Isolate and purify the resultant product in a manner similar to that described in Example 7 to obtain 21,24-dicarbomethoxy-4,7,13,16-tetraoxa-1,10,21,24-tetraazabicyclo[8,8,8]hexacosane, m.p. =86° C.
Reaction SMILES: [H][H].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][O:18]CC1C=CC=CC=1)=[O:16]>[Pd].C(O)C>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[O:16]
Reactant: NCCCCCCCCCCCC(=O)NOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCCCCCCCCCCCC(=O)NO
Reaction time: 30 h
Yield: 90.4 %

Procedure:
Hydrogenation is carried out with hydrogen in a Parr reactor. Pd—C 120 mg, 12-amino-N-(benzyloxy)dodecanamide (1.0 g, 2.4 mmol) and ethanol (40 mL) are put into the reactor. It is advisable to heat the product in the ethanol to 50° C. first in an Erlenmeyer flask. Hydrogenation lasts 30 hours, after which filtration is carried out on a porous septum with a layer of celite, washing the septum several times with ethanol. The solution is concentrated in the Rotovapor and in the high vacuum pump to give 12-amino-N-hydroxy dodecanamide as a white solid (500 mg, Yield=66%).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([N:12]1[C:19]2[CH:18]3[CH2:20][CH:17]3[CH2:16][C:15]=2[C:14]([C:21]([NH2:23])=O)=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[CH2:5]([N:12]1[C:19]2[CH:18]3[CH2:20][CH:17]3[CH2:16][C:15]=2[C:14]([C:21]#[N:23])=[N:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)c1nn(Cc2ccccc2)c2c1CC1CC21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1nn(Cc2ccccc2)c2c1CC1CC21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A flask equipped with a drying tube under N2 atmosphere was charged with anhydrous DMF (50 mL). The flask was cooled to 0° C. and thionyl chloride (4.84 mL, 66.5 mmol) was added dropwise over a period of 2 min. After stirring for an additional 10 min, a suspension of 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid amide, (14.0 g, 55.3 mmol) in DMF (90 mL) was added over 5 min using an addition funnel. The mixture was slowly warmed to rt and stirred for 20 min at which time additional thionyl chloride (3.05 mL, 41.9 mmol) was added as a pre-mixed solution in DMF (20 mL). The reaction was stirred for an additional 20 min and a second pre-mixed solution of thionyl chloride (6.0 mL, 82.5 mmol) in DMF (20 mL) was added. The reaction was stirred for an additional 15 min and NaHCO3 (sat. aq., 50 mL) was added followed by H2O (100 mL). The mixture was stirred for 10 min and concentrated to near dryness in vacuo. The residue was diluted with EtOAc (350 mL) and H2O (250 mL). The layers were separated and the aqueous phase was back-extracted with EtOAc (250 mL). The combined organics were washed with NaHCO3 (sat. aq., 400 mL), and brine (400 mL), dried over MgSO4, filtered, and concentrated to give 2-benzyl-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonitrile as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.37 (3H, m), 7.25 (2H, m), 5.31 (1H, d, J=14.8 Hz), 5.24 (1H, d, J=14.8 Hz), 2.86, (1H, dd, J=16.4, 6.4 Hz), 2.72 (1H, d, J=16.0 Hz), 2.19 (1H, m), 1.87 (1H, m), 1.07 (1H, m), 0.32 (1H, m). 13C APT NMR (100 MHz, CDCl3): δ up: 154.4, 135.3, 130.0, 118.9, 114.3, 55.9, 26.2, 16.9; down: 129.2, 128.6, 128.1, 24.2, 14.4. HPLC/MS: Discovery® C18 column (5μ, 50×2.1 mm), 5% v/v CH3CN (containing 1% v/v TFA) in H2O (containing 1% v/v TFA) gradient to 99% v/v CH3CN in H2O, 0.75 mL/min, tr=2.23 min, ESI+=236.1 (M+H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH:11]=[O:12])[CH:3]=1.[CH3:13][O:14][C@H:15]1[C@@H:20]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19][CH2:18][NH:17][CH2:16]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:24]([O:23][C:22]([NH:21][C@H:20]1[CH2:19][CH2:18][N:17]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH:11]=[O:12])[CH:3]=2)[CH2:16][C@H:15]1[O:14][CH3:13])=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1sc(Br)cc1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C=O
Yield: 20.9 %

Procedure:
The same operation as in Example (244b) was performed using methyl 5-bromo-3-formylthiophene-2-carboxylate obtained in Example (246b) (974 mg, 3.91 mmol), benzyl cis(±)-(3-methoxypiperidin-4-yl)-carbamate obtained in Example (40b) (1.10 g, 4.16 mmol), palladium acetate (176 mg, 0.78 mmol), BINAP (0.49 g, 0.78 mmol) and cesium carbonate (1.78 g, 5.47 mmol), to obtain 354 mg of the title compound as a yellow oily substance (21%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>[Cu].CC1CCCCC1>[CH:10]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:1]1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C=C1CCCCC1
Agent: [Cu]
Solvent: CC1CCCCC1
Product: CCOC(=O)C1CC12CCCCC2
Temperature: 102.5 °C
Reaction time: 12 h

Procedure:
A 250 mL round-bottom flask was charged with methylenecyclohexane (20.0 g, 0.21 mol, commercially available from Aldrich), copper powder (2.8 g), methyl cyclohexane (50 mL) and heated to 105° C. Ethyl diazoacetate (26 g, 0.23 mol, commercially available from Aldrich) was added dropwise over an 8-hour period while maintaining the temperature between 100-105° C. Upon complete addition, the mixture was heated an additional 2 hours, allowed to cool to ambient temperature and stirred for an additional 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound which was used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:31]1([C:36]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:41]5[CH:40]=[CH:39][C:38]([C:36]([N:31]6[CH2:32][CH2:33][CH2:34][CH2:35]6)=[O:37])=[CH:43][CH:42]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCCC1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)N6CCCC6)cc5)cc4)CC3)n2CCS1
Yield: 91.2 %

Procedure:
A solution of the compound (324 mg, 0.7 mmol) obtained in Example 1-2), 4-(pyrrolidin-1-ylcarbonyl)phenylboronic acid (32 mg, 0.77 mmol), tris(dibenzylideneacetone)dipalladium(0) (32 mg, 0.04 mmol), tricyclohexylphosphine (23 mg, 0.08 mmol), and tripotassium phosphate (260 mg, 1.19 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (385 mg, 91%) as a yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][S:11]([CH3:14])(=[O:13])=[O:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:4]([C:3]1[C:2]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[N:9][CH:8]=[CH:7][CH:6]=1)#[N:5]
Reactant: N#Cc1cccnc1Cl
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ncccc1C#N
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-nicotinonitrile (2 g), H2NSO2Me (1.73 g) and K2CO3 (4.44 g) in DMF (100 ml) was stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel in dichloromethane/methanol=98/2 (v/v) as eluent. Yield: 1.32 g. MS-ESI: [M+H]+=198.2
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=1.C(O)(=O)C.[Cl-]>O>[NH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:13][O:14][CH3:15])[C:10]([OH:12])=[O:11])[C:6]([Cl:1])=[CH:5][CH:4]=1
Reactant: CON=C(C(=O)O)c1cccc(N)n1
Reactant: Cl
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)O
Product: CON=C(C(=O)O)c1nc(N)ccc1Cl

Procedure:
To a mixture of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer), acetic acid (350 ml.) and water (10 ml.) was introduced chloride gas for 1.5 hours. After the removal of the excess of the chlorine gas by bubbling air into the reaction mixture, the solvent was distilled off. The residue was pulverized in diethyl ether and collected by filtration. After the addition of water and ethyl acetate to the resultant powder (9.8 g.), the aqueous layer was separated and washed with ethyl acetate. The ethyl acetate layer and washings were combined together, and further extracted with water. The aqueous layers were combined together and adjusted to pH 4 with 1N aqueous solution of sodium hydroxide, and then the solvent was distilled off under reduced pressure. The remaining water in the residue was azeotropically removed with benzene three times to yield brownish powder which was dried in a desiccator to give 2-(6-amino-3-chloropyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (3.27 g.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C1C(=O)N([I:18])C(=O)C1>C(#N)C>[I:18][C:8]1[C:7]([NH2:10])=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc2c(c1)OCC2
Solvent: CC#N
Product: Nc1cc2c(cc1I)CCO2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,3-dihydrobenzofuran-6-amine (S6-1; 95 mg, 0.7 mmol) in acetonitrile (3 mL) cooled in an ice-bath was added NIS (158 mg, 0.7 mmol). After stirring at 0° C. for 20 min, the mixture was condensed and purified by flash chromatography (hexane:EtOAc, 90:10 to 20:80) to yield S7-1 (180 mg, 98%) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.38 (s, 1H), 6.26 (s, 1H), 4.53 (t, J=8.5 Hz, 2H), 3.09 (t, J=8.4 Hz, 2H); MS (ESI) m/z 261.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][NH2:5]
Reactant: Cc1cccc(C)c1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cccc(C)c1CN

Procedure:
The preparation of 2,6-dimethyl DL-phenylalanines is disclosed by R. R. Herr, T. Enkoji & J. P. Dailey, J. Amer. Chem. Soc., 79, 4229(1957). The method involves the conversion of 2,6-dimethyl aniline into its diazonium salt, followed by treatment with potassium cyanide and cuprous cyanide to produce 2,6-dimethylbenzonitrile. The benzonitrile is reduced with lithium aluminum hydride to provide 2,6-dimethylbenzylamine, which is reacted with excess methyl iodide producing 2,6dimethylbenzyltrimethylammonium iodide. The trimethylammonium group is displaced with diethyl-2acetamidomalonate to form the amido diester, which is subsequently acidolysed to form the racemic mixture of 2,6-dimethylphenylalanine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:32])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].[NH4+].[Cl-]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH2:25][CH3:26])[C@@H:22]([OH:24])[CH3:23])[C:11](=[O:27])[C@:10]([CH2:29][C:30]([OH:32])=[O:31])([CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C(C)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H]([C@H](C)O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-2-oxopentan-3-yl)piperidin-3-yl)acetic acid (0.150 g, 0.315 mmol, Example 155, Step C) in THF/MeOH (3/1, 4 mL) was added sodium borohydride (0.060 g, 1.574 mmol) at room temperature. After being stirred at room temperature for 1 h, the reaction was acidified with sat. aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by reversed phase preparatory HPLC (eluent: 10-90% acetonitrile, water, 0.1% TFA, gradient elution) to give a mixture of two isomers (dr=93:7). Individual stereoisomers were separated by chiral HPLC (250×30 mm CHIRALPAK® IC column (CHIRAL TECHNOLOGIES, INC., West Chester, Pa., USA) with 46 g/min ispropylamine+(20 μM NH3)+84 g/min CO2 on Thar 350 SFC (Thar Technologies, Inc., Pittsburgh, Pa.)) to give the title compound as the faster eluting stereoisomer.
Reaction SMILES: [C:1]([OH:14])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OC(=O)C)(=O)C.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)(=O)C>[C:1]([N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1CCCNCC1
Reactant: CCCCCCCCCCCC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCCCCCCCCCC(=O)N1CCCCCC1
Yield: 83.4 %

Procedure:
A mixture of dodecanoic acid (20.03 g, 0.1M), acetic anhydride (13.27 g, 0.13M), hexahydro-1H-azepine (12.9 g, 0.13M) was heated with distillation of formed acetic acid. The residue on distillation gave 23.46 g (83.5%) of colorless product, b.p. 204-205/7 mm.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1C=CC=C[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Ni+2]>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:10]#[CH:11])#[CH:8].[C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccc1
Agent: [Ni+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C#Cc1ccccc1
Solvent: c1ccccc1
Product: C#Cc1ccccc1C#C
Reaction time: 2 h

Procedure:
A copolymer prepolymer of diethynylbenzene and phenylacetylene was prepared in refluxing benzene solvent. The polymerization vessel was charged with 60 parts of a 90:10 mixture of m- and p-diethynylbenzenes, 60 parts of phenylacetylene, 600 parts of benzene and 2 parts of chlorobenzene. After heating to reflux, 5 parts of a catalyst solution prepared by adding 0.3 part of nickel acetylacetonate and 0.6 part of triphenylphosphine in 15 parts benzene were added. After 2 hours, an additional 10 parts of this catalyst solution was added. After 5 hours, gas-liquid chromatographic analysis showed that 74% of the diethynylbenzenes and 35% of the phenylacetylene had been converted to copolymer. The copolymer was precipitated by adding the solution to five times its volume of petroleum ether, 26 parts being recovered. This product had a number average molecular weight of about 3,000, an acetylene content of 8.9%, and an aromatic to olefin proton ratio of 5.5:1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:3]1=[O:18].CN1C2C(=CC=CC=2)C(C2[C:30](=[O:35])NCCN=2)=C1.[H-].[Na+].S(OC)(OC)(=O)=O>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:30]=[O:35])[CH:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH3:17])[CH:9]=2)[C:3]1=[O:18]
Reactant: CN1CCN=C(c2cn(C)c3ccccc23)C1=O
Reactant: Cn1cc(C2=NCCNC2=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CN1CCN(C=O)C(c2cn(C)c3ccccc23)C1=O
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The 1-methyl-3-(1-methylindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone required as the starting material is prepared as follows: 45.5 g (0.2 mol) of 3-(1-methylindol-3-yl)-5,6-dihydro-2(1H)-pyrazinone, prepared in accordance with Example 33, are dissolved in 400 ml of dimethylformamide, 5.3 g (0.22 mol) of sodium hydride are introduced, the mixture is stirred for 4 hours at 60° C., 27.8 g (0.22 mol) of dimethyl sulphate are added dropwise and the mixture is stirred for 20 hours at 60° C. The compound which is precipitated by dilution with water is recrystallised from methanol.
Reaction SMILES: [CH2:1]([C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:43][S:44]([OH:47])(=O)=[O:45]>ClCCl>[CH2:1]([C:7]1[C:8]([C:37]2[CH:42]=[CH:41][C:40]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:39][CH:38]=2)=[C:9]([C:31]2[CH:32]=[CH:33][C:34]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:35][CH:36]=2)[C:10]([C:25]2[CH:26]=[CH:27][C:28]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:29][CH:30]=2)=[C:11]([C:19]2[CH:24]=[CH:23][C:22]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:21][CH:20]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([S:44]([Cl:43])(=[O:47])=[O:45])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c(-c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCCCCCc1c(-c2ccc(S(=O)(=O)Cl)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c(-c2ccc(S(=O)(=O)Cl)cc2)c1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
A 250 mL round bottom flask was charged with 2.0 g (0.004 mol) of 1-hexyl-2,3,4,5,6-pentaphenylbenzene and 50 mL of dichloromethane. Chlorosulfonic acid (15 mL) was added to the stirred reaction mixture at room temperature via an addition funnel. The reaction mixture turned immediately purple, and then clear orange after 1 h. The reaction mixture was stirred at room temperature for 1 d, and then poured onto crushed ice. The layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to deposit a light-gray solid. The product was recrystallized from ethyl acetate to provide 1.39 g (57%) of a white powder. 1H NMR (CDCl3) δ 7.96 (d, J=10, 4 H), 7.66 (m, 6), 7.41 (d, J=10, 4H), 7.08 (m, 6H). MS (FD) m/e 1034 (M+).