Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:8])([OH:17])=[O:16]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NCc1ccccc1
Reaction time: 8 h
Yield: 117.8 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (307 mg, 0.9 mmol) in dry THF (7 mL) under argon was added benzylamine (590 μL, 5.4 mmol) and potassium cyanide (3 mg, 0.05 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 3/1) to give 310 mg of the desired compound (80% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:39])=[C:16]([NH:18][C:19]2[N:23]([CH3:24])[C:22]3[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:30])=[CH:28][C:21]=3[N:20]=2)[CH:17]=1>CC#N.C(Cl)Cl>[Cl:39][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[CH:17][C:16]=1[NH:18][C:19]1[N:23]([CH3:24])[C:22]2[CH:25]=[CH:26][C:27]([C:29]([NH:31][CH2:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:30])=[CH:28][C:21]=2[N:20]=1
Reactant: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: CC#N
Solvent: ClCCl
Product: Cn1c(Nc2cc(CNS(=O)(=O)c3cccs3)ccc2Cl)nc2cc(C(=O)NCC3CCCCC3)ccc21

Procedure:
Thiophene-2-sulfonyl chloride (64 mg, 0.35 mmol) in MeCN (1 mL) was added to a mixture of 2-(5-aminomethyl-2-chlorophenylamino)-N-cyclohexylmethyl-1-methylbenzimidazole-5-carboxamide (150 mg, 0.35 mmol), TEA (150 L, 1.1 mmol) and MeCN (2 mL). After 12 h at rt the mixture was diluted with DCM and washed with NH3 (aq, sat) and brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give the title compound. Yield: 36 mg (18%). 200 MHz 1H-NMR (DMSO-d6, ppm) 8.50-8.36 (2H, m) 8.35-8.22 (1H, m) 7.94-7.82 (3H, m) 7.69-7.57 (2H, m) 7.42 (1H, d, J=8.2 Hz) 7.37 (1H, d, J=8.2 Hz) 7.18-7.11 (1H, m) 7.04-6.95 (1H, m) 4.09-3.96 (2H, m) 3.71 (3H, s) 3.14-3.00 (2H, m) 1.77-1.47 (7H, m) 1.29-1.07 (4H, m). MS m/z: 572 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C(C)(C)C)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5 g, 32.02 mmol), 4-dimethylaminopyridine (4.69 g, 38.42 mmol) in dry CH2Cl2 (75 ml) was cooled to 0° C. and pivaloyl chloride (4.24 g, 35.22 mmol) added dropwise in 15 min. The reaction mixture was stirred at room temperature overnight, diluted with CH2Cl2 (150 ml) and washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was purified by chromatography using hexane/EtOAc/AcOH 15:5:0.1 as the mobile phase to give 5-pivaloyl-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 11 (5.46 g, 71%).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27])=O>>[CH3:27][O:26][C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccc(OC)c(C(=O)CBr)c1
Product: COC(=S)c1cc(-c2nc(-c3cc(OC)ccc3OC)cs2)c(C)s1
Yield: 46.4 %

Procedure:
132 mg (0.534 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-2′,5′-dimethoxy acetophenone (0.587 mmol; 152 mg) in a manner similar to Example 22, step (a) to afford 97 mg (45% yield) of methyl 4-[4-(2,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([N-:15][CH:16]=[N:17]2)=[C:13]([N+](C)(C)C)[N:12]=1.Cl>CS(C)=O>[Cl:10][C:11]1[N:19]=[C:18]2[C:14]([NH:15][CH:16]=[N:17]2)=[C:13]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:12]=1
Reactant: OCc1ccccc1
Reactant: C[N+](C)(C)c1nc(Cl)nc2nc[n-]c12
Agent: Cl
Agent: [Na]
Solvent: CS(C)=O
Product: Clc1nc(OCc2ccccc2)c2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0 %

Procedure:
Sodium spheres (250 mg, 10.87 mmol) and benzyl alcohol (2 ml, 19.33 mmol) were mixed and vigorously stirred under N2 at 60°-100° (oil-bath) until all the sodium had dissolved (30 minutes) The mixture was cooled to room temperature and a suspension of 2-chloro-6-trimethylammoniopurinide (100 g, .73 mmol) in sieve-dried DMSO (10 ml) was added. This was stirred at room temperature under N2 for 13/4 hours and the reaction mixture was then added dropwise to ice-H2O (100 ml). The pH of the solution was adjusted to 7.0 using lM HCl and the white solid which formed was filtered off, washing well on the pad with H2O. This material was dried in vacuo over P2O5 at room temperature to give 0 mg (79.5% yield) of product. An analytical sample was obtained by recrystallizing from ethanol-H2O and drying the product in vacuo. Analysis Calculated for:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[N:10]1([C:4]2[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=[C:2]([C:21]3[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:27])[F:28])=[CH:23][CH:22]=3)[N:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1cc(Cl)nc(N2CCCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2ccc(OC(F)(F)F)cc2)nc(N2CCCC2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
A solution of nitrile 25A (2.58 g, 12.5 mmol) in DME (90 mL) was added with 4-trifluoromethoxy phenyl boronic acid (2.64 g, 1.0 mol eq,) and NaHCO3 (3.15 g, 3 mol eq,) suspended in water (45 mL). The mixture was degassed under vacuum, then Palladium Tetrakis was added (catalytic amount) and the reaction was stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (80 mL). The aqueous phase was extracted with EtOAc (3×60 mL) and the combined organic layer was washed with brine (80 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to afford 26C as deliquescent yellow solid (3.2 g, 9.6 mmol, 77% Yield). 1HNMR (DMSO, 400 MHz) δ 1.85 (m, 4H), 3.42 (m, 4H), 6.38 (s, 1H), 7.08 (s, 1H), 7.38 (d, 2H, J=8), 8.05 (d, 2H, J=8).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[CH:29]2.[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:31]1[C:32]2[C:28](=[CH:27][C:26]([Cl:25])=[CH:34][CH:33]=2)[CH:29]=[CH:30]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Clc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To a solution of 0.8 g (3.03 mmoles) of 18-crown-6 in 100 mL of dry ether was added 4.39 g (39.12 mmoles) potassium tert-butoxide. The mixture was stirred while 5.08 g (33.51 mmoles) of 5-chloroindole was added. The stirring was continued for 0.5 hour. Most of the solid dissolved. Then 6.69 g (39.11 mmoles) of benzyl bromide in 40 mL of ether was added during 0.5 hours. The stirring was continued for 27 hours. Water (100 mL) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 mL). The combined ether phases were washed with 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 9.17 g of orange oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 1:2 CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (2×8") (1:2 CH2Cl2 -Skellysolve B). Fractions 10-14 were combined giving 7.26 g (90%) of 1-benzyl-5-chloroindole as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=2)=[CH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([Br:21])=[CH:16][N:15]=2)=[CH:10][CH2:9]1)[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)cnc1C1=CCC(NC(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cnc1C1=CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]carbamic acid-tert-butyl ester (11.2 g) in N,N-dimethylformamide (90 ml) was added sodium hydride (1.46 g) under ice-cooling, and stirred at the same temperature for 0.5 hours. Then methyl iodide (5.7 ml) was added thereto, and stirred at the same temperature for 2 hours. After completion of the reaction, water was added thereto, and the precipitated solid was collected by filtration to give N-[4-(5-bromo-3-methylpyridin-2-yl)cyclohex-3-en-1-yl]-N-methylcarbamic acid-tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH2:15][CH:16](O)[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.CS(Cl)(=O)=O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([S:12]([CH:15]=[CH:16][CH2:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)(=[O:14])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(CC(O)CCc1cccnc1)N1CCc2ccc(Cl)cc2C1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(C=CCCc1cccnc1)N1CCc2ccc(Cl)cc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 116.6 %

Procedure:
A solution of 1-[(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl]-4-pyridin-3-ylbutan-2-ol (270 mg of crude compound) and Et3N (0.23 ml, 1.69 mmol) in anhydrous THF (3 ml) was cooled at 0° C., then methanesulfonyl chloride (0.066 ml, 0.85 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 1 hour, then at 60° C. for 15 hours. The reaction mixture was diluted with DCM, then washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried (MgSO4) and the solvents were removed under reduced pressure to give the title compound as an oil (300 mg) used in the next step without further purification. HPLC, Rt: 3.1 min (purity: 63%). LC/MS, M+(ESI): 363.2, M−(ESI): 361.1.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:8]2([CH3:12])[C:9]([CH3:11])=[CH:10][CH:5]([CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2)[N:4]1CC1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[CH3:2][CH:3]1[C:8]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:5]([CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2)[NH:4]1
Reactant: CCOC(=O)C1CC2(C)C(C)=CC1N(Cc1ccccc1)C2C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CC2(C)C(C)CC1NC2C
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]-oct-7-ene-6-carboxylate hydrochloride (26.2 g, 75 mmol), 10% palladium on carbon (2.6 g) and ethanol (200 mL) were placed on a Parr hydrogenator at 50 psi for 3.5 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to afford crude ethyl 3,4,8-trimethyl-2-azabicyclo[2.2.2]-octane-6-carboxylate hydrochloride as a yellow oil, which was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][CH:16]=1
Reactant: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.47 g (12.5 mmol) of 1-(tert-butyloxycarbonyl)-4-(5-methylpyridin-2-yl)piperazine are dissolved in 10 ml of dioxane, and 31 ml (125 mmol) of hydrogen chloride in dioxane (4 molar) are added. The mixture is stirred at RT for 2 h. The mixture is then concentrated and the residue is made alkaline using 1M aqueous sodium hydroxide solution and extracted repeatedly with dichloromethane. The combined organic phases are dried over sodium sulphate, concentrated and dried under reduced pressure.
Reaction SMILES: II.I([O-])(=O)=O.[Na+].[NH2:8][C@@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.[I:25]([O-])(=O)(=O)=O.[Na+]>C(O)(=O)C>[CH:16]1[C:11]([CH2:10][C@@H:9]([NH2:8])[C:17]([OH:19])=[O:18])=[CH:12][CH:13]=[C:14]([I:25])[CH:15]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N[C@H](Cc1ccc(I)cc1)C(=O)O
Reaction time: 24 h

Procedure:
12.3 g (48 mmol) of iodine and 5.1 g (24 mmol) of sodium iodate were added to 20 g (121 mmol) of D-phenylalanine, 14.5 ml of concentrated sulfuric acid and 110 ml of acetic acid, and they were stirred for 24 hours. After cooling, 0.5 g of sodium periodate was added thereto, and the solvent was evaporated at 35° C. under reduced pressure. Water was added to the reaction mixture and the resultant mixture was washed with dichloromethane trice. The aqueous phase was neutralized with 1 N aqueous sodium hydroxide solution. After cooling, the obtained precipitate was taken by the filtration and then washed with water and ethanol to obtain the crude product.
Reaction SMILES: [CH:1]([O:3][C@H:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)=[CH:25][CH:24]=1)[C@@H:5]([CH:19]=[O:20])[CH2:6][CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:2].P([O-])(O)(O)=[O:38].[Na+].OO.Cl([O-])=O.[Na+]>C(#N)C.O>[F:35][C:33]1[CH:34]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C@@H:4]([O:3][CH:1]=[O:2])[C@H:5]([CH2:6][CH2:7][N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[C:19]([OH:38])=[O:20])=[CH:28][CH:27]=2)[CH:30]=[C:31]([F:36])[CH:32]=1
Reactant: O=P([O-])(O)O
Reactant: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@@H](C=O)CCN1C(=O)c2ccccc2C1=O
Agent: OO
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: O=CO[C@H](CCc1ccc(-c2cc(F)cc(F)c2)cc1)[C@H](CCN1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound obtained from step d above (0.12 g) was taken in acetonitrile (6 mL) and water (1 mL). To this solution, sodium dihydrogen phosphate (0.05 g) was added. The reaction mixture was cooled to 0° C., and hydrogen peroxide (0.5 mL) and sodium chlorite (0.15 g) were added. After stirring the reaction mixture for an additional 1 hour, the solvents were evaporated on a rotary evaporator and the residue was taken into water and extracted with ethyl acetate. The organic layer was washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure, to get the title compound (0.12 g).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.[CH3:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CC1OCCC1>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CC1CCCO1
Product: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
4-Carboxybenzaldehyde (9 g, 60 mmol, 1.0 eq.) and biphenyl-2-yl-carbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (21.2 g, 60 mmol, 1.0 eq.) were combined in MeTHF (115 mL). The mixture was stirred for 0.5 hours, forming a thick slurry. Additional MeTHF (50 mL) was added to form a free-flowing slurry. 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (18 g, 63 mmol, 1.1 eq., 97% pure) was added in two portions and the funnel rinsed with additional MeTHF (50 mL). The mixture was stirred at room temperature overnight. MeCN (50 mL) was added and the mixture was filtered. The solids were washed with MeTHF (30 mL). The filtrate and washes were combined and a saturated NaHCO3 solution (100 mL) was added and stirred for 10 minutes. The layers were separated and a saturated NaCl solution (100 mL) was added and stirred for 10 minutes. The layers were separated and the aqueous layer discarded. The resulting solution was concentrated under reduced pressure and held at room temperature for three days, then used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][C:44](=[O:46])[CH3:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:47][Mg]Br>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][C:44]([CH3:47])([OH:46])[CH3:45])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C[Mg]Br
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(C)(C)O)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 29b, 200 mg of 4-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-butan-2-one and 0.5 ml of methylmagnesium bromide (1N solution in tetrahydrofuran) are used to afford the title compound as a beige oil. Rf=0.12 (EtOAc-heptane 1:1); Rt=5.14.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:9][O-:10].[Na+]>CO>[CH3:9][O:10][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: C[O-]
Reactant: Nc1nccnc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1N
Temperature: 130 °C
Yield: 58.5 %

Procedure:
A mixture of 3-chloro-2-pyrazinamine (200 mg, 1.544 mmol) and sodium methoxide (250 mg, 4.63 mmol) in methanol (3.9 ml) was heated to 130° C. via a microwave reactor for 60 min. The crude product mixture was purified by RP-HPLC to give 3-(methyloxy)-2-pyrazinamine (113 mg, 0.903 mmol, 59% yield). MS (ES+) m/z 125.8 (MH+).
Reaction SMILES: [N+:1](=[C:3]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5])=[N-].[C:16]1([NH:22][C:23](N)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClCCCl.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+4]>[CH3:14][O:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]1[N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23](=[O:24])[NH:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COCCCCC(=O)C(=[N+]=[N-])C(=O)OC
Reactant: NC(=O)Nc1ccccc1
Agent: [Rh+4]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: COCCCCc1c(C(=O)OC)[nH]c(=O)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Methyl 2-diazo-7-methoxy-3-oxoheptanoate (6.93 g) and 1-phenylurea (5.41 g) were suspended in toluene (30 ml)-1,2-dichloroethane (30 ml), rhodium tetraacetate (230 mg) was added and the mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, trifluoroacetic acid (7.5 ml) was added and the reaction mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (15:85-100:0) was concentrated under reduced pressure to give the object product (7.40 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:14][N:15](C)C=O>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[N:15])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Br)cc1OC(F)(F)F
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-(trifluoromethoxy)iodobenzene (25 g, 68 mmol) and zinc(II) cyanide (4.0 g, 34 mmol) in 150 mL of degassed dimethylformamide was added tetrakis(triphenylphosphine)palladium (3.1 g, 4 mole %). The solution was stirred at 80 ° C. for one hour, then cooled to room temperature. Additional portions of zinc(II) cyanide (800 mg) and tetrakis(triphenylphosphine)palladium (700 mg) were added, and the solution was heated at 80° C. for 3 hours. The mixture was diluted with EtOAc and extracted with saturated NaHCO3 solution and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel column chromatography (0-5% ether/hexane) gave the titled product.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[O:28]=[C:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]([C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:29]2([OH:28])[CH2:34][CH2:33][S:32][CH2:31][CH2:30]2)=[C:13]([CH3:19])[CH:12]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Reactant: O=C1CCSCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCSCC2)c(C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
n-Butyllithium (2.71 M solution in hexane, 2.8 mL, 7.6 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 1 g, 3.4 mmol) in tetrahydrofuran (17 mL) in a nitrogen atmosphere at 0° C. Then, a solution of 4-oxothiane (0.4 g, 3.4 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture, which was further stirred at 0° C. for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound (1.04 g, 74%).