Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[N:13]1([C:20]2[C:25]([CH2:26][NH:27][C:28]3[N:32]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[C:35]([Cl:40])[C:34]=4[Cl:41])[N:31]=[N:30][N:29]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:5]([OH:8])(=[O:7])[CH3:6].[C:9]([OH:12])(=[O:11])[CH3:10].[Cl:41][C:34]1[C:35]([Cl:40])=[C:36]([F:39])[CH:37]=[CH:38][C:33]=1[N:32]1[C:28]([NH:27][CH2:26][C:25]2[C:20]([N:13]3[CH2:19][CH2:18][CH2:17][N:16]([CH:2]([CH3:4])[CH3:1])[CH2:15][CH2:14]3)=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:29][N:30]=[N:31]1
Reactant: CC(C)=O
Reactant: Fc1ccc(-n2nnnc2NCc2cccnc2N2CCCNCC2)c(Cl)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CCCN(c2ncccc2CNc2nnnn2-c2ccc(F)c(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetone (0.5 mL) was added to a mixture of the product of Example 289 (80 mg, 0.183 mmol) and sodium triacetoxyborohydride (77 mg, 0.366 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was filtered and washed with dichloromethane. The filtrate was concentrated under reduced pressure and purified by preparative HPLC on a Thermoquest, hyperprep HS C18 column (250×21.2 mm., 8 μm particle size) using a gradient of 5% to 75% acetonitrile to ammonium acetate (10 mM) over 20 minutes at a flow rate of 21 mL/min to provide the title compound. MS (ESI+) m/z 479.3 (M+H)+; Rt=1.63 min. 1H-NMR (400 MHz, DMSO-d6) δ 0.96 (d, J=6.6 Hz, 1H), 1.80 (m, 2H), 1.90 (s, 2H), 2.65 (m, 2H), 2.70 (m, 2H), 2.86 (m, 1H), 3.38 (m, 4H), 4.44 (d, J=5.3 Hz, 1H), 5.75 (s, 1H), 6.84 (dd, J=4.8 Hz, J=7.5 Hz, 1H), 7.52 (dd, J=1.9 Hz, J=7.5 Hz, 1H), 7.58 (t, J=50.5 Hz, 1H), 7.73 (t, J=8.8 Hz, 1H), 7.86 (dd, J=5.3 Hz, J=9.0 Hz, 1H), 8.07 (dd, J=1.9 Hz, J=4.7 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[C:11]([OH:14])(=[O:13])[CH3:12].[OH-].[Na+]>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:11]([O-:14])(=[O:13])[CH3:12]
Reactant: CC(=O)O
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)[O-]
Product: CN(C)C(=N)NC(=N)N
Temperature: 30 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
20.0 g (1 equivalent) of metformin hydrochloride and 30 Ml of water, and then 10 Ml (1.45 equivalents) of acetic acid were added to a reactor, and stirred for 2 hours at 30° C. to dissolve thoroughly. Then 1.23 g (1.5 equivalents) of aqueous solution of sodium hydroxide was added to the reaction solution. The resulting crystal was filtered and washed with acetone, and then dried at 60° C. to obtain 16.7 g of metformin acetate (yield: 73.0%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23].[Cl:26][SiH:27]([Cl:29])[Cl:28]>>[Cl:26][Si:27]([Cl:29])([Cl:28])[CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23].[Cl:26][SiH:27]([Cl:28])[CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cl[SiH](Cl)Cl
Reactant: C[Si](C)(C)CCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[Si](C)(C)C[SiH](Cl)Cl
Product: C[Si](C)(C)C[Si](Cl)(Cl)Cl
Yield: 70 %
Yield: 7 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.20 g (0.75 mmol) of triphenylphosphine, 1.38 g (7.5 mmol) of (chloromethyl)trimethylsilane, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 1.2 g of 1,1,1,-trichloro-3,3-dimethyl-1,3-disilabutane (bp; 173-174° C., yield; 70%) and 0.1 g of 1,1-dichloro-3,3-dimethyl-1,3-disilabutane (bp; 157-159° C., yield; 7%).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[O:12][N:11]=1)#[N:2].[CH3:21][NH2:22]>C(O)C>[C:1]([N:3]=[C:4]([NH:22][CH3:21])[NH:5][CH2:6][CH2:7][S:8][CH2:9][C:10]1[N:14]=[C:13]([NH:15][C:16]([NH2:18])=[NH:17])[O:12][N:11]=1)#[N:2]
Reactant: CSC(=NC#N)NCCSCc1noc(NC(=N)N)n1
Reactant: CN
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1noc(NC(=N)N)n1
Reaction time: 18 h

Procedure:
To a solution of 3-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]-5-guanidino-1,2,4-oxadiazole (0.7 g.) in ethanol (20 ml.) was added a 33% w/v solution of methylamine in ethanol (30 ml.) The solution was kept for 18 hours at 20°, evaporated in vacuo and the residue finally dried at 30°/0.05 mm. to give 3-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]-5-guanidino-1,2,4-oxadiazole as a white solid, m.p. 185°-188°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31]C)=[O:30])=[CH:26][CH:25]=1.[OH-].[Li+].Cl>O1CCCC1.O>[O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 102.3 %

Procedure:
A mixture of methyl 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate (1.38 g, 3.17 mmol) and lithium hydroxide (0.76 g, 31.7 mmol) in tetrahydrofuran (10 mL) and water (10 mL) was stirred at 60° C. for 2 h. The reaction mixture was acidified with 1 M hydrochloric acid (50 mL) and extracted with dichloromethane (3×30 mL). The combined organic solution was washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (1.36 g, quantitative) as a colorless solid: mp 192-195° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ8.40 (br s, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.25 (d, J=3.3 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.06 (dd, J=7.5, 7.5 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.45 (d, J=3.3 Hz, 1H), 6.31 (s, 1H), 5.19 (d, J=16.5 Hz, 1H), 4.92 (d, J=9.3 Hz, 1H), 4.87 (d, J=16.5 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.21-4.07 (m, 4H); 13C NMR (75 MHz, CDCl3) δ177.4, 162.8, 155.2, 154.4, 144.8, 143.7, 141.3, 138.6, 132.3, 129.1, 124.2, 124.0, 121.1, 120.9, 111.8, 110.7, 109.0, 99.5, 80.0, 64.7, 64.0, 58.2, 37.5; MS (ES+) m/z 419.9 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[N+:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1)([O-:12])=[O:11].[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29](Cl)=[O:30]>ClCCl>[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)=[O:30]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccnc(OC2CCNCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1F)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Add triethylamine (2.57 mL, 18.5 mmol) to a suspension of 1.1 g (3.7 mmol) of 4-nitro-2-(piperidin-4-yloxy)-pyridine dihydrochloride in dry dichloromethane (50 mL). Then add 2,6-difluorobenzoyl chloride, 0.512 mL (4.07 mmol). Stir the mixture at room temperature overnight. Add water (50 mL) and separate organic layer. Dry with MgSO4 and filter. Evaporate solvents to obtain 1.22 g (91% yield) of (2,6-difluoro-phenyl)-[4-(4-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone as a yellow solid (ES+(m/z)=364 [M+H].
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=2)=[O:9])[CH:4]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)c2cccnc2)cc1
Yield: 85.1 %

Procedure:
A mixture of 1.83 g (0.01 mol) of nicotinoyl chloride hydrochloride (97%), 1.65 g of (0.01 mol) of ethyl 4-aminobenzoate, 2.22 g (0.022 mol) of triethylamine and 61 mg of 4-dimethylaminopyridine in 33 ml of dichloromethane is refluxed 24 hours. The solution is washed with water, 2N citric acid and NaHCO3 solution. The solvent is removed and the residue-triturated with methanol to give 2.3 g of ethyl 4-[(3-pyridinylcarbonyl)amino]benzoate as yellow crystals, m.p. 125°-127° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([F:8])=[C:6]([CH:9]=[O:10])[C:5]([C:11]([F:14])([F:13])[F:12])=[N:4]1)[CH3:2].[BH4-].[Na+].O.C(OCC)C>CO>[CH2:1]([N:3]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([C:11]([F:13])([F:12])[F:14])=[N:4]1)[CH3:2]
Reactant: CCn1nc(C(F)(F)F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCn1nc(C(F)(F)F)c(CO)c1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A solution of 11.1 g (52.8 mmoles) of 1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 50 ml of methanol was cooled to 0° C. Thereto was gradually added 2.1 g (55.5 mmoles) of sodium borohydride. The mixture was stirred at room temperature for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water and extraction with diethyl ether was conducted. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 9.1 g (yield: 81.3%) of (1-ethyl-5-fluoro-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19](=[O:28])[N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN(C(=O)Oc1ccc(N)cn1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)Oc1ccc(NS(=O)(=O)c2ccccc2)cn1)c1ccccc1
Reaction time: 4 h
Yield: 28.2 %

Procedure:
Benzenesulphonyl chloride (0.18 g, 1.00 mmol), dissolved in a small amount of dichloromethane, was added dropwise to a stirred solution of methyl-phenyl-carbamic acid 5-amino-pyridin-2-yl ester (0.24 g, 1.00 mmol) and triethylamine (0.10 g, 1.00 mmol) in dichloromethane (10 mL). After stirring for 4 hours the solution was extracted with water and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane 40:60 followed by 50:50) yielding the title compound (108 mg, 23% yield) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:24](=[O:25])[N:23]([CH3:26])[C:16]4[N:17]=[C:18](SC)[N:19]=[CH:20][C:15]=4[CH:14]=3)[CH:7]=2)[CH2:3][CH2:2]1.O[O:29][S:30]([O-:32])=O.[K+].[CH3:34]O>C1COCC1.O>[CH:1]1([NH:4][C:5](=[O:27])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[C:24](=[O:25])[N:23]([CH3:26])[C:16]4[N:17]=[C:18]([S:30]([CH3:34])(=[O:32])=[O:29])[N:19]=[CH:20][C:15]=4[CH:14]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc2cc(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)n(C)c2n1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(S(C)(=O)=O)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-Cyclopropyl-4-methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzamide (21 mg) was dissolved in a mixture of 2 mL MeOH, 1 mL THF and 1 mL water. OXONE™ (1.63 mg, 0.09 mmol) was added, and the reaction mixture was stirred for three hours at room temperature. The reaction mixture was then partitioned between water and EtOAc, and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 25 mg of N-cyclopropyl-3-(2-methanesulfonyl-8-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-4-methyl-benzamide.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]([OH:15])(=[O:14])[CH3:13].C(OC(=O)C)(=O)C.[CH:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]12[CH2:11][CH2:13][C:12](=[O:15])[O:14][C:26]=1[CH2:25][CH2:24][CH2:23][CH2:28][CH2:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: CC(=O)O
Reactant: c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC2=C(CCCCCCCCCC2)O1
Yield: 32.8 %

Procedure:
Five parts of the foregoing β-(2-oxocyclododecyl)propionic acid morpholine amide, 0.2 part of paratoluene sulfonic acid, 50 parts of acetic acid, and 5 parts of acetic anhydride were refluxed for 36 hours. And then 300 parts of benzene was added into the solution and washed with aqueous sodium bicarbonate to remove the catalyst and acetic acid. Thereafter, the resulting solution was treated by the same method as described in Example 1 to give 1.54 parts of 13-oxabicyclo(10.4.0)hexadec-1(12)-en-14-one in 32.8% yield.
Reaction SMILES: [C-]#N.[Na+].[N+:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])#[C-:5].C(O[C:15](=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[N:4]=[CH:5][S:22][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:8])[CH3:11]
Reactant: CCOC(=S)c1ccccc1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ncsc1-c1ccccc1
Temperature: 50 °C
Reaction time: 96 h
Yield: 62 %

Procedure:
Prepare a suspension of NaCN (0.25 g, 5.2 mmol) in ethanol (50 mL). Add dropwise ethyl isocyanoacetate (5 mL, 45.6 mmol) and thiobenzoic acid O-ethyl ester (6.9 g, 41.5 mmol) in ethanol (25 mL). Stir the reaction mixture at 50° C. for 96 hours and then concentrate in vacuo to an oil. Chromatograph (silica gel, 3:7 hexane/ethyl acetate) to afford 5-phenylthiazole-4-carboxylic acid ethyl ester (6.0 g). MS: m/e=234 (MH+).
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][O:10][C:11]([C:13]1[C:21]2[S:20][C:19](N)=[N:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12]>C1COCC1>[CH3:9][O:10][C:11]([C:13]1[C:21]2[S:20][CH:19]=[N:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1cccc2nc(N)sc12
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc2ncsc12

Procedure:
Isoamyl nitrite (22.0 mmol) is added to a solution of 2-amino-benzothiazole-7-carboxylic acid methyl ester (10.1 mmol) in THF (29 mL). The mixture is heated to reflux for 4 h, the solvents are removed in vacuo and the residue is purified by FC (gradient: heptane to EtOAc/heptane 4/6) to give the desired product.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)([OH:7])=O.[CH2:16]([NH:18][CH3:19])[CH3:17]>ClCCl.CN(C)C=O>[CH2:16]([N:18]([CH3:19])[C:5](=[O:7])[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[CH3:17]
Reactant: CCNC
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
Thionyl chloride (26 mL, 0.36 mol) was added dropwise to a solution of 4-carboxybenzaldehyde (50.0 g, 0.33 mol) in 2000 mL of dichloromethane:N,N-dimethylformamide (4:1 mixture). The mixture was stirred overnight at room temperature. Ethylmethylamine (75.0 g, 1.3 mol) was added dropwise, and stirring was continued at room temperature for 90 minutes. The solvent was removed under vacuum, the residue was dissolved in 500 mL of 0.1M sodium hydroxide, and extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum to give 23.8 g (38%) of N-ethyl-4-formyl-N-methylbenzamide as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[C:19]3[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])=[N:4][N:3]=1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[C:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][C:19]2[C:9]([CH2:8][S:7][C:5]3[S:6][C:2]([NH:1][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[N:3][N:4]=3)=[C:10]([Cl:27])[CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15]1)=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: O=CC1CC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(N)s3)c2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(NCC4CC4)s3)c2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 6-(5-amino-[1,3,4]thiadiazol-2-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.252 g, 0.59 mmol) in anhydrous DCE (1 mL), add a solution of cyclopropane carboxaldehyde (0.083 g, 1.2 mmol) in anhydrous DCE (1 mL) at room temperature. Add sodium tris(acetoxy)borohydride (0.38 g, 1.8 mmol) and a solution of glacial acetic acid (0.20 mL, 3.5 mmol) in anhydrous DCE (1 mL) to the reaction mixture at room temperature. Heat at reflux overnight, cool the reaction mixture to room temperature and add saturated aqueous NaHCO3 (25 mL) to the mixture. After stirring at room temperature for 1 h, extract the two-phase mixture with DCM (2×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 hexane/EtOAc over 33 min; 95:5 to 50:50 hexane/EtOAc over 33 min; 50:50 to 0:100 hexane/EtOAc over 30 min; 35 mL/min) to afford the desired intermediate (0.087 g, 31%). MS (ES+) m/z: 481.2 (M+H)+.
Reaction SMILES: [CH2:1]([Si:3]([CH2:21][CH3:22])([CH2:19][CH3:20])[O:4][CH2:5][C:6]([O:14][Si:15]([CH3:18])([CH3:17])[CH3:16])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][C:8]#[CH:9])[CH3:2].[CH2:23]([SnH:27]([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:21]([Si:3]([CH2:1][CH3:2])([CH2:19][CH3:20])[O:4][CH2:5][C:6]([O:14][Si:15]([CH3:18])([CH3:16])[CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7]/[CH:8]=[CH:9]/[Sn:27]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:22]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)(CO[Si](CC)(CC)CC)O[Si](C)(C)C
Reaction time: 0.08 h

Procedure:
A mixture of 20.0 g. of 4-triethylsilyloxymethyl-4-trimethylsilyloxy-1-octyne, 18.18 g. of tri-n-butylstannane and 70 mg. of azobisisobutyronitrile is stirred under argon and placed in a bath at 100° C. After 5 minutes an exotherm ensues. The mixture is heated at 130°-140° C. for one hour and then the excess tri-n-butylstannane is removed at 130° C. and reduced pressure. The residue is distilled at 130°-140° C., 0.03 mm. in a Kugelrohr apparatus, giving the desired product as a colorless liquid.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:14]O.C(N(C(C)C)CC)(C)C.[CH3:30][O:31][C:32](=[O:55])[C@H:33]([CH2:42][C:43]1[N:47]=[CH:46][N:45](C(OC(C)(C)C)=O)[CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:30][O:31][C:32](=[O:55])[C@H:33]([CH2:42][C:43]1[N:47]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:11]([CH3:10])[CH:12]=2)[CH:46]=[N:45][CH:44]=1)[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: COc1ccc(CO)cc1C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cncn1Cc1ccc(OC)c(C)c1)NC(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 24 h

Procedure:
A solution of 10.8 g methanesulfonic anhydride in 120 mL dichloromethane is chilled to -50° C. and treated dropwise with a solution of 9.4 g 3-methyl-4-methoxybenzyl alcohol, 10.8 mL diisopropylethylamine and 80 mL dichloromethane. The resulting solution is warmed to -25° C. over 30 min and treated dropwise with 20.0 g N,1-bis-BOC-histidine methyl ester dissolved in 125 mL dichloromethane. The mixture is then allowed to warm to 25° C. over 4 hr, stirring at this temperature 24 hr. The reaction mixture is poured into 700 mL 0.25M, pH=7 potassium phosphate buffer and the organic layer is separated, dried and evaporated. Chromatography on silica gel, eluting with chloroformmethanol (99:1) gives 3-(3-methyl-4-methoxyphenyl)methyl-N-BOC-histidine methyl ester as a gum. NMR (CDCl3) 1.43 (s,9H,t-Bu).
Reaction SMILES: [NH2:1][NH2:2].[H-].[Na+].[CH3:5][C:6]([C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])[C:12]#[N:13])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:8][C:6]([C:9]1[CH:10]=[C:11]([C:12]([NH:1][NH2:2])=[NH:13])[CH:14]=[C:15]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]=1[O:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])([CH3:5])[CH3:7]
Reactant: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Reactant: NN
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 66.4 %

Procedure:
97% anhydrous hydrazine (4.8 g, 0.151 mole) is added dropwise to a stirred 0° C. suspension of sodium hydride (2.8 g of a 60% dispersion in mineral oil, 0.071 mol) in tetrahydrofuran (70 m) under nitrogen. After 90 minutes, a solution of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile (6.7 g, 0.021 mole) in tetrahydrofuran (15 ml) is added dropwise. After stirring two hours at 0° C., water 2.4 ml) is added dropwise. The mixture is poured into cold, saturated aqueous sodium bicarbonate 20 ml). The product is extracted with a 1:1 ethyl acetate/ether mixture (60 ml). The organic layer is washed with saturated aqueous NaCl and dried over MgSO4. Filtration and concentration provided a solid which was recrystallized from ethyl acetate/hexane to give 4.9 g (7.3 g theor., 67%) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide, mp 133° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH2:14][CH2:15][C:16]1([CH2:29][OH:30])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:29]1[C:16]2([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]2)[CH2:15][CH2:14][O:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCOC2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
Diethyl azodicarboxylate (183 μl, 1.16 mmol) in tetrahydrofuran (0.5 mL) was added dropwise to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate Description 24, 250 mg, 0.96 mmol) and triphenylphosphine (303 mg, 1.16 mmol) in tetrahydrofuran (10 mL) and the mixture was stirred at 0° C. for 90 minutes then at room temperature overnight. The mixture was cooled to 0° C. and further triphenylphosphine (126 mg, 0.48 mmol) and diethyl azodicarboxylate (76 μl, 0.48 mmol) were added. The mixture was stirred at room temperature for 2.5 hours, then the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (80:20), to give the title compound as a colorless oil (150 mg, 65%). m/z (ES+) 186 (M+1−C4H8).