Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10]OS(C)(=O)=O)[CH2:8][C:7]1=[O:16].[I-:23].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH:9]([CH2:10][I:23])[CH2:8][C:7]1=[O:16]
Reactant: [I-]
Reactant: COc1ccc(CN2C(=O)CC2COS(C)(=O)=O)c(OC)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CN2C(=O)CC2CI)c(OC)c1
Reaction time: 8 h
Yield: 104.3 %

Procedure:
A mixture of 37.5 g (0.107 mole) of 1-(2,4-dimethoxy-benzyl)-4-(mesyloxymethyl)-2-azetidinone prepared according to the preceding paragraph, 250 ml of anhydrous acetone, and 56.3 g (0.376 mole) of sodium iodide is heated to boiling for 8 hours. To the mixture a further amount of 18.8 g (0.125 mole) of sodium iodide are added and the mixture is stirred for a further 8 hours under boiling. The mixture is evaporated to dryness on a water-bath (internal temperature 50° C.), the residue is rubbed with 100 ml of water and the oil thus obtained is extracted with 100 ml of dichloromethane. The aqueous layer is extracted three times with 50 ml of dichloromethane each. The united dichloromethane layers are dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. Thus 40.3 g of 1-(2,4-dimethoxy-benzyl)-4-(iodomethyl)-2-azetidinone are obtained. Yield: 98%.
Reaction SMILES: [K].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([O-])=O.[Cl:10][C:11]1[CH:20]=[CH:19][C:14](C(=O)CBr)=[CH:13][CH:12]=1.C([O-])(=O)C.[NH4+].[BH4-].[Na+]>C(O)(=O)C.CS(C)=O>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([CH:4]2[CH2:9][O:8][C:2](=[O:7])[CH2:3]2)=[CH:13][CH:12]=1
Reactant: COC(=O)CC(=O)[O-]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [K]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C1CC(c2ccc(Cl)cc2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To 204 ml of dimethyl sulfoxide were added 40.1 g of potassium salt of monomethyl malonate (XVI) and then 50.0 g of p-chlorophenacyl bromide (XVII), and the mixture was stirred at room temperature for 30 minutes. Then, 12.9 g of ammonium acetate were added and the mixture was stirred at room temperature for 2 hours. Subsequently, 36.6 ml of acetic acid were added and 8.5 g of sodium borohydride were added under ice-cooling over one hour. The reaction mixture was allowed to stand at room temperature for one hour to reduce the double bond. After 68 ml of ice-water were added, the mixture was heated under reflex at 125°-130° C. for 3 hours to effect decarboxylation. After completion of the reaction, the reaction mixture was poured into 500 ml of ice-water, the black precipitate thus separated was collected by filtration and subjected to distillation under reduced pressure to give 29.7 g of the title compound (yield 71%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH2:18][CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:38])C=CC=CC=1>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][N:11]2[N:10]=[C:9]1[CH:18]([OH:38])[CH2:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nn2cccc2c(=O)n1Cc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(O)c1nn2cccc2c(=O)n1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-benzyl-2-propyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (2.0 g, 7.48 mmol) in THF (45 mL) at −78° C. was added KHMDS (0.5 M in toluene, 17.2 mL, 8.6 mmol) dropwise. After stirring at −78° C. for 10 min, the orange solution was charged with a solution of racemic 2-benzenesulfonyl-3-phenyloxaziridine (2.15 g, 8.23 mmol) in THF (5 mL). The pale yellow solution was stirred at −78° C. for 25 min and was then quenched with 50 mL of saturated NaHCO3 solution. The mixture was extracted with EtOAc (3×50 mL) and the pooled organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Purification of the crude product by flash column chromatography (SiO2, EtOAc/Hexane 1:4) gave the title compound as a colorless viscous oil which solidified upon standing (1.40 g, 66%): 1H NMR (CDCl3) δ 7.25 (m, 5H), 7.12 (t, 1H, J=1.4 Hz), 7.01 (m, 1H), 6.49 (m, 1H), 5.34 (d, 1H, J=16.1 Hz), 5.18 (d, 1H, J=16.2 Hz), 4.45 (m, 1H), 2.55 (brs, 1H), 1.78 (m, 1H), 1.63 (m, 1H), 0.88 (t, 3H, J=7.36 Hz); 13C NMR (CDCl3) δ 155.4, 150.7, 136.7, 129.4, 128.2, 126.7, 121.4, 118.5, 111.5, 109.6, 71.0, 44.8, 29.8, 10.3; MS (ESI+) 284.17 (M++H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]([CH2:22][CH:23]2[CH2:25][CH2:24]2)[S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].[N:34]1([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@H:35]1[C:44](O)=[O:45].CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][C@@H:2]([NH:1][C:44]([C@@H:35]2[CH2:36][C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:43][N:34]2[C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:45])[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]([CH2:22][CH:23]3[CH2:24][CH2:25]3)[S:18]([CH3:21])(=[O:19])=[O:20])[CH2:9][CH2:10]2)=[O:4])=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CI
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2N(CC2CC2)S(C)(=O)=O)CC1

Procedure:
tert-Butyl 3-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl) (methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]carbamoyl}(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)propan-1-one (Example 58, Step 3) (224 mg, 0.457 mmol), according to the procedure for Preparation XIX using Boc-L-Tic-OH (135 mg, 0.487 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (285 mg, 0.959 mmol), HOAT (68 mg, 0.50 mmol), and DMF (7 mL). The compound was isolated (339 mg). MS (ESI, pos. ion) m/z: 750 (M+H), (ESI, neg. ion) m/z: 748 (M−H). Calc'd for C39H48ClN5O6S: 750.35.
Reaction SMILES: C1N2CCN(CC2)C1.I[C:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH:11]=1.C[Si](Cl)(C)C.[CH3:21][PH:22](=[O:27])[O:23][CH:24]([CH3:26])[CH3:25]>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>[OH:15][CH:12]1[CH2:13][CH2:14][C:10]([CH2:21][PH:22](=[O:27])[O:23][CH:24]([CH3:26])[CH3:25])=[CH:11]1
Reactant: OC1C=C(I)CC1
Reactant: CC(C)O[PH](C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Product: CC(C)O[PH](=O)CC1=CC(O)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of DABCO (11.8 g, 105 mmol) and 3-iodo-cyclopent-2-enol (5.5 g, 26.3 mmol) in anhydrous toluene (300 cm3) was added trimethylsilyl chloride (3 g, 27.6 mmol). The reaction mixture was stirred at room temperature for 15 min, after which time isopropyl methylphosphinate (4.8 g, 39.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (760 mg, 2.5 mol %) were added. The reaction mixture was heated at 70° C. for 24 h after which time a second portion of tetrakis(triphenylphosphine)palladium(0) (760 mg, 2.5 mol %) was added and heating continued for a further 24 h. The reaction mixture was filtered while still hot and aqueous ethanol (50 cm3) added to the filtrate, which was then concentrated in vacuo. The product was isolated by short column vacuum chromatography on silica gel (15% ethanol/ethyl acetate) to yield the title compound (3) as a slightly coloured oil (3.5 g, 65%): 1H NMR (300 MHz, CDCl3) δ 1.25 (3H, t, J=6.4, OCHCH3), 1.327 and 1.333 (3H, 2×d, J=6.2 and 6.2 Hz, OCHCH3), 1.49 and 1.51 (3H, 2×d, J=14.4 and 14.4 Hz, PCH3), 1.76-1.92 (1H, m, C(5)—H), 2.33-2.52 (2H, m, C(5)—H′ and C(4)—H), 2.60-2.78 (1H, m, C(4)—H′), 4.55 (1H, m, OCHCH3), 4.95 (1H, m, C(3)—H), 6.57 (1H, m, C(2)—H); 13C NMR (75.46 MHz, CDCl3) δ 13.8 and 14.0 (PCH3, d, JPC=101 and 101 Hz), 23.88 and 23.91 (POCCH3, d, 3JPOCC=4.9 and 4.6 Hz), 24.31 (POCCH3, overlapping d, 3JPOCC=3.4 Hz) 26.89 and 26.91 (C(4), d, 3JPC=12.8 and 12.5 Hz), 29.27 and 29.35 (C(5), d, 2JPC=8.8 and 8.6 Hz), 76.94 and 73.65 (POCHCH3, d, 2JPOC=6.0 and 6.3 Hz), 76.94 and 77.18 (C(3), d, 3JPC=5.0 and 7.5 Hz), 138.11 and 138.22 (C(1), d, JPC=126 and 126 Hz), 147.54 (C(2), d, J=10.6 Hz), −P NMR (121 MHz, CDCl3) δ 38.9, 39.0, (ESI) 207.1154 (MH+-C9H20O3 requires 207.1150).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([Cl:17])[CH:11]=1)/[C:5](=[N:7]/C)/[CH3:6].Cl.NO>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:7][O:18][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([Cl:17])[CH:11]=1)=[O:19]
Reactant: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)c(Cl)c1
Agent: Cl
Agent: NO
Product: COC(=O)c1c(C)noc1-c1ccc(Br)c(Cl)c1

Procedure:
Following the procedures described in Example 36: 4-bromo-3-chlorobenzoic acid and oxalyl chloride were reacted to provide 4-bromo-3-chloro-benzoyl chloride, which was then reacted with 3-methylamino-but-2-enoic acid methyl ester to provide 2-(4-bromo-3-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester. 2-(4-Bromo-3-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester and hydroxylamine hydrochloride were then reacted as described in Example 36, Step 3 to provide 5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester, which was then hydrolyzed to 5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid as described in Example 36, Step 4. 5-(4-Bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid and (R)-1-(2-chloro-phenyl)-ethanol were reacted to provide [5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester as described in Example 36, Step 5.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:42])([F:43])[F:41])[CH:34]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc(N)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc(NC(=O)c2ccccc2)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
Benzoyl chloride (66 μL, 0.5 M in anhydrous DCM, 0.03 mmol, 1.1 equiv.) was added to a solution of TFA salt of 6-amino-4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxamide (15 mg, 0.03 mmol, 1.0 equiv.) and triethylamine (16 μL, 0.09 mmol, 3.0 equiv.) in anhydrous DCM (1 mL). The resulting mixture was stirred at rt for 3 h. Purification by pre-HPLC gave the title compound in 83% yield. Mass: M+H+: 500.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[O:17]1[CH2:20][CH:19](OS(C(F)(F)F)(=O)=O)[CH2:18]1>CN(C=O)C>[I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:19]2[CH2:20][O:17][CH2:18]2)[CH:3]=1
Reactant: Ic1c[nH]c2ccncc12
Reactant: O=S(=O)(OC1COC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1cn(C2COC2)c2ccncc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 47, 2 g, 8.2 mmol) in DMF (150 mL) was added cesium carbonate (24 g, 73.8 mmol) and the mixture stirred for 20 minutes at room temperature. A solution of trifluoromethanesulfonic acid oxetan-3-yl ester (Preparation 54, 8.45 g, 41 mmol) in DMF (15 mL) was added and the reaction stirred at room temperature for 16 hours. The reaction was filtered, and the filtrate concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-5% MeOH in DCM to give a solid that was further washed with EtOAc:Heptane to afford the title compound. (4.46 g, 36%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[N:7]=1)(=O)C.[OH-].[K+]>C(O)C>[OH:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)OCc1cccc(C(=O)N2CCOCC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1cccc(CO)n1)N1CCOCC1
Yield: 55.8 %

Procedure:
To 1.13 g of 6-(morpholin-4-carbonyl)pyridin-2-ylmethyl acetate, 233 mg of potassium hydroxide and 1.5 mL of ethanol were added, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed off in vacuo. The residue was purified by chromatography on silica gel (chloroform-methanol-triethylamine=500:25:1) to give 530 mg of (6-hydroxymethyl-pyridin-2-yl)morpholin-4-ylmethanone as a white powder.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:14]([F:15])=[CH:13][C:12]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:11][C:10]=2[F:20])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]([O-])=[O:35])[N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3].[K+].C1C=CC2N(O)N=[N:44][C:42]=2C=1.C(Cl)CCl.Cl.CN.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]([C:4]1[CH:8]=[C:7]([C:9]2[C:10]([F:20])=[CH:11][C:12]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:13][C:14]=2[F:15])[S:6][C:5]=1[NH:21][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]([NH:44][CH3:42])=[O:35])[N:31]=[N:30]2)[CH:25]=[CH:24][CH:23]=1)=[O:3]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cn4cc(C(=O)[O-])nn4)n3)s2)c(F)c1
Agent: CN
Agent: Cl
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium 1-{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}-1H-1,2,3-triazole-4-carboxylate (111 mg, 0.20 mmol), HOBT (62 mg, 0.40 mmol), EDC (77 mg, 0.40 mmol), and methylamine hydrochloride (41 mg, 0.60 mmol) were combined in DMF (5.0 mL), and DIEA (105 μL, 0.60 mmol) was added. The reaction was stirred at room temperature overnight. The solution was diluted with water to precipitate an off-white solid that was collected by filtration, washed (water, MeOH, CH2Cl2), and dried to yield the title compound. 1H NMR (600 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.55 (s, 1H), 8.30 (q, 1H), 7.86 (s, 1H), 7.73-7.66 (m, 2H), 7.36 (s, 1H), 7.21 (d, 2H), 7.03 (d, 1H), 6.80 (d, 1H), 5.71 (s, 2H), 5.27 (s, 1H), 2.66 (d, 3H), 1.42 (s, 6H). Calc'd for C24H24F2N7O3S [M+H]+ 528. found 528.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][O:7][C:6]([CH3:11])([CH3:10])[CH2:5]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:10][C:6]1([CH3:11])[CH2:5][CH:4]([CH:3]=[O:2])[CH2:9][CH2:8][O:7]1
Reactant: COC=C1CCOC(C)(C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(C=O)CCO1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.4 %

Procedure:
To a solution of 4-(methoxymethylene)-2,2-dimethyltetrahydro-2H-pyran (4.00 g) in THF (20 mL) were added water (8.0 mL) and p-toluenesulfonic acid (4.90 g), and the mixture was stirred at room temperature for 20 hr. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.20 g) as a colorless oil.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[CH3:5][C:6]([O:9][CH2:10][CH:11]1[O:13][CH2:12]1)([CH3:8])[CH3:7].[OH-].[Na+]>B(F)(F)F.CCOCC.ClCCl>[C:6]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][O:3][CH2:2][CH2:1][OH:4])([CH3:5])([CH3:7])[CH3:8]
Reactant: OCCO
Reactant: CC(C)(C)OCC1CO1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OCC(O)COCCO
Reaction time: 15 h
Yield: 71 %

Procedure:
To a solution of ethylene glycol (248 g, 4 moles) and boron trifluoride etherate catalyst (1 ml) in dichloromethane (20 ml) preheated to 45° C. was added t-BGE (130 g, 1 mole) dropwise at such a rate so as to maintain a gentle reflux. After completion of addition, stirring was continued for about 15 hours. The solution was then adjusted to pH 7.5 by addition of sodium hydroxide and the product removed by distillation. Tertiary butoxymethyl diethylene glycol was obtained in 71 percent yield having a boiling point of 105° C.-115° C./1 mm.
Reaction SMILES: [CH:1]([OH:3])=O.OO.[C:6]1([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)C[CH2:9][CH2:8][CH:7]=1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:6]2[CH2:7][CH2:8][CH2:9][C:1]2=[O:3])=[CH:12][CH:13]=1
Reactant: Fc1ccc(C2=CCCC2)cc1
Reactant: O=CO
Agent: OO
Product: O=C1CCCC1c1ccc(F)cc1
Temperature: 40 °C
Yield: 69.8 %

Procedure:
A mixture of 80% formic acid (100 mL, 2618 mmol) and 30% hydrogen peroxide (23 mL, 149 mmol) was warmed at 40° C. for 10 min. The resulting solution was carefully added to 1-cyclopentenyl-4-fluorobenzene (24.155 g, 149 mmol) under stirring. The two-phase system was initially stirred at room temperature. After a certain period of time, a spontaneous exothermic reaction took place, and the temperature rose to about 50° C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by careful addition of a saturated sodium bicarbonate solution. Ether was added and the content of the separatory funnel was vigorously shaken. The organic layer was separated and the aqueous layer was extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 2-(4-fluorophenyl)cyclopentanone (18.557 g, 104 mmol, 69.9% yield) as colorless oil. LC-MS (M+H)+=177.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.12-7.18 (2H, m), 6.98-7.04 (2H, m), 3.29 (1H, dd, J=11.6, 8.5 Hz), 2.42-2.54 (2H, m), 2.27 (1H, ddd, J=19.1, 10.5, 8.9 Hz), 2.12-2.20 (1H, m), 2.01-2.12 (1H, m), 1.87-1.99 (1H, m, J=11.7, 11.7, 8.2, 6.3 Hz).
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH:29]=[CH2:30])[C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[N+:8]([O-:19])=[C:7]([NH:20][C:21](OCC(C)C)=[O:22])[N:6]=1)[CH:2]=[CH2:3].C(Cl)Cl.[OH-].[Na+]>O>[CH2:1]([N:4]([CH2:28][CH:29]=[CH2:30])[C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[N:8]2[O:19][C:21](=[O:22])[N:20]=[C:7]2[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)c1nc(NC(=O)OCC(C)C)[n+]([O-])c(NC(=O)OCC(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)OCC(C)C)n2oc(=O)nc2n1

Procedure:
18 g. of diisobutyl 6-diallylamino-s-triazine-2,4-dicarbamate-3-oxide are dissolved while stirring in 560 ml. of methylene chloride and treated with 1800 ml. of water and sufficient concentrated sodium hydroxide so that the pH value of the mixture amounts to 12.7. The mixture is then stirred for 75 minutes and the two phases are separated. The alkaline-aqueous phase is adjusted to pH 4 with 3-N hydrochloric acid and then extracted three times with methylene chloride. The organic extracts are dried over sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure isobutyl 5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate having a melting point of 161°-163° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=2)[N:3]=1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccc([N+](=O)[O-])cn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-(2-aminoethylamino)-5-nitropyridine in DME. ES-MS m/e (%): 389 (M+Na+, 15), 367 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH:4]2[C:7]([O:9][C:10](=[O:11])[CH:3]2[CH2:2]1)=[O:8].C([OH:18])CC>>[CH:1]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([OH:18])=[O:8])[CH:3]([C:10]([OH:9])=[O:11])[CH2:2]1
Reactant: CCCO
Reactant: O=C(O)C1CCC2C(=O)OC(=O)C2C1
Product: O=C(O)C1CCC(C(=O)O)C(C(=O)O)C1

Procedure:
Into a four-necked flask equipped with a thermometer, a stirring device, a condenser and a temperature controller, 198 parts by weight of cyclohexane-1,3,4-tricarboxylic 3,4-anhydride and 300 parts by weight of n-propyl alcohol were charged and allowed to react at 100° C. for 3 h. After the reaction, the excess n-propyl alcohol was distilled off under reduced pressure to obtain monopropyl ester of cyclohexane-1,3,4-tricarboxylic acid as a colorless and transparent liquid. The product was identified by confirming the disappearance of the characteristic absorption of acid anhydride group (1850 and 1790 cm−1) and the appearance of the characteristic absorption of ester group (1735 cm−1) on infrared absorption spectra, and by determining the molecular weight using a gas chromatograph-mass spectrometer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH:38]([C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[NH2:39]>C(N(CC)CC)C.C(Cl)Cl>[CH2:43]([O:42][C:40]([NH:38][NH:39][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15])=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.076 g, 5.00 mmol) was stirred under an argon atmosphere at room temperature with dehydrated methylene chloride (16 mL). Then, N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 1.15 g), 1-hydroxybenzotriazole.monohydrate (HOBt.H2O, 0.918 g), and triethylamine (1.01 g) were added, followed by stirring for 10 minutes. Benzyl hydrazinecarboxylate (1.66 g) was added, followed by stirring for 18 hours. After completion of the reaction, the reaction solution was washed with 0.5M hydrochloric acid and saturated brine, then the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, after that, the resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=4/1→0/1→ethyl acetate/methanol=30/1) to afford 1.48 g of the title compound (yield 81.6%).