Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:30])[CH2:6][CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:31]([O:10][C:9](=[O:11])[CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:7][CH2:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:30])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Temperature: 22 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
Treatment with Fmoc-Cl followed by coupling to benzyl alcohol using 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide [by] hydrochloride (EDCl) provided 2-(9H-Fluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 5-allyl ester 1-benzyl ester 6 in 82% yield. To a solution of 1.5 g (36.6 mmol) of 5 in 5 mL of CH2Cl2 was added 0.42 mL (40.3 mmol) of benzyl alcohol, 0.912 g (47.6 mmol) of EDCI, and 45 mg (3.66 mmol) of dimethylaminopyridine (DMAP). The reaction mixture was stirred at 22° C. for 6 h, diluted with 20 mL of CH2Cl2, and extracted with H2O(1×15 mL), 0.1M HCl (2×15 mL), and brine (2×10 mL). The organic layer was dried (Na2SO4), concentrated in vacuo, and chromatographed on SiO2 (Hexanes/EtOAc, 5:1) to give 1.83 g (82%) of 6 as a white solid: Mp 66.2-67.1° C. (EtOAc/Hexanes); [α]D +1.4° (c 1.64, CHCl3, 21° C.); IR (neat) 3314, 1726, 1682, 1527, 1443, 1414, 1383, 1254, 1173, 1099, 1082, 980, 754, 735 cm-1 ; 1H NMR δ 7.75 (d, 2 H, J=7.4 Hz), 7.59 (d, 2 H, J=7.1 Hz), 7.41-7.27 (m, 9 H), 5.95-5.85 (m, 1 H), 5.44 (d, 1 H, J=8.2 Hz), 5.34-5.19 (m, 4 H), 4.56 (d, 2 H, J=5.6 Hz), 4.5-4.4 (m, 3 H), 4.21 (t, 1 H, J=7.0 Hz), 2.5-2.0 (m, 4 H); 13C NMR δ 172.2, 171.6, 155.8, 143.7, 143.5, 141.1, 135.0, 131.8, 128.5, 128.3, 128.1, 127.6, 126.9, 124.9, 119.8, 118.3, 67.2, 66.9, 66.2, 53.3, 47.0, 28.0, 27.3; MS (FAB, MNBA/MeOH) m/z (relative intensity) 500 ([M+H]+, 40), 465 (8), 448 (14), 433 (12), 413 (8), 386 (38), 371 (24), 349 (9), 324 (16), 309 (26), 293 (11), 265 (10), 247 (24), 231 (56), 215 (39), 202 (26), 191 (24), 179 (67), 165 (48), 154 (67), 143 (31), 133 (71), 117 (100).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[Cl-].[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:18][CH2:17][CH2:16][CH2:15][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: ClCCCBr
Reactant: Cc1nc2ccccc2[nH]1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2ccccc2n1CCCCl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 13.2 parts of 2-methyl-1H-benzimidazole, 2 parts of N,N,N-triethylbenzenemathanaminium chloride and 150 parts of a sodium hydroxide solution 60% are added 30 parts of 1-bromo-3-chloropropane. To start the reaction, the whole is heated to about 40° C., whereupon the temperature rises to 50° C. (exothermic reaction). Stirring at about 50° C. is continued for 30 minutes. The reaction mixture is poured onto water and the product is extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-(3-chloropropyl)-2-methyl-1H-benzimidazole as a residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][OH:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1O)[C:17]([O:19][CH3:20])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[CH2:11][O:12][C:23]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[Cl:13]
Reactant: COc1ccc(CO)cc1OC
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of (3,4-dimethoxyphenyl)methanol (6.0 g, 40 mmol) (Aldrich Chemical Co., Milwaukee, Wis.) and methyl 3-chloro-4-hydroxybenzoate (2.5 g, 13.5 mmol) (Lancaster Synthesis Ltd, Windham, N.H.) in THF (100 mL) was cooled to 0° C. and treated with triphenylphosphine (8.8 g, 33.5 mmol). A solution of diethylazodicarboxylate (5.3 mL, 33.5 mmol) in THF (50 mL) was added dropwise over 30 minutes. After the addition was complete, the reaction was warmed to room temperature and stirred for an additional 30 minutes, and then concentrated to orange oil. The crude reaction was applied directly to a silica column and flushed with hexanes. The desired product was eluted from the column using 25% EtOAc in Hexanes to afford 1A as a light yellow solid (2.5 g, 56%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.[H-].[Li+].[CH3:28][N:29]([CH3:33])[C:30](Cl)=[O:31]>>[CH3:28][N:29]([CH3:33])[C:30]([C:2]1[CH:3]=[C:4]([C:23]([OH:25])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1)=[O:31]
Reactant: CN(C)C(=O)Cl
Reactant: O=C(O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [H-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2c(c(C(=O)O)c1)OC(c1ccccc1)(c1ccccc1)O2

Procedure:
6-Bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylic acid (200 mg, 0.486 mmol), LiH (10 mg, 0.97 mmol, 2 eq.) and dimethylcarbamoylchloride (0.18 mL, 1.94 mmol, 4 eq.) as the electrophile were reacted according to GP4, Method B. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH 67:30:3) to give the title compound as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].F[C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([S:27]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)(=[O:29])=[O:28])=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1>CN(C=O)C>[CH2:3]([O:4][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([S:27]([NH:30][C:31]4[CH:36]=[CH:35][N:34]=[CH:33][N:32]=4)(=[O:29])=[O:28])=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[CH:11][CH:10]=1)[CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)CO
Reactant: COc1nc(F)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(OCC(C)C)ccc1-c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40404 %

Procedure:
To a ice cold solution of 2-methylpropan-1-ol (110 mg, 1.483 mmol) in DMF (1483 μl) was added sodium hydride (59.3 mg, 1.483 mmol) under nitrogen and stirred for 10 min to this was then added a solution of 1-(6-fluoro-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (122 mg, 0.297 mmol) in DMF (1483 μl) and stirred for 16 h slowly raising the temperature to ambient temperature. The reaction mixture was quenched with MeOH, concentrated and purified via reverse phase HPLC (0.1% NH4OH in ACN and water as mobile phase) to obtain 1-(6-isobutoxy-2-methoxypyridin-3-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as light yellow solid (56 mg, 120 mmol, 41% yield). m/z (ESI) 466.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([NH:14][C:15]#[C:16][Si](C)(C)C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.[Cu]I>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[NH:14][CH:15]=[CH:16]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(NC#C[Si](C)(C)C)cc1[N+](=O)[O-]
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc[nH]c2cc1[N+](=O)[O-]
Temperature: 135 °C
Yield: 68.7 %

Procedure:
To a solution of 4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86 mmol) in DMF (100 mL) was added CuI (8.2 g, 43 mmol) under a nitrogen atmosphere. The mixture was heated at 135° C. in a sealed pressure flask overnight, cooled down to room temperature and filtered through a short plug of Celite. The filter cake was washed with EtOAc. The combined filtrate was washed with water, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (10-20% EtOAc/Hexane) to provide 5-tert-butyl-6-nitro-1H-indole as a yellow solid (12.9 g, 69%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:7]([CH3:26])[CH:6]=1)(=O)C>[OH-].[K+].CO>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C@@H:14]([CH3:25])[CH2:13]2)=[C:7]([CH3:26])[CH:6]=1
Reactant: CC(=O)Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N)ccc1CN1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 130 °C
Yield: 49.9 %

Procedure:
1,1-Dimethylethyl (2S)-4-{[4-(acetylamino)-2-methylphenyl]methyl}-2-methyl-1-piperazinecarboxylate (D79) (497 mg, 1.4 mmol) in KOH (1M aq soln., 5 mL) and methanol (5 mL) was heated to 140° C. for 1 h in a microwave reactor. The reaction mixture was diluted with methanol (5 mL) and heated for a total of 4 h 55 minutes at 130° C. in the microwave. The reaction mixture was concentrated to remove the methanol and partitioned between DCM and water. The organic layer was dried and concentrated to give the crude product which was purified by chromatography. Elution with 0-100% diethyl ether/petroleum ether followed by a column flush with 10% (2M NH3 in methanol) in DCM yielded the title compound as a yellow oil (223 mg). δH (CDCl3, 400 MHz) 6.97 (1H, d), 6.52 (1H, d), 6.46 (1H, dd), 4.17 (1H, br.s), 3.76 (1H, d), 3.57 (2H, br.s), 3.29 (2H, m), 3.01 (1H, td), 2.70 (1H, d), 2.56 (1H, d), 2.30 (3H, s), 2.10 (1H, dd), 1.90 (1H, m), 1.45 (9H, s), 1.18 (3H, d). MS (AP+): MNa+ 342.3 (MNa+), no molecular ion (MH+) observed.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.Cl[C:13]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][C:13]3[N:18]=[N:17][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:15]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)[CH:14]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccccc4)nn3)ccc2s1

Procedure:
The title compound was prepared analogous to the procedure used to prepare Example 45(f), using 2-methyl-5-benzothiazolol (117 mg, 0.7 mmol, Aldrich), 6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 13(e)), (197 mg, 0.6 mmol) and NaH (37 mg, 0.9 mmol, 60% suspension in mineral oil, Aldrich) in DMF (5 mL). Purification by flash silica gel chromatography with 2 M NH3 in MeOH/CH2Cl2 (0:1→1:49) as eluant gave the title compound as a pale-orange amorphous solid. Mp: 208-209° C. MS (ESI, pos ion.) m/z: 464 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH2:16])[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[CH3:17].Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][N:23]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:12]=[C:13]([C@@H:14]([NH:16][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)[CH3:15])[N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][CH:6]3[CH3:17]
Reactant: CC1CCc2c(F)ccc3nc([C@H](C)N)n1c23
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCc2c(F)ccc3nc([C@H](C)Nc4ncnc5[nH]cnc45)n1c23
Temperature: 90 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
A mixture of (S)-1-(7-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethylamine (15.8 mg, 0.0677 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (17.8 mg, 0.0745 mmol), and DIPEA (0.0346 mL, 0.20 mmol) in n-butanol (0.5 mL) was stirred in a sealed vial at 90° C. for 16 h. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (1.5 mL) and cooled in an ice bath. HCl in isopropanol (1.25 M, 1 mL) was added and the mixture stirred at 0° C. for 90 min and then concentrated under reduced pressure. The residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5 M NH3 in MeOH, further purification by column chromatography (Si—PCC, gradient 2-12% 2M NH3/MeOH in DCM) afforded 407 as a white solid (8 mg, 34%). Analytical data shows the product to be a mixture of diastereomers (ratio ˜1:1) which could be separated. LCMS (Method K): RT 2.59 & 2.62 min [M+H]+ 352. 1H NMR (CD3OD, 400 MHz): 8.25 & 8.24 (1H, 2 s), 8.10 & 8.08 (1H, 2 s), 7.39-7.35 (1H, m), 6.96-6.91 (1H, m), 5.93 & 5.82 (1H, 2 bs), 5.26-5.21 & 4.93-4.87 (1H, 2 m), 3.09-3.03 (1H, m), 2.97-2.88 (1H, m), 2.27-2.21 (1H, m), 2.15-2.03 (1H, m), 1.83 & 1.78 (3H, 2 d, J=6.9 Hz), 1.45 & 1.41 (3H, 2 d, J=6.7 Hz)
Reaction SMILES: O[C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1.C(Br)(=O)C([Br:13])=O>ClCCCl.CN(C=O)C>[Br:13][C:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4](=[O:9])[CH:3]=1
Reactant: CC1(C)OC(=O)C=C1O
Reactant: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)OC(=O)C=C1Br
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86.2 %

Procedure:
To a solution of 4-hydroxy-5,5-dimethyl-5H-furan-2-one (2.1 g, 16.4 mmol) in DCE (40 mL) and DMF (1.5 mL) at 0° C. was added dropwise oxalyl bromide (3.0 mL, 32 mmol, 2 equiv). The mixture was stirred at room temperature for 4-5 h, and then put in an ice bath. Ice water (100 mL) was added slowly. The mixture was extracted with CH2Cl2 (100 mL). The organic phase was washed with 10% NaHCO3 and again with water, dried over sodium sulfate and evaporated to give the title compound 2.7 g (86% yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:14][N:15]=[C:16]2[C:20](=O)[O:19][C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17]2)[CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:2][CH2:3][CH3:4].O.[NH3:29].Cl>CC(C)=O>[CH2:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:17][C:16]([C:20]([NH2:29])=[O:19])=[N:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCc1cc(NN=C2N=C(c3ccccc3)OC2=O)ccc1Cl
Reactant: N
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCCOCc1cc(-n2nc(C(N)=O)nc2-c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
In 10 ml of acetone, 1.157 g (3 mmol) of 4-[(3-butoxymethyl-4-chlorophenyl)hydrazono]-2-phenyl-2-oxazolin-5-one synthesized in the similar way to Synthesis Examples 1-3 was suspended, the suspension being then added with 0.6 ml of concentrated ammonia water and stirred at room temperature for 30 minutes. The resulting solution was made acid by adding 0.6 ml of concentrated hydrochloric acid and further stirred at 50° C. for 30 minutes. Acetone was distilled off and the residue was extracted by adding benzene and water. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvents were distilled off to obtain a crude product. This crude product was purified by silica gel chromatography using hexane/ethyl acetate (1/2, v/v) as developing solvent and further recrystallized to obtain 1.087 g (94.2% yield) of 1-(3-butoxymethyl-4-chlorophenyl)-5-phenyl-1H-1,2,4-triazole-3-carboxamide (m.p. 96°-98° C.).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([OH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O[CH2:40][C:41]1[CH:42]=[C:43]([N:47]([CH2:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[S:48]([CH2:51][CH3:52])(=[O:50])=[O:49])[CH:44]=[CH:45][CH:46]=1>C1COCC1.CCOC(C)=O>[O:38]([CH2:40][C:41]1[CH:42]=[C:43]([N:47]([CH2:53][C:54]2[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=2)[S:48]([CH2:51][CH3:52])(=[O:49])=[O:50])[CH:44]=[CH:45][CH:46]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Oc1ccccc1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(CO)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(COc2ccccc2)c1
Reaction time: 72 h

Procedure:
To a solution of triphenylphosphine (0.141 g, 0.539 mmol) in 3.5 mL THF was added diethylazodicarboxylate (0.165 g, 0.539 mmol). After 5 min phenol (0.061 g, 0.646 mmol) was added as a solution in 2 mL THF. After 5 min N-(3-(hydroxymethyl)phenyl)-N-(ethanesulfonyl)pyrid-3-ylmethylamine (0.165 g, 0.539 mmol) was added as a solution in 2 mL THF and the reaction was stirred for 3 days. The mixture was diluted with EtOAc, washed with 1 N NaOH and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with 4:1 to 2:1 DCM/EtOAc to give the title compounds as a clear oil. 1H NMR: 8.48 (d,J=1.5 Hz, 1H), 8.36 (s,1H), 7.64 (d,J=7.8 Hz, 1H), 7.36-7.23 (m,5H), 7.19 (m,2H), 6.95 (t,J=7.8 Hz, 1H), 6.91 (d,J=7.8 Hz, 1H), 5.01 (s,2H), 4.84 (s,2H), 3.03 (q,J=7.6 Hz, 2H), 1.39 (t,J=7.6 Hz, 3H). MS calcd. 382.1; MS (M+1) 383.1.
Reaction SMILES: [C:1]([C:5](=[CH:10]OC)[C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[C:1]([C:5](=[CH:10][NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[O:14][CH3:13])[C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3]
Reactant: COc1ccccc1N
Reactant: CCC(=O)C(=COC)C(=O)OC
Product: CCC(=O)C(=CNc1ccccc1OC)C(=O)OC

Procedure:
A mixture of methyl 2-propanoyl-3-methoxyacrylate (70 g) and 2-methoxyaniline (45 ml) was heated on a steam bath for 30 minutes, then diluted with petroleum ether and left to crystallize. Filtration and washing with ether gave methyl 2-propanoyl-3-(2-methoxyphenylamino)acrylate (78.2 g) as a mixture of E/Z isomers.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12](O)=[O:13])=[CH:8][CH:7]=[C:6]([CH3:15])[CH:5]=2.ClC(OC)=O.C([N:30](CC)CC)C>>[CH3:1][C:2]1[N:3]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:30])=[O:13])=[CH:8][CH:7]=[C:6]([CH3:15])[CH:5]=2
Reactant: CCN(CC)CC
Reactant: Cc1ccc2c(CC(=O)O)c(C)n(Cc3ccccc3)c2c1
Agent: COC(=O)Cl
Product: Cc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
A solution of 0.48 g (1.64 mmol) of 2,6-dimethyl-1-(phenylmethyl)-1H-indole-3-acetic acid in 25 ml of tetrahydrofuran(THF) was cooled with an ice-water bath, 0.45 ml of triethylamine was added followed by 0.13 ml (1.7 mmol) of methyl chloroformate. After 0.5 hour, gaseous NH3 was bubbled into the reaction mixture for 0.5 hour, the cooling bath removed and the mixture stirred for 2 hours. It was then poured into water and extracted with EtOAc, the EtOAc solution washed with a Na2CO3 solution, dried(Na2SO4), and concentrated at reduced pressure. The residue was crystallized from MeOH/water, to give 0.19 g (39% yield) of 2,6-dimethyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 160-163° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][NH2:12])[CH2:2]1.[F:13][C:14]([F:30])([F:29])[C@@H:15]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=1.[BH4-].[Na+].[ClH:33]>C(Cl)Cl.CO>[ClH:33].[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][NH:12][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([C@H:15]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:14]([F:29])([F:30])[F:13])=[CH:21][CH:20]=2)[CH2:2]1
Reactant: CS(=O)(=O)N[C@@H](c1ccc(C=O)cc1)C(F)(F)F
Reactant: NC[C@H]1COc2cccnc2O1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N[C@@H](c1ccc(CNC[C@H]2COc3cccnc3O2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
Combine [(3S)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-3-YL]methanamine (9.71 g, 58.4 mmol), N-[(1S)-2,2,2-trifluoro-1-(4-formylphenyl)-ethyl]-methanesulfonamide (16.43 g, 58.4 mmol) and MeOH (292 mL). Add 4 Å Molecular Sieves (30 mL) and stir the mixture at ambient temperature under a nitrogen atmosphere for 1 h. Add sodium borohydride (8.84 g, 233.7 mmol) portionwise and stir at ambient temperature for 10 minutes, monitoring the reaction via MS and 1H NMR. Slowly add H2O to quench the reaction and filter through Celite®. Collect the filtrate; remove solvents under reduced pressure; and purify via flash column chromatography using a gradient of 0-100% of (5% (2N NH3/MeOH) in DCM) in (5% MeOH/DCM) to elute the product. Combine the product fractions, and remove solvents under reduced pressure to afford the free base as a residue. Dissolve the residue in DCM, and add HCl (1N in Et2O; 87.7 mL, 87.7 mmol) while stirring. Stir for 10 minutes after the addition is complete, then remove the solvents under reduced pressure to provide the title product (12.9 g, 47.3%) as a white solid. MS (m/z): 432 (M-Cl).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=C)[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].I([O-])(=O)(=O)=[O:43].[Na+]>O1CCCC1.O.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:37][O:38][CH2:39][CH:40]=[O:43])[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCC=O)OCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
Osmium tetroxide (90 mg., 0.354 mmoles) was added to a solution of 1,2-di-O-(n-hexadecyl)-3-O-allyl-glycerol (4.5 g., 7.75 mmoles) in tetrahydrofuran:water (3:1, 120 ml.), and the resulting solution stirred for 5 minutes at room temperature. Sodium periodate (9 g., 42 mmoles) was then added and the reaction solution stirred for 16 hours at room temperature under nitrogen. The reaction solution was then diluted with water (150 ml.) and extracted with ether (2×150 ml.). The combined ether extract was washed with water (150 ml.), dried (MgSO4) and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene:ethyl acetate) [2.6 g., 57% yield, waxy solid, ir (CHCl3) 1735 cm-1, n.m.r. (CDCl3) δ9.38 (t, J=1 Hz, 1, --OCH2CHO) and 4.07 (d, J=1 Hz, 2, --OCH2CHO)].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[S:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCCc1nc(OC)c(NC(=S)Oc2ccccc2)cc1C
Product: CCCc1nc(OC)c(NC(=S)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C
Yield: 49 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.