Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1.[OH:19][CH2:20][CH2:21][C:22](=O)[CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][N:13]([CH:22]([CH3:23])[CH2:21][CH2:20][OH:19])[CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1
Reactant: CC(=O)CCO
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc3c(c2)CCN(C(C)CCO)CC3)n(C)n1
Yield: 38.5 %

Procedure:
To a stirred solution of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (0.5 g) (intermediate 3) in tetrahydrofuran (5 ml), at room temperature, 4-hydroxy-2-butanone (0.22 g), glacial acetic acid (0.12 ml) and sodium triacetoxyborohydride (0.53 g) were subsequently added. After stirring over night the mixture was made alkaline with 1N aqueous sodium hydroxide and extracted with dichloromethane. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with 70% cyclohexane-ethyl acetate to give the title compound (0.25 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:13]1[C:22]([OH:23])=[CH:21][C:16]3[O:17][CH2:18][CH2:19][O:20][C:15]=3[CH:14]=1)[C:5](=[O:12])[N:6]2[CH3:11]
Reactant: CN1C(=O)C(O)(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
To a stirred solution of 4-bromo-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one (61.0 g; 155 mmol) and triethylsilane (75.0 mL, 456 mmol) in dichloromethane (300 mL) was added trifluoroacetic acid (48 mL, 623 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 20 h and concentrated in vacuo. The residue was triturated in methanol and washed with diethyl ether to afford 4-bromo-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1-methyl-1,3-dihydro-2H-indol-2-one (57.0 g, 97%): 1H NMR (300 MHz, CDCl3) 7.31-7.17 (m, 3H), 6.87-6.83 (m, 1H), 6.62 (s, 1H), 6.17 (s, 1H), 4.97 (s, 1H), 4.22-4.08 (m, 4H), 3.18 (s, 3H); MS (ES+) m/z 376.1 (M+1), 378.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Cl.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:21]=[C:22]([Cl:24])[CH:23]=1.[CH2:31]=O>C(O)C>[ClH:17].[CH3:9][C:8]1[N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][CH2:31][N:28]1[CH2:29][CH2:30][N:25]([C:20]2[CH:19]=[C:18]([Cl:17])[CH:23]=[C:22]([Cl:24])[CH:21]=2)[CH2:26][CH2:27]1
Reactant: CC(=O)c1cnn(-c2ncccn2)c1C
Reactant: C=O
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Agent: Cl
Solvent: CCO
Product: Cc1c(C(=O)CCN2CCN(c3cc(Cl)cc(Cl)c3)CC2)cnn1-c1ncccn1
Yield: 91.5 %

Procedure:
1.75 g of 4-acetyl-1-(2-pyrimidinyl)-5-methylpyrazole was dissolved in 150 ml of ethanol and 2.21 g of 3,5-dichlorophenylpiperazine hydrochloride and 740 mg of paraformaldehyde were added thereto. The obtained mixture was heated under reflux for 24 hours. Further, 300 mg of paraformaldehyde was added and the obtained mixture was heated under reflux for 15 hours. Then the ethanol was almost halved by evaporation and the precipitate was filtered followed by the addition of chloroform thereto. Next, it was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (silica gel 90 g, chloroform:methanol=50:1). Then the obtained product was converted into hydrochloride by adding 1N hydrochloric acid and recrystallized from ethanol to thereby give 1.82 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([OH:19])=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C(N(CC)CC)C.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>C(Cl)Cl.C1C=NC2N(O)N=NC=2C=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)O)cc2C1
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccc(C(=O)N3CCOCC3)cc2C1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-5-carboxyisoindoline (D13) (300 mg), EDC (440 mg), HOAT (10 mg), triethylamine (0.4 ml) and morpholine (0.12 ml) in DCM (10 ml) was stirred overnight and then evaporated. The residue was redissolved in EtOAc (10 ml), washed with saturated NaHCO3 solution (10 ml), water (10 ml), brine (10 ml), dried (MgSO4) and evaporated. The residue was chromatographed on a silica gel flash column [step gradient 70-90% EtOAc in light petroleum 40-60] to give the title compound (D19) (314 mg). MS electrospray (+ion) 333 (MH+). 1H NMR δ (CDCl3): 7.30 (3H, m), 4.70 (2H, m), 4.67 (2H, m), 3.70 (8H, m), 1.52 (9H, s).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH3:32]>C(Cl)Cl>[CH3:27][O:28][CH2:29][CH2:30][N:31]([CH3:32])[S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CNCCOC
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C)S(=O)(=O)c1ccc(-c2sc(NC(C)=O)nc2C)s1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83 %

Procedure:
5-[2-(acetylamino)-4-methyl-1.3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (500 mg; 1.48 mmol; 1.00 eq) in DCM (30 ml). The solution is degassed with N2 and cooled down to 0° C. Triethylamine (1.0 ml; 7.42 mmol; 5.00 eq) followed by N-(2-methoxyethyl)methylamine (0.80 ml; 7.42 mmol; 5.00 eq) are added. After 45 minutes at 0° C., the reaction is complete. The reaction mixture is washed with NaHCO3 sat. (twice) and water (twice). The organic phase is dried over MgSO4, filtered and concentrated under vacuum, affording Compound (21) as a beige solid (478 mg; 83%).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16](O)=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].C[N:21]1CCOCC1.ClC(OCC)=O>O1CCCC1.C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([NH2:21])=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: CN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(N)=O)NC1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.30 g, 1.05 mmol) is dissolved in tetrahydrofuran (5.0 mL). 4-Methylmorpholine (0.14 mL, 1.05 mmol) is then added, and the reaction is cooled to -20° C. Ethyl chloroformate (0.1 mL, 1.05 mmol) is then added, and the reaction is stirred at -20° C. for 30 minutes. The reaction is then filtered, and the filtrate is concentrated to give a yellow oil. This oil is dissolved in methylene chloride (20.0 mL), and anhydrous ammonia gas is bubbled through the solution for 1 hour. The bubbling is stopped, and the reaction is stirred an additional 1 hour. The solvent is evaporated, and the residue is partitioned between ethyl acetate and water. The aqueous layer is extracted several times with ethyl acetate, the combined organic layers are dried (Na2SO4), and the solvent is evaporated to give trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxamide, MS:M+1=287.
Reaction SMILES: [CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:39][NH:38][CH2:37]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:45])[CH3:44])[NH:31][CH:32]=4)=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5].[CH3:58][N:59]=[C:60]=[O:61].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:1][CH:2]([CH3:57])[C@H:3]([NH:52][C:53](=[O:56])[O:54][CH3:55])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[C:11]1[NH:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:40][C:36]6([CH2:37][N:38]([C:60]([NH:59][CH3:58])=[O:61])[CH2:39]6)[CH2:35][N:34]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]([CH3:44])[CH3:45])[NH:31][CH:32]=4)=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[N:15]=1)=[O:5]
Reactant: CN=C=O
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CNC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CNC(=O)N1CC2(CC(c3nc(-c4ccc(-c5ccc(-c6c[nH]c([C@@H]7CCCN7C(=O)[C@@H](NC(=O)OC)C(C)C)n6)cc5)cc4)c[nH]3)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of methyl [(1S)-2-methyl-1-({(2S)-2-[4-(4′-{2-[6-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct-7-yl]-1H-imidazol-4-yl}-4-biphenylyl)-1H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate (Example 24) (45 mg, 0.06 mmol) in anhydrous CH2Cl2 (0.6 mL) was added methyl isocyanate (0.01 mL, 0.17 mmol) and the reaction stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue dissolved in methanol (1 mL) and potassium carbonate (40 mg, 0.29 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction was partitioned between CH2Cl2 (10 mL) and water (5 mL), the aqueous layer was extracted with CH2Cl2 (5 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a yellow solid (34 mg, 70% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.64 (br. s., 10H) 7.33 (br. s., 2H) 5.06-5.22 (m, 1H) 4.03-4.46 (m, 3H) 3.73-4.04 (m, 8H) 3.54-3.73 (m, 6H) 3.46 (q, J=7.0 Hz, 2H) 2.52-2.76 (m, 5H) 2.10-2.53 (m, 4H) 2.02 (br. s., 3H) 0.70-1.09 (m, 12H). HRMS for C44H57N10O7 (M+H)+ calc: 837.4412, found: 838.4416. Purity (LC-MS): 91%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1.C(O)(=O)C.[Si:33]([O:40][CH2:41][CH:42]=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Si:33]([O:40][CH2:41][CH2:42][NH:1][CH2:2][CH2:3][NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([NH:14][C@H:15]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([OH:27])=[O:26])[C:18]=3[O:17][B:16]2[OH:28])=[O:13])[CH2:7][CH2:6]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: NCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCNCCN[C@H]1CC[C@H](CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (R)-3-(2-(trans-4-(2-aminoethylamino)cyclohexyl)acetamido)-2-hydroxy-3,4-dihydro-2H-benzo[e][1,2]oxaborinine-8-carboxylic acid from Example 15 (92 mg) in MeOH (2 mL) was added TEA (70 μL), acetic acid (30 μL), 2-(tert-butyldimethylsilyloxy)acetaldehyde (35 mg) and sodium triacetoxyborohydride (212 mg). The reaction mixture was stirred overnight at RT. Solvent was removed under reduced pressure and the product was carried on to next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.[NH2:25][O:26][CH2:27][CH2:28][OH:29]>C1COCC1>[OH:29][CH2:28][CH2:27][O:26]/[N:25]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[N:3]=[CH:4]4)=[CH:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: NOCCO
Reactant: CC(=O)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Agent: Cl
Solvent: C1CCOC1
Product: C/C(=N\OCCO)c1ccc2ncc(Cc3ccc4c(cnn4C)c3)n2n1
Yield: 58.8 %

Procedure:
A solution of 1-(3-((1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazin-6-yl)ethanone (20.0 mg, 0.07 mmol) and 2-(aminooxy)ethanol hydrochloride (14.87 mg, 0.13 mmol) in 10 mL THF was stirred at 40° C. overnight. Solvent was removed in vacuo. The crude product was purified on flash chromatography (DCM:MeOH=50:1) to give the title compound as a yellow solid (15.0 mg, 57%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.04 (d, 1H), 7.94 (s, 1H), 7.68˜7.61 (m, 3H), 7.54 (d, 1H), 7.39 (d, 1H), 4.41 (s, 2H), 4.23 (s, 2H), 3.98 (s, 3H), 3.68 (s, 2H), 2.29 (s, 3H). LCMS (method A): [MH]+=365, tR=4.70 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][OH:14])[CH2:8]1)=[O:6].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][N:29]=[N:28]2)=[CH:23][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C@@:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)([CH2:12][CH2:13][O:14][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCO)(c2ccc(Cl)c(Cl)c2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 0.5 h

Procedure:
Combine (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (600 mg, 1.3 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.87 mmol) in dichloromethane (13 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.12 mL, 1.55 mmol). After 15 minutes add more methanesulfonyl chloride (0.03 mL, 0.39 mmol). After 30 minutes, extract with 5% sodium bicarbonate solution and water. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound: Rf= 0.15 (silica gel, ethyl acetate).
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[SH:27][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)COc1cccc2c1CCCC2O
Solvent: Cc1ccccc1
Product: COC(=O)COc1cccc2c1CCCC2S
Yield: 80.1 %

Procedure:
A solution of 1-hydroxy-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.42 g) and Lawesson's reagent (0.40 g) in toluene (4 ml) was refluxed under N2 atmosphere for 1 hour. The reaction mixture was purified by chromatography on silica gel to give 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.20 g). A solution of 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.26 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.32 g) and potassium carbonate (0.14 g) in DMF (5 ml) was stirred for 6 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylthio]-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.29 g). MS (m/z): 486 (M+ +1) NMR (CDCl3, δ): 1.75-1.92 (1H, m), 2.00-2.22 (3H, m), 2.45-2.72 (1H, m), 2.80-3.02 (1H, m), 3.79 (3H, s), 3.91 (1H, s), 3.94 (1H, s), 4.36 (1H, m), 4.60 (2H, s), 6.50-6.55 (1H, m), 7.04-7.06 (2H, m), 7.33-7.40 (6H, m), 7.59-7.68 (4H, m)
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](OC)(OC)OC.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[C:20]=1[Br:27]>CCCCCC>[Br:27][C:20]1[C:21]([O:25][CH3:26])=[N:22][CH:23]=[CH:24][C:19]=1[NH:18][CH:11]=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5]
Reactant: COC(OC)OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1nccc(N)c1Br
Solvent: CCCCCC
Product: COc1nccc(NC=C2C(=O)OC(C)(C)OC2=O)c1Br
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A two necked round bottomed flask equipped with a reflux condenser was charged with Meldrum's acid (15.6 g, 108 mmol) and trimethyl orthoformate (143 mL). The reaction mixture was heated 100° C. for 2 h. 4-amino-3-bromo-2-methoxypyridine (22 g, 108 mmol) was added and heating was continued for an additional 4 h at 100° C. The reaction mixture was allowed to cool to RT, diluted with hexane and filtered to obtain the product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:6][CH2:5]1)=[O:3].[O-:7][CH2:8][CH3:9].[Na+]>C(OCC)(=O)C.C(O)C>[CH:4]1([C:2](=[O:3])[CH2:1][C:8](=[O:7])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC(=O)C1CC1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)CC(=O)C1CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 8.4 g (0.1 mol) of cyclopropyl methyl ketone in 100 mL of ethyl acetate under nitrogen was added dropwise 39 mL (0.1 mol) of a 21 wt % solution of sodium ethoxide in absolute ethanol. The flask was fitted with a condenser and Dean-Stark trap and was heated. The ethanol was removed by azeotropic distillation. Additional ethyl acetate was added to the flask as needed. After three hours the temperature of the distillate had reached 75° C. and the reaction was allowed to cool and stand overnight. The white solid which precipitated out was collected by filtration and the filtrate was set aside. The solid was dissolved in water and this solution was acidified at 0° C. with 10% aqueous hydrochloric acid. This solution was extracted three times with ethyl ether. The ethyl acetate filtrate was washed with water three times, acidified with 10% aqueous hydrochloric acid, and extracted with ethyl ether. The ether extracts from both extractions were combined, dried over magnesium sulfate, and filtered. Removal of solvents gave 3.5 g of 1-cyclopropyl-1,3-butanedione as an oil. Analysis by GC showed 75% purity. This intermediate was used without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH:8]([CH3:11])[CH2:9][CH3:10].C(N(CC)CC)C>ClCCl.O>[CH3:1][S:2]([O:6][CH:7]([C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1)[CH:8]([CH3:11])[CH2:9][CH3:10])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(C)C(O)c1ccc(C#N)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)C(OS(C)(=O)=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
Add methanesulfonyl chloride (540 mg, 4.72 mmol) to a solution of 4-(1-hydroxy-2-methyl-butyl)-benzonitrile (800 mg, 4.23 mmol) and triethylamine (0.88 mL, 6.35 mmol) in dichloromethane (10 mL) at 0° C. Warm the mixture to room temperature and stir for 1 h. Dilute the mixture with water and dichloromethane. Extract the aqueous layer with dichloromethane. Wash the combined organic extracts with water. Dry the organic solution over Na2SO4, filter and concentrate in vacuo to provide the desired intermediate as a clear oil (1.38 g) that was used without further purification. MS (APCI) m/z: 268 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.17 %

Procedure:
To a 100 mL of two neck RB flask was charged ethyl 3-(4-hydroxyphenyl)-3-phenylpropanoate (0.6 g, 2.2 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.6 g, 2.2 mmol) in 20 mL of THF. To this added triphenyl phosphine (0.755 g, 2.88 mmol) at 0° C. and added DIAD (0.59 g, 2.88 mmol) portion wise over a period of 15 min at 0° C. After 12 h of stirring at RT, the mixture was diluted with Ethyl acetate, washed with water and brine solution successively. Organic phase was dried over anhydrous Na2SO4 and concentrated to afford yellow oil as product (0.6 g, yield: 52.17%); 1H NMR (300 MHz, DMSO-d6): δ 7.57-7.60 (m, 2H), 7.06-7.31 (m, 12H), 6.84-6.86 (m, 4H), 5.12 (s, 2H), 4.84 (s, 2H), 4.39-4.45 (t, 1H), 3.86-4.01 (m, 5H), 2.92-2.95 (d, 2H), 1.00-1.05 (t, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:16][C:17]1[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:19][N:20]([CH3:28])[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:13][CH2:14][CH3:15].[OH-:35].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:16]([C:17]1[C:18]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:19][N:20]([CH3:28])[C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:9])=[O:35])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCSc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)c1c(-c2ccccc2)nn(C)c1-c1ccccc1
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of m-chloroperbenzoic acid (10.15 g, 85%, 0.05 mole) in dry chloroform (100 ml) is added to 4-(n-butylthio)-1-methyl-3,5-diphenylpyrazole (6.5g, 0.02 mole) in dry chloroform (50 ml) and the reaction mixture stirred overnight at 10° to 12°C. The mixture is poured into 10% aqueous sodium hydroxide (200 ml) and extracted with chloroform. The chloroform layer is separated, dried and stripped in vacuo to give a light-orange oil. The oil is chromatographed on silca gel with benzene. The fractions containing the product are combined, stripped in vacuo, extracted with methanol, filtered, stripped in vacuo and then recrystallized from hexane to give a white fluffy solid 4.37 g (61%), m.p. 92.5° to 93°C.