Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+]>C1COCC1.CO.[Pd]>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOC(=O)c1ncc2ccc(Oc3ccc(N)cc3)cc2c1O
Yield: 69.8 %

Procedure:
100 mg of 1-chloro-4-hydroxy-6-(4-nitro-phenoxy)-isoquinoline-3-carboxylic acid butyl ester was dissolved in 3 ml THF and 3 ml methanol. 20 mg of sodium acetate and 25 mg of 10% palladium on carbon were added to the mixture, and the stirring reaction was placed under hydrogen atmosphere (balloon) overnight. The resultant solution was filtered through a pad of celite and concentrated to a residue. The crude material was purified by column chromatography on silica gel, eluting the product with a gradient of 0-20% ethyl acetate in dichloromethane, to produce 59 mg of product; MS (−): m/z 351.27 (M−1).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:34])([F:33])[C:13]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][C:17]1=[O:24].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[F:34][C:12]([F:11])([F:33])[C:13]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:14]=1[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]=[O:23])[CH2:18][C:17]1=[O:24]
Reactant: O=C1CC(CO)CCN1Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
To a solution of oxalyl chloride (4.5 mL) in dichloromethane (80 mL) was added a solution of dimethyl sulfoxide (7.3 mL) in dichloromethane (50 mL) under cooling to −78° C. The reaction mixture was stirred for 30 min under cooling to −78° C., and to the reaction mixture was added dropwise a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-4-(hydroxymethyl)piperidin-2-one (10 g) in dichloromethane (50 mL). The reaction mixture was stirred for 40 min under cooling to −78° C., triethylamine (19.7 mL) was added, and the mixture was further stirred at room temperature for 30 min. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over 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 (3.7 g).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=CC=C[C:3]=1[NH:8][NH2:9].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16].[C:20]1(C)[CH:25]=CC=C[CH:21]=1>>[NH2:16][C:15]1[C:3]([N:8]2[CH:25]=[CH:20][CH:21]=[N:9]2)=[C:2]([CH3:10])[CH:7]=[C:13]([C:12]([CH3:19])([CH3:18])[CH3:11])[CH:14]=1
Reactant: Cc1ccccc1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccccc1NN
Agent: Cl
Product: Cc1cc(C(C)(C)C)cc(N)c1-n1cccn1
Yield: 92 %

Procedure:
A solution of tolyl hydrazine hydrochloride (8.0 g, 50 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (6.3 g, 50 mmol) in toluene (30 mL) was heated to reflux overnight. Removal of the volatiles in vacuo provided a residue, which was purified by silica gel chromatography using 30% ethyl acetate in hexanes as the eluent. Concentration in vacuo provided 3-amino-5-tert-butyl-2-tolyl-2H-pyrazole as a brown solid (10.5 g, 92%). LC-MS analysis of the compound indicates the desired product is present with a purity >99%. Calculated mass=229. Observed mass=230.
Reaction SMILES: [C:1](OCC)(=[O:5])[CH2:2][CH2:3][CH3:4].[OH:9][C@@H:10]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[C:25](=[O:31])[CH2:24][C@@:23]2([CH3:32])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1.[H-].[Na+].CO>CS(C)=O>[C:1]([CH2:21][C:20](=[O:22])[C@@H:19]1[C@:23]2([CH3:32])[C@H:16]([C@H:15]3[C@H:26]([C:25](=[O:31])[CH2:24]2)[C@:27]2([CH3:30])[C@H:12]([CH2:11][C@H:10]([OH:9])[CH2:29][CH2:28]2)[CH2:13][CH2:14]3)[CH2:17][CH2:18]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CCCC(=O)CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 4 h

Procedure:
Ethyl butyrate (0.84 ml) was added to a mixture of 3α-hydroxy-5α-pregnane-11,20-dione (665 mg) and sodium hydride (150 mg.) in dry dimethyl sulphoxide (10 ml.). The mixture was stirred, under N2, for 13/4 hrs. The reaction mixture was treated with methyl alcohol to destroy excess sodium hydride, then poured into 2N-hydrochloric acid. The product was extracted with ethyl acetate and the combined extracts were washed with water, dried and evaporated. Preparative t.l.c. of the residue (859 mg.) gave two fractions. The more polar fraction was title compound (244 mg.) [α]D + 74.0°, λmax. 278 nm (ε 12,980).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][CH:8]([C:11]1[N:12]=[C:13]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:18])[S:14][CH:15]=1)CO.CO>O>[C:20]1([NH:19][C:17](=[O:18])[NH:16][C:13]2[S:14][CH:15]=[C:11]([CH:8]=[O:7])[N:12]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Nc1ccccc1)Nc1nc(C(O)CO)cs1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: O=Cc1csc(NC(=O)Nc2ccccc2)n1
Reaction time: 2 h

Procedure:
A solution of 0.76 g of sodium metaperiodate in 15 ml of water was added dropwise at room temperature to a mixture comprising 0.5 g of 4-(1,2-dihydroxyethyl)-2-(3-phenylureido)thiazole and 15 ml of methanol, and the mixture was stirred for 2 hours after completion of the dropwise addition. The solvent was then evaporated off under reduced pressure and the residue was washed with water, giving the desired compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH3:12])=[CH:9]/[CH2:10]O)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:15].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8](=[CH:9][CH3:10])[CH:12]=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: C/C(=C\CO)c1cccc(Br)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC=C(C=O)c1cccc(Br)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (E)-3-(3-bromophenyl)-but-2-en-1-ol (1.03 g, 4.54 mmol) in DCM (10 mL) at 0 deg C., was added Dess-Martin periodinane (2.11 g, 5 mmol). The resulting suspension was warmed to 23° C. and stirred for approx. 30 min. until the reaction was complete by TLC. The mixture was poured into 50 mL of saturated aqueous NaHCO3, containing Na2S2O3 (1 g). This mixture was stirred vigorously until both layers became clear. The aqueous layer was extracted with DCM (2×) and the combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by flash chromatography (10% EtOAc/hexanes) to afford the titled compound as a white solid (910 mg, 89% yield) that was a 5:1 ratio of E:Z isomers.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.[N:21]([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][NH:32][CH3:33]>O>[CH2:13]([C:4]1[N:5]([CH3:12])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([N:1]=[N:21][N:32]([CH3:33])[CH3:31])[N:3]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=N[O-]
Reactant: CCOC(=O)c1c(N)nc(Cc2ccccc2)n1C
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(N=NN(C)C)nc(Cc2ccccc2)n1C
Temperature: 0 °C
Yield: 27 %

Procedure:
4-Amino-2-benzyl-5-carbethoxy-1-methyl-imidazole (30g.) was suspended in water (12 ml.) containing conc. HCl -- (12 ml) and a solution of sodium nitrite (0.96 g.) in water (5 ml.) slowly added with stirring at 0° C. After addition was complete this solution was added to a stirred solution of Na2CO3 (118 ml, 30%) and aqueous dimethylamine (2.5 ml, 25%) added dropwise at 0° C added with stirring. After half an hour the brown precipitate was filtered off, washed with water and dried. Crystallisation from ethylacetate/petrol yielded 2-benzyl-5-carbethoxy-(3,3-dimethyltriazeno)-1-methylimidazole (1g, 27%) m.p. 107°-108° C (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl.Cl[CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[C:2]([NH:1][S:27]([C:19]2[O:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH:20]=2)(=[O:28])=[O:29])[CH:7]=1
Reactant: CN(C)CCCCl
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: Cl
Product: CN(C)CCCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1

Procedure:
Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (3-chloro-propyl)-dimethyl-amine hydrochloride and 1-benzofuran-2-sulfonyl chloride.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: NC(=O)NCCC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and L-(+)-citrulline using Raney nickel or palladium/activated carbon as a catalyst and heating for 2 hours to 50° C. and 4 hours to 70° C. A product was obtained which had a melting point of 176° C. and an RF -value of 0.7 (determined on DC-finished plates of silica gel G (Merck) with a transporting liquid made up of 50 parts by volume of methanol and 50 parts by volume of water).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[O:20]([CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccc(OCCCOc2ccccc2)cc1C(=O)OC

Procedure:
A mixture of dimethyl 4-hydroxyphthalate (2.1g; 0.01 mole), 1-bromo-3-phenoxypropane (2.15g; 0.01 mole) and anhydrous potassium carbonate (1.52g; 0.015 mole) in dry butanone (30 ml) was stirred at reflux overnight and the cooled mixture filtered. Evaporation in vacuo afforded the title compound in quantitative yield. νmax (film) 1730, 1605 cm-1 ; τ(CDCl3) 7.77 (2H, quintet, J 6.5Hz); 6.16 (3H,s); 6.11 (3H, s); 5.86 (2H, t, J 6.5Hz; 5.78 (2H, t, J 6.7Hz); 3.20-2.55 (7H, m); 2.19 (1H, d, J 8.5Hz); (Found; C, 65.98; H, 5.89; C19H20O6 requires; C, 66.27; H, 5.85%).
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[C@H:22]1([NH:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH2:42])[CH:38]=3)[N:33]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1>>[C@H:22]1([NH:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH:42][C:1]([NH:21][CH2:20][CH2:19][N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[O:12])[CH:38]=3)[N:33]=2)[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCN1CCOCC1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Product: O=C(NCCN1CCOCC1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, 2-morpholin-4-yl-ethylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=432.6 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C:6]([C:7]#[N:8])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1cccs1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1cccs1

Procedure:
Prepare by the method of example 1.1.2 using thiophen-2-yl-acetonitrile (0.161 mol) and ethyl bromoacetate (0.325 mol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.CCN(CC)CC>C1COCC1>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][CH:2]([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(N)CNS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
N-(2-Amino-propyl)-methanesulfonamide (325 mg, 2.14 mmol, 1.5 eq.) in THF (20 mL) was cooled to 0 C and 2,4,5-trichloropyrimidine (261 mg, 1.43 mmol, 162 μL, 1.0 eq.) was added. The reaction was stirred for 5 minutes and then NEt3 (711 mg, 7.04 mmol, 516 μL, 4.9 eq) was added. After 5 minutes, external cooling was removed and the reaction was stirred under a nitrogen atmosphere for 3 hours. The reaction was then partitioned between CH2Cl2 (30 mL) and sat. NaHCO3 (30 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (15 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure onto silica gel. Purification by silica gel chromatography (dry loaded) using a gradient of 0-10% MeOH/CH2Cl2 as the eluting solvent to obtain N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-propyl]-methanesulfonamide as a white solid (365 mg, 85%). m.p.=160° C.; LCMS (m/e) 299 (M+1); 1H-NMR (d6-DMSO, 400 MHz) δ 8.18 (s, 1H), 7.59-7.50 (m, 1H), 7.26-7.15 (m, 1H), 4.36-4.22 (m, 1H), 3.21-3.05 (m, 2H), 2.91 (s, 3H), 1.18 (d, 3H, J=6.6 Hz).
Reaction SMILES: C1C=CC=CC=1.C(N(CC)CC)C.[CH3:14][N:15]1[C:19]([OH:20])=[C:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:17]([CH3:31])=[N:16]1.[C:32](Cl)(=[O:35])[O:33][CH3:34]>O>[CH3:14][N:15]1[C:19]([O:20][C:32]([O:33][CH3:34])=[O:35])=[C:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:17]([CH3:31])=[N:16]1
Reactant: COC(=O)Cl
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)Oc1c(C(=O)c2ccc(Cl)cc2Cl)c(C)nn1C
Reaction time: 12 h
Yield: 92 %

Procedure:
In a mixture of 20 ml. of dry benzene and 0.28 g. of triethylamine is dissolved 0.72 g. of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxypyrazole and then 0.26 g. of methyl chlorocarbonate is added dropwise at room temperature with stirring. After completion of the dropwise addition, the mixture is stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture is allowed to stand for 12 hours and then 30 ml. of water is added thereto. Then, a benzene layer is separated and an aqueous layer is extracted with benzene. The benzene layer and the benzene extract are combined and the mixture is washed with water and dried over anhydrous sodium sulfate. Then, the solvent is distilled off from the benzene solution and the resulting residue is recrystallized from a small amount of n-hexane to give 0.77 g. of the desired product as white crystals melting at 86°-88° C. Yield 92%.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:8][S:9][CH3:10])=[O:4]
Reactant: CSCCl
Reactant: CCC(C)C(=O)O
Solvent: CCN(CC)CC
Product: CCC(C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting 2-methylbutyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 75°-77° C./12 mm Hg, n20 1.4505.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]2OCC[O:16]2)[CH:11]=[CH:12][C:13]=1[F:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.O>S(=O)(=O)(O)O.C(OCC)C>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][C:13]=1[F:14])[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2OCCO2)cc1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=Cc1ccc(F)c(Cc2ccccc2)c1
Reaction time: 16 h

Procedure:
A mixture of 2-(3-benzyl-4-fluorophenyl)-1,3-dioxolane (0.7 h) acetone (10 cm3), water (1 cm3) and concentrated sulphuric acid (5 drops) was stirred for 16 hours. The reaction mixture was poured into diethyl ether and the organic layer washed with sodium bicarbonate solution, water and brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvents under reduced pressure gave 3-benzyl-4-fluorobenzaldehyde (0.59 g), which was used without further purification.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:26])[C:12]([CH3:25])=[CH:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=2[NH2:24])=CC=1)([O-])=O.C[N:28]([CH3:31])C=O>>[CH2:31]([NH:28][C:11](=[O:26])[C:12]([CH3:25])=[CH:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:15]=1[NH2:24])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:14]1([CH2:13][CH2:12][NH2:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(N)c(C=C(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Reactant: CN(C)C=O
Product: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Product: NCCc1ccccc1

Procedure:
Into 30 ml of dimethylformamide, 0.72 g (2.0 mmol) of (E) 3-(2-amino-4,5-dimethoxyphenyl)-2-methyl-2-propenoic acid p-nitrophenyl ester obtained above and 0.48 g (4.0 mmol) of 2-phenylethylamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.) were dissolved; and the mixture was reacted at room temperature for one night. The reaction liquid was concentrated under a reduced pressure, and the resulting residue was dissolved in ethyl acetate. After the resulting solution was washed and was dried with magnesium sulfate anhydride, the solvent was eliminated under a reduced pressure, whereby a crude product was obtained. This product was refined by an aminopropyl-modified type silica gel column chromatography (n-hexane/ethyl acetate=1/1), whereby 0.68 g of the aimed compound was obtained (yield: quantitative).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:33]=[CH:32][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].[CH2:34](O)[CH2:35][OH:36].Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C1C=CN=CC=1.C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([O:31][CH2:34][CH2:35][OH:36])=[O:30])[CH:25]=3)[CH:19]=2)=[CH:32][CH:33]=1)=[O:11]
Reactant: OCCO
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)OCCO)c[nH]4)c3)cc2)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 5-{4-[4 ({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (50 mg, 0.11 mmol), ethylene glycol (1 ml), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 25 mg, 0.13 mmol) and 4-dimethylaminopyridine (DMAP, 5 mg, 0.04 mmol) in anhydrous THF (10 ml) was stirred at 60° C. for 16 hours. The mixture was poured into 100 ml of water. 2M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography with a gradient of 3˜5% MeOH/CHCl3 to give 2-hydroxyethyl 5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylate as white solid. Yield: 36 mg, 67%.
Reaction SMILES: [O:1]=[O+][O-].[C:4]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([O:17][CH2:18][CH:19]=C)[C@H:12]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:4]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([F:16])[C@@H:13]([O:17][CH2:18][CH:19]=[O:1])[C@H:12]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: O=[O+][O-]
Reactant: C=CCO[C@H]1[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C[C@@H]1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](OCC=O)[C@H]1C(=O)NCc1cccc(Cl)c1F

Procedure:
Ozone was bubbled through a solution of (2S,3S,4S)-3-allyloxy-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (59 mg, 0.137 mmol) in CH2Cl2 (20 mL) at −78° C. When the solution turned blue, ozone addition was stopped and nitrogen was passed through the solution until the blue color was discharged. Triphenylphosphine (35.9 mg, 0.137 mmol) was added to the ozonide solution at −78° C. and the reaction mixture was allowed to slowly reach RT. The reaction mixture was concentrated and the material thus obtained used without further purification in the next step. MS (UPLC): 433.4/435.4 [M+H]+, 477.4/579.5 [M+HCOO]−.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25]([CH:26]2[CH2:28][CH2:27]2)=[C:24]([CH:29]2[CH2:32][CH:31]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.CO>[Pd].O1CCCC1>[CH:26]1([C:25]2[C:21]([CH:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[N:22][O:23][C:24]=2[CH:29]2[CH2:30][CH:31]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:32]2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CC1CC(c2onc(C(CCCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 6-benzyloxy-3-{4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3-yl]hexanoate (980 mg), methanol (10 mL) and tetrahydrofuran (3 mL) were mixed. To the mixture was added 7.5 w/w % palladium on activated carbon (200 mg). The mixture was stirred at RT under hydrogen atmosphere (1 atm) for 5 hr. The catalyst was freshened up, and the mixture was stirred at RT under hydrogen atmosphere (1 atm) overnight. The 7.5 w/w % palladium on activated carbon was filtered off and the filtrate was concentrated in vacuo.