Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>C(Cl)(Cl)Cl>[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[NH:33][C:34]([NH:20][C:19]1[CH:21]=[C:22]([CH3:23])[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:17][C:18]=1[CH3:24])=[O:35]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Nc4ccc(F)cc4F)cc3C)c2cc1OC
Yield: 97 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (200 mg) was dissolved in chloroform (15 ml), and 2,4-difluorophenyl isocyanate (88 μl) was then added to the solution. The mixture was heated under reflux for one hr. The reaction solution was purified by chromatography on silica gel by development with chloroform/acetone (4/1) to give 287 mg (yield 97%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Br:15][CH2:16][C:17](Br)=[O:18]>C1(C)C=CC=CC=1>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:18]
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(Br)CBr
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(CBr)Nc1ccc(Cl)cc1

Procedure:
To a solution of 5 g 4-Chloro-phenylamine and 1.5 ml pyridine in 30 ml toluene, 8 g bromo-acetyl bromide dissolved in 10 ml toluene was added dropwise under ice cooling. After 2 h the precipitate was isolated by filtration and recrystallized from toluene to yield a white solid.
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH2:7]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O)(=O)C>CO>[CH3:3][N:14]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:33])[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccc(-n2cncn2)cc1)N1CCC(NCc2ccccc2)CC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.9 %

Procedure:
0.7 ml of a 37% aqueous formaldehyde solution and 0.21 g of sodium cyanoborohydride were added to 30 ml of a solution of 0.82 g of 4-benzylamino-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine in methanol, under ice-cooling. To the mixture was dropwise added 0.7 ml of acetic acid. The mixture was stirred at room temperature for 1 hour and then subjected to distillation to remove the solvent. The residue was extracted with methylene chloride. The extract was washed with a 1 N aqueous sodium hydroxide solution and water, dried with anhydrous magnesium sulfate, and then concentrated. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=50/1), followed by recrystallization from methylene chloridediethyl ether to obtain 0.28 g of 4-(N-methyl-N-benzylamino)-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33]>CC(C)=O.CO>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 83.1 %

Procedure:
Fluvastatin methyl ester (3.0 g) was dissolved in acetone (45 ml), a solution of NaOH (0.58 g) in MeOH (8 ml) was added and the mixture was stirred at room temperature for another 3.75 h. The product was isolated by filtration under nitrogen, washed with acetone (40 ml) and dried at 50EC in a vacuum oven for 21 h to obtain 2.54 g of fluvastatin sodium crystal Form LXVII.
Reaction SMILES: CO[C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1.[Li][CH2:11][CH2:12][CH2:13][CH3:14]>C(OCC)(=O)C>[CH2:11]([C:3]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH:4]=1)[CH2:12][CH2:13][CH3:14]
Reactant: COC1=CC(=O)CCC1
Reactant: [Li]CCCC
Solvent: CCOC(C)=O
Product: CCCCC1=CC(=O)CCC1
Yield: 97.2 %

Procedure:
The general procedure for the preparation of substrates using 3-methoxycyclohexenone (1.26 g, 10 mmol) and n-BuLi (20 mmol, 1.6 M in hexane) gave, after flash chromatography (4:1 hexanes:ethyl acetate) the title compound as a colorless liquid (1.48 g, 97%). Spectroscopic data were consistent with previously reported data for this compound.2
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=1>CN(C)C=O.O>[Cl:1][C:2]1[N:6]([CH2:14][C:15]2[O:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:19]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 18 h

Procedure:
Combine 2-chlorobenzimidazole (10.0 g, 66 mmol), and dimethylformamide (100 mL). Add portionwise sodium hydride (1.63 g, 68 mmol). After the evolution of gas ceases, add a solution of ethyl 2-chloromethyl-5-furoate (12.45 g, 0.66 mmol) in dimethylformamide (20 mL). After 18 hours, dilute the reaction mixture with water and extract four times with diethyl ether. Combine the organic layers and extract with water and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue eluting with 5% methanol/0.2% concentrated aqueous ammonia solution/dichloromethane to give 2-chloro-1-(5-ethyoxycarbonylfur-2-ylmethyl)-1H-benzimidazole.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].[C:19]1([CH:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:26](=[O:27])[CH:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:29][CH3:30])#[N:12]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: N#Cc1c(N)sc2c1CCOC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCC(C(=O)Nc1sc2c(c1C#N)CCOC2)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
To a stirred suspension of 2-Amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyran (361 mg; 2.0 mmol; prepared as described in Example 2, Step 1) and potassium carbonate (1.40 g; 10.1 mmol) in diethylether (6.0 mL) was added 2-phenylbutyryl chloride dropwise. The resulting mixture was stirred at room temperature for 24 h. The solvent was then removed in vacuo, the residue taken up into methylene chloride and washed with water. The organic layer was dried (sodium sulfate) filtered and concentrated in vacuo to give crude product which was triturated with diethyl ether to provide 428 mg (66%) of N-(3-Cyano-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-2-phenyl-butyramide as a beige colored solid. EI-HRMS m/e calcd for C18H18N2O2S (M+) 326.1809, found 326.1809.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.Cl.[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH2:18].[Cl:28][C:29]1[N:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[CH3:14][O:15][C:16](=[O:27])[C@H:17]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)[NH:18][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[N:37][C:29]=1[Cl:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
EDC.HCl (2.11 g, 11 mmol) was added to a mixture of L-tyrosine methyl ester hydrochloride (2.32 g, 10 mmol), 2-chloronicotinic acid (1.58 g, 10 mmol), HOBT (1.49 g, 11 mmol) and NMM (2.31 ml, 21 mmol) in DMF (50 ml). The mixture was stirred overnight at room temperature. The solvent was removed in vacuo. the residue dissolved in EtOAc (300 ml) and washed with dilute HCl (100 ml), saturated aqueous NaHCO3 (100 ml), water (3×100 ml) and brine (50 ml), dried (Na2SO4) and solvent removed in vacuo to give the title compound as a yellow gum (3.27 g, 98%). δH (DMSO-d6, 300 MHz) 9.21 (1H, s, OH), 9.03 (1H, d, J 7.9 Hz, CONH), 8.45 (1H, dd, J 4.8, 1.9 Hz, pyrH), 7.67 (1H, dd, J 7.4, 1.9 Hz, pyrH), 7.47 (1H, dd, J 7.5, 4.8 Hz, pyrH), 7.05 (2H, d, J 8.5 Hz, ArH), 6.67 (2H, d, J 8.5 Hz, ArH), 4.58 (1H, ddd, J 9.6, 7.9, 5.4 Hz, CHα), 3.65 (3H, s, CO2Me), 3.01 (1H, dd, J 13.9, 5.4 Hz, CHAHBAr) and 2.85 (1H, dd, J 13.9, 9.6 Hz, CHAHBAr), m/z (ESI, 60V) 335 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH3:15]>C(O)C.C(Cl)Cl>[NH2:15][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3]
Reactant: N
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Solvent: CCO
Product: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Yield: 843.8 %

Procedure:
A solution of 5-chlorosulphonyloxindole (2 g, 0.86 mmol) in ethanol (30 ml), methylene chloride (150 ml) and 2.8M methanolic ammonia (6.2 ml, 17 mmol) was stirred overnight at ambient temperature. The volatiles were removed by evaporation and the solid residue was purified by column chromatography eluting with methanol/methylene chloride (15/85) to give 5-aminosulphonyloxindole (1.54 g, 84%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH:17]1[CH2:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:17]1([CH2:16][N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:20][CH2:19][CH2:18]1
Reactant: BrCC1CCC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CC3CCC3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), (bromomethyl)cyclobutane (58 mg, 0.39 mmol, Aldrich, Cat. No. 226998), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 h. After cooling it was quenched with water. The product was extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 64 mg of the product which was directly used in the next step reaction without further purification.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)[CH3:3].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:9][C:5]1[S:6][CH:7]=[CH:8][C:4]=1[CH:2]([OH:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)c1ccsc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(O)c1ccsc1Br
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(1-hydroxyethyl)thiophene (61.4 g, 0.48 mol) in carbon tetrachloride (550 ml) was added N-bromosuccinimide (89.4 g, 0.504 mol) portionwise over 11/2 hours at 40° C. Stirring was continued for an additional 2 hours at ambient temperature. The reaction mixture was filtered and the filtrate was washed with water, saturated NaHCO3 and again with water. The solution
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1cncc(C2CCNC2)c1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(c4cccnc4)C3)c(F)cc2c1=O
Yield: 73 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.06 g, 4.0 mmol) and 3-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.15 g, 73%) as an off-white solid, mp 233°-236° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26](=[O:33])(=[O:32])[NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][CH:15]=2)[C:9](=[O:12])[NH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].[CH:34](I)([CH3:36])[CH3:35].O>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26](=[O:32])(=[O:33])[NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:18][CH:19]=2)[C:9](=[O:12])[N:10]([CH:34]([CH3:36])[CH3:35])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(C)I
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a suspension of 54 mg (1.35 mmole) of sodium hydride (60% in oil) in 1 ml of dry DMF was added 200 mg (0.452 mmole) of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G). The resulting mixture was stirred under N2 at room temperature for 2 hours. Then 270 μL (460 mg, 2.70 mmole) of isopropyl iodide was added dropwise, and the orange mixture was stirred at room temperature overnight. Next, the mixture was treated with H2O and extracted 4× with ethyl acetate. The combined organic fractions were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was flash chromatographed twice on silica gel (elution with 1.5% MeOH in CH2Cl2) to yield 106 mg (48%) of the title compound; satisfactory purity by TLC in 98.5:1.5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 485 (M+1)+.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=O)[CH:16]([CH3:18])[CH3:17].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[S:29])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Nc1ccc2c(c1)Cc1ccccc1-2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)C(=S)Nc1ccc2c(c1)Cc1ccccc1-2
Temperature: 130 °C
Yield: 196.3 %

Procedure:
In a 500 mL three-neck flask were put 20 g (80 mmol) of N-(9H-fluoren-2-yl)isobutyramide, 16 g (40 mmol) of 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), and 150 mL of toluene, and the mixture was heated and refluxed at 130° C. for 4 hours. After that, the precipitated solid was washed with toluene and subjected to suction filtration to give 21 g of a yellow solid of N-(9H-fluoren-2-yl)isobutyrthioamide in a yield of 100%. The synthesis scheme of Step 2 is shown in (c-2) below.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:8][C@:7]2([O:13][C@@H:12]3[CH2:14][CH:15]=[C:16]([CH3:38])[CH2:17][C@@H:18]([CH3:37])[CH:19]=[CH:20][CH:21]=[C:22]4[CH2:23][O:24][C@@H:25]5[C@H:30]([OH:31])[C:29]([CH3:32])=[CH:28][C@@H:27]([C:33]([O:35][C@@H:10]([CH2:11]3)[CH2:9]2)=[O:34])[C@:26]45[OH:36])[CH2:6][CH2:5][C@@H:4]1[CH3:39].CCCCCC.C(COC)[O:47]C>>[CH3:1][CH2:2][C@H:3]1[O:8][C@:7]2([O:13][C@@H:12]3[CH2:14][CH:15]=[C:16]([CH3:38])[C@H:17]([OH:47])[C@@H:18]([CH3:37])[CH:19]=[CH:20][CH:21]=[C:22]4[CH2:23][O:24][C@@H:25]5[C@H:30]([OH:31])[C:29]([CH3:32])=[CH:28][C@@H:27]([C:33]([O:35][C@@H:10]([CH2:11]3)[CH2:9]2)=[O:34])[C@:26]45[OH:36])[CH2:6][CH2:5][C@@H:4]1[CH3:39]
Reactant: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)C[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Reactant: COCCOC
Agent: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(/C)[C@H](O)[C@@H](C)/C=C\C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)C[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Solvent: CCCCCC
Product: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@H](O)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2

Procedure:
0.2 g of milbemycin A4 is added to a 2-day-old preculture of S. violascens produced according to H1 in 450 ml of medium 2, and the whole is shaken at 250 rpm. at 28° C. The course of the reaction is monitored by means of HPLC (high pressure liquid chromatography) (column 25 cm/0.5 cm, eluant hexane/dimethoxyethane 3:1, 1 ml/min., UV detector 220 nm). After shaking for 4 days and a 37% conversion rate, 70% 13β-hydroxymilbemycin A4 and 30% 14,15-epoxymilbemycin A4 are obtained.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C:37]1([O:40]C(=O)C)[CH2:39][CH2:38]1)=[O:36]>>[OH:40][C:37]1([C:35]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[C:28]6[O:27][CH2:26][O:25][C:24]=6[CH:23]=[CH:22][C:21]=5[O:29][CH2:30][CH:31]5[CH2:33][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:36])[CH2:39][CH2:38]1
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Product: O=C(N[C@H]1CC[C@@H](NC(=O)C2(O)CC2)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][Br:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(Br)nc1CBr
Yield: 98.8 %

Procedure:
2-Bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (17 g, 68.0 mmol, purchased from Ryan Scientific), N-bromosuccinimide (12.7 g, 71.4 mmol), and benzoyl peroxide (1.65 g, 6.8 mmol) were suspended in 222 mL of benzene and heated at reflux temperature for 16 h. The reaction mixture was cooled and diluted with ethyl acetate. The reaction mixture was washed successively with saturated bicarbonate solution, brine, saturated ammonium chloride solution, and brine. The organic solvent was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-20% ethyl acetate in hexanes to produce 22.1 g of a light yellow solid. 1H NMR (CDCl3, 200 MHz): δ=4.88 (s, 2H), 4.37 (q, 2H, J=7.0 Hz), and 1.39 (t, 3H, J=7.0 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[CH3:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][C:9]=1/[CH:14]=[C:15]1\[C:16](=[O:27])[N:17]([C:24](Cl)=[O:25])[C:18]2[C:23]\1=[CH:22][CH:21]=[CH:20][CH:19]=2>N1C=CC=CC=1.C1COCC1>[OH:4][CH:3]([CH2:5][OH:6])[CH2:2][O:1][C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:15](=[CH:14]/[C:9]2[NH:10][C:11]([CH3:13])=[CH:12][C:8]=2[CH3:7])/[C:16]1=[O:27])=[O:25]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: OCC(O)CO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CO)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the solution of glycerol (460 mg, 2.5 mmol) in 1.0 mL of pyridine and 2.0 mL of THF was added a suspention of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride in 2.0 mL of THF at 0° C. The reaction mixture was gradually warmed to room temperature, stirred for 2.5 h, and concentrated. The residue was triturated with ethyl acetate and filtered. The solid was then washed with ethyl acetate, water, ether, and dried to yield 87 mg of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3-dihydroxy-propyl ester. The combined filtrate was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 120 mg of crude product which was suspended in water, filtered, and washed with small amount of ethyl acetate to afford another 67 mg of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2,3dihydroxy-propyl ester. The combined yield is 83%. 1H NMR (400 MHz, CDCl3) δ 12.51 (s, 1H, NH-1′), 7.90-7.92 (m, 1H), 7.45-7.48 (m, 1H), 7.37 (s, 1H, H-vinyl), 7.18-7.24 (m, 2H), 6.04 (d, J=1.96 Hz, 1H, H-4′), 4.68 (dd, J=3.13, 11.24 Hz, 1H, OCH2CH(OH)CH2OH), 4.45 (dd, J=4.89, 11.24 Hz, 1H, OCH2CH(OH)CH2OH), 4.09 (m, br, 1H, OCH2CH(OH)CH2OH), 3.86-3.99 (m, 2H, OCH2CH(OH)CH2OH), 3.60 (d, J=6.65 Hz, 1H, OCH2CH(OH)CH2OH), 3.45 (dd, J=5.52, 7.82 Hz, 1H, OCH2CH(OH)CH2OH), 2.41 (s, 3H, CH3), and 2.32 (s, 3H, CH3). MS m/z (relative intensity, %) 357 (100, [M+1]+.).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:8]=1[CH2:9][O:10][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: OCc1ccc(C(F)(F)F)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C(F)(F)F)cc1Cl
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (1.1 ml) was added dropwise to a solution of 2-chloro-4-(trifluoromethyl)benzyl alcohol (2.64 g) and anhydrous triethylamine (2.3 ml) in anhydrous dichloromethane (30 ml) in a nitrogen stream under ice-cooling and the mixture was stirred for 30 minutes under the same conditions. The reaction mixture was successively washed with water, aqueous sodium hydrogencarbonate, and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 2-chloro-1-((methanesulfonyloxy)methyl)-4-(trifluoromethyl)benzene as white crystals (3.62 g).