Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][C:32](OC)=[O:33])(=[O:30])=[O:29])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[BH4-].[Na+].CO>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][S:28]([CH2:31][CH2:32][OH:33])(=[O:29])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: COC(=O)CS(=O)(=O)N[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NS(=O)(=O)CCO)no2)cc1C#N
Temperature: 75 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
Prepared using General Procedure 18: To a stirred solution of (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (0.72 g, 1.5 mmol) in THF (25 mL) was added sodium borohydride (0.24 g, 6.2 mmol) at room temperature. The reaction was heated to 75° C. and methanol (0.06 mL, 1.5 mmol) was added dropwise. After 1 h, the reaction was cooled and concentrated. The residue was partitioned between DCM and 0.5N HCl. The organic layer was dried over MgSO4, concentrated, and recrystallized from methanol to give 0.40 g (60%) of (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 186. LCMS-ESI (m/z) calculated for C23H24N4O5S: 468.2. found 491.1 [M+Na]+, tR=8.64 min (Method 2). Elemental Analysis determined for C23H24N4O5S; C calculated=58.96%. found=58.86%; H calculated=5.16%. found=5.08%; N calculated=11.96%. found=11.78%. 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=2.2 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.10 (d, J=7.7 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.1 Hz, 1H), 5.05 (q, J=7.9 Hz, 1H), 4.94-4.69 (m, 2H), 4.30-3.91 (m, 2H), 3.49 (ddd, J=17.4, 8.8, 3.5 Hz, 1H), 3.39 (td, J=4.8, 1.6 Hz, 2H), 3.25-3.07 (m, 1H), 2.71 (dtd, J=11.5, 8.0, 3.6 Hz, 1H), 2.11-1.95 (m, 1H), 1.48 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.30, 168.79, 162.95, 143.72, 142.80, 134.25, 134.04, 129.06, 127.76, 127.23, 123.52, 116.84, 115.41, 113.72, 104.06, 72.94, 59.01, 57.56, 55.84, 34.85, 31.61, 21.88. Chiral HPLC: (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide was eluted with methanol (Chiral Method 2): 99.9% ee, tR=8.59 min. (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 187 was synthesized in an analogous fashion from (S)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate: >99.9% ee, tR for (S)-enantiomer=6.62 min (Chiral Method 2).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25]C(C)(C)[C:23](C)(C)[O:22]3)=[C:17](C=O)[CH:16]=2)[CH:7]=1)[CH3:4]>CO.C(Cl)Cl>[CH2:3]([O:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[B:21]([OH:25])[O:22][CH2:23][C:19]=3[CH:20]=2)[CH:7]=1)[CH3:4]
Reactant: CCOc1cc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(C=O)c2)ncc1C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOc1cc(Oc2ccc3c(c2)COB3O)ncc1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of NaBH4 (0.10 g, 2.6 mmol) in anhydrous methanol (20 mL) was added to a solution of 4-ethoxy-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (3.53 g, 8.95 mmol) in CH2Cl2 (80 mL) and stirred at room temperature for 5 minutes. Solid NaBH4 (0.58 g, 15.3 mmol) was then added portionwise over 30 minutes at room temperature. The reaction mixture was stirred for an additional 30 minutes, quenched by the addition 70% aqueous acetic acid (3 mL) then stirred for an additional 1 hour at room temperature. The reaction was concentrated and the residue purified by silica gel flash column chromatography (AcOH/MeOH/CH2Cl2 1:1:100 v/v/v) to give the title compound as a viscous oil. The oil was lyophilized to give a white solid (0.781 g, 29% yield).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C([O:32]C(N[C@H]1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[C:22]([OH:32])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Product: Cl
Product: N[C@@H]1CCN(S(=O)(=O)c2cccc3c(O)ncc(Cl)c23)C1

Procedure:
Intermediate 16b can be used in the method of Example 6-1, Step A instead of Intermediate 1a, then the resultant can be used in the method of Step B in a similar manner, and then the title compound can be obtained as hydrochloride according to the method described in Example 7-1.
Reaction SMILES: C1N[C:4](=[O:5])NC1.[NH2:7][C:8]1[C:13]([OH:14])=[CH:12][C:11]([C:15]2[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=2[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:10][C:9]=1[OH:26].[Cl-].[Na+]>>[C:22]([C:16]1[C:17]([CH3:20])([CH3:21])[CH2:18][O:19][C:15]=1[C:11]1[CH:10]=[C:9]([OH:26])[C:8]2[N:7]=[C:15]([C:11]3[CH:12]=[CH:13][C:8]([O:5][CH3:4])=[CH:9][CH:10]=3)[O:14][C:13]=2[CH:12]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C1=C(c2cc(O)c(N)c(O)c2)OCC1(C)C
Reactant: O=C1NCCN1
Agent: [Cl-]
Agent: [Na+]
Product: COc1ccc(-c2nc3c(O)cc(C4=C(C(C)(C)C)C(C)(C)CO4)cc3o2)cc1
Temperature: 150 °C
Yield: 81.9 %

Procedure:
In nitrogen atmosphere at a room temperature, to 310 mg (1.46 mmol) of trimethyl 4-methoxy-1-orthobenzoate was added 1 ml of ethyleneurea dissolving 133 mg (0.48 mmol) of 5-(4-amino-3,5-dihydrophenyl)-4-t-butyl-3,3-dimethyl-2,3-dihydrofuran (Compound [8]), and the mixture was heated for 1.0 hours at 150° C. The resulting mixture was poured in saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried with magnesium sulfate anhydride, and concentrated. The residue was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane: ethyl acetate=3:1), and then followed by recrystallization from the mixture of methylene chloride and hexane to obtain 155 mg of 4-t-butyl-5-(4-hydroxy-2-(p-methoxyphenyl)benzo[d]-oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [67]) as a colorless granular micro-crystal. Yield 81.9%.
Reaction SMILES: [Mg].C(O)C.[C:5]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:6][C:7]([CH3:9])=[O:8].[CH2:16]([S:23][CH2:24][CH2:25][C:26](Cl)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS(O)(=O)=O>C(OCC)C.C(Cl)(Cl)Cl>[CH2:16]([S:23][CH2:24][CH2:25][C:26](=[O:27])[CH:6]([C:5]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:7](=[O:8])[CH3:9])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: O=C(Cl)CCSCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(=O)C(C(=O)CCSCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 12 °C

Procedure:
10.7 g (0.44 mol) of magnesium, 2 ml of chloroform and 46 g (1 mol) of absolute ethanol are initially placed, with the exclusion of moisture, in a 1 1 flask equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and are heated under reflux for 1 hour, with stirring. 300 ml of diethyl ether are then added dropwise and the mixture is stirred for 1.5 hours. The mixture is then cooled to approx. 12° C. 63.2 g (0.4 mol) of tert-butyl acetoacetate are added dropwise at this temperature. The reaction mixture is cooled further to approx. -3° C., and 85.8 g (0.4 mol) of benzylthiomethylacetyl chloride in 100 ml of absolute diethyl ether are added dropwise at this temperature in the course of 45 minutes. The mixture is then stirred for a further hour at approx. -3° C. and is then stirred for a further 2 hours without cooling, in the course of which it reaches room temperature. The reaction mixture is stirred into 400 g of ice-water and 48 g of concentrated H2SO4. The organic phase is separated off and is washed with 150 ml of water, 100 ml of bicarbonate and 150 ml of water again and is then dried and concentrated.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH2:13][CH:12]=[CH:11]2.[CH3:19][Si:20]([CH3:23])(Cl)Cl>CCCCCC.C1COCC1>[CH3:19][Si:20]([CH3:23])([CH:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH3:6])=[C:16]([O:17][CH3:18])[CH:15]=2)[CH:11]=[CH:12]1)[CH:1]1[C:10]2[C:4](=[CH:15][C:16]([O:17][CH3:18])=[C:8]([O:7][CH3:6])[CH:9]=2)[CH:3]=[CH:2]1
Reactant: COc1cc2c(cc1OC)CC=C2
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(cc1OC)C([Si](C)(C)C1C=Cc3cc(OC)c(OC)cc31)C=C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
23.6 ml (59 mmol) of a 2.5M butyllithium solution in hexane were added at room temperature to a solution of 10.4 g (59 mmol) of 5,6-dimethoxyindene (prepared by the method of Eberson et al., Acta Chem. Scand. B 30 (1976) 527) in 150 ml of THF, and the mixture was stirred at room temperature for 2 hours and added dropwise to a solution of 3.6 ml (29.5 mmol) of dimethyldichlorosilane in 20 ml of THF. The mixture was stirred overnight, poured into ice water and extracted with ether. The extracts were dried using Na2SO4, and the solvent was stripped off. The residue was stirred with diethyl ether, 2.2 g (18%) of the ligand system crystallizing.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:24])[CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14]([NH:25][CH3:26])[CH:13]=1.[OH2:27]>ClC(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:24])[CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:14]([CH:13]=1)[N:25]([CH3:1])[CH:26]=[O:27]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc(F)ccc1C(=O)CS(C)(=O)=O
Reactant: O
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CN(C=O)c1cc(F)ccc1C(=O)CS(C)(=O)=O

Procedure:
A mixture of acetic anhydride (19.8 ml) and formic acid (13.5 ml) was stirred and heated at 60° under nitrogen for 2 hours. 1-(4-Fluoro-2-methylaminophenyl)-2-methylsulphonylethanone (10.0 g), was added portionwise to the mixture at ambient temperature with stirring. The mixture was stirred at 30° for 30 minutes. Water (30 ml) was added to the reaction mixture which was then stirred at 30° for 30 minutes. Concentration of the reaction mixture by evaporation in vacuo gave a green oil. The oil was dissolved in trichloromethane (50 ml) and washed with aqueous sodium hydrogen carbonate solution (7% w/w; 2×30 ml). The trichloromethane extract was dried (magnesium sulphate) and evaporated in vacuo to give a green oil which solidified at ambient temperature. Recrystallisation from toluene gave 5'-fluoro-N-methyl-2'-methylsulphonylacetylformanilide, m.p. 94.5°-95.5°.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][NH:5][CH:6]=[O:7].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Cl:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>O>[Cl-:16].[CH3:1][N+:2]([CH3:8])([CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH2:3][CH2:4][NH:5][CH:6]=[O:7]
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: CN(C)CCNC=O
Solvent: O
Product: COc1ccc(C[N+](C)(C)CCNC=O)cc1[N+](=O)[O-]
Product: [Cl-]

Procedure:
A stirred solution of 24.6 parts of N-(2-dimethylaminoethyl)formamide and 30 parts of water was heated to 60° and over a period of one hour there was added 40.3 parts of 4-methoxy-3-nitrobenzylchloride. Heating between 60° and 65° C. was continued for three and one-half hours at which time the pH of the mixture stabilized above 7.0. To the cooled mixture was added 20 parts of water and the resulting mixture was clarified by filtration. An aqueous solution of N,N-dimethyl-N-(3-nitro-4-methoxybenzyl)-N-2-formamidoethylammonium chloride was obtained. This solution was used directly for reduction of the nitro group.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.CCN=C=NCCCN(C)C.Cl.C[O:27][C:28](=[O:79])[C@@H:29]([NH:46][C:47]([C@@H:49]1[CH2:58][C:57]2[CH:56]=[C:55]3[O:59][CH2:60][C@H:61]([C:63]4[CH:68]=[CH:67][C:66]([O:69][CH2:70][C:71]5[CH:76]=[CH:75][C:74]([Cl:77])=[C:73]([Cl:78])[CH:72]=5)=[CH:65][CH:64]=4)[O:62][C:54]3=[CH:53][C:52]=2[CH2:51][NH:50]1)=[O:48])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[C:39]=2[CH3:45])=[CH:33][CH:32]=1>C(Cl)Cl>[Cl:78][C:73]1[CH:72]=[C:71]([CH:76]=[CH:75][C:74]=1[Cl:77])[CH2:70][O:69][C:66]1[CH:67]=[CH:68][C:63]([C@H:61]2[CH2:60][O:59][C:55]3=[CH:56][C:57]4[CH2:58][C@@H:49]([C:47]([NH:46][C@@H:29]([CH2:30][C:31]5[CH:36]=[CH:35][C:34]([O:37][C:38]6[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[C:39]=6[CH3:45])=[CH:33][CH:32]=5)[C:28]([OH:79])=[O:27])=[O:48])[N:50]([C:6](=[O:8])[C:5]5[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=5)[CH2:51][C:52]=4[CH:53]=[C:54]3[O:62]2)=[CH:64][CH:65]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)N2Cc3cc4c(cc3C[C@H]2C(=O)N[C@@H](Cc2ccc(Oc3ccnc(C)c3C)cc2)C(=O)O)OC[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)O4)cc1OC
Reaction time: 16 h

Procedure:
3,4-Dimethoxybenzoic acid (1 eq.) was stirred in dry DCM with 0.5 eq EDCl at RT for 1 h. (S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester in dry DCM (10 eq benzoic acid relative to amine) was added and the resulting mixture stirred 16 h, then directly purified by flash chromatography. The resulting compound was hydrolyzed according to General Procedure B to give the title compound (5 mg). LCMS (m/z) 919.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[C:17](CCCC2C=CC=CC=2)=[C:18](S([O-])(=O)=O)C=CC=1C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]([NH:39][CH2:40][CH2:41][CH:42]([C:49]1[CH:54]=[C:53]([CH3:55])[CH:52]=[CH:51][C:50]=1[O:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:38])[CH3:37].O>CS(C)=O>[CH2:57]([O:56][C:50]1[CH:51]=[CH:52][C:53]([CH3:55])=[CH:54][C:49]=1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41][CH2:40][N:39]([CH2:18][CH2:17][CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:36]([CH3:38])[CH3:37])[C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C(CCNC(C)C)c2ccccc2)c1
Reactant: Cc1ccc(OCc2ccccc2)c(-c2c(C)ccc(S(=O)(=O)[O-])c2CCCc2ccccc2)c1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(OCc2ccccc2)c(C(CCN(CCC(c2ccccc2)c2cc(C)ccc2OCc2ccccc2)C(C)C)c2ccccc2)c1
Temperature: 65 °C

Procedure:
A mixture of 3-(2-(benzyloxy)-5-methylphenyl)-3-phenylpropyl-4-methylbenzenesulfonate of Formula IVa (120 g) and N-isopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenylpropylamine (92 g) in dimethylsulfoxide (600 ml) was heated at 60-70° C. for 18-20 hours. The reaction mass was cooled to 25-35° C., decomposed with water (600 ml), and extracted with toluene (600 ml). The toluene layer was washed with a mixture of concentrated hydrochloric acid (60 ml) and water (606 ml). The organic layer was then washed with 10% sodium hydroxide solution (240 ml), followed by water (600 ml). The organic layer was distilled completely to obtain the title compound as a syrup. Yield: 128 g (75.4%).
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(Cl)(Cl)Cl>[BrH:1].[Br:1][CH:5]([C:4](=[O:3])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: BrBr
Reactant: CCOC(=O)CC(=O)c1ccccn1
Solvent: ClC(Cl)Cl
Product: Br
Product: CCOC(=O)C(Br)C(=O)c1ccccn1
Reaction time: 1 h
Yield: 196.1 %

Procedure:
Bromine (0.83 g, 5.2 mmol) in chloroform (2 mL) was added slowly to a solution of ethyl 3-oxo-3-pyridin-2-ylpropanoate (1.0 g, 5.2 mmol) and chloroform (25.0 mL) at room temperature. The reaction mixture was stirred for 1 h and was concentrated under reduced pressure to give 1 ethyl 2-bromo-3-oxo-3-pyridin-2-ylpropanoate hydrobromide salt as an amber oil (1.8 g, 100%). LCMS calc. for C10H11BrNO3 (M+H)+: m/z=272.0, 274.0. found: 272.0, 274.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]=2[CH:3]=1.[CH3:32][O:33][CH:34](OC)[N:35]([CH3:37])[CH3:36]>>[CH:25]1([O:33][CH3:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.[Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:34]/[N:35]([CH3:37])[CH3:36])[C:5]2[C:9]([I:31])=[N:10][N:11]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:4]=2[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CN(C)/C=C/c1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC1CCCC1

Procedure:
6-chloro-3-iodo-trityl-1H-pyrazolo[4.3-c]pyridine (Intermediate 1C, 2 g, 3.73 mmol), N, N-dimethylformamide-dimethyl acetal (DMF-DMA) (4.45 g, 37.3 mmol) were stirred at 125° C. for 12 hrs. Reaction was concentrated and excess DMF-DMA azeotroped with toluene. Trituration with cylopentylmethylether gave (E)-2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N,N-dimethylethenamine. MS ESI calc'd. for C29H24ClIN4 [M+H]+ 591. found 591.
Reaction SMILES: O.[NH2:2][NH2:3].C1O[CH:7]([C:8]2[C:9](I)=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)OC1.C(N(CC)CC)C.Cl>CO>[NH:2]1[C:9]2=[N:10][C:11]3[C:16]([CH:17]=[C:8]2[CH:7]=[N:3]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: NN
Reactant: Ic1nc2ccccc2cc1C1OCCO1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: c1ccc2nc3[nH]ncc3cc2c1
Reaction time: 1 h

Procedure:
Hydrazine hydrate (10 g, 0.20 mol) is added dropwise to a suspension of 2-iodoquinoline-3-carboxaldehyde ethylene ketal (65.5 g, 0.20 mol), (O. Meth-Cohn, J. Chem. Soc., Perkin I, 2509 (1981), m.p. 104.5°-106.5° C. in methanol (250 mL) containing triethylamine 28 mL) at reflux. After refluxing overnight additional hdyrazine hydrate (10 g) is added and the mixture is stirred at reflux for another six and one-half hours. Concentrated hydrochloric acid (75 mL) is then added dropwise, while the mixture is refluxing and the reaction continued for one hour. The reaction mixture is cooled, poured onto ice and allowed to stand for two days. A red solid is removed by filtration and the filtrate is concentrated by rotary evaporation to remove methanol. The remaining solution is adjusted to pH 9 with concentrated ammonium hydroxide and the cream colored precipitate is filtered, washed with water and air dried. Recrystallization from ethanol gives an analytical sample, melting point 207°-208° C., calcd. for C10H7N3 : C, 70.99; H, 4.17; N, 24.84. Found: C, 70.82: H, 4.06; N, 24.18.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([N:13](CC)CC)C.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19]>C(Cl)Cl>[CH2:18]([S:20]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH2:13])[CH:6]=[CH:5]2)(=[O:22])=[O:21])[CH3:19]
Reactant: CCN(CC)CC
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc2c(ccn2N)c1
Temperature: 23 °C
Yield: 99.1 %

Procedure:
To a solution of 5-amino-1H-indole (10.0 g, 76 mmol) and triethylamine (15.8 mL, 114 mmol) in 100 mL CH2Cl2 at 0° C. was added dropwise a solution of ethanesulfonyl chloride (7.9 mL, 83 mmol) in 25 mL of CH2Cl2. The solution was allowed to slowly warm to 23° C. over 20 h. The reaction mixture was concentrated in vacuo and the residue dissolved in 400 mL of ethyl acetate. The organic layer was washed with 100 mL of water, 50 mL of 0.1 M HCl, 50 mL of saturated NaHCO3 solution, and 50 mL of saturated NaCl solution. The organic layer was dried over anhydrous K2CO3, filtered, and concentrated in vacuo to obtain 5-ethanesulfonyl-amino-1H-indole (16.9 g, >99%) which was used without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:11](=[O:13])[CH3:12])([OH:10])[CH2:6][CH2:5]1)(=[O:3])C.ClC([O:17][CH2:18][CH:19]=[CH2:20])=O.[H-].[K+]>Cl.O1CCCC1.O.C(OCC)(=O)C>[C:11]([C:7]1([OH:10])[CH2:8][CH2:9][N:4]([C:1]([O:17][CH2:18][CH:19]=[CH2:20])=[O:3])[CH2:5][CH2:6]1)(=[O:13])[CH3:12]
Reactant: C=CCOC(=O)Cl
Reactant: CC(=O)N1CCC(O)(C(C)=O)CC1
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1CCC(O)(C(C)=O)CC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
1,4-Diacetyl-4-hydroxypiperidine (0.2 g) was dissolved in 1N hydrochloric acid (4 ml) and the solution was heated at 100° C. for 15 hours. After cooling to 0° C., the reaction mixture was diluted with a mixture of tetrahydrofuran (10 ml) and water (10 ml). To the mixture was added dropwise at 0° C. a solution of allyl chloroformate (0.15 ml) in tetrahydrofuran (2 ml) while adjusting pH to around 10 with aqueous potassium hydride. After stirring at 0° C. for 30 minutes, the reaction mixture was diluted with a mixture of ethyl acetate and water. The organic layer was separated, washed in turn with water and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (10 g) eluting with a mixture of n-hexane and ethyl acetate (9:1-1:1, V/V) to give 4-acetyl-1-allyloxycarbonyl-4-hydroxypiperidine (0.26 g).
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].CS(C)=[O:42]>CCCCCC.C(COC)OC>[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:42])[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: CS(C)=O
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
Solvent: COCCOC
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
Reaction time: 72 h

Procedure:
0.25 g of milbemycin A4 and 5 ml of DMSO are added to a 1-day-old culture of S. violascens in 200 ml of medium 3 and the whole is shaken at 250 rpm. at 28° C. After 3 days, a further 50 ml of medium 3 is added. The course of the reaction is monitored by HPLC (column Kontron LiSi 60, 25 cm/0.5 cm, eluant hexane/dimethoxyethane 3:1, 1 ml/min., UV detector 220 nm). After shaking for 7 days and a 91% conversion rate, 92% 13β-hydroxymilbemycin A4 and 8% 14,15-epoxymilbemycin A4 are obtained.