Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7](=[O:45])[CH2:8][C:9]1[N:10]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:42][CH3:43])([C:23]3[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[C:25]([CH3:41])[CH:24]=3)[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:44])[S:12][CH:13]=1)C.Cl>CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[S:12][CH:13]=[C:9]([CH2:8][C:7]([OH:45])=[O:6])[N:10]=2)=[C:15]([CH3:44])[CH:16]=1)([C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:40])([C:36]([F:37])([F:38])[F:39])[C:32]([F:34])([F:35])[F:33])=[C:25]([CH3:41])[CH:24]=1)[CH2:42][CH3:43])[CH3:22]
Reactant: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c3)cc2C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2nc(CC(=O)O)cs2)c(C)c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 93.9 %

Procedure:
A mixed solution of a 6 N sodium hydroxide aqueous solution (0.11 mL) with water (0.033 mL) was added to a solution of [2-(4-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (Example 76-(1); 9.7 mg, 0.016 mmol) in methanol (0.22 mL) at room temperature, and the mixture was stirred at room temperature for 6.5 hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane:methanol=10:1) to give the title compound (8.8 mg, 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[S:5][C:6]=1[O:7][CH3:8].[CH3:13][N:14]1[C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=[N:15]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:8][O:7][C:6]1[S:5][C:4]([C:9]([O:11][CH3:12])=[O:10])=[CH:3][C:2]=1[C:18]1[N:14]([CH3:13])[N:15]=[CH:16][CH:17]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(OC)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2ccnn2C)c(OC)s1
Temperature: 85 °C
Yield: 143 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-bromo-5-(methyloxy)-2-thiophenecarboxylate (772 mg, 3.07 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (773 mg, 3.72 mmol) [prepared according to the procedure of Preparation 7], K2CO3 (1.419 g, 10.27 mmol) and Pd(Pt-Bu3)2 (103 mg, 0.20 mmol) in 1,4-Dioxane (12 mL) and Water (3 mL). The reaction was heated at 85° C. for 2 hours. The mixture was partitioned between CHCl3/H2O and the aqueous layer made acidic with 6N HCl. The separated organic layer was dried over Na2SO4 and evaporated. The resulting material was adsorbed onto silica and purified via column chromatography (0-50% EtOAc/Hexane) affording the title compound (967 mg, 4.39 mmol, 85%): LC-MS (ES) m/z=253 (M+H)+.
Reaction SMILES: I[C:2]1[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:10]1([N:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:10]1([N:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]2[CH:18]=[C:19]([NH:23][C:2]3[C:3]([NH:8][CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=3)[CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CNc1ncccc1I
Reactant: Nc1cccc(N(c2ccccc2)c2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: CNc1ncccc1Nc1cccc(N(c2ccccc2)c2ccccc2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A 1 L round-bottomed flask was charged with 3-iodo-N-methylpyridin-2-amine (8.95 g, 38.3 mmol), N1,N1-diphenylbenzene-1,3-diamine (9.96 g, 38.3 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.183 g, 0.384 mmol) and sodium 2-methylpropan-2-olate (5.15 g, 53.6 mmol) in toluene (500 mL). Nitrogen was bubbled through for 10 minutes. Then Pd2 dba3 (88 mg, 0.10 mmol) was added and this was stirred at 120° C. for overnight. The mixture was then filtered and the filtrate was concentrated and chromatographed using a mobile phase gradient of 0-20% ethyl acetate in dichloromethane to give N3-(3-(diphenylamino)phenyl)-N2-methylpyridine-2,3-diamine (12.2 g, 91% yield).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])([CH3:4])[CH3:3].N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:23]([O:29][CH2:30][CH3:31])(=[O:28])[CH2:24][C:25]([CH3:27])=O.[OH-].[K+]>O.C(O)C>[CH2:30]([O:29][C:23]([C:24]1[NH:11][C:8]2[C:9]([C:25]=1[CH3:27])=[CH:10][C:5]([CH:2]([CH3:4])[CH3:3])=[C:6]([O:12][CH3:13])[CH:7]=2)=[O:28])[CH3:31]
Reactant: COc1cc(N)ccc1C(C)C
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c2cc(OC)c(C(C)C)cc2c1C
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 32.5 %

Procedure:
4-Isopropyl-3-methoxy-phenylamine HCl salt (3.1 g, 19 mmol) was cooled to −5 C (Ice/Methanol bath), and a mixture of 8 ml water and 5 ml concentrated. HCl was added dropwise. The reaction mixture was stirred for five minutes, and sodium nitrite (1.42 g, 21 mmol) disolved in 3 ml water was added dropwise over 10 minutes. The reaction mixture was stirred for 45 min, then sodium acetate (1.3 g, 16 mmol) was added. In a separate flask, to a stirring mixture of ethyl alpha-acetoacetate (3.26 g, 21 mmol) in 15 ml absolute ethanol was added KOH (1.2 g, 21 mmol) dissolved in 3 ml water and then added ice (10 g). This mixture was added to the diazonium salt, and the reaction mixture was stirred at zero degrees C for 3.5 hours. The reaction mixture was stored at −10 C for 16 hours, then extracted with EtOAC. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to a liquid residue. In a separate flask, mixed 100 ml EtOH was mixed slowly with 22 ml acetyl chloride, with cooling in an ice bath. The EtOH/acetyl chloride solution was heated to 70 degrees C, and added the residue was added via pipette over 10 min. The reaction mixture was heated to reflux for 2.5 hours, cooled, evaporated under reduced pressure to give a slurry; diluted with water (100 ml) and filtered. The solid was washed with water. The solid was triturated with hexanes to give 5-Isopropyl-6-methoxy-3-methyl-1H-indole-2-carboxylic acid ethyl ester (1.7 g, 34% ) as a solid.
Reaction SMILES: Cl.C(Cl)CCl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[CH:17]=[N:18][C:19]([CH2:22][CH2:23][C:24]([OH:26])=O)=[N:20][CH:21]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][NH2:41])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][NH:41][C:24](=[O:26])[CH2:23][CH2:22][C:19]2[N:20]=[CH:21][C:16]([C:10]3[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=3)=[CH:17][N:18]=2)[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Reactant: COc1ccc(-c2cnc(CCC(=O)O)nc2)cc1OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(-c2cnc(CCC(=O)NCC3CCCN(C(=O)OC(C)(C)C)C3)nc2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
The mono HCl salt of EDC (0.86 g, 4.5 mmol, 1.5 equiv) was added to a suspension of 3-(5-(3,4-dimethoxy-phenyl)pyrimidin-2-yl)-propanoic acid (0.95 g, 3.3 mmol, 1.1 equiv), 3-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.64 g, 3.0 mmol), HOBT (0.61 g, 4.5 mmol, 1.5 equiv), and diisopropylethylamine (1.3 mL, 7. mmol, 2.5 equiv) in a 50 mL solvent (THF:DMF, 7:3). After stirring overnight at rt, the mixture was concentrated and the residue was dissolved in 50 mL ethyl acetate. The solution was poured into 50 mL of a saturated NaHCO3 solution and extracted thoroughly with ethyl acetate. The combined organic layers were washed with brine and water, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (0→10% MeOH in CHCl3). Clean fractions containing the desired product were combined and concentrated to give 3-({3-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-propionylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.22 g, 84%) as a dark brown solid. The solid was dissolved into CH2Cl2 (30 mL) and neat TFA (5 mL) added dropwise. After about 30 min, the solution was concentrated to an oil on the teflon dryvac, then under high vacuum. LCMS analysis indicated quantitative conversion to 3-[5-(3,4-dimethoxy-phenyl)-pyrimidin-2-yl]-N-piperidin-3-ylmethyl-propionamide 2c.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[NH:26][CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][C:12]=1[F:32])[CH3:9].C(OC=O)=O>C1COCC1>[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH:1]=[O:3])[CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][C:12]=1[F:32])[CH3:9]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1F
Reactant: CC(=O)O
Agent: O=COC=O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To anhydrous acetic acid (0.63 ml) was added formic acid (0.31 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, cooled and diluted with THF (10 ml). In THF (10 ml) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (510 mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0° C. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 7-(4-ethoxy-3-fluoropheny)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (490 mg, 89%) as white crystals.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C(O[C:14](=[O:25])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)C.[CH3:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=1[OH:35])=[O:28]>O1CCCC1>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:14](=[O:25])[CH2:26][C:27]([C:29]2[CH:30]=[CH:31][C:32]([OH:36])=[CH:33][C:34]=2[OH:35])=[O:28])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCOC(=O)c1ccc(OC)c(OC)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)c2ccc(O)cc2O)cc1OC

Procedure:
A solution of 20% lithiumhexamethyldisilazane in tetrahydrofuran (335 mL, 400 mmol), 2,4-dihydroxy acetophenone, 14 (15.2 g, 100 mmol) in tetrahydrofuran (150 mL) and ethyl-3,4-dimethoxy benzoate, 7 (21 g, 100 mmol) in tetrahydrofuran (100 mL) were reacted to afford 21, 1-(3,4-dimethoxy-phenyl)-3-(2,4-dihydroxy-phenyl)-propane-1,3-dione (37 g), which was cyclized with Dowex-H+ (15 g) in 2-propanol (250 mL) in a similar way as described for 22 to afford 27. Yield 15.4 g, (52%); mp 263-265° C.; MS (FAB) 299 (M++1); IR (KBr) 3452, 1625; 1H NMR (200 MHz, CDCl3+DMSO-d6) δ 9.83 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.97 (dd, J=8.5 Hz, 1.7 Hz, 1H), 6.83 (d, J=1.7 Hz, 1H), 6.43 (d, J=8.5 Hz, 1H), 6.34 (s, 1H), 6.30 (dd, J=9.7 Hz, 2.0 Hz, 1H), 6.08 (s, 1H), 3.35 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:13]1[S:14][C:10]([Br:9])=[CH:11][CH:12]=1)(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(Br)s2)c1Br
Yield: 30 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-bromothiophene-2-sulfonyl chloride in 30% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 240° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>[Cu]I.O1CCCC1>[C:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8])#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Fc1ccccc1Br
Reactant: C#CCCCCCCCCCC
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCCCCCCCCCC#Cc1ccccc1F
Temperature: 55 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a solution of 2-bromofluorobenzene (49 g), 1-dodecyne (210 ml) triethylamine (210 ml), and tetrahydrofuran (50 ml) was added (bis)triphenylphosphine palladium(II)chloride (532 mg) and copper(I)iodide (532 mg). The reaction mixture was warmed to 55° C. and stirred for 24 hr. The mixture was allowed to cool to room temperature and filtered. The precipitate was washed with ethyl acetate, and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel (eluted with hexane). The appropriate fractions were collected and evaporated. The residue was distilled to afford 11 g (15%) of product, bp 175°-180° C. at 1 mm Hg.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[CH:16]1([CH2:19][C@H:20]([NH2:27])[C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][C@H:20]([NH:27][C:12]([C:10]2[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:21]2[N:25]=[C:24]([CH3:26])[O:23][N:22]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Product: Cc1nc([C@H](CC2CC2)NC(=O)c2ccc(C)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e) as starting materials, MS (EI): m/e 357.2 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][N:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][N:15]=[CH:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: C1=C(c2c[nH]c3cnccc23)CC2CCCN2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2=CCN3CCCC3C2)c2ccncc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-6-Azaindole (12 mg, 0.055 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4]([C:11](=O)[CH2:12][CH3:13])[C:5](=[O:10])[O:6][C:7]=1[CH2:8][CH3:9].[CH2:16]([O:18][NH2:19])[CH3:17]>C(O)C>[Br:1][C:2]1[C:3](=[O:15])[C:4](=[C:11]([NH:19][O:18][CH2:16][CH3:17])[CH2:12][CH3:13])[C:5](=[O:10])[O:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCON
Reactant: CCC(=O)c1c(O)c(Br)c(CC)oc1=O
Solvent: CCO
Product: CCONC(CC)=C1C(=O)OC(CC)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.4 g of 5-bromo-6-ethyl-4-hydroxy-3-propionyl-pyrone (a melting point of 76.5° C to 77.5° C) was dissolved in 10 c.c. of ethanol and further 0.5 g of ethoxyamine was added in it and the resulting solution was agitated at room temperature during 4 hours. Further, it was agitated at a temperature of 40°-50° C during 30 minutes. Then, above ethanol was distilled off from the resulting reaction mixture under a reduced pressure and thereby, a crude white crystal was obtained. Further, the crude white crystal was recrystallized by using n-hexane and thus, a white spicular crystal was obtained as an objective compound.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7](Br)=[N:6][C:5]=2[N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:40]=[CH:39][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:10]2[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:7]([C:28]3[CH:29]=[CH:30][C:31]([CH2:32][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:39][CH:40]=3)=[N:6][C:5]=2[N:4]([CH:17]([CH3:19])[CH3:18])[N:3]=1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCOC(=O)c1cc(Br)nc2c1c(Br)nn2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2c1c(Br)nn2C(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
A solution of ethyl 3,6-dibromo-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1.2 g, 3.08 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.935 g, 3.08 mmol) and Pd(PPh3)4 (0.178 g, 0.154 mmol) in 1,4-dioxane (33 mL) was purged with argon for 10 min. Then, 2M Na2CO3 solution (1.17 g, 11.10 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.8 g, 67.1%).
Reaction SMILES: C1CO[C:3]([C@@H:5]2[C@:22]3([CH3:23])[C@H:8]([C@H:9]4[C@H:19]([C:20](=[O:24])[CH2:21]3)[C@:17]3([CH3:18])[C@H:12]([CH2:13][C@H:14]([OH:25])[CH2:15][CH2:16]3)[C@H:11]([CH3:26])[CH2:10]4)[CH2:7][CH2:6]2)([CH3:4])[O:2]1.[BH4-].[Na+]>CC(O)C.O.CC(C)=O.Cl>[OH:25][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([C@H:11]([CH3:26])[CH2:10][C@@H:9]3[C@@H:19]2[C@@H:20]([OH:24])[CH2:21][C@@:22]2([CH3:23])[C@H:8]3[CH2:7][CH2:6][C@@H:5]2[C:3](=[O:2])[CH3:4])[CH2:13]1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CC[C@H](C4(C)OCCO4)[C@@]3(C)CC(=O)[C@@H]2[C@@]2(C)CC[C@@H](O)C[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3C[C@@H](C)[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
20,20-Ethylenedioxy-3α-hydroxy-6β-methyl-5α-pregnan-11-one (1.36 g) was dissolved in propan-2-ol (90 ml) and a solution of sodium borohydride (500 mg) in water (10 ml) was added. The solution was stirred at 20° overnight and then diluted with water (200 ml). Extraction with chloroform (2×100 ml) gave, on evaporation of the extract, a colourless gum which was dissolved in a mixture of acetone (50 ml) and 2N-hydrochloric acid (5 ml). After 2 hours the solution was diluted with water (100 ml) and extracted with chloroform (2×50 ml). Evaporation of the extract gave a colourless gum which was crystallised from methanol (25 ml) to give the title compound (700 mg), m.p. 211°-213°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]([OH:28])[CH2:19][N:20]([C:24](=[O:27])[CH2:25]Cl)[CH:21]([CH3:23])[CH3:22])[C:11]=1[O:29][CH3:30])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>C1COCC1>[Cl:16][C:14]1[C:13]([CH3:17])=[C:12]([CH:18]2[O:28][CH2:25][C:24](=[O:27])[N:20]([CH:21]([CH3:22])[CH3:23])[CH2:19]2)[C:11]([O:29][CH3:30])=[C:10]([CH:8]([NH:7][C:6](=[O:31])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH3:9])[CH:15]=1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C(O)CN(C(=O)CCl)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(C)C)C(=O)CO1
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a solution of tert-butyl[1-(5-chloro-3-{2-[(chloroacetyl)(isopropyl)amino]-1-hydroxyethyl}-2-methoxy-4-methylphenyl)ethyl]carbamate (22 mg, 0.047 mmol) in THF (1.0 mL) cooled at 0° C., sodium hydride (3.6 mg, 0.094 mmol; 60% dispersion in mineral oil) was added and the mixture was stirred for 1 hour. The mixture was quenched with water and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the desired compound (20 mg, 97%). LCMS calculated for C22H33ClN2O5Na (M+Na)+: m/z=463.2. found: 463.1.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CCN(CC)CC.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:15][CH2:16][C:17]([N:4]1[CH2:5][CH2:6][CH2:7][C@H:3]1[CH2:2][OH:1])=[O:18]
Reactant: O=C(Cl)CCl
Reactant: OC[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCC[C@H]1CO
Temperature: -20 °C
Reaction time: 18 h

Procedure:
To a solution of 2(S)-hydroxymethylpyrrolidine (25.32 g, 250.3 mmol) in CH2Cl2 (720 mL) under argon was added Et3N (38.0 mL, 273 mmol). After cooling this mixture to -20° C., chloroacetyl chloride (20.0 mL, 251 mmol) was added dropwise over 0.75 h maintaining the reaction temperature at -20 ±3° C. The reaction was stirred at ambient temperature for 18 h and evaporated in vacuo. An impurity which precipitated during concentration was removed by filtration. The crude product was purified by chromatography (silica gel, 1:39 to 1:19 MeOH/CH2Cl2) to give the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ4.37 (dd, J=8, 3 Hz, 1H), 4.22 (qd, J=7, 3 Hz, 1H), 4.08 (s, 2H), 3.71 (td, J=8, 3 Hz, 1H), 3.68-3.50 (m, 3H), 2.14-1.86 (m, 3H), 1.72-1.62 (m, 1H).