Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH3:17])=[CH:9][O:8]1)[CH3:5])[CH3:2].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@H:11]2[C@@H:10]([CH3:17])[CH2:9][O:8]1)[CH3:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@H](C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC[C@H](C)[C@@H]2CC[C@H](C)[C@@H]12
Yield: 69.4 %

Procedure:
28.0 g of (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran was dissolved in 500 ml of ethyl acetate, and after 90 mg of 10% palladium carbon was added, the reaction mixture was stirred at room temperature for 48 hours in a hydrogen gas atmosphere of 1 atm. The catalyst was filtered by celite, and the solvent was distilled off under a reduced pressure. There was thus obtained a colorless oily substance, (1S, 4R, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran. 28.0 g of this (1S, 4R, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran was dissolved in 400 ml of tetrahydrofuran without purification, and after 50 ml of 2N hydrochloric acid solution wad added, the reaction mixture was stirred for 12 hours while being cooled by ice. 300 ml of saturated sodium hydrogen carbonate solution was added to the reaction mixture, extraction was made with ethyl acetate (500 ml×3). The joined organic layer was dried by magnesium sulfate, and after filtration, the solvent was distilled off under a reduced pressure. The residue was purified by column chromatography using 200 g of silica gel, and 13.5 g of a colorless oily substance (yield=69.4%) was obtained from the hexane:ether=1:1 eluent. Since various spectral data of this colorless oily substance were in agreement with the data described in the reference ("Tetrahedron Lett.", 5325, 1968), it was determined as 4R, 4aR, 7S, 7aR)-1, 3, 4, 4a, 5, 6, 7, 7a-octahydro-4, 7-dimethylcyclopenta[c]pyran-1-ol.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3]1.[C:16]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])#[N:17]>>[C:16]([CH2:18][CH2:19][CH2:20][C:21]([N:7]1[CH2:6][CH2:5][N:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=2)[CH2:3][CH:2]1[CH3:1])=[O:22])#[N:17]
Reactant: N#CCCCC(=O)O
Reactant: CC1CN(c2ccc(C#N)cn2)CCN1
Product: CC1CN(c2ccc(C#N)cn2)CCN1C(=O)CCCC#N
Yield: 85 %

Procedure:
This compound was synthesized from 6-(3-methylpiperazin-1-yl)nicotinonitrile and 4-cyanobutyric acid as described for example 37 step 3 (900 mg, yield 85%) and it was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 8.41-8.40 (dd, J=2.3 Hz, 0.5 Hz, 1H), 7.67-7.63 (dd, J=9.0 Hz, 2.2 Hz, 1H), 6.61-6.58 (d, J=9.0 Hz, 1H), 4.46-4.19 (m, 4H), 3.54-3.36 (m, 2H), 3.16-3.11 (m, 2H), 2.59-2.51 (m, 3H), 2.06-2.01 (m, 2H), 1.26 (m, 3H). MS (ESI) m/z: Calculated for C16H19N6O: 297.16. found: 298.0 (M+H)+
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]3([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:23][CH:22]=2)[C:10]=1[CH3:35])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[OH:34][C:29]1([CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:11]3[NH:12][C:13]4[C:18]([C:9](=[O:8])[C:10]=3[CH3:35])=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:22][CH:23]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: Cc1c(COc2ccc(CCC3(O)CCCC3)cc2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(CCC3(O)CCCC3)cc2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
To a solution of 1-[2-(4-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}phenyl)ethyl]cyclopentanol (128 mg) in ethanol-THF (1:1, 4 mL) was added 10% palladium-activated carbon (30 mg) under nitrogen atmosphere, followed by stirring at room temperature under hydrogen atmosphere for 3 hours. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=92/8). The resulting solid was washed with ether and dried to obtain 2-({4-[2-(1-hydroxycyclopentyl)ethyl]phenoxy}methyl)-3-methylquinolin-4(1H)-one (51 mg) as a crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[OH-].[K+].S(OC)(O[CH3:20])(=O)=O>CO>[CH3:20][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(NC=O)c(C)c1C

Procedure:
N-(4-Hydroxy-2,3,6-trimethylphenyl)formamide (30.0 g, 167 mmol) was dissolved into a mixed solvent of a 4 N aqueous solution of potassium hydroxide (100 ml) and methanol (300 ml) and dimethyl sulfate (42.0 g, 334 mmol) was added to the resulting solution at room temperature. The resulting mixture was refluxed with heating for 14 hours. After the reaction solution was cooled down, the crystals precipitated were collected by filtration to obtain N-(4-methoxy-2,3,6-trimethylphenyl)formamide as a crude product. To a suspension of this compound in methanol (200 ml) was added concentrated hydrochloric acid (50 ml) and the resulting mixture was refluxed with heating for 3 hours. The reaction mixture was cooled down and neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined extracts were washed with a 10% aqueous solution of sodium hydrosulfite, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether to obtain 21.0 g (yield 76%) of the title compound. Melting point: 70-72° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=3)[N:27]=[CH:26][N:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68]O)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]>C(Cl)Cl>[C:57]([N:60]1[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][CH2:68][O:34][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][C:30]=2[O:35][CH3:36])[N:27]=[CH:26][N:25]=[C:24]3[O:23][C:22]2[C:14]([F:13])=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([CH3:37])=[CH:16]3)[CH2:62][CH2:61]1)(=[O:59])[CH3:58]
Reactant: CC(=O)N1CCN(CCCO)CC1
Reactant: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
Diethyl azodicarboxylate (0.178 g, 1.02 mmol) was added to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.267 g, 0.787 mmol), triphenylphosphine (0.31 g, 1.18 mmol) and 3-(4-acetylpiperazin-1-yl)propan-1-ol (0.176 g, 0.945 mmol) in methylene chloride (10 nm). After stirring for 15 minutes at ambient temperature, further triphenylphosphine (0.062 mg, 0.236 mmol) and diethyl azodicarboxylate (0.041 mg, 0.3 mmol) were added. After stirring for 1 hour at ambient temperature, the mixture was poured onto a column of silica and eluted with increasingly polar mixtures of ethyl acetate and methylene chloride followed by methylene chloride and methanol. The fractions containing the expected product were combined and evaporated. The residue was triturated under diethyl ether and the solid was filtered, washed with ether and dried under vacuum to give 6-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-7-methoxyquinazoline 0.210 g, 60%).
Reaction SMILES: [Br:1]Br.[C:3]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl>[C:3]([C:6]([Br:1])([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH3:4]
Reactant: BrBr
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(CCCC(Br)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O

Procedure:
Bromine (16.7 g., 0.104 mole) dissolved in carbon tetrachloride (100 ml.) is added dropwise to a stirred solution of ethyl 8-acetyl-12-acetoxyheptadecanoate (Example 1, Step C) (37.4 g., 0.094 mole) in carbon tetrachloride (200 ml.) during one hour. The solvent is distilled in vacuo. The residual oil is dissolved in ether and washed with dilute sodium bicarbonate, water and brine and dried over sodium sulfate. Evaporation of the ether leaves the crude bromo ester as a yellow oil weighing 43 g. It is purified by column chromatography on silica gel with benzene as the eluant. This procedure serves to separate the desired bromo ester from a small amount of a by-product, ethyl 8-bromoacetyl-8-bromo-12-acetoxyheptadecanoate. Ethyl 8-acetyl-8-bromo-12-acetoxyheptadecanoate is thus obtained as a pale yellow oil weighing 12.7 g. (28%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([CH:18]=[C:19]3[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:20]3=[O:28])[CH:9]=2)=[CH:4][CH:3]=1.[OH:29]O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:17])[F:15])=[C:10]([CH:18]3[C:19]4([C:20](=[O:28])[C:21]([CH3:27])([CH3:26])[O:22][C:23]4([CH3:24])[CH3:25])[O:29]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3)ccc2C(F)(F)F)C1=O
Temperature: 35 °C
Reaction time: 0.75 h
Yield: 99.6 %

Procedure:
To a solution of 4-[1-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (2.50 g, 6.12 mmol) in methanol (75 ml) at 35° C. is added 50% aqueous hydrogen peroxide solution (0.70 ml, 12.2 mmol), followed immediately by a solution of 2M aqueous lithium hydroxide (0.76 ml, 1.52 mmol). This mixture is stirred at 35° C. for 45 minutes, then allowed to cooled to room temperature and quenched with saturated sodium metabisulfite solution. The crude product is extracted with diethyl ether (×2), then all organics are combined and dried over magnesium sulfate. After filtration the filtrate is concentrated in vacuo to afford 2-(4′-chloro-4-trifluoromethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (2.59 g) as a yellow gum. This material is used directly in the next step.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13].C(N(CC)CC)C.CS([Cl:25])(=O)=O>C(Cl)Cl>[Cl:25][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH3:13]
Reactant: Cc1c(CO)ccc2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CCl)ccc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of 10.1 g of 2-hydroxymethyl-1-methylnaphthalene, 14.0 ml of triethylamine and 120 ml of methylene dichloride, cooled in an ice-salt bath was added dropwise 5.5 ml of methanesulfonyl chloride. The reaction mixture was allowed to warm to room temperature, washed with water, dried and concentrated in vacuo to obtain 8.4 g of 2-chloromethyl-1-methylnaphthalene as a waxy solid.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH3:8])[O:4][CH:5]([Cl:7])[CH3:6]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCOCCOCCOCCOC(=O)OC(C)Cl

Procedure:
In a manner similar to the method described in Example 3, 1-chloroethyl chloroformate (Aldrich) was reacted with octaethylene glycol monomethyl ether (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give 1-chloroethyl 2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl carbonate. This was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), 27-oxo-2,5,8,11,14,17,20,23,26,28-decaoxatriacontan-29-yl-4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C51H68Cl2F2N3O15: [(M+H)+]: 1071, found: 1070.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:29]=1.[C:31](OCC)(=[O:34])[NH:32][NH2:33]>>[CH3:1][C:2]1[C:3]([CH3:30])=[CH:4][C:5]2[N:11]([C:12](=[O:23])[CH2:13][N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)[C:10]3[N:24]=[CH:25][CH:26]=[CH:27][C:9]=3[C:8]3[N:7]([C:31](=[O:34])[NH:32][N:33]=3)[C:6]=2[CH:29]=1
Reactant: Cc1cc2c(cc1C)N(C(=O)CN1CCN(CCO)CC1)c1ncccc1C(=S)N2
Reactant: CCOC(=O)NN
Product: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN1CCN(CCO)CC1

Procedure:
In the manner given in Example 11, 8,9-dimethyl-6,11-dihydro-11-[[4-(2-hydroxyethyl)piperazino]acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 6,7-dimethyl-2,9-dihydro-9-[[4-(2-hydroxyethyl)piperazino]acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin- 3-one.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-chlorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (94% yield). 1H NMR (500 MHz, CDCl3) δ 8.05, 7.85, 7.43-7.46, 7.31-7.40, 7.00, 4.04-4.10, 3.75-3.94, 3.34-3.52, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 416 (M+1).
Reaction SMILES: [ClH:1].[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]2[O:29][C@@H:14]32)[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3].O>O1CCCC1>[C:2]([O:5][C@:6]1([C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[O:19][CH2:20]2)[C@H:15]([Cl:1])[C@H:14]3[OH:29])[CH2:11][CH2:10]1)[C:7](=[O:9])[CH3:8])(=[O:4])[CH3:3]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Reactant: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3[C@H](O)[C@@H](Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Concentrated hydrochloric acid (0.1 ml) was added to a solution of 97 mg of 17α-acetoxy-6α,7α-epoxy-2-oxa-4-pregnene-3,20-dione in 4 ml of tetrahydrofuran, and the solution was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 102 mg of 17α-acetoxy-6β-chloro-7α-hydroxy-2-oxa-4-pregnene-3,20-dione.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:4]([N+:14]([O-])=O)[CH:3]=1.O1CCCC1>O>[NH2:14][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1-n1cccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)c(Cl)cc1-n1cccc1

Procedure:
A stirred solution of 42.4 g (0.165 mole) of 1-(4,5-dichloro-2-nitrophenyl)pyrrole in 730 ml. of tetrahydrofuran and 365 ml. of water is treated according to the manipulative procedure described above in Example 13(b) to give 1-(2-amino-4,5-dichlorophenyl)pyrrole, m.p. 57°-58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:17]([NH:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:38]#[N:39])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)[C:17]([NH:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[O:18])[C:10](=[O:37])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccccc1NC(=O)C(CC1CCCCO1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COc1cn(C(CC2CCCCO2)C(=O)Nc2ccccc2C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.24 g (2.25 mmol) of methyl ({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[tetrahydro-2H-pyran-2-yl]propanoyl}amino)benzoate (mixture of racemic diastereomers) in 30 ml of methanol/water (4/1) were reacted with 1.47 g (4.51 mmol) of caesium carbonate according to General Method 4. Yield: 1.17 g (85% of theory)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH:10]([O:12][Si](C(C)(C)C)(C)C)[CH3:11])(=[O:3])[CH3:2]>C(O)(=O)C.O>[C:1]([O:4][C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH:10]([OH:12])[CH3:11])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1C(C)O[Si](C)(C)C(C)(C)C
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)O[C@@H]1NC(=O)[C@H]1C(C)O
Reaction time: 2.5 h
Yield: 24.9 %

Procedure:
Trans-4-acetoxy-3-[1-(tert-butyldimethylsilyloxy)-ethyl]-2-azetidinone (0.20 g) is dissolved in a mixture of acetic acid (5 ml) and water (2 ml), and the solution is stirred at 70°-80° C. for 2.5 hours and then concentrated under reduced pressure. The residue is subjected to silica gel column chromatography to give 0.03 g of trans-4-acetoxy-3-(1-hydroxyethyl)-2-azetidinone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:18]=[CH:17][C:16]3[O:15][CH2:14][O:13][C:12]=3[CH:11]=2)[N:5]=[C:4]([S:19][CH2:20][C:21]#[N:22])[N:3]=1.Cl.[NH2:24][OH:25].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[O:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([CH2:9][NH:8][C:6]3[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([S:19][CH2:20][C:21](=[N:24][OH:25])[NH2:22])[N:5]=3)[C:11]=2[O:15][CH2:14]1
Reactant: NO
Reactant: Cc1cc(NCc2ccc3c(c2)OCO3)nc(SCC#N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NCc2cccc3c2OCO3)nc(SCC(N)=NO)n1

Procedure:
A mixture of 6.20 g. (0.02 mole) of (4-methyl-6-piperonylamino-2-pyrimidinylthio)acetonitrile, 2.76 g. (0.04 mole) of hydroxylamine hydrochloride and 8.48 g. (0.08 mole) of sodium carbonate in 100 ml of N,N-dimethylformamide was heated on a steam bath for four hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with ether and the insoluble material was collected and recrystallized from a mixture of ethanol-N,N-dimethylacetamide to give 3.5 g. of product, m.p. 190°-192° dec.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][OH:41])[CH:35]=2)=[O:33])=[CH:26][C:25]=1[C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]2[CH2:54][CH2:53][N:52](C(OC(C)(C)C)=O)[CH2:51][CH2:50]2)[CH:43]=1>CN(C=O)C>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][O:41][CH2:40][C:36]3[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=3)[C:32]([NH:31][CH2:30][C:27]3[CH:26]=[C:25]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][N:49]5[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]5)[CH:43]=4)[C:24]([F:23])=[CH:29][CH:28]=3)=[O:33])[C:4]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CCl
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CO)c4)ccc3F)c2)CC1
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1COCc1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 5.8 %

Procedure:
To a solution of 5-(chloromethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (73.9 mg, 0.229 mmol) in DMF (0.5 mL) was added 1,1-dimethylethyl 4-({2′-fluoro-5′-[({[3-(hydroxymethyl)phenyl]carbonyl}-amino)methyl]-3-biphenylyl}methyl)-1-piperazinecarboxylate (122 mg, 0.229 mmol). The mixture was stirred at room temperature for 15 h then more 5-(chloro-methyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (73.9 mg, 0.229 mmol) was added. The mixture was stirred for another 24 h. The reaction was quenched with H2O (1 drop), diluted with MeOH (0.5 mL), purified using a Gilson HPLC (with TFA). To the Fractions containing the product was added TFA (1 drop in each tube ˜12 mL) and solvent was concentrated on a GeneVav EZ-2 evaporator. The compound was purified again with a Gilson HPLC (with TFA) and concentrated on GeneVav EZ-2 evaporator. Residue was basified with an amine cartridge to afford 0.0095 g (6%) of the title compound. LC-MS m/z 720 (M+H)+; 1H-NMR (400 MHz, CD3OD) δ ppm 1.29 (t, J=7.65 Hz, 3 H) 1.50 (t, J=7.28 Hz, 3 H) 1.62-1.75 (m, 2 H) 1.97-2.06 (m, 2 H) 2.96 (q, J=7.53 Hz, 2 H) 3.38-3.47 (m, 4 H) 3.47-3.54 (m, J=4.52 Hz, 4 H) 3.56-3.64 (m, 2 H) 3.85-3.93 (m, 2 H) 4.25-4.33 (m, 1 H) 4.36 (s, 2 H) 4.47 (q, J=7.28 Hz, 2 H) 4.60 (s, 2 H) 4.70 (s, 2 H) 4.83 (s, 2 H) 7.19 (dd, J=10.67, 8.41 Hz, 1H) 7.37-7.43 (m, 1 H) 7.46-7.59 (m, 5 H) 7.65 (d, J=6.78 Hz, 1 H) 7.72 (s, 1 H) 7.81 (d, J=7.78 Hz, 1 H) 7.89 (s, 1 H) 8.27 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([CH:13]=1)[C:7](N(OC)C)=[O:8].[CH3:15][Mg]Br.C(OCC)C.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:7](=[O:8])[CH3:15])[CH:13]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc(Br)ccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 6.5 h
Yield: 97 %

Procedure:
To a stirred solution of compound 14 (106 g, 404 mmol) in anhydrous THF (1.7 L) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 270 mL, 808 mmol) at 0° C. under nitrogen. After addition was completed, the reaction mixture was stirred at 0° C. for 6.5 h. After this time, the solution was poured to a cold 2 N hydrochloric acid (1 L) and warmed to room temperature. The resulting mixture was extracted with ethyl acetate (2×1 L). The combined extracts were washed with saturated aqueous NaHCO3 (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 15 (85.2 g, 97%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.98 (dd, J=6.4, 2.6 Hz, 1H), 7.61 (ddd, J=8.7, 4.3, 2.6 Hz, 1H), 7.05 (dd, J=10.4, 8.7, 1H), 2.64 (d, J=4.9, 3H); ESI MS m/z 217 [M+H]+.