Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][CH:8]3[C:10](=[O:11])[CH:4]([CH2:5]2)[CH2:3][CH:2]1[CH2:9]3.[CH3:12][Li].[NH4+].[Cl-]>CCOCC>[CH3:12][C:10]1([OH:11])[CH:4]2[CH2:5][CH:6]3[CH2:1][CH:2]([CH2:3]2)[CH2:9][CH:8]1[CH2:7]3
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(O)C2CC3CC(C2)CC1C3
Temperature: 0 °C
Yield: 95 %

Procedure:
To a solution of 2-adamantone (1.50 g, 10 mmol) in ether was added CH3Li (7.5 ml, 1.6M in ether, 12 mmol) dropwise at 0° C. under a N2 atmosphere. The mixture was stirred for another hr at 0° C., then brought to ambient temperature and stirred overnight. Saturated NH4Cl solution was added and extracted with ether for three times. The combined ether was dried over MgSO4 and concentrated in vacuo. The crude residue was separated by flash column chromatography (CH2Cl2 to 5% CH3OH/CH2Cl2) to give 56 as white solid (1.58 g, 95%). 1H-NMR (360 MHz, CDCl3) δ 2.20-2.16 (m, 2H), 1.89-1.75 (m, 6H), 1.68 (br s, 4H), 1.57-1.54 (m, 2H), 1.48 (br s, 1H), 1.35 (s, 3H); 13C-NMR (90 MHz, CDCl3) δ 74.06, 39.30, 38.49, 35.33, 33.16, 27.73, 27.60, 27.22; ESI-MS: Calculated for C11H18O (M+H)+ 167.3. Found: 167.3.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:19]1[CH2:20][O:21][C:22](=[O:26])[C:23]=1[CH:24]=C.I([O-])(=O)(=O)=[O:28].[Na+]>CC(C)=O.O>[CH:24]([C:23]1[C:22](=[O:26])[O:21][CH2:20][C:19]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[C:2]1=[O:1])=[O:28]
Reactant: C=CC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(C=O)C(=O)OC1)C2=O
Reaction time: 0.08 h

Procedure:
tert-butyl 1-oxo-2-(5-oxo-4-vinyl-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (1.6 g, 4.4 mmol) was dissolved in acetone (36 mL) and water (36 mL), then K2OsO4.2H2O was added and the mixture was stirred for ˜5 min. Solid sodium periodate (3.77 g, 17.6 mmol) was added in 4 portions during 1 hour and the reaction temperature was maintained below 40° C. using an ice-bath. The resulting mixture was stirred for 1 hour at room temperature. LCMS after 2 hours showed complete consumption of starting material. The suspension was filtered and the filtrate was concentrated to remove acetone. The aqueous layer was extracted with DCM (3×). Combined organic layers were washed with 10% Na2S2O3 solution (2×), dried over anhydrous Na2SO4, filtered, concentrated to obtain the title compound, which was taken to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[OH:21][CH:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]1=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:23]3[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][CH:22]3[OH:21])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC1(C)CC(=O)C(O)C1
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CC(C)(C)CC3O)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-2-hydroxy-4,4-dimethyl-cyclopentanone using decaborane yielded a mixture of epimers of the title compound as white solid. MS (ESI): m/z=391.4 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1.O>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Potassium tert-butoxide (2.03 g, 21.1 mmol) in tetrahydrofuran (20 mL) was mixed with diethyl cyanomethylphosphonate (3.54 g, 20.0 mmol) in tetrahydrofuran (20 mL) under cooling with ice and stirred for 30 minutes. The reaction mixture was mixed with tert-butyl 3-oxoazetidine-1-carboxylate (2.96 g, 17.3 mmol) obtained in Reference Synthetic Examplea 112 in-tetrahydrofuran (20 mL) under cooling with ice and then stirred at room temperature for 1 day. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 (v/v)) to give the title compound as a colorless solid (1.93 g, yield 58%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2)=[O:2]>C1COCC1>[OH:2][CH2:1][C:3]1[C:4]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccc2nc(NCCNC(C)=O)c(C=O)cc2c1
Solvent: C1CCOC1
Product: COc1ccc2nc(NCCNC(C)=O)c(CO)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of N-(2-((3-formyl-6-methoxyquinolin-2-yl)amino)ethyl)acetamide SLA 41086 (147 mg, 512 μmol) in THF (20 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added sodium borohydride NaBH4 (19 mg, 502 μmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (40 mL). After stirring for 15 min at that temperature, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (100 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to give N-(2-((3-(hydroxymethyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide SLA 41088 as an orange solid (113 mg, 76% yield).
Reaction SMILES: C([CH:9]([C:19]([OH:21])=[O:20])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])(=O)C1C=CC=CC=1.Cl.C(=O)(O)[O-].[Na+].[C:28](Cl)([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29]>O1CCOCC1.O>[C:28]([CH:9]([C:19]([OH:21])=[O:20])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29]
Reactant: CCCCN(CCCC)C(C(=O)O)C(=O)c1ccccc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCN(CCCC)C(C(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 mmol of compound (80) is dissolved in 30 mL of dioxane, and 10 mL of 6N hydrochloric acid solution is added, and the solution is refluxed overnight. The reaction is cooled to room temperature, concentrated to dryness, redissolved in 30 mL of tetrahydrofuran, and 10 mL of water and 30 mmol of sodium bicarbonate is added, followed by 15 mmol of Fmoc-Cl. The biphasic solution is stirred for 1 hour, and the tetrahydrofuran removed under vacuum. The aqueous solution is extracted with 1×50 mL of diethyl ether, acidified with 1N hydrochloric acid solution, and extracted with 2×50 mL of ethyl acetate. The ethyl acetate layers are combined, dry over sodium sulfate, and concentrated. Compound (81) is purified by silica gel column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CC(C)=O>[C:25]([O:24][C:22]([CH2:21][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CCl
Reactant: O=C(O)CCc1ccc(O)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COC(=O)CCc1ccc(O)cc1

Procedure:
To a mixture of 3-(4-hydroxy phenyl) propionic acid (20 grams, 120.35 mmol) and triethyl amine (30 grams, 296.47 mmol) in acetone (150 mL) is added t-butyl chloroacetate (19.6 grams, 130 mmol) drop wise, later it is stirred under reflux for 10 hours. The resulting solids are filtered off, acetone is distilled off, and water (100 mL) is added. The crude 4 is extracted into chloroform, and is washed with 5% sodium bicarbonate (2×25 mL), water (2×25 mL), and the product is dried over sodium sulphate, and is distilled to give crude 4 which can be purified from an appropriate solvent.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[H-].[Na+]>CN(C=O)C>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][C:3]1=[O:12]
Reactant: BrCCCCCBr
Reactant: O=C1COc2ccccc2CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1COc2ccccc2CN1CCCCCBr
Reaction time: 1.5 h
Yield: 69.5 %

Procedure:
In 20 ml of DMF was dissolved 100 mg of 2,3,4,5-tetrahydro-1,4-benzoxazepin-3-one and the solution then ice-cooled. Then, to the resulting solution were added 0.125 ml (1.5 equivalent) of 1,5-dibromopentane and 29.4 mg (1.2 equivalent) of a 60% sodium hydride oil dispersion and the mixture was stirred for 1.5 hour with ice-cooling. Thereafter, the reaction solution was reacted and/or treated and purified in the same manner as in Reference Example 1 to give 133 mg (yield: 69.5%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:55])[C:36]1[CH:41]=[CH:40][C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][N:37]=1>>[CH3:34][N:35]([CH3:55])[C:36]1[N:37]=[CH:38][C:39]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:14][CH:15]=4)[CH2:10][CH2:9][N:8]3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:32][CH:33]=2)=[CH:40][CH:41]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N(C)C)nc1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Product: CN(C)c1ccc(-c2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)cn1
Yield: 90 %

Procedure:
The title compound was prepared as described in Example 135, using 1-(4-bromobenzyl)-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.60 g, 0.12 mmol) and 2-(dimethylamino)-5-(tributylstannyl)pyridine to provide the title compound (0.581 g, 90% yield): 1H NMR (CDCl3) 8.42 (dd, 1H), 7.68 (dd, 1H), 7.32-7.45 (m, 7H), 7.06 (d, 2H), 6.91 (m, 2H), 6.72-6.80 (m, 5H), 6.58 (d, 1H), 5.04 (s, 2H), 4.77 (t, 1H), 3.62 (m 1H), 3.48 (m, 1H), 3.19 (dd, 1H), 3.13 (s, 6H), 2.96 (m, 2H), 2.72 (dt, 1H); ES-MS m/z 544 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1.Br[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=1[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.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>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=2[CH3:38])=[CH:10][CH:11]=1
Reactant: Cc1nccc(Br)c1C
Reactant: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(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: Cc1ccccc1
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
Suzuki Coupling. To a mixture of (S)-2-tert-butoxycarbonylamino-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (8.22 g) in 140 mL toluene and 40 mL water was added 4-bromo-2,3-dimethyl-pyridine (6.77 g), Na2CO3 (7.5 g), and Pd(PPh3)4. The mixture was purged with nitrogen and stirred under nitrogen at 80° C. for 18 h. The mixture was then cooled to rt and poured into water-EtOAc. The organic layer was washed with water and saturated brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-butoxycarbonylamino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (4.5 g). LCMS (m/z) 386.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:13][C:12](S(C)(=O)=O)=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:33][N:34]([CH2:36][CH2:37][NH2:38])[CH3:35].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:13][C:12]([NH:38][CH2:37][CH2:36][N:34]([CH3:35])[CH3:33])=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Reactant: CN(C)CCN
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCNc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Yield: 40.7 %

Procedure:
The solution of 7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine from Example 25 (50 mg, 0.1 mmol) and unsym-dimethylethylenediamine (100 mg, 1.1 mmol) in DMSO was irradiated by microwave at 150° C. for 10 min. The reaction mixture was poured into water and extracted by ethyl acetate. Solids between two phases were filtered out and this solid was dissolved in methanol and undissolved solid was filtered out. Filterate was concentrated to yield the product as beige powder (20 mg, 41%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1>[O-][V](=O)=O.[Ag+]>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: O=[V](=O)[O-]
Agent: [Ag+]
Product: CC1(C)COC(=O)C1=O

Procedure:
Silver vanadate on ceramic is used as the catalyst in the reactor described in Example 1 and the temperature of the air bath is adjusted to 250° C. 60 l of air and 27 g of pantolactone are subsequently added hourly to the evaporator. 98.4% of the pantolactone are transformed and ketopantolactone is formed with a selectivity of 84.4%.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[CH2:14][CH:15]=[C:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:28])[CH2:17]4)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[CH2:14][CH2:15][C:16]4[C@:21]([C:23]=3[CH2:24][CH2:25]2)([CH3:22])[CH2:20][CH2:19][C:18](=[O:28])[CH:17]=4)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)CC1=CC3
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CCC(=O)C=C1CC3
Yield: 69.9 %

Procedure:
A solution of 2.20 g cholesta-5,8-dien-3β-ol in 27 ml toluene and 6 ml cyclohexanone is refluxed for 10 minutes in a Dean-Stark apparatus. 0.57 g aluminum isopropoxide are added and the reaction mixture is refluxed for 30 minutes. After cooling and addition of sulfuric acid (2 N), the resulting mixture is extracted with ethyl acetate. The organic layer is separated, washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulphate and filtered. After evaporation of the solvent the residue is chromatographed with a mixture of hexane and ethyl acetate to give 1.53 g cholesta-4,8-dien-3-one as a white solid.
Reaction SMILES: [C:1](OC1C2C(=CC=C(C)C=2)N(CC)C1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:28](=[O:37])[C:27]2=[O:38]>>[C:1]([O:38][CH:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=2)[N:29]([CH2:33][CH:34]([CH3:35])[CH3:36])[C:28]1=[O:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CC(C)CN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-chloro-1-isobutylindoline-2,3-dione. 1H NMR δ 8.11 (d, 2H), 7.60 (dd, 1H), 7.52-7.32 (m, 4H), 6.80 (d, 1H), 6.10 (s, 1H), 3.75 (m, 2H), 1.72-1.57 (m, 1H), 1.01 (dd, 6H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][C:13](O)([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1)[CH3:3].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:3][N:2]([CH2:4][CH:5]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6]1)[CH3:1]
Reactant: CN(C)CC1CC(O)(c2ccc(Cl)cc2)c2ccccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CN(C)CC1C=C(c2ccc(Cl)cc2)c2ccccc2O1
Yield: 84.8 %

Procedure:
A solution of 2-(N,N-dimethylaminomethyl)-4-hydroxy-4 (4'-chlorophenyl)-chroman (1.35 g) and tosic acid (10 mg) in benzene (75 ml) was heated under reflux with azeotropic removal of water for 31/2 hours. The solvent was removed under reduced pressure, the residue taken up in diethyl ether and washed with 2 N sodium hydroxide (20 ml). The organic phase was dried (MgSO4) and evaporated to give the title compound (1.08 g) as an oil.
Reaction SMILES: [NH2:1][CH:2]([P:7]([O:11][CH3:12])([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:13]([NH:1][CH:2]([P:7]([O:11][CH3:12])([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(N)P(=O)(OC)OC
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccccc1)P(=O)(OC)OC
Reaction time: 4 h
Yield: 46.4 %

Procedure:
A stirred solution of methyl amino(dimethoxyphosphoryl)acetate (6 g) in dichloromethane (50 mL) is treated with benzoyl chloride (5 g) and the mixture allowed to stand at room temperature for 4 hours. The reaction mixture is washed twice with saturated aqueous sodium bicarbonate solution (75 mL), brine (50 mL), dried over magnesium sulphate and evaporated. The residual pale yellow oil is dissolved in ether (5 mL) and pentane added to give methyl benzoylamino(dimethoxyphosphoryl)acetate (4.25 g) as a white solid.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH:9]([NH:24][C:25]([CH:27]1[N:31]2[C:32](=[O:51])[CH:33]([NH:38][C:39]([C:41]3[CH:50]=[CH:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=3)=[O:40])[CH2:34][CH:35]=[CH:36][CH2:37][CH:30]2[CH2:29][CH2:28]1)=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][CH:9]([NH:24][C:25]([CH:27]1[N:31]2[C:32](=[O:51])[CH:33]([NH:38][C:39]([C:41]3[CH:50]=[CH:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=3)=[O:40])[CH2:34][CH:35]=[CH:36][CH2:37][CH:30]2[CH2:29][CH2:28]1)=[O:26])[C:10](=[O:23])[CH2:11][O:12][C:13](=[O:22])[C:14]1[C:15]([CH3:21])=[CH:16][CH:17]=[CH:18][C:19]=1[CH3:20])([OH:7])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)OC(C)(C)C)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1C(=O)OCC(=O)C(CC(=O)O)NC(=O)C1CCC2CC=CCC(NC(=O)c3ccc4ccccc4c3)C(=O)N21
Reaction time: 2 h

Procedure:
To a solution of 2,6-dimethyl-benzoic acid 4-tert-butoxycarbonyl-3-({6-[(naphthalene-2-carbonyl)-amino]-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carbonyl}-amino)-2-oxo-butyl ester, 112, (188 mg 0.27 mmol) is treated with solution of trifluoroacetic acid (10 ml) and dichloromethane (10 ml). The mixture is stirred for 2 hours and solvent is removed in vacuo. The residue is purified over silica (dichloromethane/methanol 95:5) to afford 120 mg of the desired product as a white solid. 1H NMR (CDCl3): δ 8.32 (d, J=5.9 Hz, 1H), 7.84 (m, 4H), 7.71 (m, 1H), 7.51 (m, 2H), 7.23 (dd, J-16.1, 8.1 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 5.87 (m, 2H), 5.65 (m, 2H), 5.13–4.80 (m, 3H), 4.51 (m, 1H), 4.24 (m, 1H), 3.02–2.86 (m, 4H), 2.37 (s, 6H), 2.43–1.83 (m, 5H). 13C NMR (CDCl3): δ 200.4, 200.1, 174.2, 172.9, 171.6, 171.4, 169.3, 167.6, 135.9, 135.1, 132.7, 131.2, 130.8, 129.9, 129.3, 128.7, 128.4, 128.3, 127.9, 127.0, 126.1, 125.7, 123.9, 66.9, 62.3, 61.7, 59.4, 59.1, 53.2, 52.9, 50.8, 35.3, 34.4, 34.2, 33.3, 32.2, 27.4, 26.9, 20.1. (excess carbons due to rotamers). ESI MS 639.69 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.[P:18]([O-])([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19].CCN(CC)CC>C1(C)C=CC=CC=1.[NH4+].[Cl-].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>[NH2:9][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:18](=[O:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:3][CH:4]=1
Reactant: CCOP(=O)([O-])OCC
Reactant: COc1ccc(C(N)c2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(C(N)c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a mixture of (4-bromophenyl)(4-methoxyphenyl)methanamine, 1-1-c, (2 g, 6.8 mmol), diethyl phosphate (1.1 g, 8.2 mmol) and Et3N (1.3 g, 10.2 mmol) in toluene (25 ml) was added Pd(PPh3)4 (1.5 g, 20%). The mixture was allowed to stir for two days at 100° C. The mixture was then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated, and purified over silica gel (5% MeOH/DCM) to obtain as an oil, 1-1-d, (1.00 g). 1HNMR (300 MHZ, DMSO-d): 1.29 (m, 6H), 3.77 (s, 3H), 4.10 (m, 4H), 5.19 (s, 1H), 6.82 (d, 2H), 7.26 (d, 2H), 7.48 (d, 2H), 7.74 (d, 2H).
Reaction SMILES: Br[C:2]1[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[N:3]=1.[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][S:13][C:4]1[N:3]=[C:2]([NH:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26])[C:11]2[N:10]=[CH:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=1
Reactant: NC(CO)CO
Reactant: O=c1cnc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Product: O=c1cnc2c(NC(CO)CO)nc(SCc3cccc(F)c3F)nc2[nH]1
Yield: 69.4 %

Procedure:
The titled compound (57 mg) was prepared from the product of step (b) (80 mg) and 2-amino-1,3-propanediol (29 mg) using the method of Example 2 step (f).