Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.[CH3:14][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23](O)=[O:24])=[O:19])[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:16][C:15]([CH3:35])([O:17][C:18]([NH:20][C@H:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=1)[CH2:22][C:23]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:24])=[O:19])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(F)c(F)c1
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (64.3 mg, 0.34 mmol, from Step B) and (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (105.9 mg, 0.34 mmol) in dichloromethane (5 mL) was added HOBT (54.5 mg, 0.42 mmol) at 0° C. The reaction was stirred at 0° C. for 10 min, then EDC (96.6 mg, 0.50 mmol) was added. After removal of the ice-bath, the reaction was allowed to stir at ambient temperature for 14 h. The mixture was concentrated and purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.1% trifluoroacetic acid) to give 115 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CDCl3) δ 1.36 (s, 9H), 2.62 (m, 2H), 2.86 (m, 2H) 3.34 (bs, 1H), 3.86 (m, 1H), 4.05 (m, 4H). 4.85 (m, 1H) 5.30-5.38 (m, 1H) 6.97 (m, 3H), 7.28 (m, 1H). LC/MS 489 (M+1).
Reaction SMILES: [OH:1][C:2]1([CH3:26])[CH:8](Br)[CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:26])[CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccccc2OCc2ccccc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(CCc2ccccc2OCc2ccccc2)C1
Yield: 75.6 %

Procedure:
The product obtained by reducing 0.489 g of 3-hydroxy-3-methyl-4-bromo-7-(o-benzyloxyphenyl)-5-heptanolide with 1.34 g of tri-n-butyltin hydride in 4 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was purified by a thin layer chromatography affording 0.300 g of the desired compound as an oily substance.
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([C:8](=O)[CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)[CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1)[CH2:6]2
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(C(=O)CCc3ccsc3)CC21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccsc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
To a solution of N-(3-{6-methyl-3-[3-(3-thienyl)propanoyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 126, 200 mg, 0.49 mmol) in anhydrous tetrahydrofuran (7.5 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.99 ml, 0.99 mmol) and the mixture was stirred at room temperature for 2 h. The rapidly stirred reaction mixture was treated sequentially with water (1 ml), sodium hydrogen carbonate (1.0 g) and ethyl acetate (25 ml). After 15 min the reaction mixture was filtered and concentrated in vacuo to afford a light yellow oil. This was purified by chromatography using a Biotage Flash 12™ cartridge packed with silica gel (8 g) eluting with hexane:ethyl acetate (100:0 to 0:100) to afford the title compound as a colourless oil (108 mg, 56%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]1>>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:18][CH2:19][O:20][CH:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[NH:24][C:25]([CH3:27])([CH3:28])[CH2:26]2)=[CH:7][CH:6]=1
Reactant: Oc1ccc(-c2nc3ccccc3s2)cc1
Reactant: CC1(C)CC(OCCBr)CC(C)(C)N1
Product: CC1(C)CC(OCCOc2ccc(-c3nc4ccccc4s3)cc2)CC(C)(C)N1

Procedure:
A hot solution of 16 g. of zinc, o-aminophenylmercaptide and 12.5 g. of p-hydroxybenzaldehyde in 1 l. of acetic acid was treated with hydrogen sulfide for two hours, filtered hot, diluted with an equal volume of water and cooled. 2-(p-Hydroxyphenyl)benzothiazole (47% yield, m.p. 227°-229° F.) was obtained. The 2-(p-hydroxyphenyl)benzothiazole was reacted with 4-(2-bromoethoxy)-2,2,6,6-tetramethylpiperidine as in Example 1 to produce 4-{2-[4-(2-benzothiazolyl)phenoxy]ethoxy}-2,2,6,6-tetramethylpiperidine.
Reaction SMILES: [Cl-].[Li+].C(OP([CH:11]([CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[CH2:48]([O:55][C:56]([N:58]1[C@@H:62]([CH2:63][CH:64]([CH3:66])[CH3:65])[C@H:61]([CH:67]=O)[O:60][C:59]1([CH3:70])[CH3:69])=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl>O1CCCC1>[CH2:48]([O:55][C:56]([N:58]1[C@@H:62]([CH2:63][CH:64]([CH3:65])[CH3:66])[C@H:61]([CH:67]=[C:11]([CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:60][C:59]1([CH3:69])[CH3:70])=[O:57])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)C(CCOC1CCCCO1)P(=O)(OCC)OCC
Reactant: CC(C)C[C@H]1[C@H](C=O)OC(C)(C)N1C(=O)OCc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)CCOC1CCCCO1
Yield: 67.1 %

Procedure:
79.6 mg of lithium chloride was suspended in 5 ml of dry tetrahydrofuran under an argon atmosphere. Then, a solution prepared by dissolving 670 mg of ethyl 2-diethylphosphono-4-(2-tetrahydropyranyloxy)butanoate in 0.6 ml of dry tetrahydrofuran, was added thereto under stirring. The mixture was stirred for 5 minutes at room temperature, and then 1.75 ml of a 20% dry tetrahydrofuran solution of diazabicycloundecene was added thereto. The mixture was stirred for 10 minutes at room temperature. Then, a solution prepared by dissolving 506 mg of (4S,5R)-3-benzyloxycarbonyl-2,2-dimethyl-5-formyl-4-isobutyloxazolidine in 1.0 ml of dry tetrahydrofuran, was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0° C. and neutralized with 1N hydrochloric acid. Then, the mixture was extracted three times with ethyl acetate, and the ethyl acetate layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (20 g of Kieselgel 60) by using a mixture of hexane/ethyl acetate (10/1) to obtain 550 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-[2-(2-tetrahydropyranyloxy)ethyl]- 2-propenoate (E/Z (50/50)) as a colorless oily substance.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([F:15])[CH:9]=2)[C:3]1=[O:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C@@H:25]2[CH2:30][CH2:29][NH:28][CH2:27][C@H:26]2[OH:31])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C.[Cl-].[NH4+]>[F:15][C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][C:11]=1[CH3:14])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([N:28]2[CH2:29][CH2:30][C@@H:25]([C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[C@H:26]([OH:31])[CH2:27]2)[C:3]1=[O:16]
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1F
Reactant: COc1ccc([C@@H]2CCNC[C@H]2O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc([C@@H]2CCN(C3CCN(Cc4ccc(C)c(F)c4)C3=O)C[C@H]2O)cc1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
To a solution of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (Intermediate 6, 200 mg, 0.7 mmol) and (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (145 mg, 0.7 mmol, from Example 46, step B) in acetonitrile (15 mL) was added triethylamine (0.1 mL, 0.7 mmol) and the resulting mixture was heated in the microwave at 100° C. for 1 h. The cooled reaction mixture was diluted with a saturated ammonium chloride solution and extracted with ethyl acetate (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure to give (±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (280 mg, 0.51 mmol, 73% yield, mixture of 4 diaseteroisomers), which was used directly in the next step. LCMS (Method F) RT 1.99 min m/z 413.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[N:7]2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=1)=[C:5]([CH3:26])[C:6]([N:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Temperature: 0 °C

Procedure:
The tert-butyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)-quinolin-2-yl)piperazine-1-carboxylate (32 mg, 0.059 mmol) was dissolved in DCM (1.0 mL) and cooled to 0° C. The trifluoroacetic acid (1.00 mL, 13.0 mmol) was then added and the reaction mixture was allowed to slowly warm to rt over a period of 1 h. The reaction was then cond to dryness. The crude TFA salt was treated with satd sodium bicarbonate solution. The organic layer was dried over sodium sulfate and the filtrate was cond to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.85 (1H, d, J=2.5 Hz), 7.63 (1H, d, J=2.2 Hz), 7.23 (1H, ddd, J=10.2, 2.5, 1.4 Hz), 6.79 (1H, d, J=12.9 Hz), 6.71 (1H, ddd, J=13.9, 8.8, 2.5 Hz), 6.49 (1H, t, J=2.3 Hz), 3.70-3.83 (4H, m), 3.19-3.32 (4H, m), 3.03-3.12 (4H, m), 2.92-3.03 (4H, m), 2.00 (3H, s). Mass Spectrum (ESI) m/e=441.2 (M+1).
Reaction SMILES: [C:1]([C:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11](OC)[O:12]C)[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([C:4]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])([CH2:16][C:17]#[C:18][CH2:19][CH3:20])[CH:5]([CH:11]=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(CC(=O)OC)C(OC)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Product: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(C=O)CC(=O)OC
Temperature: 28 °C
Reaction time: 12 h

Procedure:
Methyl 4-acetyl-4-tert-butoxycarbonyl-3-dimethoxymethyl-6-nonynoate (546 mg) is dissolved in 30 ml of tetrahydrofuran, and 25 ml of 1.5% aqueous solution of perchloric acid is added to the solution. The mixture is stirred at 28° C. for 12 hours. Subsequently the reaction mixture is neutralized with sodium bicarbonate and concentrated in a vacuum. The residue is extracted with ethyl acetate. The extract is dried and then concentrated to give methyl 4-acetyl-4-tert-butoxycarbonyl-3-formyl-6-nonynoate (compound (9), R1 =t-Bu, R2 =CH3) in a yield of 98.0%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C([Li])CCC.Br[C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[C:19]([F:26])[CH:18]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:19]1[CH:18]=[C:17]([C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=3[N:7]=2)[CH:25]=[CH:24][C:20]=1[CH2:21][C:22]#[N:23]
Reactant: Cc1ccc2ocnc2c1
Reactant: N#CCc1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2oc(-c3ccc(CC#N)c(F)c3)nc2c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-methylbenzoxazole (173 mg, 1.3 mmol) in THP (5 mL) at −78° C. was added n-Butyllithium (640 μL, 2.5M in hexanes, 1.6 mmol). The reaction mixture was stirred for 15 min at −78° C. followed by the addition of ZnCl2 (3.9 mL, 1M in Et2O, 3.9 mmol) via a syringe. The reaction mixture was warmed at 0° C. for 1 h and a solution of 4-bromo-2-fluoro benzyl cyanide (214 mg, 1.0 mmol) in THF (2 mL) was added, along with Pd0 (a fresh suspension prepared as follows: 200 μL n-Butyllithium, 2.5M in hexanes added to 144 mg PdCl2(PPh3)2 in 5 mL of THF). The mixture was refluxed overnight and quenched with sat. NaHCO3 (50 mL). After extraction with EtOAc (3×75 mL), the organic layers were combined, washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexanes:EtOAc (5:1) to afford the desired [2-fluoro-4-(5-methyl-1,3-benzoxazol-2-yl)phenyl]acetonitrile as yellow solid. 1H NMR (CD3OD, 300 MHz), δ 8.07 (d, 1H), 7.95 (d, 1H), 7.64 (m, 2H), 7.40 (s, 1H), 7.20 (d, 1H), 3.90 (s, 1H). MS (ESI) 267 (M+H)+.
Reaction SMILES: ClC(Cl)C.[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S:17][CH2:18][CH2:19][CH2:20][OH:21].[O-:22]O.C1(C(C)C)C=CC=CC=1>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[S@:17]([CH2:18][CH2:19][CH2:20][OH:21])=[O:22]
Reactant: [O-]O
Reactant: Cc1ccccc1-n1ccnc1SCCCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CC(C)c1ccccc1
Solvent: CC(Cl)Cl
Product: Cc1ccccc1-n1ccnc1[S@@](=O)CCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 38.2 %

Procedure:
To 3 l of dichloroethane were added 123 g of 3-[1-(2-methylphenyl)-2-imidazolylthio]propanol, 414 g of L-(+)-diethyl tartarate and 120 g of a powder of Molecular Sieve 4A. The mixture was stirred at room temperature for 2 days. Thereto was added 142 g of titanium tetraisopropoxide. The mixture was stirred at room temperature for 30 minutes. Thereto was added 91 g of cumene hydroperoxide. The mixture was stirred at 5° C. for 24 hours. The reaction mixture per se was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=50/1). Recrystallization from methyl ethyl ketone was repeated to obtain 50 g of (S)-(+)-3-[1-(2-methylphenyl)2-imidazolylsulfinyl]propanol.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].S(Cl)(Cl)=O.[CH3:15][CH:16](O)[CH3:17]>>[NH2:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH:16]([CH3:17])[CH3:15])=[O:9]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)c1ccccc1N

Procedure:
1.0 g (7.3 mmol) anthranilic acid are dissolved in 5 ml propan-2-ol, combined with 795 μl (10.9 mmol) thionyl chloride and refluxed for 3 days. Then thionyl chloride is eliminated in vacuo, the residue is taken up in 50 ml dist. water and extracted three times with 30 ml of ethyl acetate. The organic phase is washed with 20 ml of a saturated aqueous NaHCO3 solution, dried with MgSO4 and the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH2:30][OH:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[N:20]=[C:19]([C:21]3[O:29][C:28]4[CH:27]=[CH:26][N:25]=[C:24]([CH:30]=[O:31])[C:23]=4[CH:22]=3)[O:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(CO)nccc4o3)n2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(OCc2noc(-c3cc4c(C=O)nccc4o3)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of 4-[5-(4-hydroxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 24, 25 mg, 58 μmol) in CH2Cl2 was added Dess-Martin periodinane (32 mg, 75 μmol). After 3 h at 20° C., the mixture was diluted with MeOH, adsorbed onto SiO2 and purified by column chromatography to furnish the title compound: RT=3.27 min; m/z (ES+)=429.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[CH:4]=1.[C-:19]#[N:20].[Na+]>CN(C=O)C.CCOCC.O>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:7]1[C:3]([CH2:2][C:19]#[N:20])=[CH:4][C:5]([C:15]([F:18])([F:17])[F:16])=[N:6]1
Reactant: FC(F)(F)c1cc(CBr)n(-c2ccccc2Cl)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: N#CCc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Into a 250 mL flask was weighed 11.3 g of 5-(bromomethyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole (33 mmol) which was then dissolved in 40 mL of dry DMF. The resulting solution was treated with 2.5 g of sodium cyanide (52 mmol). The resulting suspension was heated to 50° C. After 4 hours at 50° C., heating was discontinued and the reaction was allowed to cool to room temperature. After standing at room temperature for 2 days the reaction was diluted with ether and H2O. The layers were separated and the aqueous layer was extracted with ether (4×). The combined organic layers were washed with H2O (3×), then brine (2×), dried (Na2SO4), filtered and concentrated in vacuo to afford crude 2-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)acetonitrile as a red oil, yield 8.2 g (86%), 1H NMR (400 MHz, CDCl3): δ 7.62-7.46 (m, 4H), 6.82 (s, 1H), 3.9-3.4 (broad hump, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH2:5][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:7]2.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>C1COCC1.N1C=CC=CC=1>[CH2:27]([NH:29][C:30](=[O:31])[O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:6]1[CH2:7][C:8]2[C:4](=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])[CH2:5]1)[CH3:28]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)C2
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCNC(=O)OCCCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxyindan-2-yl)octanol (1.20 g) and ethyl isocyanate (0.517 ml) in THF (12 ml) was added one drop of pyridine. After being stirred for 12 hr at 40° C., the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the entitled compound (1.42 g) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9]1.[Li]CCCC.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cccnc1
Reactant: O=C1CCCC1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: OC1(c2ccncc2Br)CCCC1
Yield: 33.8 %

Procedure:
Using analogous reaction condition and reagents as described in Example 20 for the preparation of I-20a above, 3-bromo pyridine solution (1.0 g, 6.36 mmol) was reacted with cyclopentanone solution (0.6 mL, 7.0 mmol) in dry THF (6 mL), n-BuLi solution (4.0 mL, 7.6 mmol) and diisopropylethyl amine (1.0 mL, 7.0 mmol) in dry THF (6 mL) to afford the crude product. The crude was purified by column chromatography on silica gel (20% ethyl acetate in hexane) afforded 520 mg of the product (34% yield).
Reaction SMILES: [P:1]([O:19][C:20]1[CH:32]=[CH:31][C:30]2[NH:29][C:28]3[CH:27]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:25]4[C:39](=[O:43])[NH:40][C:41](=[O:42])[C:24]=4[C:23]=3[C:22]=2[CH:21]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2]>CO.O1CCCC1.[Pd]>[P:1]([OH:3])([OH:11])([O:19][C:20]1[CH:32]=[CH:31][C:30]2[NH:29][C:28]3[CH:27]=[C:26]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:25]4[C:39](=[O:43])[NH:40][C:41](=[O:42])[C:24]=4[C:23]=3[C:22]=2[CH:21]=1)=[O:2]
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1[nH]c3ccc(OP(=O)(OCc4ccccc4)OCc4ccccc4)cc3c21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1[nH]c3ccc(OP(=O)(O)O)cc3c21
Reaction time: 3 h
Yield: 70.6 %

Procedure:
A solution of the dibenzyl phosphate (336) (100 mg, 0.17 mmol) prepared as described in example 447 in methanol/tetrahydrofuran (3:1, 70 mL) was hydrogenated at 60 psi over Pd-C (5%, catalytic) with stirring for 3 hours. The reaction mixture was then filtered through celite and concentrated in vacuo. Trituration from ethyl acetate/hexane gave the phosphate (337) (49 mg, 71%) as a yellow solid, mp 285–295° C. 1H NMR δ [(CD3)2SO] 12.01 (br s, 1H), 11.09 (br s, 1H), 8.66 (br s, 1H), 7.63 (m, 3H), 7.57 (br d, J=8.6 Hz, 1H), 7.50–7.44 (m, 4H). Found: C, 55.19; H, 3.29; N, 6.34; P, 6.84. C20H13N2O6P.1/2H2O requires: C, 55.18; H, 3.71; N, 6.43; P, 7.12.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1.[CH2:30]1[CH2:43][O:42][C:37]23[O:38][CH2:39][CH2:40][O:41][C:32]2([C@:33]2([CH2:56][CH2:55][C@H:54]4[C@@H:44]([CH2:45][C:46](=[CH2:57])[CH:47]5[C@:52]4([CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]5)[C@@H:35]2[CH2:36]3)[CH3:34])[O:31]1>>[CH2:40]1[CH2:39][O:38][C:37]23[O:42][CH2:43][CH2:30][O:31][C:32]2([C@:33]2([CH2:56][CH2:55][C@H:54]4[C@@H:44]([CH2:45][C@H:46]([CH:57]=[CH2:1])[CH:47]5[C@:52]4([CH3:53])[CH2:51][CH2:50][CH2:49][CH2:48]5)[C@@H:35]2[CH2:36]3)[CH3:34])[O:41]1
Reactant: C[C@]12CCCCC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Yield: 70 %

Procedure:
17,17-Bis(ethylendioxy)-6α-vinylandrostane was prepared in 70% yield from 3,3:17,17-bis(ethylendioxy)-6α-formylandrostane by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 8). The crude was purified by flash chromatography (SiO2, n-hexane/EtOAc 88/12). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.47 (m, 1H), 4.91 (m, 2H), 3.94-3.73 (m, 8H), 2.00-0.67 (m, 21H), 0.88 (s, 3H), 0.83 (s, 3H),