Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:17][CH2:18][C:19](OCC)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>C(OCC)C>[C:7]1([CH2:17][CH2:18][CH2:19][OH:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CCc1cccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCCCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1.3 grams (0.033 mole) of lithium aluminum hydride in 40 mL of diethyl ether was stirred for one hour. The mixture was then cooled, and a solution of 10.0 grams (0.044 mole) of ethyl 3-(naphth-1-yl)propanoate in 35 mL of diethyl ether was added dropwise at a rate to keep the reaction mixture temperature below 25° C. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for one hour. The reaction mixture was again cooled, and 50 mL of ethyl acetate was added to destroy excess lithium aluminum hydride. After this time 30 mL of an aqueous 10% sodium hydroxide solution was added dropwise. The reaction mixture was then acidified with aqueous 6N hydrochloric acid, and then it was poured into 300 mL of water. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 8.2 grams of 3-(naphth-1-yl)propanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][C:3]=1[Cl:18].C[O:20][CH:21]1[CH:25]([CH:26]=O)[CH2:24][CH:23](OC)O1.O.C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[Cl:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:1]1[CH:23]=[CH:24][C:25]([CH:21]=[O:20])=[CH:26]1)[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7](=[O:17])[NH:6]2
Reactant: COC1CC(C=O)C(OC)O1
Reactant: CCOC(=O)c1nc2cc(N)c(Cl)cc2[nH]c1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nc2cc(-n3ccc(C=O)c3)c(Cl)cc2[nH]c1=O
Reaction time: 0.67 h
Yield: 25.7 %

Procedure:
To a solution of ethyl 7-amino-6-chloro-3,4-dihydro-3-oxoquinoxaline-2-carboxylate (500mg, 1.87 mmol) in acetic acid (10 ml) was added dropwise 2,5-dimethoxytetrahydrofuran-3-aldehyde (318 μl, 2.24 mmol) at 50° C., and the mixture was stirred for 40 minutes at the same temperature. The reaction mixture was poured into water (100 ml), which was extracted with ethyl acetate. After dried over anhydrous sodium sulfate, solvent was distilled off. The residue obtained was submitted to silica gel column chromatography [ethyl acetate-hexane=3:2] to obtain 166 mg of title compound as yellowish brown oily product. Yield 26%.
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[NH:6][CH:5]=1)[CH2:2][CH3:3].[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:18][C:19]=1[CH2:20][CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:14][C:15]1[N:16]=[C:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[S:18][C:19]=1[CH2:20][CH2:21][O:13][C:9]1[CH:8]=[C:7]2[C:12]([C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][NH:6]2)=[CH:11][CH:10]=1
Reactant: CCCc1c[nH]c2cc(O)ccc12
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1c[nH]c2cc(OCCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc12

Procedure:
In analogy to the procedure described in example 3 c], 3-propyl-1H-indol-6-ol was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield 6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-3-propyl-1H-indole as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([C@@H:12]1[CH2:16][C@@H:15]([C:17](O)=[O:18])[C@H:14]([C:20]([N:22]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23]2)=[O:21])[CH2:13]1)(=[O:11])=[O:10].[CH2:29]1[C:31]([NH2:34])([C:32]#[N:33])[CH2:30]1.Cl>>[C:32]([C:31]1([NH:34][C:17]([C@@H:15]2[CH2:16][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:13][C@H:14]2[C:20]([N:22]2[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23]2)=[O:21])=[O:18])[CH2:29][CH2:30]1)#[N:33]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@H]1C(=O)N1CCC(F)(F)C1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1

Procedure:
The title compound was prepared in analogy to example 117 step 7 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (example 186 step 6) and 1-amino-cyclopropyl cyanic hydrochloride. Yellow foam (85%). MS (EI): 504.1 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH:13]([CH2:35][OH:36])[CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:36][CH2:35][CH:13]1[CH2:12][NH:11][CH2:16][CH2:15][N:14]1[C:17]1[C:26]2[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=2)[N:20]=[C:19]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[N:18]=1
Reactant: Cc1ccc2c(N3CCN(C(=O)OCc4ccccc4)CC3CO)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CCNCC3CO)nc(-c3ccccc3O)nc2c1
Reaction time: 3 h

Procedure:
To 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (200 mg, 0.41 mmol) in 1.7 mL of methanol was added 39 mg of Pd/C (10% wt Pd on carbon). The reaction mixture was stirred under a hydrogen atmosphere for 3 h. The mixture was filtered through Celite, and the solvent was removed to give 2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol. LCMS: m/z 351.2 (M+H)+ at 2.11 min (10%-99% CH3CN/H2O).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:30][CH:31]=[CH:32][N:33]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.C(N(CC)CC)C.[C:43]([N:47]=C=O)([CH3:46])([CH3:45])[CH3:44]>CO>[C:43]([NH:47][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:34][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[NH:33][CH:32]=[CH:31][N:30]=5)[CH:24]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)NC(=O)N1CC=C(c2cc3c(Nc4cccc(-c5ncc[nH]5)c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into the solution of 4-{4-[3-(1H-imidazol-2-yl)-phenylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (59.4 mg, 0.118 mmol) in methanol (1.0 mL) was added HCl in methanol (9 M, 11.0 mL). The above mixture was stirred at rt for 4 h. After that time, the mixture was concentrated in vacuo and was then suspended in DMF (2 mL). Into the above suspension were added triethylamine (159 μL, 1.18 mmol) and tert-butyl isocyanate (14.8 μL, 0.130 mmol). The above mixture was stirred at rt under an atmosphere of N2 for 1 h. After that time, the mixture was concentrated in vacuo to obtain brown oil that was purified by HPLC to yield the title compound. 1H NMR (CD3OD, 400 MHz): δ=1.35 (s, 9H), 2.55 (brs, 2H), 3.59 (t, 2H, J=4.2 Hz), 4.05 (brs, 2H), 6.28 (brs, 1H), 6.65 (s, 1H), 7.13 (d, 2H, J=1.2 Hz), 7.42 (t, 1H, J=8.4 Hz), 7.55 (dd, 1H, J=0.8 & 7.6 Hz), 7.74 (dd, 1H, J=0.8 & 8.0 Hz), 7.75-8.19 (m, 1H), 8.23 (d, 1H, J=1.2 Hz). MS (ES+): m/z 457.12 (100) [MH+]. HPLC: tR=2.00 min (ZQ2000, polar—5 min).
Reaction SMILES: [P:1]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[O:27])=[CH:22][CH:21]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Mn]([O-])(=O)(=O)=[O:29].[K+].OS([O-])=O.[Na+].CO.C(Cl)Cl>CC(C)=O.O.Cl>[CH2:4]([O:3][P:1]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:29])=[O:27])=[CH:24][CH:25]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: Cl
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Yield: 90.1 %

Procedure:
To a solution of dibenzyl 4-formylphenyl phosphate (1.00 g, 2.62 mmol) in acetone (50 mL) was added a solution of potassium permanganate (0.837 g, 5.30 mmol) in acetone (40 mL) and water (40 mL) at rt over 1.5 hr. To the resulting purple mixture was poured 10% NaHSO3 in 1N HCl (100 mL) at rt. The purple solution became colorless and extracted with AcOEt (3×60 mL). The combined extract was washed with brine and dried anhydrous MgSO4. The title compound (0.940 g, 90% yield) was isolated as a white solid by ISCO (5% MeOH/CH2Cl2).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11][CH2:12][C:13]2[C:14]([C:19]3[NH:23][N:22]=[CH:21][C:20]=3[CH3:24])=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl.[OH-].[Na+]>O>[CH3:24][C:20]1[CH:21]=[N:22][NH:23][C:19]=1[C:14]1[C:13]([CH2:12][O:11][C:8]2[C:5]([CH:6]=[O:7])=[CH:4][C:3](=[O:2])[NH:10][CH:9]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(C=O)c(OCc2cccnc2-c2[nH]ncc2C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cn[nH]c1-c1ncccc1COc1c[nH]c(=O)cc1C=O
Reaction time: 20 h
Yield: 21.8 %

Procedure:
To 2-methoxy-5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)isonicotinaldehyde (862 mg, 2.66 mmol, 1 equiv) suspended in water (5.0 mL) was added HCl (6 N, 4.43 mL, 26.6 mmol, 10 eq.). Once the mixture turned into a homogeneous solution, it was freeze at −78° C. to an solid and pump under high vacuum O/N. The yellow solid was continued to pump at 45° C. for 20 h, dissolved in water (2.0 mL), and basified to pH 11 with NaOH (2 N). The aqueous layer was washed with DCM three times and the pH of the mixture was adjusted to pH 6-7. The solid was collected and dried to give 5-((2-(4-methyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-oxo-1,2-dihydropyridine-4-carbaldehyde (180 mg, 44% based on 50% recovered of SM) as a white solid. 1H NMR (400 MHz, DMSO at 90° C.) δ 10.14 (s, 1H), 8.63 (s, 1H), 8.09-8.03 (br, 1H), 7.56-7.50 (br, 2H), 7.42-7.35 (br, 1H), 6.70 (s, 1H), 5.39 (s, 2H), 2.18 (s, 3H). LRMS (M+H+) m/z 311.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[C:18]([C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH:25]=2)[N:17]=[C:16]2[N:30]([CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[N:31]=[CH:32][C:15]=12)=[O:13]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:32]=[N:31][N:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][C:22]([CH3:28])([CH3:29])[NH:23][C:24]([CH3:26])([CH3:27])[CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCNCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl) carbamoyl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)piperidine-1-carboxylate (0.5 g, 0.8 mmol) in DCM (10 mL), TFA (0.3 mL) was added at 0° C. and reaction stirred at room temperature for 1 h. After completion of reaction, solvent was removed under reduced pressure and residue neutralized with saturated NaHCO3 solution Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. Finally the residue was washed with diethyl ether to provide the desired compound (0.4 g, 95.7%).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:19]([O:26][CH2:27][CH2:28][C@@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32](Cl)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[Si:19]([O:26][CH2:27][CH2:28][C@@H:29]1[CH2:40][CH2:39][C:38]2[S:37][C:36]3[N:35]=[CH:34][N:33]=[C:32]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:6][CH2:5]4)[C:31]=3[C:30]1=2)([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CCc2sc3ncnc(Cl)c3c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.96 g, 49.00 mmol, 4.02 equiv) was treated with tert-butyl N-(4-hydroxycyclohexyl)-N-methylcarbamate (3.92 g, 17.09 mmol, 1.40 equiv) in distilled THF (50 mL) at 0° C. for 1 h under nitrogen. Then a solution of 22.1 (4.5 g, 12.20 mmol, 1.00 equiv) in 15 mL of THF was added to the reaction mixture, which was stirred for a further 2 h at 60° C. The reaction was then quenched by the addition of 20 mL of water at 0° C. and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:5) and purified to afford tert-butyl N-(4-[[(3S)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (22.2, 6.5 g, 95%) as yellow oil. MS: m/z 562 (M+H)+.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[C:11]([O:13]CC)=[O:12].C(O)(=O)C.O>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)[C@H](CCCCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NCCCCCC[C@H](N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
A solution of 3(R)-[7-amino-1(S)-ethoxycarbonylheptyl]amino-4oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride (0.16 g) obtained in Example 72 in 1N sodium hydroxide (4 ml) is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2 ml) and water (5 ml), the mixture is submitted to Amberlite XAD-2 column chromatography eluting with methanol-water (1:1). The eluate is concentrated under reduced pressure and lyophilized to yield 3(R)-[7-amino-1(S)-carboxyheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.11 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH2:18])=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:24][C:25]1[C:26]([CH2:31]Br)=[CH:27][CH:28]=[CH:29][CH:30]=1.O>CN(C=O)C>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]([N:18]4[CH2:31][C:26]5[C:25](=[CH:30][CH:29]=[CH:28][CH:27]=5)[CH2:24]4)=[O:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: BrCc1ccccc1CBr
Reactant: NC(=O)CN1CCC(c2noc3cc(F)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2noc3cc(F)ccc23)CC1)N1Cc2ccccc2C1
Reaction time: 3 h

Procedure:
To a mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]acetamide (2.56 g, 9.2 mmol) in DMF (40 ml) was chipped in sodium hydride (770 mg, 60% in oil, 20.1 mmol) at room temperature under N2. The mixture was heated to 65 C. for 3 hours. α,α'-dibromoxylene (2.43 g, 9.2 mmol) was added and the resulting mixture was heated at 70 C. for 4 hours, then left standing overnight for 16 hours. The DMF mixture was poured into H2O (400 ml) and the organics were extracted into ethyl acetate (250 ml). The ethyl acetate solution was washed with brine and dried over MgSO4. The solvent was removed and the residue was purified by flash chromatography over a silica gel column (SiO2, 45 gm; eluted with 1% CH3OH:99% DCM). The product thus purified as a white solid weighed 1.73 g. Recrystallization from a small amount of ethanol yielded white crystals: 1.65 g, m.p. 184°-185° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11])([O-:3])=[O:2].[CH3:12][O:13][CH:14]([O:18][CH3:19])N(C)C.CN(C)C=O.C[Si](Cl)(C)C>C(OCC)(=O)C.CO>[CH3:12][O:13][CH:14]([O:18][CH3:19])[CH2:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(Cc1cccc(C)c1[N+](=O)[O-])OC
Temperature: 25 °C
Yield: 14 %

Procedure:
Combine 2-nitro-meta-xylene (5 mL, 0.037 mol), N,N-dimethylformamide dimethylacetal (5.4 mL, 1.1 eq) and N,N-dimethylformamide (60 mL) in a flask and reflux under nitrogen for 2 days. Let cool to room temperature then concentrate to approximately one-half volume. Add methanol (40 mL) and trimethylsilylchloride (6.6 mL, 1.4 eq). Reflux overnight. Dilute with ethyl acetate after cooling to room temperature then extract with saturated sodium bicarbonate followed by brine. Dry over magnesium sulfate, filter and concentrate. Purification by column chromatography (9:1 Hexanes:ethyl acetate) gives 1.15 g (14%) product as a light yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.80 (d, J=5.36 Hz, 2H), 3.19 (s, 6H), 4.45 (m, 1H), 7.32 (m, 2H), 7.42 (m, 1H).
Reaction SMILES: OC1C=CC(CC(OC)=O)=CC=1.ClCCCl.F[N+:18]1[C:23]([S:24]([O-:27])(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:28]>O>[Cl:28][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([S:24]([OH:27])(=[O:26])=[O:25])[N:18]=1
Reactant: O=S(=O)([O-])c1cccc(Cl)[n+]1F
Agent: COC(=O)Cc1ccc(O)cc1
Solvent: ClCCCl
Solvent: O
Product: O=S(=O)(O)c1cccc(Cl)n1

Procedure:
A 25 ml egg-plant type flask was flushed with argon, and 83.0 mg (0.5 mmol) of methyl 4-hydroxyphenylacetate, 2 ml of dry 1,2-dichloroethane and 105.7 mg (0.5 mmol) of N-fluoro-2-chloropyridinium-6-sulfonate were charged. The flask was immersed in an oil bath of 80° C. and heated for 22 hours. After completion of the reaction, 20 ml of water was added thereto, and the mixture was extracted three times with 20 ml of methylene chloride. 2-Chloropyridine-6-sulfonic acid formed after the reaction was all transferred to the aqueous layer. The organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography (eluent: hexane/diethyl ether=2/1) to obtain 49.4 mg (conversion yield: 63%) of methyl 3-fluoro-4-hydroxyphenylacetate, and 11.2 mg of methyl 4-hydroxyphenylacetate was recovered (recovery rate: 14%).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]1[N:15]=[C:14]([NH:16][C:17](OCC)=[O:18])[N+:13]([O-:22])=[C:12]([NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:11]=1)[CH2:2]2>CN(C)C=O>[CH:5]12[CH2:6][CH2:7][CH:1]([CH2:9][CH2:8]1)[CH2:2][N:3]([C:10]1[CH:11]=[C:12]([NH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:13]3[O:22][C:17](=[O:18])[N:16]=[C:14]3[N:15]=1)[CH2:4]2
Reactant: CCOC(=O)Nc1cc(N2CC3CCC(CC3)C2)nc(NC(=O)OCC)[n+]1[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cc(N2CC3CCC(CC3)C2)nc2nc(=O)on12

Procedure:
4.1 G. of diethyl 6-{3-azabicyclo[3.2.2]non-3-yl}-2,4-pyrimidine-dicarbamate-3-oxide are suspended in 50 ml. of dimethylformamide and warmed to 140° C. for 30 minutes under an argon atmosphere. After cooling the solution, the dimethylformamide is distilled off under reduced pressure and the residue is filtered over silica gel. Elution with chloroform and ethanol yields ethyl 5-{3-azabicyclo[3.2.2]non-3-yl}-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 210°-215° C. (decomposition). Analytically pure product is obtained by recrystallization from methylene chloride/ether.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13]([C:14](=O)[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4].Cl.[NH2:35][OH:36]>>[F:32][C:2]([F:33])([F:1])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][C@@H:11]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[CH:13](/[C:14](=[N:35]/[OH:36])/[CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C:20]2=[O:30])[CH2:12]1)=[O:4]
Reactant: C[C@]12CC[C@@H](SCCCCNC(=O)C(F)(F)F)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: NO
Agent: Cl
Product: C[C@]12CC[C@@H](SCCCCNC(=O)C(F)(F)F)CC1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 40 %

Procedure:
Following the reaction conditions described in Example 1 and starting from 3α-(4-trifluoroacetamidobutylthio)androstane-6,17-dione and hydroxylamine hydrochloride, 3α-(4-trifluoroacetamidobutylthio)-6-(E)-hydroxyiminoandrostane-17-one (238 mg, 40%) was obtained. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.35 (1H, s), 9.40 (1H, t), 3.20 (4H, m), 2.55-0.90 (25H, m), 0.76 (3H, s), 0.67 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[O:13])[CH2:9][C:10]=2[CH:11]=1.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>C1(C)C=CC=CC=1.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>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([N:8]2[CH2:7][CH2:6][C:5]3[N:4]=[CH:3][C:2]([CH:21]=[CH2:22])=[CH:11][C:10]=3[CH2:9]2)=[O:13])=[CH:15][CH:16]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(c1ccc(F)cc1)N1CCc2ncc(Br)cc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cnc2c(c1)CN(C(=O)c1ccc(F)cc1)CC2
Temperature: 120 °C
Yield: 92.1 %

Procedure:
(3-Bromo-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)(4-fluorophenyl)methanone (150 mg, 0.4 mmol; prepared as described above), tributyl(vinyl)tin (185 mg, 0.6 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) were combined in toluene (12 mL) and heated at 120° C. for 1 h. The reaction mixture was cooled to RT, filtered through celite, adsorbed onto silica gel, and eluted with CH2Cl2:MeOH (9:1) to give 104 mg (82%) of (4-fluorophenyl)(3-vinyl-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)methanone. LC-MS (M+H)=283.1.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[CH:7]=[CH:8][N:9]3[CH:15]=[CH:14][CH:13]=[C:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1)#[N:2].Cl.C(O)(=[O:21])C>>[C:1]([C:3]1[CH:17]=[CH:16][C:6]2[CH:7]=[CH:8][N:9]3[CH:15]=[CH:14][CH:13]=[C:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1)(=[O:21])[NH2:2]
Reactant: N#Cc1ccc2ccn3cccc3c(=O)c2c1
Reactant: CC(=O)O
Agent: Cl
Product: NC(=O)c1ccc2ccn3cccc3c(=O)c2c1
Temperature: 25 °C

Procedure:
9-Cyano-11H-pyrrolo[2,1-b][3]benzazepin-11-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid is refluxed for 2 hours. It is then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution is left to cool to room temperature and filtered to afford 9-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepin-11-one.