Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:23])[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=2)[CH2:9]1.[OH-].[Na+]>C1COCC1.O.C(OCC)C>[NH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH:10]2[CH2:11][CH2:12][CH2:13][C:8]([CH3:23])([CH3:7])[CH2:9]2)=[CH:20][N:19]=1
Reactant: CC1(C)CCCC(Oc2ccc(C#N)nc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CC1(C)CCCC(Oc2ccc(CN)nc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere, add lithium aluminum hydride (264 mg, 6.95 mmol) to THF (15 mL) at 0° C. Add a solution of 5-(3,3-dimethylcyclohexyloxy)-pyridine-2-carbonitrile (0.4 g, 1.74 mmol) in THF (5 mL), stir at 0° C. for 1 h and warm to room temperature overnight. Cool the mixture at 0° C. and carefully add water (0.3 mL). Add diethyl ether (25 mL), 3N aqueous NaOH (0.3 mL) and water (0.9 mL), and stir for 1 h at room temperature. Filter the solid residue and concentrate the filtrate in vacuo to obtain the title compound as a colorless oil (360 mg, 88%). MS (APCI+) m/z: 235 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22]#[N:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2].C(N(CC)CC)C.[SH2:31]>N1C=CC=CC=1>[CH2:1]([N:3]([CH2:5][CH:6]([N:8]1[C:21]2[CH:20]=[C:19]([C:22](=[S:31])[NH2:23])[CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:7])[CH3:4])[CH3:2]
Reactant: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCN(C)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reaction time: 16 h

Procedure:
A solution of 10-[(2RS)-1-(N-ethyl-N-methyl-amino)-2-propyl]-2-phenothiazinecarbonitrile (3 g) and triethylamine (1.3 cc) in anhydrous pyridine (60 cc) is treated with excess hydrogen sulphide, and stirring is then continued for 16 hours at a temperature in the region of 20° C. The solution obtained is purged with a stream of nitrogen for 1 hour, poured into ethyl acetate (100 cc), washed with distilled water (3×200 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at.40° C. The residual brown oil is purified by chromatography on a column (height: 40 cm; diameter: 3 cm) of silica gel (0.2-0.06 mm), eluting successively with methylene chloride (1 liter), a mixture (95:5 by volume) (1 liter) of methylene chloride and methanol and a mixture (80:20 by volume) (3 liters) of methylene chloride and methanol, and collecting 150-cc fractions. Fractions 26 to 30 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-[(2RS)-1-(N-Ethyl-N-methylamino)-2-propyl]-2-phenothiazinecarbothioamide (2.15 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:16]([O-])=O)=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([CH:8]=[CH:9]N(C)C)[CH:7]=1>CCO.[Ni]>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[NH2:16])[NH:13][CH:9]=[CH:8]2
Reactant: CN(C)C=Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc2[nH]ccc2cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
A suspension of [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine (8 g, 31.4 mmol) and Raney Ni (8 g) in EtOH (80 mL) was stirred under H2 (40 psi) at room temperature for 1 h. After filtration, the filtrate was concentrated and the residue was purified by chromatography (Pet.Ether/EtOAc=5/1) to give 5-fluoro-1H-indol-6-ylamine (B-20) as a brown solid (1 g, 16%). 1H NMR (DMSO-d6) δ 10.56 (br s, 1H), 7.07 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8 Hz, 1H), 6.17 (s, 1H), 3.91 (br s, 2H); ESI-MS 150.1 m/z (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1cccc(C(F)(F)F)c1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1cccc(C(F)(F)F)c1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 3-trifluoromethylaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)([O-])O.[Na+].[CH:25](B1OC(C)(C)C(C)(C)O1)=[CH2:26].O>[Cl-].[Na+].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.O1CCOCC1>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH:25]=[CH2:26])=[CH:15][CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)cc1
Temperature: 95 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
2-Aminocarbonylamino-5-(4-bromophenyl)pyrrole-3-carboxamide (Compound No. 1-1, 80 mg, 0.25 mmol), sodium hydrogencarbonate (52 mg, 0.62 mmol), vinylboronic acid pinacol ester (63 μL, 0.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.012 mmol) in mixed solvent (4 mL), which consists of water and 1,4-dioxane (1:3), were stirred overnight at 95° C. The brine (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), and then the organic layer was dried over magnesium sulfate. The layer was filtered with celite and the solvent was removed under reduced pressure. The obtained solid was washed with diethyl ether (2 mL), and dried under reduced pressure to give the target compound (22 mg) as a pale brown solid (Yield 33%).
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:2]1=2.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[O:1]1[CH:6]([C:7]([O:9][CH2:23][CH3:24])=[O:8])[CH2:5][CH2:4][C:3]2[CH:10]=[CH:11][C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=3[C:2]1=2
Reactant: CCO
Reactant: O=C(O)C1CCc2ccc3c(c2O1)CCCC3
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2ccc3c(c2O1)CCCC3
Yield: 100 %

Procedure:
A mixture of 20 parts of 3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-carboxylic acid, 200 parts of ethanol and 4.6 parts of sulfuric acid was stirred and refluxed for 2 hours. The reaction mixture was evaporated. Water and a sodium hydroxide solution were added to the residue. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 21 parts (100%) of ethyl 3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-carboxylate as a residue (intermediate 30).
Reaction SMILES: S(Cl)(Cl)(=O)=O.[SH:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.Cl.[CH3:17][C:18]1([CH3:32])[O:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[O:27][C:28]([NH:30][CH3:31])=[O:29])[CH2:19]1>C1C=CC=CC=1.N1C=CC=CC=1.O>[S:8]1[C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=[C:7]1[S:6][N:30]([CH3:31])[C:28](=[O:29])[O:27][C:24]1[C:25]2[O:26][C:18]([CH3:17])([CH3:32])[CH2:19][C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: Sc1nc2ccccc2s1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Agent: Cl
Solvent: c1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Product: CN(Sc1nc2ccccc2s1)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 2 h

Procedure:
A solution of 6.75 of sulfuryl chloride in 20 ml of benzene was added dropwise, with vigorous stirring under nitrogen, to a solution of 8.4 g of 2-mercaptobenzothiazole in 150 ml of benzene. The mixture was heated slowly to reflux and maintained under gentle reflux until evolution of hydrogen chloride had ceased. A solution of 11 g of carbofuran in 150 ml of pyridine was added dropwise and the mixture stirred for two hours at reflux under nitrogen. The mixture was poured into water. The organic phase was separated, washed with dilute hydrochloric acid, water and saturated aqueous sodium chloride, then dried. The dry solution was concentrated under reduced pressure and the residue recrystallized from ethanol to give 2,3-dihydro-2,2-dimethyl-7-benzofuranyl (2-benzothiazolylthio)(methyl)carbamate, m.p. 92°-3°. Recrystallization from hexane-benzene increased the melting point to 97°. The n.m.r. spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[H-].[Na+].Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(CNc2nc(C)nc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of 4-chloro-N-(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (160 g, 604 mmol) in DMF (800 mL) at 0° C., was added sodium hydride (18.86 g, 786 mmol) slowly over 5 min. 1-(Chloromethyl)-4-methoxybenzene (91 mL, 665 mmol) was slowly added over 15 min. The reaction mixture was stirred at 0-5° C. for 30 min and allowed to warm to room temp 25° C. After 1 h, cold water (2.5 L) was added and the mixture was stirred overnight. The resulting slurry was filtered, washed with water (150 mL, ×2) and dried to afford 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine as a solid (215.3 g, 559 mmol, 93% yield). LCMS (ES, pos.): Cacld for C20H21ClN4O2: 384.1; found: 385.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.16 (t, J=8.12 Hz, 4H); 6.81-6.95 (m, 4H); 4.74 (s, 2H); 4.69 (s, 2H); 3.81 (s, 6H); 2.45 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[Li+].[OH-].Cl>O.C1COCC1>[O:19]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:20])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(CCC(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl ester 47 (195 mg, 0.73 mmol) in water/THF (1:1, 0.07M) was added LiOH (46 mg, 1.1 mmol). The resulting solution was stirred overnight at room temperature or until no starting material was detected by TLC. HCl 1N was added and the solution was extracted with EtOAc and the organic layer was dried over anhydrous MgSO4. Filtration and evaporation of the solvent under vacuum followed by purification by column chromatography using 10% MeOH/CH2Cl2, gave the title compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:43]I>C1(C)C=CC=CC=1>[I:43][CH2:2][CH2:3][CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]/[C:9]1[CH:18]=[CH:17][C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: II
Reactant: OCCCOC/C=C/c1ccc2c(c1)OCCO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: ICCCOC/C=C/c1ccc2c(c1)OCCO2
Yield: 193.6 %

Procedure:
Following the procedure described in example 7§C, but starting from trans-2,3-dihydro-6-[3-(3-hydroxypropoxy)prop-1-en-1-yl]benzo[1,4]dioxine (280 mg), triphenylphosphine (455 mg), imidazole (114 mg) and diiodine (355 mg) in toluene (2.6 mL) affords 780 mg of trans-2,3-dihydro-6-[3-(3-iodopropoxy)prop-1-en-1-yl]benzo[1,4]dioxine as a clear oil used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[C:7]=1[NH2:8].[C:31](O)(=[O:35])[C@@H:32]([CH3:34])[OH:33].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[NH2:8][C:7]1[N:6]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:17]=3)=[C:5]2[N:4]=[C:3]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:35])[C@H:32]([OH:33])[CH3:34])[CH2:27][CH2:26]2)[C:2]=1[Br:1]
Reactant: Nc1c(Br)c(OC2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Reactant: C[C@@H](O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the crude 6-bromo-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yloxy)pyrazolo[1,5-a]pyrimidin-7-amine, D-(−)-lactic acid (18.5 mg, 0.20 mmoL), EDC (78.7 mg, 0.41 mmoL), HOBt (27.7 mg, 0.20 mmoL) and DIEA (238 uL, 1.37 mmoL) in DMF (4 mL) was stirred at room temperature for 2 hr. Purification with prep-LC provided (R)-1-(4-(7-amino-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidin-1-yl)-2-hydroxypropan-1-one, LCMS tR=4.39 Min (10 min run, UV254nm). Mass calculated for, M+ 513.0, observed LC/MS m/z 514.43 (M+H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([O:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[CH3:22]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:27]4[CH2:28][CH2:29][CH:24]([O:23][CH2:21][CH3:22])[CH2:25][CH2:26]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC1CCNCC1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Product: CCOC1CCN(c2cc3c(c(C)c2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 40 %

Procedure:
The condensation of 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid with 4-ethoxypiperidine in a similar manner as described in example 1 give the titled product. Yield 40%, m.p 180–82° C., C21H21FN2O4, m/z 388 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:15][O:14][CH2:13][C:12]2[C:16]([O:29][Si](C(C)(C)C)(C)C)=[CH:17][C:18]([O:21][Si](C(C)(C)C)(C)C)=[C:19]([CH3:20])[C:11]=2[C:10](=[O:37])[S:9][C@H:8]([CH3:38])[C:7](=[O:39])[NH:6]1)=[O:4].[F-].[NH4+]>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:15][O:14][CH2:13][C:12]2[C:16]([OH:29])=[CH:17][C:18]([OH:21])=[C:19]([CH3:20])[C:11]=2[C:10](=[O:37])[S:9][C@H:8]([CH3:38])[C:7](=[O:39])[NH:6]1)=[O:4]
Reactant: COC(=O)[C@H]1COCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)S[C@H](C)C(=O)N1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)[C@H]1COCc2c(O)cc(O)c(C)c2C(=O)S[C@H](C)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A mixture of 35 mg of (4R,7R)-11,13-bis-(tert-butyl-dimethylsilanyloxy)-7,10-dimethyl-6,9-dioxo-3,4,5,6,7,9-hexahydro-1H-8,2,5-benzoxathiaazacyclo-undecine-4-carboxylic acid methyl ester and 20 mg ammonium fluoride in 2 ml of methanol was stirred at room temperature for 1 h. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel using ethyl acetate as eluent. The pure product was crystallized from dichloromethane to give 13 mg of (4R,7R)-11,13-dihydroxy-7,10-dimethyl-6,9-dioxo-3,4,5,6,7,9-hexahydro-1H-8,2,5-benzoxathiaazacycloundecine-4-carboxylic acid methyl ester as white crystals, m.p. 216°-218° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([CH:28]=O)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:28][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[CH:10]([C:14]([O:16][CH3:17])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cccc2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc2ccccc12
Reaction time: 8 h

Procedure:
The product from Step B was dissolved in methanol (20 mL) with naphthalene-1-carboxaldehyde (0.67 mL, 4.7 mmol), sodium cyanoborohydride (0.350 g, 5.6 mmol) at pH 6 (adjusted with acetic acid) and the reaction stirred overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was chromatographed on silica gel with ethyl acetate in hexane, and the title compound isolated as an oil. NMR (CDCl3, 300 MHz) d 8.34 (1H, d, J=7 Hz), 7.85 (1H, dm, J=7 Hz), 7.79 (1H, m), 7.51 (2H, m), 7.39 (2H, m), 4.34 (1H, d, J=12 Hz), 3.98 (1H, br s), 3.91 (1H, dd, J=12, 6 Hz), 3.75 (3H, s), 3.60 (1H, br s), 3.44 (1H, d, J=12 Hz), 3.27 (1H, t, J=3 Hz), 3.19 (1H, d, J=12 Hz), 3.09 (1H, td, J=10, 3 Hz), 2.42 (1H, br s), 1.44 (9H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C:15]1[CH:33]=[CH:32][C:18]([C:19]([NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=O)=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1OCC1C=CC(CNC(C2C(N)=NC(N)=CN=2)=O)=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][NH:21][C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)=[CH:32][CH:33]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc2ncccc2c1)c1ccc(OCc2ccccc2)cc1
Agent: Nc1cnc(C(=O)NCc2ccc(COc3ccccn3)cc2)c(N)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: c1ccc(COc2ccc(CNc3ccc4ncccc4c3)cc2)cc1
Yield: 70 %

Procedure:
To a solution of lithium aluminum hydride (58 mg, 1.54 mmol) in tetrahydrofuran (10 mL) was added a solution of 4-benzyloxy-N-quinolin-6-yl-benzamide described in Preparation Example Z+-3 (218 mg, 0.615 mmol) in tetrahydrofuran (1 mL), and the solution was stirred under reflux for 7 hours. The reaction solution was allowed to room temperature, an aqueous solution of saturated ammonium chloride was added, the solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate), and the title compound (147 mg, 70%) was obtained as a yellow solid.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[Br:12][C:13]1[CH:14]=[C:15]([CH:19]([C:21]2[C:22]([NH:39][CH3:40])=[N:23][CH:24]=[C:25]([C:27]3([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[O:31][CH2:30][CH2:29][O:28]3)[CH:26]=2)[OH:20])[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl>[Br:12][C:13]1[CH:14]=[C:15]([C:19]([C:21]2[C:22]([NH:39][CH3:40])=[N:23][CH:24]=[C:25]([C:27]3([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[O:31][CH2:30][CH2:29][O:28]3)[CH:26]=2)=[O:20])[CH:16]=[CH:17][CH:18]=1
Reactant: CNc1ncc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CNc1ncc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
PCC (13.61 g, 63.28 mmol) was added to a solution of compound F (20 g, 42.19 mmol) in DCM (400 mL). The mixture was stirred at RT overnight and filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography to obtain 8.5 g (33%, two steps) of compound G.
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH:7]=[CH:6]1)(=O)C.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:19]([Si:16]([CH3:18])([CH3:17])[O:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH:7]=[CH:6]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)O[C@@H]1C=C[C@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (1.0 g, 7.03 mmol) (Fluka) and imidazole (960 mg, 14.06 mmol) (Aldrich) in tetrahydrofuran (65 mL) at 0° C. was added tert-butyldimethylsilyl chloride (1.27 g, 8.44 mmol) (Aldrich). The mixture was allowed to warm slowly to room temperature, stirred overnight and then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was dissolved in methanol (approximately 45 mL). To this solution was added potassium carbonate (1.17 g, 8.44 mmol) and the mixture stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by silica gel column chromatography with a 0–30% diethyl ether in hexanes gradient to give (+)-(1S,4R)-4-(tert-butyl-dimethyl-silanyloxy)-cyclopent-2-enol as a colorless oil. (Yield 1.43 g, 95%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([NH2:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37](O)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]>>[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([CH2:36][C:37]([NH:15][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:38])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:23]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: Cc1cccc(N2CCCCC2)c1C(N)c1ccccc1
Product: CCOC(=O)c1ccc(CC(=O)NC(c2ccccc2)c2c(C)cccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from 6-methyl-α-phenyl-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:41])[C:23]([NH:25][C:26]1[C:31]([F:32])=[CH:30][C:29]([F:33])=[C:28]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[C:27]=1[F:40])=[O:24]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]([NH:5][CH2:4][CH2:3][CH2:2][N:37]2[CH2:38][CH2:39][CH:34]([C:28]3[C:27]([F:40])=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:41])[C:31]([F:32])=[CH:30][C:29]=3[F:33])[CH2:35][CH2:36]2)=[O:20])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCCCBr)C(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCNCC2)c1F
Product: CC(C)C(=O)Nc1c(F)cc(F)c(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1F

Procedure:
Example 171 was prepared from N-(3-bromopropyl)-2,2-diphenylacetamide and 2-methyl-N-[2,4,6-trifluoro-3-(4-piperidinyl)phenyl]propanamide according to the procedures described in Scheme 14; ESMS m/e: 552.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[Na+].O.[Br:14][CH2:15][CH2:16]Br>>[Br:14][CH2:15][CH2:16][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccccc1OCCBr
Temperature: 107 °C
Yield: 63 %

Procedure:
To 2-nitrophenol (25.0 g, 0.180 mol) in sodium hydroxide (14.4 g, 359 mmol) and Water (6.0 mL, 330 mmol) in a 500 mL flask at 107° C. with a reflux condenser was added 1,2-dibromoethane (61.9 mL, 719 mmol), and the flask was heated at 107° C. for three days (FIG. 18). Then, the product was extracted twice with 100 mL DCM, washed with 2M NaOH and brine, dried with sodium sulfate, and concentrated. Silica gel chromatography eluting with hexanes and ethyl acetate provided the bromide 82 in 63% yield. 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J=8.4, 1.6 Hz, 1H), 7.53 (td, J=8.1, 1.6 Hz, 1H), 7.12-7.01 (m, 2H), 4.45-4.34 (m, 2H), 3.67 (t, J=6.5 Hz, 2H), according to: WO 2002076926