Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]([O:6]C)=[O:5].O>CS(C)=O.[OH-].[Na+]>[Br:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)ccnc1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
To a solution of 50.0 g (0.15 mol) of methyl 2-bromo-4-(4-chlorophenyl)nicotinate in 300 ml of dimethylsulfoxide, 60 ml of 30% sodium hydroxide was added and stirred at 80° C. for 3 hours. The mixture was then poured into water and washed with 300 ml of ethyl acetate. Thereafter, the aqueous layer was acidified with 10% HCl to precipitate a crystal, which was then filtrated out. The crystal thus precipitated was washed with water and isopropyl ether, and dried to obtain 41.0 g of a white crystal of the aimed product.
Reaction SMILES: CN(C)C=O.[C:6]1([SH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].Br[C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=1>O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([S:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:17][CH:18]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(Sc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To an N,N-dimethylformamide (20 mL) solution of thiophenol (1.02 g, 9.28 mmol) was added sodium hydride (446 mg, 9.28 mmol, 50% in oil), which was stirred for 15 minutes at room temperature. 2,5-Dibromopyridine (2.00 g, 8.44 mmol) was then added to this reaction mixture and stirred for 35 minutes at room temperature, and then for a further 45 minutes at 55° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate:=4:1) to obtain the title compound (2.24 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.[Li][CH3:35]>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)([OH:13])[CH3:35])[CH:10]=2)[N:5]=[C:4]([O:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:28][CH:29]=1
Reactant: COc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: COc1nc2ccc(C(C)(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
To a flask containing (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (408 mg, 0.86 mmol, Intermediate 8: step b) was added THF (20 mL) and the solution was cooled to −78° C. MeLi (1.6 M in Et2O, 0.6 mL, 0.96 mmol) was then introduced. After 25 minutes, the reaction mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (4×40 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (5% MeOH-DCM increasing to 10% MeOH) provided the title compound as a white amorphous solid. 1H NMR (500 MHz, CDCl3) δ 8.26 (d, J=1.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.2 Hz, 3H), 7.40 (d, J=8.1 Hz, 2H), 7.04 (d, J=10.7 Hz, 1H), 4.35 (s, 2H), 4.07 (s, 3H), 3.14 (s, 3H), 2.29 (s, 3H), 1.95 (s, 3H); MS (ESI): mass calcd. for C25H23ClF3N3O2, 489.1, m/z found 490.1 [M+H]+. 1-(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)-1-(1,2-dimethyl-1H-imidazol-5-yl)ethanol was purified by chiral chromatography (Chiracel OD (20 μM) diacel, 50×41 cm, heptane:ethanol with 2% isopropylamine (90:10)), to give 2 enantiomers. The first eluting enantiomer was Example 12b and the second eluting enantiomer was Example 12c.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([NH:16]C)=[O:15])=O)=[CH:5][CH:4]=1.[NH2:22]N>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:12]3[C:13](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:15])[NH:16][N:22]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: CNC(=O)c1ccccc1C(=O)Cc1ccc(OC)cc1
Solvent: CCO
Product: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1

Procedure:
To 2-(2-(4-methoxyphenyl)acetyl)-N-methylbenzamide (1.76 g, 6.20 mmol) in EtOH (20 mL) was added hydrazine (3.50 ml, 112 mmol). A water condenser was attached and the mixture was heated to reflux under a nitrogen atmosphere for 5 days. After concentration, the reaction was diluted with EtOAc and extracted with water. The organics were dried over sodium sulfate, filtered and concentrated. The crude was purified by washing the resulting solid with diethyl ether and filtering to yield 4-(4-methoxybenzyl)phthalazin-1(2H)-one as a white solid. MS m/z=267 [M+1]+. Calc'd for C16H14N2O2: 266.30.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C:12](=O)[N:11]1[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>O1CCCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][C:12](=[S:26])[N:11]1[CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN1C(=O)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CN1C(=S)CC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 181.5 %

Procedure:
To a solution of (2S)-2-t-butyldimethylsilyloxymethyl 1-methyl-5-pyrrolidone (16 g) in tetrahydrofuran (160 ml) was added Lawesson's Reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (14.6 g) at ambient temperature. After stirring at 60° C. under nitrogen for 1 hour, the solvent was removed. The residue was chromatographed on silica gel eluting with a mixture of acetone and dichloromethane (1:9 V/V) to give (2S)-2-t-butyldimethylsilyloxymethyl-1-methyl-5-thioxopyrrolidine (17.0 g).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](Cl)=[O:10])[C:5](=[O:12])[C:4]1=[O:13])[CH3:2].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([CH:37]3[CH2:42][CH2:41][N:40](S(C4C=CC(C)=CC=4)(=O)=O)[CH2:39][CH2:38]3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24]C)C>>[CH3:14][O:16][C:17]1[CH:18]=[C:19]([C:26]2[C@@H:35]3[C@@H:30]([CH2:31][CH:32]=[CH:33][CH2:34]3)[C:29](=[O:36])[N:28]([CH:37]3[CH2:42][CH2:41][N:40]([C:9]([N:6]4[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:13])[C:5]4=[O:12])=[O:10])[CH2:39][CH2:38]3)[N:27]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CCN1CCN(C(=O)Cl)C(=O)C1=O
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Product: CCN1CCN(C(=O)N2CCC(N3N=C(c4ccc(OC)c(OC)c4)[C@H]4CC=CC[C@H]4C3=O)CC2)C(=O)C1=O

Procedure:
Prepared from 4-ethyl-2,3-dioxo-piperazine-1-carbonyl chloride and starting compound A1 as described for compound 1. Crystallisation from ethyl acetate/diethyl ether. M.p. 226-228° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:28])[F:29])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12

Procedure:
0.32 g (7.63 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.94 g (2.54 mmol) of 3-methoxycarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 15 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with 50 cm3 of ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.73 g of 3-carboxy-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum: m/e 356 (M+•).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:23])[C:8]2[CH:12]([CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[O:11][B:10]([OH:21])[C:9]=2[CH:22]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH3:23])[C:8]2[CH:12]([CH2:13][C:14]([OH:16])=[O:15])[O:11][B:10]([OH:21])[C:9]=2[CH:22]=1)#[N:2]
Reactant: Cc1cc(OCC#N)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCC#N)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of tert-butyl 2-(6-(cyanomethoxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (120 mg, 0.38 mmol) in 5 ml DCM was added TFA (5 mL) at 0° C. The reaction mixture was stirred for 30 min at room temperature and concentrated to dryness. The residue was purified by prep HPLC to give the title compound as a white solid (60 mg, yield: 60.8%). 1H NMR (400 MHz, DMSO-d) δ12.31 (s, 1H), 9.24 (s, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 5.48-5.45 (m, 1H), 5.15 (s, 2H), 3.06-3.02 (m, 1H), 2.28 (s, 3H), 2.12-2.05 (m, 1H); MS (ESI) m/z=262 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:26])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nnc(-c2c(F)cccc2-c2cncc(Cl)c2)n1
Solvent: ClCCl
Product: Cn1nnc(-c2c(F)cccc2-c2cc(Cl)c[n+]([O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]pyridine (2.90 g, 9.98 mmol) and 3-chloroperoxybenzoic acid (2.238 g, 12.97 mmol) in 40 mL CH2Cl2 was stirred at room temperature overnight. Additional 3-chloroperoxybenzoic acid (861 mg, 4.99 mmol) was added in the morning to drive the reaction to completion. The solution was washed with 0.5 N NaOH and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]pyridine 1-oxide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 306.13 for M+H+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[NH:9][N:8]=2)[N:6]=1.[NH2:15][C@@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:10]3[CH:11]=[C:7]([C:5]4[N:6]=[C:2]([CH3:1])[S:3][CH:4]=4)[NH:8][N:9]=3)=[O:14])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: Cc1nc(-c2cc(C(=O)O)[nH]n2)cs1
Product: Cc1nc(-c2cc(C(=O)N[C@@H](C)Cn3ccc(-c4ccc(C#N)c(Cl)c4)n3)n[nH]2)cs1
Yield: 18 %

Procedure:
3-(2-Methylthiazol-4-yl)-1H-pyrazole-5-carboxylic acid (0.586 mmol) was coupled with (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile using the method of Example 34(d). Crude product was purified by CombiFlash (silica column, eluent: 50-100% EtOAc in heptane) to obtain 24 mg (18%) of the title compound 1H-NMR (400 MHz; CDCl3): δ 1.24 (d, 3H), 2.77 (s, 3H), 4.28 (dd, 1H), 4.44 (dd, 1H), 4.55-4.67 (m, 1H), 6.59 (d, 1H), 7.06 (s, 1H), 7.38 (s, 1H), 7.49 (d, 1H), 7.60 (d, 1H), 7.74 (dd, 1H), 7.82 (d, 1H), 8.06 (d, 1H), 11.75 (bs, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[N:3]=1.[Cu][C:20]#[N:21].[Cl-].[NH4+]>C(#N)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:20]#[N:21])=[N:3][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CCCOc1nc(Br)c([N+](=O)[O-])cc1Cl
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)CCCOc1nc(C#N)c([N+](=O)[O-])cc1Cl
Yield: 89.2 %

Procedure:
In a 10 ml single-necked round-bottomed flask equipped with an efficient condensor, 2-bromo-5-chloro-6-(4-methyl-pentyloxy)-3-nitro-pyridine (200 mg) is dissolved in dry acetonitrile (3.00 ml). To the reulting yellow solution, copper(I) cyanide (109 mg) is added. The resulting suspension is stirred under heating to reflux for 6 hours whereupon a brown solution is obtained. The progress of the transformation is followed by GC-MS. The mixture is allowed to reaxch ambient temperature. Saturated ammonium chloride solution (20 ml) along with some ice is then added and the mixture extracted with ether (2×20 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo to give 150 mg of the title compound in the form of a yellow oil (89%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][C@@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][N:10](CC=C)[C@@H:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(#N)C.O>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:6][O:7][C@@H:8]1[O:13][C@H:12]([CH3:14])[CH2:11][NH:10][C@@H:9]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C=CCN1C[C@@H](C)O[C@@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN[C@H](c2ccccc2)[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Yield: 63.9 %

Procedure:
A solution of 115 mg (0.25 mmol) of the 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-4-(2-propenyl)-6-(R)-methyl morpholine (from Example 23, Step A) and 230 mg (0.25 mmol) of tris(triphenylphosphine)rhodium chloride in 15 mL of 4:1 v/v acetonitrile/water was heated at reflux for 30 min. The reaction was cooled and partitioned between 50 mL of ethyl acetate and 15 mL of water. The layers were separated and the organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 2×25 mL of ethyl acetate; the extracts were dried and combined with the original organic layer. The combined organics were concentrated in vacuo. The residue was filtered through a pad of silica gel (~20 g) using 2:1 v/v ether/hexanes as the solvent. The filtrate was concentrated; flash chromatography on 5 g of silica gel using 17:3 v/v hexanes/ether as the eluant afforded 67 mg (64%) of 2-(R)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(R)-phenyl-6-(R)-methyl morpholine as an oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH:21][S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2)c1ccccc1
Yield: 74.6 %

Procedure:
Prepared from N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 108, step B) (155 mg, 0.50 mmol, HPLC 0.691 min) and benzenesulfonyl chloride (70 ul, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white foam (158 mg, 75%, HPLC 1.452 min), MS (ISP) m/e=424.1 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br)([O-:29])=[O:28].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]2[C:19]3[C:18](=[O:20])[CH2:17][CH:16]([CH2:21][CH2:22][CH3:23])[CH2:15][C:14]=3[NH:13][C:12]([CH3:24])=[C:11]2[C:25]#[N:26])[CH:5]=[C:6]([Br:9])[C:7]=1[O:8][CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([N+:27]([O-:29])=[O:28])[CH:31]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(N)c(OCc2cccc([N+](=O)[O-])c2)c(Br)c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
A mixture of 4-(3-amino-5-bromo-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (5 g), 3-nitrobenzyl bromide (2.72 g), potassium carbonate (3.65 g) and potassium iodide (400 mg) in DMF (100 ml) was stirred for 65 h at room temperature. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silicagel in heptane/ethyl acetate 1/0→0/1 (v/v) as eluent.
Reaction SMILES: [C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2C(=O)C3=CC=CC=C3C2=O)=[C:7]([O:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.C(Cl)Cl>[C:1]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][NH2:10])=[C:7]([O:23][CH:24]2[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(C(C)(C)C)ccc2CN)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of N-[4-tert-butyl-2-(1-Boc-piperidin-4-yloxy)benzyl]phthalimide (0.243 g, 0.49 mmol) in 3 mL absolute ethanol was added hydrazine (0.062 mL, 1.98 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, diluted with methylene chloride; and the resulting white solid filtered off. The solvent of the filtrate was evaporated in vacuo. The remaining material was re-dissolved in a minimum amount of chloroform, sonicated, and any additional white solid filtered off. The filtrate was concentrated in vacuo to afford the amine (0.170 g, 95%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[O:4][CH:3]1C(OC)=O.CO.Cl>O>[O:1]=[C:2]1[CH2:3][O:4][C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[O:7][CH2:8]1
Reactant: COC(=O)C1Oc2ccccc2OCC1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: O=C1COc2ccccc2OC1

Procedure:
3-Oxo-4-carbomethoxy-3,4-dihydro-2H-1,5-benzodioxepin (110 g.) is added to a mixture of methanol (210 ml.), concentrated hydrochloric acid (50 ml.) and water (160 ml.) and the mixture then is refluxed for 18 hours. The product is extracted with ether, and the ether extract washed with four 50 ml. portions of sodium bicarbonate solution, then twice with 50 ml. portions of water. After drying the washed ether extract over magnesium sulfate and evaporation to remove the solvent there is obtained 3-oxo-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[N:14]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[C:17](=O)[CH2:16][CH2:15]2.Cl.O1CCOCC1>C(O)(=O)C>[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:17]3[CH:18]4[CH2:21][CH2:22][N:14]([CH2:15][C:16]=3[C:8]=2[CH:7]=1)[CH2:20][CH2:19]4)(=[O:5])=[O:4]
Reactant: O=C1CCN2CCC1CC2
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 80 °C

Procedure:
A mixture of (4-(methylsulfonyl)phenyl)hydrazine hydrochloride (1105 mg, 5.0 mmol; Acros), 1-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol; Example 2A), 4 N HCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and acetic acid (15 mL) was heated to 80° C. overnight (16 hours), then cooled to room temperature. The solvent was removed, and the residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were concentrated in vacuo and purified by reverse-phase HPLC [Waters XBridge RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.05-2.14 (m, 4H), 3.02-3.15 (m, 6H), 3.20-3.28 (m, 2H), 4.29 (s, 2H), 7.47 (d, J=8 Hz, 1H), 7.57-7.62 (m, 1H), 7.95 (d, J=1 Hz, 1H); MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][O:9][CH2:8][C@H:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3]1=[O:27].[OH:28][C:29]1[C:30]([C:37](O)=[O:38])=[N:31][CH:32]=[CH:33][C:34]=1[O:35][CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>C(Cl)Cl>[CH2:12]([O:11][C@@H:7]1[C@@H:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][O:4][C:3](=[O:27])[C@@H:2]([NH:1][C:37](=[O:38])[C:30]2[C:29]([OH:28])=[C:34]([O:35][CH3:36])[CH:33]=[CH:32][N:31]=2)[CH2:10][O:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccnc(C(=O)O)c1O
Reactant: N[C@H]1COC[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)COC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccnc(C(=O)N[C@H]2COC[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)COC2=O)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a mixture of (3S,7S,8S)-3-amino-7,8-bis(benzyloxy)-1,5-dioxonan-2-one (47 mg, 0.127 mmol), 3-hydroxy-4-methoxypicolinic acid (32.1 mg, 0.190 mmol) and HATU (80 mg, 0.202 mmol) in a vial were added CH2Cl2 (1.5 mL), followed by 4-methylmorpholine (0.083 mL, 0.759 mmol), and the resulting suspension was stirred at room temperature for 12 h. The resulting orange solution was directly purified by flash chromatography (SiO2) to afford the title compound as a white foam (32 mg, 48%): 1H NMR (400 MHz, CDCl3) δ 11.90 (d, J=0.6 Hz, 1H), 8.61 (d, J=8.2 Hz, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.43-7.24 (m, 11H), 6.86 (d, J=5.2 Hz, 1H), 5.03 (ddd, J=8.2, 6.8, 6.0 Hz, 1H), 4.80-4.62 (m, 5H), 4.21-4.07 (m, 2H), 3.93 (s, 3H), 3.85 (s, 1H), 3.79-3.65 (m, 2H), 3.55-3.47 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 170.83, 168.92, 155.37, 148.76, 140.66, 137.97, 137.94, 130.17, 128.48, 128.43, 127.91, 127.89, 127.87, 127.81, 109.61, 81.52, 79.29, 73.80, 73.44, 73.24, 72.97, 63.91, 56.10, 52.25; ESIMS m/z 524.1 ([M+H]+).