Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.[ClH:39]>CO.CCOCC>[ClH:39].[ClH:39].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:24])([F:26])[F:25])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 50 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(4-(trifluoromethyl)phenyl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (95 mg, 0.18 mmol) was dissolved in MeOH (2 mL) and 2 N HCl in Et2O (10 mL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et2O to provide the title compound (45 mg, 50%) as a pale yellow solid: mp 318-323° C.; 1H NMR (500 MHz, CD3OD) δ 7.95 (d, J=8.2 Hz, 2H), 7.84 (d, J=8.2 Hz, 2H), 7.81 (d, J=7.1 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.14 (dd, J=8.3, 1.3 Hz, 1H), 6.96 (d, J=1.6 Hz, 1H), 6.87 (dd, J=7.1, 1.7 Hz, 1H), 4.50 (s, 2H), 3.76 (s, 3H), 3.68 (t, J=6.1 Hz, 2H), 3.22 (t, J=6.1 Hz, 2H); ESI MS m/z 424 [M+H]+; HPLC (Method B) 97.6% (AUC), tR=13.9 min.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CON(C)[C:12](=[O:29])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])=[CH:18][CH:17]=1.O.[ClH:32]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[ClH:32].[C:1]1([C:12](=[O:29])[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH3:23])=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON(C)C(=O)CCCc1ccc(C(C)N2CCCC2)cc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(c1ccc(CCCC(=O)c2ccccc2)cc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenylmagnesium bromide (2 mol/l THF solution, 1.6 ml) in toluene (7 ml) was added dropwise a solution of N-methoxy-N-methyl-4-{4-[1-(1-pyrrolidinyl)ethyl]phenyl}butanamide (200 mg, 0.66 mmol) obtained in Reference Example 89 in toluene (3 ml) under a nitrogen atmosphere under ice-cooling. After stirring at room temperature for 1 hr, the reaction solution was poured into water (40 ml), and extracted with ethyl acetate (40 ml×2). The extract was washed successively with 10% sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (developing solvent; hexane:ethyl acetate=10:1) to give a colorless oil. The oil was dissolved in ethyl acetate (10 ml), and 4N-hydrochloric acid (ethyl acetate solution; 0.2 ml) was added dropwise under ice-cooling. The mixture was stirred for 5 min., and the solvent was evaporated under reduced pressure. The residue was powderized with isopropyl ether and hexane, and washed with hexane to give the title compound.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[CH:11][CH:10]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[CH:14][C:15](=[O:19])[N:16]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:11][CH:10]=1
Reactant: O=c1cnc2ccc(Cl)cc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)cnc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen gas flow, to a mixture of NaH (55% in oil, 515 mg) and DMF (5 mL) was added a mixture of 7-chloroquinoxalin-2(1H)-one (2.00 g) and DMF (35 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction mixture was ice-cooled and ethyl bromoacetate (1.3 mL) was added thereto, followed by stirring at room temperature for 7 hours. The reaction mixture was added to water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/MeOH=100/0-98/2). The obtained solid was washed with Hex to obtain ethyl (7-chloro-2-oxoquinoxalin-1(2H)-yl)acetate (2.21 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[NH2:15])=[O:5])[CH3:2].C(O[BH-](O[C:26](=O)[CH3:27])OC(=O)C)(=O)C.[Na+].Cl[CH2:31][CH2:32]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[NH:15][CH2:31][CH2:32][CH2:26][CH3:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)nc2n1CCCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCCl
Agent: [Na+]
Solvent: ClCCl
Product: CCCCNc1nc2n(c1C(=O)OCC)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
Compound E was dissolved in DCE (150 mL) and n-butylaldehyde (49.7 mmol, 4.4 mL, 1.5 eq.) was added thereto. Sodium triacetoxyborohydride (11.93 g, 56.3 mmol, 1.7 eq.) was then gradually added and the reaction mixture was stirred for four hours at room temperature. The reaction mixture was diluted with DCM (500 ml) and washed with saturated aqueous NaHCO3 solution (500 mL). The aqueous phases were extracted with DCM (100 mL) and the combined organic phases were washed with saturated aqueous NaCl solution (500 mL), dried over sodium sulphate and the solvent was removed under vacuum. The untreated product was purified by means of column chromatography (SiO2, heptane/EtOAc 4:1→3:1) and 5.7 g (65%) of the desired product 2-butylamino-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (F) were obtained.
Reaction SMILES: [C:1]([C@@:3]1([CH2:31][CH3:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([N:21](S(C)(=O)=O)[S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:30])#[N:2].[OH-].[Li+].[Cl-:35].[NH4+]>O1CCCC1>[ClH:35].[C:1]([C@@:3]1([CH2:31][CH3:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:30])#[N:2]
Reactant: [Cl-]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3)n2)C1=O
Agent: [Li+]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3cccc(NS(C)(=O)=O)c3)n2)C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude N-(3-((4-((3R)-3-cyano-3-ethyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)phenyl)-N-(methylsulfonyl)methanesulfonamide (100 mg) in tetrahydrofuran (3.0 mL) was added 4 M aqueous lithium hydroxide solution (52 μL), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the residue in ethanol (3.0 mL) was added 1 N hydrochloric acid (72 μL), and the mixture was stirred at room temperature for 5 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (12 mg).
Reaction SMILES: N[C:2]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[Cl:26])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].C(O)(=O)C.[N+:31]([O-:34])(O)=[O:32].OO>O>[Cl:26][C:17]1[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][C:16]=1[O:15][C:12]1[CH:13]=[CH:14][C:2]([N+:31]([O-:34])=[O:32])=[C:3]([CH:11]=1)[C:4]([NH:6][S:7]([CH3:10])(=[O:8])=[O:9])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1N
Agent: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
A stirred solution is prepared containing 39.5 g of 2-amino-5-(2-chloro-4-trifluoromethylphenoxy)-N-methanesulphonyl benzamide of the formula (V), R1 =methyl, 1380 ml of glacial acetic acid and 1.0 g of concentrated nitric acid at about 40° C. To the solution is added 138 g of a 30% by weight hydrogen peroxide in water solution and the reaction mixture is raised to and maintained at about 70° C. for 20 hours. The solution is then poured slowly into about 3 liters of ice water with precipitation of crude product. After filtration, the product is isolated as a solid, m.p. 175°-183° C., containing 68% of the compound of formula (I), R1 =methyl, as determined by high pressure liquid chromatography, thin layer chromatography and its mass spectrum. Recrystallization from aqueous methanol yields the product 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitro-N-methanesulphonyl benzamide, m.p. 216°-218° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([CH3:28])=[N:7][C:8]3[C:13]([N:14]=2)=[C:12]([C:15]2[NH:19][C:18]4[C@H:20]([C@H:24]([OH:26])[CH3:25])[NH:21][C:22](=[O:23])[C:17]=4[CH:16]=2)[C:11]([F:27])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[Li+].[OH-:30].Cl>O1CCOCC1.O>[NH2:21][C@H:20]([C:18]1[NH:19][C:15]([C:12]2[C:11]([F:27])=[CH:10][CH:9]=[C:8]3[C:13]=2[N:14]=[C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)[C:6]([CH3:28])=[N:7]3)=[CH:16][C:17]=1[C:22]([OH:23])=[O:30])[C@H:24]([OH:26])[CH3:25]
Reactant: Cc1nc2ccc(F)c(-c3cc4c([nH]3)[C@H]([C@@H](C)O)NC4=O)c2nc1NC1CC1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2ccc(F)c(-c3cc(C(=O)O)c([C@@H](N)[C@@H](C)O)[nH]3)c2nc1NC1CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
The yellow foam (352b) (184.5 mg) in 1,4-dioxane (6.0 mL) was treated with 1.0 M aq. LiOH (3.0 mL, 3.0 mmol). The mixture was heated at 100° C. for 16 h. The mixture was lyophilized to give a yellow solid containing m/z (ESI, +ve) 614.1 (M+H). The yellow solid was dissolved in 1 mL of dioxane and treated with a solution of 4 M HCl in 1,4-dioxane (5 mL) with a few drops of water added to aid solubility. The mixture was stirred at RT for 4 h, after which time bis-deprotection was observed by LC-MS. The mixture was lyophilized to give 2-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (352c) as a brown solid. A solution of the 2-((1R,2R)-1-amino-2-hydroxypropyl)-5-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (352c) in DMF (3.0 mL) was treated with TEA (0.20 mL, 1.44 mmol) followed by PyBOP (NovaBiochem) (300 mg, 0.57 mmol). The mixture was stirred at RT for 16 h. The mixture was concentrated, dissolved in DMSO (5.0 mL), and purified by preparative HPLC (Gradient: 10-100% MeCN in H2O, modified with 0.1% TFA) to give (R)-2-(3-(cyclopropylamino)-6-fluoro-2-methylquinoxalin-5-yl)-6-((R)-1-hydroxyethyl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one bis(2,2,2-trifluoroacetate) (352) (54 mg, 0.089 mmol) as a red gum. LC-MS m/z 382.1, [M+H]+; 19F NMR (DMSO-d6; 376 MHz): δ −108.08 (s, 1F), −74.95 (s, 6F).
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1.S(Cl)([Cl:13])=O>>[ClH:13].[Cl:13][CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH2:8][CH2:9][CH3:10])[CH:7]=1
Reactant: CCCn1cnc(CO)c1
Reactant: O=S(Cl)Cl
Product: CCCn1cnc(CCl)c1
Product: Cl
Temperature: 90 °C

Procedure:
To 4-hydroxymethyl-1-propylimidazole (2.5 g), thionyl chloride (25 ml) was added by portions at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol. The solvent was distilled off again under reduced pressure, to give 4-chloromethyl-1-propylimidazole hydrochloride (3.47 g) as brown oil.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([OH:24])=O)[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:4]=1[CH3:36])#[N:2].C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([CH2:21][C:22]([NH2:38])=[O:24])[C:6](=[O:25])[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[C:4]=1[CH3:36])#[N:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(=O)O)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(CC(N)=O)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 0.33 h
Yield: 94.4 %

Procedure:
The reaction was carried out under argon. 2-[(6S)-5-Cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidin-1(2H)-yl]acetic acid (90 mg, 174 μmol; Example 21) was initially charged in DMF (3 ml), HATU (330 mg, 868 μmol, 5 eq.) was added at 0° C. and the mixture was stirred for 20 min. Ammonium chloride (18.1 mg, 340 μmol, 5 eq.) and N,N-diisopropylethylamine (224 mg, 1736 μmol, 10 eq.) were then added, and the mixture was stirred at RT until complete conversion had been achieved (after a number of hours; HPLC control). The reaction mixture was then concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave the title compound as a colorless solid (85 mg, 94% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1ccccc1Nc1ccccc1)c1ccccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Brc1ccccc1-c1nc2ccccc2n1-c1ccccc1
Temperature: 100 °C
Yield: 66 %

Procedure:
To a solution of 2-bromo-N-(2-(phenylamino)phenyl)benzamide (10.7 g, 29 mmol) in anhydrous 1,4-dioxane (˜100 mL), was added POCl3 (6.92 g, 45 mmol) slowly. The whole was heated to about 100° C. under argon overnight. After cooling the mixture to room temperature, the mixture was poured into ice (˜150 g), and then neutralized with NaHCO3. After filtration, the solid was collected then dissolved in dichloromethane (˜250 mL), which was washed with water (˜250 mL). The aqueous solution was extracted with dichloromethane (˜100 mL×2). The organic phase was combined and dried over Na2SO4, concentrated, and recrystallized in dichloromethane/hexanes to give a light grey solid (6.68 g, 66% yield).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CO.[CH2:9]([O:16][C:17](=[O:30])[CH:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:20]=O)C1C=CC=CC=1.COP(C(=[N+]=[N-])C(=O)C)(=O)OC>C(OCC)C>[CH3:9][O:16][C:17](=[O:30])[CH:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:19][C:20]#[CH:1]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC(CC=O)C(=O)OCc1ccccc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 0.17 h

Procedure:
Potassium carbonate (1.687 g, 12.2 mmol) was added to an anhydrous methanol (91.5 mL) solution of 2-tert-butoxycarbonylamino-4-oxo-butyric acid benzyl ester (1.875 g, 6.10 mmol) and the reaction stirred 10 minutes. (1-Diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (1.407 g, 7.32 mmol) was added and the reaction was stirred at room temp temperature 1 hour. The reaction was poured into diethyl ether and washed 4 times with 5% sodium bicarbonate, dried over magnesium sulfate and concentrated (1.05 g, crude product mixture). The crude product was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 5.39-5.31 (m, 1H), 4.49-4.41 (m, 1H), 3.77 (s, 3H), 2.79-2.65 (m, 2H), 2.03 (s, 1H), 1.59 and 1.44 (2 singlets, rotamers, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[CH:7][CH:8]=2)[C:3]1=[O:14].[CH3:15][O:16][C:17]1[CH:25]=C2C(CC(C)C2=O)=CC=1.C([OH:30])C.C(O)(=O)C>O>[OH:14][C:3]1([CH2:25][C:17]([O:16][CH3:15])=[O:30])[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: CCO
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Reactant: CC1Cc2ccc([N+](=O)[O-])cc2C1=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CC1(O)C(C)=Cc2ccc([N+](=O)[O-])cc21

Procedure:
The procedure of Example 1C is followed using 2-methyl-6-nitro indanone in equivalent quantities in place of 6-methoxy-2-methyl-indanone used therein. After the mixture is condensed, 30 ml. of ethanol and 50 ml. of acetic acid are added. The mixture is then poured into 700 ml. of water. Extraction with ether gives methyl 3-hydroxy-2-methyl-5-nitro-3-indenylacetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.Cl[CH2:22][CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][C:25]1=[O:33].[C:34]([O-])([O-:36])=[O:35].[K+].[K+]>CN(C=O)C>[C:25]([OH:33])(=[O:8])[C:34]([OH:36])=[O:35].[O:33]=[C:25]1[N:24]([CH2:23][CH2:22][N:1]2[CH2:2][CH2:3][CH:4]([CH:7]3[C:13]4=[CH:14][CH:15]=[CH:16][N:12]4[CH2:11][C:10]4[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=4[O:8]3)[CH2:5][CH2:6]2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26]1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)C(=O)O
Product: O=c1[nH]c2ccccc2n1CCN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 50 ml DMF, were added 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (4.0 g, 0.015 mole), 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one (3.9 g, 0.02 mole), milled K2CO3 (20 g, 0.15 mole) and KI (0.01 g). After stirring at 80° C. for three hours, the mixture was cooled, filtered and evaporated to an oil, which was stirred with water and extracted with ethyl acetate. The ethyl acetate layer was washed twice with water and dried (saturated NaCl, anhydrous MgSO4).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[O:27]([CH2:34][CH2:35][C:36](O)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:36]([CH2:35][CH2:34][O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)CCOc1ccccc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(CCOc3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 3-phenoxypropanoic acid, the title compound was obtained in 84% purity by HPLC. MS(ESI+): m/z=483.3.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH2:2]1.Cl.[CH3:11][NH:12][CH3:13].Cl.[C:15]([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:11][N:12]([CH2:15][CH:7]1[C:6](=[O:9])[CH2:5][CH2:4][C:3]2([CH2:2][CH2:1]2)[CH2:8]1)[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC2(CC1)CC2
Reactant: CNC
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: CN(C)CC1CC2(CCC1=O)CC2
Yield: 38.4 %

Procedure:
Stir a mixture of spiro[2.5]octan-6-one (252 mg, 2.03 mmol), (HCHO)n (61 mg, 2.03 mmol), dimethylamine hydrochloride (166 mg, 2.03 mmol) and 0.3 mL of conc. HCl in MeCN (30 mL) at 60° C. for 6 hours. Quench the reaction with saturated aqueous NH4Cl solution (15 mL). Basify the aqueous solution with K2CO3 to pH=9. Extract the aqueous mixture with EtOAc (30 mL×2). The combined organic layers are washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purify the residue by silica gel chromatography (CH2Cl2:MeOH=30:1) to afford 5-Dimethylaminomethyl-spiro[2.5]octan-6-one as brown oil (142 mg, yield: 38.4%). MS (m/z): 182 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:6])[CH3:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl.O>[CH3:5][C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][C:14](=[O:16])[NH:1][CH2:2][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)(CCN)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC1(c2ccccc2)CCNC(=O)O1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
A solution of 4-amino-2-phenylbutan-2-ol (5.0 g, 0.03 mol) in CH2Cl2 (50 mL) was added triphosgene (2.97 g, 0.01 mol) and Et3N (9.09 g, 0.09 mol) at 0° C. After stirring for 1 h, the mixture was diluted with water and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by chromatography to afford 6-methyl-6-phenyl-1,3-oxazinan-2-one (1.14 g, 20%). 1H NMR (CDCl3): 1.60 (s, 3H), 1.80-2.00 (m, 1H), 2.30-2.40 (m, 1H), 3.15-3.21 (m, 1H), 6.00 (s, 1H), 7.30-7.45 (m, 5H), 8.90-9.01 (m, 1H).
Reaction SMILES: I[CH3:2].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([OH:23])[CH3:22])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:12]1.[H-].[Na+]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH:21]([O:23][CH3:2])[CH3:22])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:12]1
Reactant: CC(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Iodomethane (6.0 μL, 0.10 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (40 mg, 0.10 mmol) and sodium hydride (60% dispersion in mineral oil; 6.7 mg, 0.15 mmol) in tetrahydrofuran (1 mL) at 0° C. After 2 h, the mixture was allowed to warm to ambient temperature. Additional iodomethane (6.0 μL, 0.10 mmol) and sodium hydride (60% dispersion in mineral oil; 2.2 mg, 0.05 mmol) were added every 1.5 h over a total of 4.5 h, after which the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (16 mg). MS 422.2 (M+1).