Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB(/[CH:26]=[CH:27]/[CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:31][CH2:30]2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]2[NH:7][C:6](=[O:14])[C:5]3[S:15][CH:16]=[CH:17][C:4]=3[C:3]=2[C:2]=1/[CH:26]=[CH:27]/[CH2:28][N:29]1[CH2:30][CH2:31][CH:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH2:34]1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NC1CCN(C/C=C/B2OC(C)(C)C(C)(C)O2)CC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1/C=C/CN1CCC(NC(=O)OC(C)(C)C)CC1
Yield: 57.2 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (180 mg, 0.48 mmol) was reacted with (E)-tert-butyl 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]piperidin-4-ylcarbamate (100 mg, 0.32 mmol) to afford the desired product (86 mg, 57%) as a brown solid: ESI MS m/z 470 [C25H31N3O4S+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=2[C:6](OC)=[O:7])[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]1([C:4]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:5]=2[CH2:6][OH:7])[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(F)cccc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1c(F)cccc1C1CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of methyl 2-cyclopropyl-6-fluorobenzoate (3, 4.54 g, 23.4 mmol) in anhydrous tetrahydrofuran (30 mL) at room temperature was added lithium aluminium hydride (1.42 g, 37.4 mmol) in small portions and the mixture was stirred overnight. The reaction mixture was cooled to 0° C. and water (3 mL) was added dropwise, the mixture was warmed to room temperature and an additional portion of water (30 mL) was added. The solids were removed by filtration, and the aqueous filtrate was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate and evaporated. Purification by column chromatography over silica using n-hexane:ethyl acetate (8:1) as eluent afforded the title compound (3.28 g, 19.8 mmol, 84%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:12]1([CH:15](O)[CH3:16])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH:12]1([CH:15]([O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH3:16])[CH2:14][CH2:13]1
Reactant: CC(O)C1CC1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(OC(C)C2CC2)c1
Temperature: 25 °C

Procedure:
Methyl 3-hydroxybenzoate (10.0 g, 65.7 mmol) in toluene (65.7 ml) was cooled to 0° C. and added 1-cyclopropylethanol (6.43 ml, 65.7 mmol), triphenylphosphine (18.9 g, 72.3 mmol), and DIAD (14.1 ml, 72.3 mmol). The reaction warmed to rt for sixteen hours. The reaction mixture was filtered through a fritted funnel to remove precipitated triphenylphosphine oxide and washed with toluene. The filtrate was concentrated. The residue was purified by column chromatography on silica gel Biotage 65i, eluting with 10% ethyl acetate/hexanes to give a colorless oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
To 60% sodium hydride (9.8 g, 245 mmol) in 250 mL dimethylformamide at 5° C. under nitrogen is added portionwise 3-bromophenol (42.6 g, 246 mmol). After thirty minutes a solution of 2-(chloromethyl)quinoline (43.6 g, 246 mmol) in 250 mL dimethylformamide is rapidly added. The reaction is allowed to warm to room temperature. After overnight stirring, the reaction is freed of solvent and then partitioned between 1N sodium hydroxide and methylene chloride. The organic layer is separated, dried over magnesium sulfate and evaporated to 67.9 g of a yellow solid. Recrystallization from acetonitrile affords 42.8 g (55%) of brown crystals, m.p. 79°-81° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[C:11]([O:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)(=[O:19])=[O:18])[CH:12]=[C:13]([CH3:15])[CH:14]=1
Reactant: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Yield: 97.3 %

Procedure:
A mixture of 3-trifluoromethylbenzenesulfonic acid 3-benzyloxy-5-methylphenyl ester (633 mg, 1.5 mmol), as prepared in the preceding step, and 10% palladium on carbon (100 mg) in ethanol (20 mL) was hydrogenated (balloon) for 3 h. The catalyst was removed by filtration through diatomaceous earth (methanol washes) and the filtrate was evaporated in vacuo to give the title compound as a colorless syrup (485 mg, 97%). 1H-NMR (300 MHz, CDCl3 /CD3OD) δ 2.20 (s, 3H), 6.26 (s, 1H), 6.30 (t, 1H), 6.57 (s, 1H), 7.74 (t, 1H), 7.96 (d, 1H), 8.05 (d, 1H), 8.09 (s, 1H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+].C(OCC)C>C(O)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Nc1ccc(S)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(N)cc2)s1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
The product of Example 430A (1.0 g, 4.244 mmol), 4-aminothiophenol (0.797 g, 6.366 mmol), and anhydrous sodium acetate (1.74 g, 21.22 mmol) were heated in anhydrous ethanol (40 mL) under a nitrogen atmosphere at reflux for 30 minutes. The reaction was cooled to room temperature, partitioned with ethyl acetate (100 mL) and water (50 mL), separated layers, and washed organic phase with water (2×50 mL) and brine (50 mL). The organic extract was dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Trituration of the resulting solid with ethyl ether (2×30 mL) afforded the title compound as a bright yellow solid (1.167 g, 3.598 mmol, 85%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.24 (t, J=7.17 Hz, 3 H) 4.24 (q, J=7.23 Hz, 2 H) 5.94 (s, 2 H) 6.71 (d, J=8.82 Hz, 2 H) 7.35 (d, J=8.46 Hz, 2 H) 8.08 (s, 1 H); MS (ESI+) m/z 325 (M+H)+, MS (ESI−) m/z 323 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Cl.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CN(C)CCCl
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Agent: Cl
Product: CN(C)CCN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-[2-(dimethylamino)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 238) and 2-(dimethylamino)ethyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(N(C(C)C)C(C)C)C.[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>C(Cl)Cl>[CH3:27][O:26][C:22](=[O:25])[CH2:23][S:24][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: COC(=O)CS
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CSc1nc(SC)nc(Cl)c1C=O
Temperature: 25 °C

Procedure:
To an ice-cooled solution (−10° C.) of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde (2.0 g, 8.97 mmol) and iPr2EtN (0.82 mL, 8.97 mmol) in DCM (40 mL) was added methyl thioglycolate (1.56 mL, 8.97 mmol) in DCM (20 mL) over 15 min. The reaction mixture was let warm to RT, then washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated. The product was used without further purification. ESIMS calcd 293 (M++H), found 293 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[CH3:14][CH:13]([CH3:15])[CH2:12][C:11]([NH:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:16]
Reactant: Nc1cnccc1C(=O)O
Reactant: CC(C)CC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(=O)Nc1cnccc1C(=O)O
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-aminoisonicotinic acid 1-1 (3.89 g, 28.16 mmol) in DMF at 0° C. was added isovaleryl chloride (3.73 g, 30.97 mmol) and the reaction was stirred at 0° C. After 2.5 h, water was added to the reaction mixture and a precipitate formed which was collected by filtration and washed with ether to afford the title compound as a bone colored powder. 1H NMR (500 MHz, CDCl3) δ 0.95 (d, J=7 Hz, 6H), 2.06-2.13 (m, 1H), 2.27 (d, J=7 Hz, 2H), 7.73 (d, J=4.5 Hz, 1H), 8.41 (d, J=5 Hz, 1H), 9.37 (s, 1H). MS [M+H] C11H14N2O3=223.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([NH2:17])[C:6](=[O:16])[NH:7]2.Cl.N[OH:20].O>C(O)CCC>[Br:1][C:2]1[CH:11]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[N:17][OH:20])[C:6](=[O:16])[NH:7]2
Reactant: Nc1nc2c(Br)cc(C(F)(F)F)cc2[nH]c1=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Br)c2[nH]c1=NO
Temperature: 25 °C
Yield: 86.1 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973) was used. A mixture of 5-bromo-7-trifluoromethyl-3-aminoquinoxalin-2(1H)-one (75 mg, 0.24 mmol) and hydroxylamine hydrochloride (38 mg, 0.54 mmol; Aldrich Co.) in 3 mL of 1-butanol was heated to reflux. The resulting suspension was stirred under reflux for 12 h. The resulting suspension was cooled to 25° C., and H2O was added (6 mL). A pale yellow precipitate appeared. The mixture was vacuum filtered and the solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 67 mg (86% ) of 5-bromo-7-trifluoromethyl-3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one (tentatively named as this since the regiochemistry is not sure) as a pale yellow solid of a new compound: mp 221°-223° C. 1H NMR (300 MHz, DMSO-d6) δ 11.205 (br s, 1H, NH), 10.393 (br s, 1H, NH), 7.639 (s, 1H, H-7), 7.435 (s, 1H, H-5). LRMS: 323 (M+, 80%), 293 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(=[CH:47][C:48]([O:50][CH3:51])=[O:49])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=[CH:47][C:48]([O:50][CH3:51])=[O:49])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 3.08 g (7.5 mmol) of 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanal in 40 mL chloroform is added 2.88 g (8.4 mmol) of methyl (triphenylphosphoranylidene)-acetate and then subjected to reflux for 3 hours. The solvent is evaporated and the residue taken up in ether and extracted with 0.5N HCl (3×20 mL). The aqueous extracts are combined and washed with ether. The aqueous phase is adjusted to pH 8 and then extracted with methylene chloride (3×50 mL). Combined organic extracts are dried (MgSO4), filtered and then evaporated to give an amber oil. This is purified by flash chromatography using 7:3 EtOAc: hexane as the eluent to give methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-oct-2-enoate as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][CH:23]=[C:22]([N:4]2[C:5]3[C:6](=[N:7][C:8]([C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]#[N:14])=[CH:9][CH:10]=3)[N:2]([CH3:1])[C:3]2=[O:19])[CH:21]=1
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(-c2cccc(-c3ccccc3)c2)c2ccc(-c3ccccc3C#N)nc21
Reaction time: 96 h

Procedure:
To a solution of 4-1 (13 mg, 0.052 mmol) in DCM (0.25 mL) was added copper (II) acetate, biphenyl-3-ylboronic acid (30 mg, 0.16 mmol) and triethylamine (0.022 mL, 16 mg, 0.16 mmol) at room temperature. After 4 days, the crude mixture was diluted in DCM (4 mL), filtered, concentrated and purified via reverse phase chromatography (1-100% Acetonitrile, 0.1% TFA in H2O) and the desired fractions were concentrated to give 76-1. MS (M+H)+: observed=403.0, calculated=403.2.
Reaction SMILES: [Br-].[Al+3].[Br-].[Br-].[CH3:5][C:6]12[CH2:14][C:10]1([C:11]([OH:13])=[O:12])[N:9]1[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:8]1[S:7]2.Cl>C(=S)=S>[CH3:5][CH:6]1[CH:14]=[C:10]([C:11]([OH:13])=[O:12])[N:9]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:8]2[S:7]1
Reactant: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)Cc3ccccc3)[C@H]1S2
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: S=C=S
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reaction time: 20 h
Yield: 50 %

Procedure:
A solution of aluminum bromide (1.7 g.) in carbon disulfide (40 ml.) was dropwise added under stirring at room temperature to a suspension of 2-methyl-2,3-methylene-6-(2-phenylacetamido)penam-3-carboxylic acid (0.66 g.) in carbon disulfide (70 ml.) and the mixture was stirred for 20 hours at the same temperature. After the reaction was completed, the reaction mixture was poured into 5% hydrochloric acid (200 ml.) and the hydrochloric acid layer was separated and then extracted with ethyl acetate. The extract was washed with water and dried, after which the solvent was distilled off. The residue was recrystallized from acetonitrile to give 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylic acid (0.33 g.), mp 109° C. (dec.).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[C:18]4[C:17]5[CH:19]=[C:20]([NH:23]C(C6C(Cl)=NC=CC=6)=O)[CH:21]=[CH:22][C:16]=5[CH2:15][CH2:14][C:13]=4[C:12]([C:33]([NH2:35])=[O:34])=[N:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.N>C(O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:16]2[CH2:15][CH2:14][C:13]3[C:12]([C:33]([NH2:35])=[O:34])=[N:11][N:10]([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[C:18]=3[C:17]=2[CH:19]=1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(NC(=O)c3cccnc3Cl)cc1-2
Agent: N
Solvent: CCO
Product: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
The title product of Step 3 was dissolved in anhydrous ethanol and then an approximately equal volume of liquid ammonia was added. The resulting mixture was sealed in a pressure vessel and then stirred overnight at 100° C. After cooling, the mixture was concentrated. The residue was taken up in dichloromethane-methanol and chromatographed over silica gel using ethyl acetate as eluent to give the title compound, 890 mg, as an oil which crystallized on standing. Anal. for C19H16N4O3.0.75H2O (MW 361.87): Calc'd.: C, 63.06; H, 4.46, N, 15.48. Found: C, 63.24; H, 4.70, N, 14.58.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]([F:26])([F:25])[CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]1.CI>O1CCCC1>[CH3:1][C:18]1([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16][CH:15]([C:14]([F:25])([F:26])[F:13])[CH2:20][CH2:19]1
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C1CCC(C(F)(F)F)CC1
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCC(C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 104.1 %

Procedure:
To a solution of diisopropylamine (22.0 mL, 124.0 mmol) in tetrahydrofuran (60 mL) was added n-BuLi (2.0 M solution in hexane, 59.0 mL, 95.0 mmol) at 0° C. and the reaction mixture was allowed to stir at same temperature for 20 minutes before cooled to −78° C. Methyl 4-(trifluoromethyl)cyclohexanecarboxylate (10.0 g, 48.0 mmol) in tetrahydrofuran (60 mL) was added dropwise at −78° C. The reaction mixture was stirred at same temperature for 2 hours and then neat methyl iodide (4.5 mL, 72.0 mmol) was added dropwise. After stirring at −78° C. for 1 hour, the reaction mixture was warmed to ambient temperature and stirred for 16 hours, before quenched with 25% aqueous ammonium chloride solution (100 mL) at 0° C. and extracted with ethyl acetate. The organic layer was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo to afford the title compound (11.2 g, 99%) as a brown colored oil: 1H NMR (300 MHz, CDCl3) δ 3.70 (s, 3H), 2.32-2.28 (m, 2H), 2.01-1.80 (m, 3H), 1.42-1.08 (m, 7H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].CC[N:15](C(C)C)[CH:16]([CH3:18])[CH3:17].CC(N)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[NH:15][CH:16]([CH3:18])[CH3:17]
Reactant: Clc1nc2ccncc2nc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)N
Product: CC(C)Nc1nc2ccncc2nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of 2,3-dichloropyrido[3,4-b]pyrazine (2.5 g, 12.50 mmol) and DIPEA (6.53 mL, 37.5 mmol) in DCM (25 mL) was added propan-2-amine (1.065 mL, 12.50 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min, warmed slowly to 23° C., and stirred for 12 h. The crude mixture was partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl (100 mL). The layers were separated and the aqueous phase was washed with EtOAc (4×100 mL). The organic extracts were combined, washed with brine (50 mL), dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo. The crude material was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a gradient eluant of 50% to 75% EtOAc in heptane on a 80 g silica gel column (Single Step™) to give the title compound (1.828 g, 65.7%) as a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=6.6 Hz, 6H), 4.39-4.49 (m, 1H), 7.49 (dd, J=5.8, 0.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.95 (d, J=0.8 Hz, 1H); ESI-MS m/z [M+H]+ 223.1.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[C:30]([F:31])=[CH:29][C:10]([O:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[C:20](=[O:25])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:28])=[C:9]([O:32]C)[CH:8]=1)[CH3:6].[Cl-].[NH4+]>ClCCl>[CH2:5]([C:7]1[C:30]([F:31])=[CH:29][C:10]([O:11][C:12]2[CH:27]=[CH:26][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[C:20](=[O:25])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:28])=[C:9]([OH:32])[CH:8]=1)[CH3:6]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCN(C)C(=O)C3)cc2F)cc1F
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCN(C)C(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A commercial solution of boron tribromide (1N in DCM, 1.33 mL, 1.32 mmol) was added to a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoyl]-1-methylpiperazin-2-one (which may be prepared in accordance with the experimental described in Example 5, step 2; 200 mg, 0.49 mmol) in dichloromethane (1.6 mL) placed under argon at −30° C. The reaction mixture was stirred at room temperature overnight and diluted by addition of dichloromethane (30 mL) and a saturated solution of ammonium chloride (30 mL). After separation, the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a yellow solid (135 mg, 70%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[O:20]1[CH2:21][CH2:22][N:17]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:9]2[C:4]([NH2:1])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:18][CH2:19]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ncccc1Oc1cccc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ncccc1Oc1cccc(N2CCOCC2)c1
Yield: 96.7 %

Procedure:
In a 125 mL round-bottom flask, 4-(3-(2-nitropyridin-3-yloxy)phenyl)morpholine (0.92 g, 3.05 mmol) was dissolved in 30 mL of ethanol and 200 mg of 10% Pd/C (Degussa type, 50% wet) added. The resulting mixture was agitated overnight under the atmospheric pressure of hydrogen. The mixture was filtered and the solvent was evaporated to give the title compound (0.80 g, 97%) as thick oil.
Reaction SMILES: O.[OH-].[Li+:3].C[O:5][C:6]([C:8]1[O:9][C:10]2[CH2:11][N:12]([CH3:17])[CH2:13][CH2:14][C:15]=2[N:16]=1)=[O:7]>O1CCCC1>[CH3:17][N:12]1[CH2:13][CH2:14][C:15]2[N:16]=[C:8]([C:6]([O-:7])=[O:5])[O:9][C:10]=2[CH2:11]1.[Li+:3]
Reactant: COC(=O)c1nc2c(o1)CN(C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2nc(C(=O)[O-])oc2C1
Reaction time: 0.17 h
Yield: 107.6 %

Procedure:
Water (6.0 ml) and lithium hydroxide (99.7 mg) were added to a solution of 2-methoxycarbonyl-5-methyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (800 mg) in tetrahydrofuran (24 ml) at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (825 mg).
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][CH2:13][N:14]1[CH2:17][CH:16]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15]1.[NH4+].[Cl-]>[Fe]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][CH2:13][N:14]2[CH2:15][CH:16]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17]2)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc([N+](=O)[O-])cc2F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)NCC1CN(CC#Cc2cnccc2Oc2ccc(N)cc2F)C1

Procedure:
The title compound was prepared by the reduction of tert-butyl (1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-ynyl)azetidin-3-yl)methylcarbamate (30 mg, 0.66 mmol) in the same manner as in Step E of Example 35 using Fe powder (50 mg, 0.091 mmol) and NH4Cl (96 mg, 1.82 mmol). The product was used in subsequent reactions without any purification. MS (ESI+): m/z 371.24 (100), [(M-C4H9)]+; m/z 427.27 (25), (M+H)+.