Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH:3]\[CH2:4][S:5][CH2:6][C@@H:7]([C:19]([OH:21])=[O:20])[NH:8][C:9](=[O:18])[NH:10][CH2:11][CH2:12][C:13](=[O:17])[O:14]CC.[Li+].[OH-].C(OCC)(=O)C.Cl>C1COCC1.O>[C:13]([CH2:12][CH2:11][NH:10][C:9](=[O:18])[NH:8][C@@H:7]([CH2:6][S:5][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:22][CH2:23]/[CH:24]=[C:25](\[CH3:32])/[CH2:26][CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C:19]([OH:21])=[O:20])([OH:17])=[O:14]
Reactant: CCOC(=O)CCNC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)NCCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 100 mL round bottom flask, Compound D of Example 6 (100 mg, 0.21 mmol) was dissolved in THF (10 mL). LiOH (500 mg, 20 mmol) in water (5 mL) was added to the reaction solution. The reaction mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added to the reaction mixture. The reaction mixture was acidified by 1 N HCl solution (pH=4.0). The organic portion was separated and dried over Na2SO4, concentrated and purified by HPLC (40 mg, 41%) to yield Compound G. 1H-NMR (500 MHz, MeOH-d4): δ 1.62 (bs, 6H), 1.69 (s, 3H), 1.70 (s, 3H), 1.99 (m, 2H), 2.08 (m, 6H), 2.51 (t, J=6.5, 2H), 2.79 (dd, J=7.0, 14.0 Hz, 1H), 2.93 (dd, J=4.5, 8.1 Hz, 1H), 3.17 (dd, J=7.0, 13.0 Hz, 1H), 3.28 (dd, J=9.0, 15.0 Hz, 1H), 3.40 (t, J=6.5 Hz, 3H), 4.50 (dd, J=5.0, 6.5 Hz, 1H), 5.11 (m, 2H), 5.23 (t, J=7.5, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 16.1, 16.2, 17.8, 26.0, 27.4, 27.8, 30.5, 34.4, 35.7, 36.8, 40.8, 40.9, 54.1, 121.7, 125.2, 125.5, 132.1, 136.3, 140.5, 160.3, 175.1, 175.7; ES-MS: mass calcd for Chemical Formula: C22H36N2O5S 440.6. Found (M+Na) m/z 463.3.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12.[CH3:15][O:16][N:17]=[C:18]([C:22]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[CH2:23][Br:24])[C:19](O)=[O:20].O(Cl)Cl.CN(C)C=O>O1CCCC1.CC(C)=O.O>[CH3:15][O:16][N:17]=[C:18]([C:22]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[CH2:23][Br:24])[C:19]([NH:1][CH:2]1[C:13](=[O:14])[N:4]2[CH:5]([C:10]([OH:12])=[O:11])[CH:6]([OH:9])[CH2:7][S:8][C@H:3]12)=[O:20]
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)O
Agent: ClOCl
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 68.7 %

Procedure:
7-Amino-3-hydroxycepham-4-carboxylic acid (10.9 g, purity 84.8%), 2-methoxyimino-3,3,diethoxy-4-bromobutyric acid (syn isomer, 17.9 g), phosporus oxychloride (6.8 ml), N,N-dimethylformamide (5.5 ml), water (100 ml), acetone (50 ml.) and tetrahydrofuran (44 ml) were treated in a similar manner to that of Example 25 (1) to give 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 17.1 g.). The I.R. spectrum and N.M.R. spectrum of the compound were the same as those of Example 28.
Reaction SMILES: [C:1]([O:7][CH2:8]N1C2N=CN=C(C3C=NN(C(C4CCCC4)CC(N)=O)C=3)C=2C=C1)(=O)C(C)(C)C.CC([O-])(C)C.[K+].[NH2:39][C:40]1[C:45]([CH:46]=O)=[C:44]([Cl:48])[N:43]=[CH:42][N:41]=1>C1COCC1>[Cl:48][C:44]1[N:43]=[CH:42][N:41]=[C:40]([NH2:39])[C:45]=1[CH:46]=[CH:1][O:7][CH3:8]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC(N)=O)C4CCCC4)c3)ncnc21
Reactant: Nc1ncnc(Cl)c1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1c(N)ncnc1Cl
Temperature: -2 °C
Reaction time: 1 h

Procedure:
A suspension of (methoxymethyl)triphenyl-phosphonium chloride (11, 276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to −2° C. and 1M KOtBu in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 hr at −2 to −3° C. The deep red-orange mixture was stirred for 1 hr at −2 to −3° C. 4-Amino-6-chloropyrimidine-5-carbaldehyde (10, 115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from −3 to 13° C. and a brown color developed. When the reaction temperature dropped to 10° C., the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred 42 hr. The reaction mixture was cooled to −2° C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2N HCl (4×250 mL) followed by 3N HCl (2×250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6N aqueous NaOH solution and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 hr. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 hr to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (12, 72.3 g, 136.2 g theoretical, 53.1%). The crude 12 was used in the following reaction without further purification. A sample of crude 12 (2.3 g) was purified by chromatography on silica gel, eluting with 0-35% EtOAc/heptane to give 1.7 g of pure 12 as a white solid, which is a 1:2 mixture of E/Z isomers. For 12: 1H NMR (DMSO-d6, 300 MHz) for E-isomer: δ ppm 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) and for Z-isomer: 6 ppm 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H); C7H8ClN3O (MW, 185.61), LCMS (EI) m/e 186/188 (M++H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([O:21]C(OC)=O)[C:18]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:17][C:16]=3[CH:31]3[CH2:36][CH2:35][N:34]([C:37](OC(C)(C)C)=O)[CH2:33][CH2:32]3)=[O:13])[CH2:9][NH:8][C:7]=2[CH:44]=1)#[N:2].C(O)(C(F)(F)F)=O.C=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].[OH-].[K+].Cl>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([NH:14][C:15]3[CH:20]=[C:19]([OH:21])[C:18]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:17][C:16]=3[CH:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[O:13])[CH2:9][NH:8][C:7]=2[CH:44]=1)#[N:2]
Reactant: COC(=O)Oc1cc(NC(=O)C2CNc3cc(C#N)ccc3O2)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2cc(C3CCCC3)c(O)cc2NC(=O)C2CNc3cc(C#N)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 7.7 %

Procedure:
Tert-butyl 4-[2-[(6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carbonyl)amino]-5-cyclopentyl-4-methoxycarbonyloxy-phenyl]piperidine-1-carboxylate (100 mg, 0.17 mmol) was taken up in dichloromethane (3 mL) and TFA (1 mL, 13 mmol) and allowed to stir for 10 min at room temperature. The mixture was concentrated in vacuo and the residue was dissolved in 1,2-dichloroethane (2 mL). Paraformaldehyde (5 mg, 0.17 mmol) and acetic acid (9 μL, 0.17 mmol) were added and the mixture was heated at 60° C. for 10 min. Sodium triacetoxyborohydride (105 mg, 0.50 mmol) was added and the reaction was stirred for an additional 10 min. The mixture was added to saturated aqueous NaHCO3 (50 mL) and was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The residue was dissolved in methanol (3 mL) and treated with solid KOH (93 mg, 1.65 mmol). The reaction was stirred for 20 min at room temperature, poured into 1 N HCl (50 mL) and was extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. HPLC purification (10-99% CH3CN/0.05% HCl) provided 6-cyano-N-(4-cyclopentyl-5-hydroxy-2-(1-methylpiperidin-4-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (6 mg, 7% yield). LC/MS m/z 461.4 [M+H]+. 1H NMR (400.0 MHz, MeOD) 7.09 (d, J=1.8 Hz, 3H), 7.02 (s, 1H), 6.63 (d, J=1.6 Hz, 1H), 5.11 (dd, J=3.2, 4.6 Hz, 1H), 3.64 (dd, J=4.7, 12.0 Hz, 1H), 3.49-3.38 (m, 3H), 3.26 (q, obscured by solvent peak, J=9.2 Hz, 1H), 2.95 (s, 3H), 2.74-2.64 (m, 3H), 1.98-1.93 (m, 2H), 1.84-1.58 (m, 10H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+].[OH-].[Na+]>O.O1CCOCC1>[Cl:11][C:12]1[N:13]=[CH:14][N:15]=[C:16]([NH:1][CH2:2][C@@H:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[OH:4])[CH:17]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NC[C@H](O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccccc1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
To a solution consisting of (R)-(−)-2-amino-1-phenylethanol (4.80 g, 35.0 mmol) in and 1,4-dioxane (150 mL) at rt was added dropwise a solution consisting of 4,6-dichloropyrimidine (5.21 g, 35.0 mmol) and 1,4-dioxane (75 mL). Upon complete addition, NaHCO3 (17.6 g, 0.210 mol) was added and the mixture was heated to reflux (100° C.) for 17 h. The reaction mixture was cooled, diluted with water (60 mL) and the pH was adjusted to 12 by the addition of a 1 N NaOH (25 mL). The solution was extracted with CH2Cl2 (75 mL), washed with satd. aq. NaCl (50 mL), and the organic extract was dried (Na2SO4) and concentrated. The crude material (8.2 g) was suspended in CH2Cl2 (40 mL) and warmed to 50° C. to give a homogeneous solution. The solution was cooled to rt and treated with a few drops of hexanes to give the title compound as a pale yellow solid (7.0 g, 81%). MS (ESI): mass calcd. for C21H20F3N3O2, 403.2; m/z found, 404.2 [M+H]+. 1H NMR (CD3OD): 8.44 (s, 1H), 8.15 (s, 1H), 8.09 (dd, J=8.8, 2.2 Hz, 1H), 7.43 (d, J=7.7 Hz, 2H), 7.34 (t, J=7.7 Hz, 2H), 7.27-7.25 (m, 2H), 6.86 (s, 1H), 4.91-4.88 (m, 1H), 4.21 (q, J=7.1 Hz, 2H), 3.76-3.68 (m, 1H), 3.58 (dd, J=13.7, 7.7 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH2:14]([Li])[CH2:15][CH2:16]C.C(Br)C=C.Cl.[Cl-].[NH4+].[BH4-].[Na+]>O1CCCC1>[CH2:12]([CH:11]([CH2:16][CH:15]=[CH2:14])[CH:4]([OH:3])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:13]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [Li]CCCC
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(CC)C(O)CC(=O)OCC
Reaction time: 0.17 h

Procedure:
Sodium hydride (>63% oil, 2.09 g, 55 mmol) was added to a tetrahydrofuran solution (50 mL) of ethyl 3-oxohexanoate (7.91 g, 50 mmol) under ice cooling, and the mixture was stirred in this state for 10 minutes. To the reaction solution, n-butyllithium (1.58 M hexane solution, 34.8 mL, 55 mmol) was added dropwise, and the mixture was further stirred for 10 minutes under ice cooling. Then, allyl bromide (4.7 mL, 55 mmol) was added thereto, and the mixture was stirred in this state for 1 hour and then further stirred at room temperature for 4 hours. To the reaction solution, 1 N hydrochloric acid and a saturated aqueous solution of ammonium chloride were added, followed by extraction with n-pentane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethanol (80 mL). To the solution, sodium borohydride (1.51 g, 40 mmol) was added under ice cooling, and the mixture was stirred in this state for 2 hours. 1 N hydrochloric acid (50 mL) was added thereto, and the mixture was stirred for 30 minutes. Then, saturated saline was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the compound of interest as a pale yellow oil substance (3.64 g, 37%, mixture of diastereomers).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[C:29]([O:35][CH3:36])[CH:28]=1)=[O:26]>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:14]3[CH2:16][CH2:15]3)[C:10](=[O:13])[N:11]([CH2:33][C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][C:29]=3[O:35][CH3:36])[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(C3CC3)c2=O)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
An amount of 800 mg (3.39 mmol) of 5-(4-chlorophenyl)-4-cyclopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one (preparation as per WO 2007/134862 Example 36A) and 1.66 g (5.09 mmol) of caesium carbonate were suspended in 10 ml of acetone and admixed with 1.14 g (4.41 mmol) of methyl-4-(bromomethyl)-3-methoxybenzenecarboxylate. The mixture was stirred at 60° C. for 2 h. The suspension was diluted with water. It was extracted with twice 15 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification by flash chromatography over silica gel with elution with cyclohexane/ethyl acetate (gradient 4:1→1:1) gave 910 mg (64% of theory) of the target compound.
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13]2)=[CH:8][CH:7]=1.Cl.[CH3:21][NH:22][O:23][CH3:24].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:24][O:23][N:22]([CH3:21])[C:17]([CH:14]1[CH2:15][CH2:16][N:12]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=2)[CH2:13]1)=[O:19]
Reactant: CNOC
Reactant: O=C(O)C1CCN(c2ccc(Cl)cc2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
EDC (1.70 g, 8.86 mmol) was added portionwise to a stirred solution of 1-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid (1.0 g, 4.43 mmol), DMAP (5 mg) and N,O-dimethylhydroxylamine hydrochloride (865 mg, 8.86 mmol) in dichloromethane (20 mL). To this solution was added dropwise triethylamine (1.79 g, 2.47 mL, 17.7 mmol) and the reaction mixture was stirred at room temperature overnight. At the end of stirring, the reaction mixture was poured into water, and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (1.10 g. 98%); 1H NMR (CDCl3, 300 MHz) δ 7.14 (d, J=8 Hz, 2H), 6.46 (d, J=8 Hz, 2H), 3.74 (s, 3H), 3.50-3.56 (m, 2H), 3.40-3.47 (m, 2H), 3.33 (m, 1H), 3.23 (s, 3H), 2.20-2.36 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=2)[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(F)cc2)C2C1CCN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
Bicyclic alcohol 43 (4.2 g, 11.59 mmol) and 4-fluoro-benzyl bromide (2.2 mL, 17.4 mmol) were dissolved in DMF (115 mL) and cooled to 0° C. Sodium hydride (930 mg, 23.2 mmol) was added and, after ˜5 min, the ice bath was removed. After 15 min, the reaction mixture was diluted with toluene (250 mL) and saturated aqueous NH4Cl (500 mL) and extracted with 1:1 Et2O/hexanes (600 mL). The organic layer was washed successively with 1N HCl, water, saturated aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (10:1 to 1:1 hexanes/EtOAc) to afford 5.15 g of 44 as a viscous oil (94%): 1H NMR (300 MHz, CDCl3): δ7.36 (m, 6H), 7.07-6.92 (m, 3H), 5.15 (m, 2H), 4.63 (m, 1H), 4.50 (m, 1H), 4.32 (m, 1H), 4.19 (m, 1H), 3.97 (m, 1H), 3.87-3.64 (m, 2H), 3.25-3.08 (m, 2H), 2.35 (m, 0.5H), 2.17 (m, 0.5H), 1.88 (m, 1H), 1.46 (s, 9H) ppm. Mass spectrum, m/z [414.7] (M−t-Bu)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]([OH:16])=O)=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=1>C(N(CC)CC)C>[CH3:17][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C:14]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[C:32]([F:41])[CH:31]=3)=[O:16])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCOc2cc(OCC(=O)O)ccc21
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: CC1(C)CCOc2cc(OCC(=O)NCc3ccc(NS(C)(=O)=O)c(F)c3)ccc21
Yield: 19.7 %

Procedure:
[(4,4-Dimethyl-3,4-dihydro-2H-chromen-7-yl)oxy]acetic acid (118 mg, 0.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (89 mg, 0.55 mmol), triethylamine (0.33 ml) and N{4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (140 mg, 0.55 mmol) were treated in the same procedure described in Example 2(b). The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethyl acetate (3/1 to 1/1) to furnish 43 mg (20% yield) of the title compound as a white solid.
Reaction SMILES: CO.[H-].[Na+].[C:5]([O:12][CH3:13])(=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[C:17]=1[CH2:25]Br>CCOCC>[CH3:10][O:9][C:7]([C:6]1([C:5]([O:12][CH3:13])=[O:11])[CH2:25][C:17]2[C:16](=[CH:21][CH:20]=[CH:19][C:18]=2[N+:22]([O-:24])=[O:23])[CH2:15]1)=[O:8]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1cccc(CBr)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1(C(=O)OC)Cc2cccc([N+](=O)[O-])c2C1
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To a solution stirred under nitrogen at room temperature, to 5.0 mL methanol in 15.0 mL ether was added 60% sodium hydride (0.84 g, 0.021 mol) in small portions. After the addition was complete, the nearly clear and colorless solution was stirred for 5 minutes. To it was then added 1.3 g dimethyl malonate, giving a slightly cloudy colorless solution. To this was rapidly added a suspension of 3.1 g 1,2-bis(bromomethyl)-3-nitrobenzene, which immediate gave a precipitate suspended in a dark green solution. This was removed by filtation and the filtrate was concentrated. The residue was purified on silica (20%-100% CH2Cl2 in hexanes) to give 1.93 g off-white solid (67%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].N1C=CC=CC=1>C1COCC1>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:12]([C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][N:6]=2)=[CH:9][CH:10]=1)=[O:13]
Reactant: Nc1ccccc1F
Reactant: O=C1CCC(c2ccc(C(=O)Cl)cc2)=NN1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1CCC(c2ccc(C(=O)Nc3ccccc3F)cc2)=NN1
Yield: 38.5 %

Procedure:
120 mg (0.5 mmol) of 4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)benzoyl chloride from example I are stirred, at 60° C. for 2 hours, in 5 ml of THF together with 56 mg (0.5 mmol) of 2-fluoroaniline and 0.1 ml of pyridine. The mixture is cooled down and inspissated. The inspissation residue is purified on a silica gel column. The clean fractions are combined, inspissated, crystallized using methanol, filtered-off with suction and washed with methanol. This results in 60 mg of colorless crystals having a melting point of 242-244° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10](I)=[CH:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]=12.[C:19]([O:23][C:24](=[O:28])[CH2:25][Zn]Cl)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.[Pd].C(P)(C)(C)C.C(P)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([O:23][C:24](=[O:28])[CH2:25][C:10]1[C:6]2[C:7](=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=2)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)C[Zn]Cl
Reactant: CC(C)(C)OC(=O)n1cc(I)c2ccnc(Cl)c21
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)nccc12
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To a solution of tert-butyl 7-chloro-3-iodo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (500 mg, 1.3 mmol), bis-(tert-butyl-phosphine) palladium (67.5 mg, 0.13 mmol), and palladium acetate (7.4 mg, 0.003 mmol) in THF (10 mL) was added (2-tert-butoxy-2-oxoethyl)(chloro)zinc (6.6 mL, 3.3 mmol, 0.5 M in diethyl ether). The mixture was then heated to 50 C overnight, cooled to r.t. and quenched by addition of MeOH (1 mL). EtOAc was added and the solution was extracted with 5% KHSO4. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified on silica (gradient elution, 0-25% EtOAc/hexanes) to yield the title product (382 mg). HRMS (ESI) calc (M+H)+=367.1419. found 367.1422.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH:18]=[O:19])=[CH:13][CH:12]=1)([CH3:10])[CH3:9].CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:18]=2[OH:19])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(C(=O)C=O)cc1
Reactant: CNN=CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 4.2 %

Procedure:
2-Oxopropanal methylhydrazone (10.44 mmol, 1.05 g) and (4-isopropylphenyl)(oxo)acetaldehyde (10.44 mmol, 1.84 g) synthesized in Reference Synthetic Example 12 were dissolved in acetic acid (37 mL) and stirred at 100° C. for 4.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) and then by silica gel thin layer chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as an orange solid (113 mg, yield 4%).