Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[NH2:17][NH2:18]>C1COCC1>[NH:17]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)[NH2:18]
Reactant: NN
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C(F)(F)F)nc1NN
Yield: 96 %

Procedure:
A solution of ethyl 4-chloro-2-trifluoromethylpyrimidine-5-carboxylate (0.20 g, 0.79 mmol), hydrazine (0.18 g, 6.0 mmol) and THF was stirred for 1 h at room temperature. The solution was filtered and dried to give the title compound in a 96% yield; 1H NMR (CDCl3) δ 9.26 (bs, 1H), 8.90 (s, 1H), 4.40 (q, 2H), 4.24 (bs, 2H), 1.41 (t,3H).
Reaction SMILES: CN=[C:3]([OH:21])[C:4]1[C:5](=[C:9]([S:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].Cl>[OH-].[Na+]>[CH2:17]([S:16][C:9]1[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=[C:4]2[C:3]([O:7][C:6](=[O:8])[C:5]=12)=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCSc1cc([N+](=O)[O-])cc2c1C(=O)OC2=O

Procedure:
883 mg (3 mmols) of 3-n-butylthio-5-nitrophthalic acid N-methylimide are kept under reflux overnight in 9 ml of 1N sodium hydroxide solution and the mixture is acidified with 10 ml of 2N hydrochloric acid and, after 5 minutes under reflux, cooled. The mixture is extracted with tetrahydrofuran/toluene and the extracts are washed with saturated NaCl solution, dried over sodium sulfate and evaporated. The resulting acid is converted to the anhydride with 1 ml of acetic anhydride and 10 ml of toluene, by heating and evaporation. After recrystallisation from cyclohexane, 790 mg (94% of theory) of the title anhydride are obtained as a yellow product; melting point: 95°-97° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:31])([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[CH:14]=[CH:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:32]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([N:12]2[C:28]3[C:15](=[CH:16][C:17]4[O:18][CH2:19][C:20]5[N:25]([C:26]=4[CH:27]=3)[C@H:24]([CH3:29])[C:23](=[O:30])[NH:22][N:21]=5)[C:14]([I:32])=[CH:13]2)([CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc4ccn(C5(C)CN(C(=O)OC(C)(C)C)C5)c4cc3N21
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)NN=C2COc3cc4c(I)cn(C5(C)CN(C(=O)OC(C)(C)C)C5)c4cc3N21
Temperature: 0 °C
Reaction time: 3 h
Yield: 30.9 %

Procedure:
To a solution of 3-methyl-3-((R)-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-azetidine-1-carboxylic acid tert-butyl ester (Example #148, Step J, 1 g, 2.35 mmol) in THF (20 mL) was added 1-iodopyrrolidine-2,5-dione (0.582 g, 2.59 mmol) in portions at −5-0° C. The reaction mixture was stirred at 0° C. for 3 h. Saturated aqueous sodium sulphite solution (5 mL) was added to quench the reaction and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10%˜100% EtOAc in petroleum ether) to give 3-((R)-8-iodo-1-methyl-2-oxo-1,2,3,5-tetrahydro-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-10-yl)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.4 g, 30%) as a yellow solid. 1H NMR (400 MHz, methanol-d4): δ 7.39 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 4.97 (m, 1H), 4.53 (d, J=8.5 Hz, 2H), 4.59 (m, 2H), 4.54 (m, 2H), 4.29 (m, 2H), 1.81 (s, 3H), 1.51-1.48 (m, 12H). LC/MS (Table 1, Method 2) Rt=1.279 min.; MS m/z: 552 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[O:6]1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C.C([O-])([O-])=O.[Na+].[Na+]>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:7]1[O:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:30]([CH3:32])[CH3:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=1
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCN)c1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NCCCC1(c2ccccc2)OC(c2cc(F)ccc2F)=NN1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 24.8 %

Procedure:
To a solution of 1-[2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-[1,3,4]oxadiazol-3-yl]-2-methylpropan-1-one (12 mg, 0.031 mmol) in acetonitrile (0.5 mL) was added acetone (60 μL, 0.082 mmol) and sodium triacetoxyborohydride (10 mg, 0.045 mmol). After stirring at room temperature for 45 minutes, more sodium triacetoxyborohydride (10 mg, 0.045 mmol) was added. The mixture stirred at room temperature for 5 hours. The reaction mixture was diluted with 10% Na2CO3 (30 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine (45 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (40% to 100% ethyl acetate in hexanes with 2% triethylamine) to provide the final product (3.3 mg, 25%). MS ESI (+) m/z 430 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 2H), 7.50 (m, 1H), 7.36 (m, 3H), 7.15 (m, 2H), 3.36 (m, 1H), 3.01 (m, 1H), 2.78 (m, 1H), 2.67 (m, 2H), 2.53 (m, 1H), 1.66 (m, 2H), 1.20 (d, 3H, J=7 Hz), 1.14 (d, 3H, J=6 Hz), 1.04 (d, 6H, J=6 Hz).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])=[CH:26][CH:25]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: Fc1ccc(N=C=S)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(F)cc4)CC3)nc21

Procedure:
Pipemidic acid (35 mg, 0.1154 mmol) and 4-fluorophenyl isothiocyanate (17.7 mg, 0.1154 mmol) were used. Purification on silica yielded compound 23 in Table 1, below (30 mg, 57%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.69 (s, 1H), 7.33 (s, 1H), 7.25-7.16 (m, 2H), 7.13-7.03 (m, 2H), 4.34 (q, J=7.00 Hz, 2H), 4.28-3.96 (m, 8H), 1.50 (t, J=7.36 Hz, 3H) ppm.
Reaction SMILES: C([NH:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH3:8])(=O)C>[OH-].[K+]>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]([CH3:8])[CH2:6][CH2:5][NH2:4])=[CH:10][CH:11]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)NCCC(C)c1ccc(-c2ccc(F)cc2)cc1
Agent: [K+]
Agent: [OH-]
Product: CC(CCN)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 28.5 g of 1-acetamido-3-(4'-fluoro-4-biphenylyl)-butane in 800 ml of 10% methanolic KOH solution is boiled for 48 hours. The solution is concentrated and worked up using water and ether to give 3-(4'-fluoro-4-biphenylyl)-butylamine; hydrochloride, m.p. 222° - 224°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[NH:18][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[S:34]1[C:38]2[CH:39]=[C:40]([S:43](Cl)(=[O:45])=[O:44])[CH:41]=[CH:42][C:37]=2[N:36]=[CH:35]1>C(Cl)Cl>[S:34]1[C:38]2[CH:39]=[C:40]([S:43]([N:18]3[CH:15]4[CH2:14][CH2:13][CH2:12][CH:11]3[C:10](=[O:19])[N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]4)(=[O:44])=[O:45])[CH:41]=[CH:42][C:37]=2[N:36]=[CH:35]1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: COc1ccc(OCCN2CCC3CCCC(N3)C2=O)cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCCN2CCC3CCCC(C2=O)N3S(=O)(=O)c2ccc3ncsc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (24 mg, 0.07 mmol) in 3 ml DCM was treated with DIPEA (11 mg, 0.09 mmol) and stirred for 30 min at room temperature followed by addition of 1,3-benzothiazole-6-sulfonyl chloride (20 mg, 0.09 mmol). After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-TLC in 10% MeOH in CHCl3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH2:25])[O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:32]=[C:31]1[NH:25][C:24]2[CH:23]=[CH:22][C:4]([O:5][CH2:6][C@H:7]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][C:2]=2[NH:1]1
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1ccc(N)c(N)c1)c1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl [(1R)-2-(3,4-diaminophenoxy)-1-phenylethyl]carbamate (Intermediate 6) (318 mg, 0.93 mmol) was placed in a 50-mL RBF under a nitrogen atmosphere and dissolved in DMF (5 mL). CDI (135 mg, 0.83 mmol) was added, and the reaction was stirred at room temperature for four hours. The reaction was added to a separatory funnel containing ethyl acetate (125 mL) and dilute aqueous NaHCO3 (75 mL); the phases were separated, and the organic layer was washed with brine (75 mL), dried over anhydrous Na2SO4 and then concentrated in vacuo. The crude product mixture was then purified by silica gel chromatography to afford tert-butyl {(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}carbamate as a white solid. 1H NMR (500 MHz, C2D6SO) δ 10.49 (s, 1H), 10.37 (s, 1H), 7.54 (d, 1H), 7.34 (m, 4H), 7.25 (t, 1H), 6.77 (d, 1H), 6.48 (s, 2H), 4.86 (q, 1H), 3.98 (m, 2H), 1.37 (s, 9H). LRMS (ESI) calc'd for (C16H16N3O4) [M−C4H8+H]+, 314.1; found 314.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:21][C:20]=3[CH3:30])/[CH3:18])/[C:9]2=[O:31])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[C:40]([CH3:42])=[CH2:41]>ClCCl>[C:39]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:15])[CH3:16])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[S:21][C:20]=3[CH3:30])/[CH3:18])/[C:9]2=[O:31])=[CH:4][CH:3]=1)(=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1cc(-c2ccccc2)sc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(-c4ccccc4)sc3C)C2=O)cc1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution obtained by dissolving 430 mg of N-(4-hydroxyphenyl)-2-[(E)-1-(2-methyl-5-phenyl-3-thienyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 8 in 10 ml of dichloromethane, 202 mg of triethylamine was added, followed by dropwise addition of 209 mg of methacryloyl chloride in 10 minutes. The reaction was carried out at room temperature for further 1 hour. After the reaction, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solution of n-hexane and ethyl acetate) to give organce crystals of N-(4-methacryloyloxyphenyl)-2-[(E)-1-(2-methyl-5-phenyl-3-thienyl)ethylidene]-3-isopropylidenesuccinimide in yield of 44.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:8]=2[O:9][C:10]=1[CH3:11])=O.CO.[OH-].[Na+]>O1CCCC1>[C:16]([C:14]1[CH:13]=[CH:12][C:8]2[O:9][C:10]([CH3:11])=[C:6]([CH2:4][C:3]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=3[Cl:1])[C:7]=2[CH:15]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl

Procedure:
A mixture of 3-(2,4-dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan (0.57 g, 1.6 mmol), methanol (6 ml), tetrahydrofuran (6 ml) and a 2M aqueous sodium hydroxide solution (8.5 ml) was refluxed under heating for 40 min. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with 3N hydrochloric acid and the precipitated solid was extracted with hot ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (0.54 g, quantitative) as colorless crystals.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][CH:15]([CH3:17])[CH3:16])[C@@H:10]([CH2:18][N:19]([CH:36]([CH3:38])[CH3:37])[C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH2:9]1)C1C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[O:54][CH3:55])[C:48](O)=[O:49].CC#N.O.CC#N>O>[CH:36]([N:19]([CH2:18][C@@H:10]1[C@H:11]([CH2:13][N:14]([CH:15]([CH3:17])[CH3:16])[C:48](=[O:49])[C:47]2[CH:51]=[CH:52][C:53]([O:54][CH3:55])=[C:45]([O:44][CH2:43][CH2:42][CH2:41][O:40][CH3:39])[CH:46]=2)[CH2:12][NH:8][CH2:9]1)[C:20](=[O:35])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=1)([CH3:38])[CH3:37]
Reactant: COCCCOc1cc(C(=O)N(C[C@H]2CN(Cc3ccccc3)C[C@H]2CNC(C)C)C(C)C)ccc1OC
Reactant: COCCCOc1cc(C(=O)O)ccc1OC
Solvent: CC#N
Solvent: O
Product: COCCCOc1cc(C(=O)N(C[C@H]2CNC[C@H]2CN(C(=O)c2ccc(OC)c(OCCCOC)c2)C(C)C)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 361 by coupling N-[(3R*,4R*)-1-benzyl-4-(isopropylamino-methyl)-pyrrolidin-3-ylmethyl]-N-isopropyl4-methoxy-3-(3-methoxy-propoxy)-benzamide and 3-(3-methoxy-propoxy)-4-methoxy-benzoic acid in step J. MS (LC-MS): 658.3 [M+H]+; tR (HPLC, Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/2.5 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.20 min.
Reaction SMILES: [NH2:1][C:2](=[N:25][OH:26])[CH2:3][N:4]([C:9]1[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:23][CH3:24])[C:13]([O:21][CH3:22])=[N:14]2)[S:5]([CH3:8])(=[O:7])=[O:6].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>N1C=CC=CC=1>[NH2:1][C:2](=[N:25][O:26][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:3][N:4]([C:9]1[C:18]([Cl:19])=[C:17]([Cl:20])[CH:16]=[C:15]2[C:10]=1[N:11]=[C:12]([O:23][CH3:24])[C:13]([O:21][CH3:22])=[N:14]2)[S:5]([CH3:8])(=[O:6])=[O:7]
Reactant: CCOC(=O)Cl
Reactant: COc1nc2cc(Cl)c(Cl)c(N(CC(N)=NO)S(C)(=O)=O)c2nc1OC
Solvent: c1ccncc1
Product: CCOC(=O)ON=C(N)CN(c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
The product of step (a) (852 g, 2.008 mmol) was dissolved in dry pyridine (12 ml) and cooled to 0° C. Ethyl chloroformate (479 mg, 4.418 mmol) was added over 5 minutes. The mixture was stirred at room temperature for 16 hours and poured into ice-cold water (40 ml). The resulting precipitate was collected by filtration and dried under reduced pressure at 60° C. to give N-(2-amino-2-ethoxycarbonyloxyiminoethyl)-N-(6,7-dichloro-2,3-dimethoxyquinoxalin-5-yl)methanesulphonamide (757 mg, 76%).
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24](O)=[O:25])[O:21][C:22]=3[CH3:23])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36]>>[F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([S:16][CH2:17][C:18]3[CH:19]=[C:20]([C:24]([NH:38][S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH3:28])(=[O:36])=[O:37])=[O:25])[O:21][C:22]=3[CH3:23])=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Cc1oc(C(=O)O)cc1CSc1ccc(-c2ccc(OC(F)F)cc2)cc1
Reactant: Cc1ccccc1S(N)(=O)=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CSc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1

Procedure:
Compound (154) was prepared from compound (153) and 2-D methyl-benzenesulphonamide by adapting the procedure of Example 34(c). LC/MS System D; Rt=11.61 mins, m/z (ES+)=544 (M+H for C27H23F2NO5S2).
Reaction SMILES: [Cl:1][C:2](=[N:10][OH:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[Cl:1][C:2](=[N:10][O:11][C:12](=[O:14])[CH3:13])[C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)ON=C(Cl)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
To 19 g (0.1 mol) of α-chloro-4-chlorobenzaldoxime prepared above was added 20.6 g (2.0 mol) of acetic anhydride followed by heating on a water bath at a temperature of from 80° to 90° C for about 2 hours. After completion of the reaction, the reaction mixture was poured into water to give pale yellow crystals. The product thus obtained was filtered, dried and recrystallized from ligroin to give 18 g of the desired product as white crystals having a melting point of 76°-77° C. Yield, 77%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:19][CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[CH2:13]1)[N:6]=[CH:5]2.[Br:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24]>>[Br:20][C:21]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:16]1[CH2:17][CH:18]2[CH:14]([CH2:13][N:12]([C:7]3[N:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=3)[CH2:19]2)[CH2:15]1)=[O:24]
Reactant: O=C(O)c1cccc(F)c1Br
Reactant: Fc1ccc2nc(N3CC4CNCC4C3)ncc2c1
Product: O=C(c1cccc(F)c1Br)N1CC2CN(c3ncc4cc(F)ccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 43 and 2-bromo-3-fluorobenzoic acid. MS (ESI): mass calculated for C21H17BrF2N4O, 458.1; m/z found 459.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.95 (d, J=19.8, 1H), 8.01 (s, 1H), 7.59 (dt, J=13.3, 6.7, 1H), 7.52-7.40 (m, 1H), 7.40-7.28 (m, 1H), 7.18-7.05 (m, 2H), 4.01 (dt, J=12.8, 8.4, 2H), 3.95-3.85 (m, 1H), 3.80-3.48 (m, 4H), 3.27-3.04 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[C:18](O)=[O:19]>C1COCC1>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[CH2:18][OH:19]
Reactant: COC(=O)CCc1ccc(Cn2cccn2)cc1C(=O)O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(Cn2cccn2)cc1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-(4-(pyrazol-1-ylmethyl)-2-carboxyphenyl)propanoic acid methyl ester (600 mg) in anhydrous THF (8.0 ml) was added dropwise a solution of borane-tetrahydrofuran complex in THF (3.2 ml) at 0° C. and the mixture was stirred at room temperature for 2.5 hours. To the mixture was added a solution of borane-tetrahyrofuran complex in THF (3.5 ml) and the mixture was stirred for 1 hour. To the reaction solution was added ice and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:2) to give the title compound (420 mg) having the following physical data.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH3:26][C:27]1[N:32]=[C:31]2[NH:33][CH:34]=[C:35]([CH:36]=O)[C:30]2=[CH:29][CH:28]=1>CO.N1CCCCC1>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:36]/[C:35]3[C:30]4[C:31](=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=4)[NH:33][CH:34]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc2c(C=O)c[nH]c2n1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.058 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.010 g, 0.063 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 50° C. for 2 hours. The solid formed was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({6-hydroxy-2-[(6-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:24])[O:4][N:3]=1.[H-].[Na+].[CH3:27]I>C1COCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH3:27])[C:11](=[O:16])[C:10]3([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:24])[O:4][N:3]=1
Reactant: CI
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(3,5-Dimethyl-isoxazol-4-yl)-3-methyl-3-phenyl-1,3-dihydro-indol-2-one (54 mg, 0.196 mmol) and NaH (5.5 mg, 0.203 mmol) in THF (10 mL) is stirred at room temperature for 1.5 h. MeI (48 mg, 0.338 mmol) is added to the mixture and stirred overnight. The solvent is removed in vacuo. The residue is purified by chromatography (ethyl acetate:petroleum ether=1:2) to give the desired compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:39]4[CH2:40][CH2:41][C@H:37]([N:36]([CH3:42])[CH3:35])[CH2:38]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Reactant: CN(C)[C@H]1CCNC1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CC[C@H](N(C)C)C4)n3)sc2c1-c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40 mg, 0.08 mmol) in dioxane (1 mL) was added (S)—N,N-dimethylpyrrolidin-3-amine (89 mg, 0.78 mmol) at room temperature. The reaction mixture was allowed to stir for an additional 30 minutes and then concentrated in vacuo to provide the desired product. LCMS-ESI+: calc'd for C31H37ClN5O3S: 594.2 (M+H+); Found: 594.4 (M+H+).