Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][S:4](C1C=CC=CC=1O)(=[O:6])=[O:5])[CH3:2].[Cl:14][C:15]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:16]=1[C:17]([NH:19][CH2:20][C:21]1([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:18].Cl>O1CCOCC1>[Cl:14][C:15]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:16]=1[C:17]([NH:19][CH2:20][C:21]1([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:22][CH2:23][N:24]([S:4]([NH:3][CH2:1][CH3:2])(=[O:6])=[O:5])[CH2:25][CH2:26]1)=[O:18]
Reactant: O=C(NCC1(c2ncccc2F)CCNCC1)c1ccc(Cl)cc1Cl
Reactant: CCNS(=O)(=O)c1ccccc1O
Agent: Cl
Solvent: C1COCCO1
Product: CCNS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2ncccc2F)CC1

Procedure:
A solution of N-ethyl-2-hydroxyl-benzenesulfonamide (30 mg, 0.137 mmol) and 2,4-dichloro-N-{[4-(3-fluoropyridin-2-yl)piperidin-4-yl]methyl}benzamide (57.5 mg, 0.150 mmol) (prepared by the method in Example 1) in dioxane (2 ml) was refluxed under nitrogen for 4.5 hours. The mixture was allowed to cool then poured into 1 M HCl solution and extracted with diethyl ether (2×20 ml). The organic phase was washed with water (20 ml) and brine (20 ml), dried over MgSO4, filtered, and evaporated. The crude product was purified by preparatory TLC eluted with 50% ethyl acetate in isohexane to give the title product as a white foamy solid. 1H NMR δ (ppm)(CDCl3): 8.39-8.35 (1 H, m), 7.55 (1 H, d, J=8.4 Hz), 7.43-7.35 (2 H, m), 7.30-7.01 (2 H, m), 6.76-6.69 (1 H, m), 4.00-3.94 (3 H, m), 3.54-3.45 (2 H, m), 3.26-3.20 (2 H, m), 3.17-3.09 (2 H, m), 2.74-2.63 (2 H, m), 1.88-1.80 (2 H, m), 1.19 (3 H, t, J=7.2 Hz). m/e=489/491 (3:2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([C:22]1[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=1)=[O:21])[NH2:19].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([C:22]3[S:26][C:25]([C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:23]=3)=[O:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(Cl)c(Cl)c3)c2O)s1
Yield: 86.5 %

Procedure:
From 2-(3,4-dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (57.4 mg, 0.2 mmol), methyl 5-hydrazinocarbonyl-2-thiophenecarboxylate (40.0 mg, 0.2 mmol) and tosylic acid monohydrate (11.4 mg, 0.06 mmol), 81.2 mg of the desired product was obtained in the same manner as in Synthetic Example 65 as a pale yellow solid (yield 87%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([N:12]([CH2:15][CH3:16])CC)C.[CH2:17]1[CH2:21]O[CH2:19][CH2:18]1>>[CH:5]([C:4]1[CH:3]=[C:2]([C:19]#[C:18][C:17]2[CH:21]=[C:3]([C:4]#[C:16][C:15]#[N:12])[CH:2]=[CH:9][CH:8]=2)[CH:9]=[CH:8][CH:7]=1)=[O:6]
Reactant: O=Cc1cccc(I)c1
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Product: N#CC#Cc1cccc(C#Cc2cccc(C=O)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 55 %

Procedure:
87 mg of (3-ethynyl-phenyl)-1-propyne nitrile 63 (0.576 mmol), 120.3 mg of 3-iodobenzaldehyde, and 0.8 ml triethylamine (58.5 mg, 0.576 mmol) were dissolved in 1.5 ml of anhydrous THF, and the solution was deoxygenated by purging argon in it. To this solution was added 22 mg of tetrakistriphenylphosphine palladium (0.019 mmol) then the reaction was allowed to stir for 20 min at room temperature. To this stirring mixture was added 0.9 mg of cuprous iodide (4.5×10−3) then stirred at room temperature for 2 hr, followed by heating further at 50° C. for 2 hr. The solvent was then evaporated in rotatory evaporation to give brown solid. The residue was then purified by silica gel column chromatography using 1:9 dichloromethane:hexane to collect starting material. The polarity was increased to 2:8 dichloromethane:hexane to afford 80 mg of 61 as a golden solid in 55% yield. 1H NMR δ 10.2 (s, 1H), 8.04 (sm, 1H), 7.89 (dm, 1H, J=7.7), 7.78 (m, 2H), 7.69 (dm, 1H, 7.8), 7.60 (dm, 1H, J=7.8), 7.56 (t, 1H, J=7.7), 7.44 (t, 1H, J=7.8); 13C NMR δ 191.30, 137.13, 136.59, 136.27, 134.81, 133.21, 132.90, 129.61, 129.26, 123.99, 123.69, 118.16, 105.22, 89.72, 88.64, 81.77, 63.62; LRMS (GC/MS, CH2Cl2) m/e 255 (M+)
Reaction SMILES: CN.[ClH:3].[S:4]1(=[O:11])(=[O:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5]1.S1(=O)(=O)CC=C[CH2:13]1>>[ClH:3].[CH3:13][NH:9][CH:6]1[CH2:7][CH2:8][S:4](=[O:11])(=[O:10])[CH2:5]1
Reactant: O=S1(=O)CC=CC1
Reactant: NC1CCS(=O)(=O)C1
Agent: CN
Agent: Cl
Product: CNC1CCS(=O)(=O)C1
Yield: 82.2 %

Procedure:
The procedure of Example 1 was repeated substituting 50 percent aqueous monomethylamine (174 ml.) for the ammonium hydroxide of Example 1. Sixty-four and seven-tenths grams of a white crystalline solid was obtained for a yield of 82.2 percent of theory based upon the 2,5-dihydrothiophene 1,1-dioxide. The solid sublimes over 180° C. and melts between 205° and 210° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>C(OC(=O)C)(=O)C>[CH2:14]([O:13][CH:12]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)OCC
Temperature: 159 °C
Yield: 95.1 %

Procedure:
160.2 g (1.0 mol) of diethyl malonate, 474.2 g (3.2 mol) of triethyl orthoformate, 4 g of acetic anhydride and 0.5 g of catalyst from Example 1 were initially introduced into the apparatus described in Example 1 and the mixture was heated to boiling. A mixture of 10 g of acetic anhydride and 30 g of triethyl orthoformate were continuously added dropwise in the course of 6 hours. The low-boiling component formed was distilled off at a head temperature of 78° to 79° C. The reaction temperature slowly increased to 159° C. The mixture was kept at this temperature for a further hour. The unreacted orthoester was then distilled off at reduced pressure, the catalyst was filtered off and the crude product was purified by distillation at 0.5 mbar. In this way 205.6 g of diethyl ethoxymethylenemalonate were obtained, which corresponds to a yield of 95.1% of the theoretical yield.
Reaction SMILES: ClCC(O)=[O:4].S[C:7]1[NH:12][C:11](=[O:13])[CH:10]=[C:9]([CH2:14][CH3:15])[N:8]=1.Cl>O>[OH:4][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([CH2:14][CH3:15])[N:8]=1
Reactant: O=C(O)CCl
Reactant: CCc1cc(=O)[nH]c(S)n1
Agent: Cl
Solvent: O
Product: CCc1cc(O)nc(O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
A mixture solution of chloroacetic acid(33.3 g, 0.352 mol), water(400 ml) and 2-mercapto-6-ethylpyrimidine-4-one(29 g, 0.186 mol) prepared in the above Step 1 was heated to reflux for 14 hours and cooled to a room temperature. To the reaction mixture was added conc. HCl(95 ml) and the mixture was heated to reflux for 1 day. After the reaction mixture was cooled to a room temperature and concentrated under a reduced pressure, the residue was diluted with water. After stirring for 2 hours, the resulting solid was filtered and dried to give 11.16 g of the titled compound. (Yield: 43%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[CH2:14][NH:15][CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:6][NH:7][C:8](=[O:10])[CH3:9].[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:36]2[C:37]([CH:42]=O)=[N:38][CH:39]=[CH:40][CH:41]=2)([CH3:35])[CH3:34])=[CH:29][CH:28]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([C:36]2[C:37]([CH2:42][N:15]([CH2:14][C:13]3[CH:12]=[CH:11][C:5]([CH2:6][NH:7][C:8](=[O:10])[CH3:9])=[CH:4][C:3]=3[CH2:2][OH:1])[CH:16]3[C:25]4[N:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:19][CH2:18][CH2:17]3)=[N:38][CH:39]=[CH:40][CH:41]=2)([CH3:35])[CH3:34])=[CH:31][CH:32]=1
Reactant: CC(=O)NCc1ccc(CNC2CCCc3cccnc32)c(CO)c1
Reactant: CC(C)(c1ccc(F)cc1)c1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccc(CN(Cc2ncccc2C(C)(C)c2ccc(F)cc2)C2CCCc3cccnc32)c(CO)c1

Procedure:
Using General Procedure B: Reaction of N-{3-hydroxymethyl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzyl}-acetamide in CH2Cl2 with 3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridine-2-carbaldehyde and NaBH(OAc)3 gave N-(4-{[{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-3-hydroxymethyl-benzyl)-acetamide as a white foam. 1H NMR (CDCl3) δ 1.45 (m, 1H), 1.55 (s, 3H), 1.63 (s, 3H), 1.72 (m, 1H), 1.83 (m, 1H), 2.00 (s, 3H), 2.10 (m, 1H), 2.57 (m, 2H), 2.79 (m, 1H), 3.48 (s, 2H), 3.72-3.90 (m, 4H), 4.35 (d, 2H, J=6.0 Hz), 4.60 (d, 1H, J=12.0 Hz), 4.72 (d, 1H, J=12.0 Hz), 5.67 (br s, 1H), 6.79 (t, 2H, J=6.0 Hz), 6.91 (d, 1H, J=6.0), 7.03 (br s, 3H), 7.21 (m, 2H), 7.27 (d, 1H, J=9.0 Hz), 7.79 (d, 1H, J=9.0 Hz), 8.41 (d, 1H, J=3.0 Hz), 8.53 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 22.4, 23.6, 27.2, 29.4, 29.6, 32.6, 42.3, 43.8, 54.8, 55.2, 59.0, 63.7, 115.2, 115.5, 121.6, 121.8, 127.1, 127.4, 127.5, 130.7, 132.4, 133.9, 134.6, 136.8, 138.0, 142.9, 145.7, 146.8, 146.9, 157.6, 158.1, 159.5, 162.7, 170.3. HPLC: 95%. ES-MS m/z 567 [M+H]+. Anal. Calcd. for C35H39N4O2F.0.3 CH2Cl2: C, 71.60; H, 6.74; N, 9.46. Found: C, 71.48; H, 6.81; N, 9.58.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH2:19])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
To a solution of [4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]-acetonitrile (6.1 g, 23.6 mmol) in dry THF (235 ml) was added (dropwise) lithium aluminum hydride (LAH) (28:4 mmol, 1.0M in THF) at room temperature, under nitrogen. Upon complete addition, the reaction mixture was warmed to reflux for 3 hours. After cooling to 0° C. in an ice bath, the reaction was carefully quenched with water (4.0 ml). The solids were removed via filtration and washed with THF. The combined filtrates were concentrated to give 5.6 g of the desired product. This material was suspended in DCM and filtered to give the product as an off-white solid, m.p. 125°-128° C.
Reaction SMILES: [CH2:1](I)[CH3:2].[NH2:4][N:5]1[C@H:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C@@H:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=2)[CH2:8][C@@:7]([CH2:26][C:27]([O:29][CH3:30])=[O:28])([CH3:25])[C:6]1=[O:31].[CH3:32][CH2:33]N(C(C)C)C(C)C>CN(C=O)C>[Cl:24][C:20]1[CH:19]=[C:18]([C@@H:9]2[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:5]([N:4]([CH2:1][CH3:2])[CH2:32][CH3:33])[C:6](=[O:31])[C@:7]([CH2:26][C:27]([O:29][CH3:30])=[O:28])([CH3:25])[CH2:8]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(N)C1=O
Reactant: CCN(C(C)C)C(C)C
Reactant: CCI
Solvent: CN(C)C=O
Product: CCN(CC)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Ethyl iodide (67.1 μL, 0.831 mmol) was added to a solution of methyl 2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (Example 429, step B, 35 mg, 0.083 mmol) and DIEA (145 μL, 0.831 mmol) in DMF. The resulting mixture was stirred at 80° C. for 12 h. The mixture was concentrated and purified by reversed phase HPLC (Sunfire™ Prep C18 OBD 10 μm column; Waters, Milford, Mass.; 40-90% water/acetonitrile gradient with 0.1% TFA). Desired fractions were pooled and concentrated to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=C(C#N)[C:5]1=[O:14])([CH3:3])[CH3:2].[OH-:15].[K+].[CH2:17]([OH:19])[CH3:18]>O>[CH:1]([N:4]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:18]([C:17]([OH:15])=[O:19])[C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: Cc1cc(C#N)c(=O)n(C(C)C)c1C
Reactant: CCO
Agent: [K+]
Solvent: O
Product: Cc1cc(C(=O)O)c(=O)n(C(C)C)c1C
Yield: 91 %

Procedure:
A mixture or 1-isopropyl-5,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile as prepared in 3(1) (840 mg, 4.42 mmol), potassium hydroxide (1.84 g, 32.7 mmol), ethanol (12 μL) and water (3 mL) was refluxed for 16 h. After cooling, the mixture was concentrated in vacuo. The aqueous residue was diluted with water (80 mL), washed with ethyl acetate (80 mL), and acidified with 2N hydrochloric acid aqueous solution (pH˜5) at 0° C. The aqueous suspension was extracted with dichloromethane (50 mL×3). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give 838 mg (91%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:16]=[C:15]([C:26]([NH:28][CH:29]3[CH2:34][CH2:33][N:32]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:31][CH2:30]3)=[O:27])[C:14]=2[CH3:42])=[CH:9][CH:8]=1
Reactant: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NC2CCN(S(C)(=O)=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Methanesulfonyl chloride (2 eq., 0.01 mL, 0.15 mmol) was added to tert-Butyl 4-[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-amido]piperidine-1-carboxylate (1 eq., 35 mg, 0.076 mmol) and triethyamine (3 eq., 0.03 mL, 0.227 mmol) in tetrahydrofuran (2 mL). The reaction was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-methanesulfonyl-piperidin-4-yl)-4-methyl-1H-pyrazole-3-carboxamide (36 mg, 87%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.53-1.78 (m, 2H) 2.06-2.22 (m, 2H) 2.37 (s, 3H) 2.67-3.00 (m, 5H) 3.82 (d, J=12.24 Hz, 2H) 4.01-4.17 (m, 1H) 6.88 (d, J=8.01 Hz, 1H) 7.07 (s, 2H) 7.19-7.36 (m, 4H) 7.43 (d, J=1.70 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]#N)[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CC[O:32]CC>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:18]=[O:32])[CH:15]3[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:17][CH:9]2[CH2:10]4)[CH2:14]3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2(C#N)C3CC4CC(C3)CC2C4)cc1
Reactant: CCOCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: Cc1ccc(C2(C=O)C3CC4CC(C3)CC2C4)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A flame dried flask under argon was charged with 2-(4-methylphenyl)adamantane-2-carbonitrile (5.90 g, 23.5 mmol) and anhydrous ether (120 mL) and the solution was cooled to 0° C. Diisobutylaluminium hydride (47 mL, 46.9 mmol, 1-M in heptane) was added dropwise and the reaction left to warm to room temperature. After stirring for 1 h the reaction mixture was quenched with dilute HCl (20 mL) and then filtered through celite. The filtrate was partitioned between EtOAc (100 mL) and water (100 mL), separated, dried (MgSO4) and concentrated in vacuo to afford the title compound (5.11 g, 86%) as a white solid: mp 93-97° C.: NMR δH(400 MHz, CDCl3) 1.61-1.64 (2H, d, J 12.8 Hz), 1.71 (2H, br s), 1.78-1.97 (8H, m), 2.33 (3H, s), 2.86 (2H, br s), 7.18-7.20 (2H, d, J 8.4 Hz), 7.25-7.27 (2H, dd, J 2, 8.4 Hz) and 9.27 (1H, s); Retention time 7.99 min (λ=220 nm).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]([C:11](O)=O)=[N:8][NH:9][CH:10]=1.[NH2:19][C:20]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].C(Cl)CCl.C1C=CC2N([OH:44])N=NC=2C=1>CN(C=O)C>[CH3:25][O:24][C:22]([C:21]1[C:20]2[N:19]=[C:11]([C:7]3[C:6]([NH:5][C:4](=[O:44])[C:3]4[C:2]([F:1])=[CH:17][CH:16]=[CH:15][C:14]=4[F:18])=[CH:10][NH:9][N:8]=3)[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:23]
Reactant: O=C(O)c1n[nH]cc1NCc1c(F)cccc1F
Reactant: On1nnc2ccccc21
Reactant: COC(=O)c1cccc(N)c1N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
A mixture of 4-(2,6-difluorobenzylamino)-1H-pyrazole-3-carboxylic acid (690 mg, 2.6 mmol) Example 16D), methyl 2,3-diaminobenzoate (415 mg, 2.6 mmol), EDC (590 mg, 3.1 mmol) and HOBt (415 mg, 3.1 mmol) in DMF (10 ml) was stirred at ambient temperature for 16 h and then reduced in vacuo. The residue was partitioned between EtOAc and brine and the organic portion dried (MgSO4), filtered, reduced then crystallised from hot EtOH. The amide intermediate (480 mg) was dissolved in AcOH (10 ml) then heated at reflux for 3 h. The reaction mixture was reduced in vacuo and then azeotroped with toluene (2×20 ml) to afford 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid methyl ester (420 mg) as a fawn coloured solid. (LC/MS: Rt 3.82, [M+H]+ 398).
Reaction SMILES: [H-].[Na+].Cl[CH:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12].I[CH3:21].Cl>CN(C)C=O>[CH3:21][C:4]([C:17]1[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1)([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CI
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCOC(=O)C(C)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A 250 mL oven-dried flask capped with a rubber septum was evacuated and backfilled with argon. The flask was charged with NaH (7.26 g, 181 mmol, 60% dispersion in oil) anhydrous dimethylformamide (50 mL) and the flask was cooled to 0° C. Ethyl 2-chloropropionate (10.0 g, 73.2 mmol) and nitrobenzene (9.92 g, 80.5 mmol) were dissolved in anhydrous dimethylformamide (50 mL) and added dropwise to the sodium hydride slurry. The reaction was stirred for 30 min at 0° C., the cooling bath removed and the reaction was allowed to reach ambient temperature. After 1 h iodomethane (10.4 g, 73.2 mmol) was added and the mixture was stirred for an additional 30 min. The contents of the flask were poured into a mixture of ice and 1N HCl followed by three extractions with dichloromethane. The combined organic layers were washed five times with water, three times with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification was performed by silica gel flash chromatography eluting with a gradient of hexanes and dichloromethane (30% hexanes in dichloromethane to 100% dichloromethane) to yield ethyl 2-methyl-2-(4-nitrophenyl)propanoate (7.32 g, 42.2%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][NH2:8])[N:6]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(CN)cs1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)cs1
Yield: 74 %

Procedure:
Following the procedure as described in Example 25, making variation only as required to use (2-methylthiazol-4-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 74% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.74 (t, J=5.7 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.45-7.31 (m, 5H), 7.16 (s, 1H), 6.38 (dd, J=8.1, 2.7 Hz, 1H), 6.23 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.42 (d, J=5.7 Hz, 2H), 2.59 (s, 3H), 2.54 (s, 3H); MS (ES+) m/z 453.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.[Cl-].[NH4+]>C1COCC1.CCO.O.[Fe]>[Br:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)cc(F)c1N
Temperature: 95 °C
Reaction time: 22 h
Yield: 99.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-6-nitroaniline (0.5 g, 2.1 mmol) in THF (4.6 mL), EtOH (4.6 mL) and H2O (1.5 mL) was added iron powder (0.6 g, 10.6 mmol) and ammonium chloride (0.17 g, 3.2 mmol). The resulting mixture was stirred at 95° C. for 22 hours. The mixture was cooled to room temperature and filtered through diatomaceous earth. The solid was washed with EtOH until no further color came through the filter. The filtrate was concentrated and the residue was dissolved in EtOAc, washed with H2O and brine, dried over Na2SO4, filtered and concentrated to give the title compound (0.43 g, 99%) as a brown, waxy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]([OH:6])=O.N1[CH:17]=[CH:16]N=C1.C(Cl)(=O)C.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]2[C:3]=1[C:4](=[O:6])[N:23]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:16]([CH3:17])=[N:1]2
Reactant: NC1CCC(=O)NC1=O
Reactant: c1c[nH]cn1
Reactant: COc1cccc(N)c1C(=O)O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CC#N
Solvent: CC(=O)Cl
Solvent: O
Product: COc1cccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a stirred mixture of 2-amino-6-methoxybenzoic acid (2.0 g, 12 mmol) and imidazole (1.0 g, 14 mmol) in acetonitrile (20 mL), was added acetyl chloride (1.0 mL, 14 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.0 g, 12 mmol), imidazole (1.8 g, 26 mmol) and triphenyl phosphite (3.8 mL, 14 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was filtered and washed with water (2×50 mL), ethyl acetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50 mL) to give 3-(5-methoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (1.3 g, 35% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 15/85 CH3CN/0.1% H3PO4, 3.37 min (99.4%); mp: 274-276° C.; 1H NMR (DMSO-d6) δ 2.09-2.16 (m, 1H, CHH), 2.51-2.63 (m, 5H, CH3, 2CHH), 2.72-2.89 (m, 1H, CH h, 3.83 (s, 3H, CH3), 5.14 (dd, J=6, 11 Hz, 1H, NCH), 6.98 (d, J=8 Hz, 1H, Ar), 7.12 (d, J=8 Hz, 1H, Ar), 7.69 (t, J=8 Hz, 1H, Ar), 10.96 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.84, 23.36, 30.55, 55.85, 56.16, 107.96, 109.91, 118.26, 134.98, 149.24, 155.30, 158.13, 159.42, 169.63, 172.63; LCMS: MH=302; Anal Calcd for C15H15N3O4+1.6H2O: C, 54.57; H, 5.56; N, 12.73. Found: C, 54.19; H, 5.42; N, 12.55.