Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42]O)[CH3:39].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:20]3[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[O:10])[CH2:12][CH2:13]4)=[O:15])=[CH:18][C:19]=3[F:37])=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])[CH3:39]
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccnc2cc1O
Reactant: CCN(CC)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCN(CC)CCOc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a mixture of cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide (186 mg, 0.36 mmol) in CH2Cl2 (10 mL) was added 2-(diethylamino)ethanol (63 mg, 0.54 mmol), and PPh3 (141 mg, 0.54 mmol). DIAD (109 mg, 0.54 mmol) was then added as a CH2Cl2 (1 mL) solution. The resulted solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. To the residue was added 1 N HCl (50 mL), and it was washed with EtOAc (50 mL×2). The aqueous phase was basified by adding 15% NaOH aqueous solution until pH=11-13, and then extracted with ether (50 mL×2). The combined organic layer was dried (MgSO4), and concentrated in vacuo. The residue was purified on preparative HPLC to give N-(4-{[7-{[2-(diethylamino)ethyl]oxy}-6-(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluoro-phenyl)cyclopropane-1,1-dicarboxamide (74 mg, 34%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.40 (br s, 1H), 10.02 (br s, 1H), 8.47 (d, J=5.2 Hz, 1H), 7.91 (br d, J=13.9 Hz, 1H), 7.54-7.52 (m, 2H), 7.55-7.50 (m, 1H), 7.52 (s, 1H), 7.50-7.40 (m, 1H), 7.41 (s, 1H), 7.16 (br t, J=8.7 Hz, 2H), 6.41 (br d, J=4.7 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H), 3.94 (s, 3H), 2.87 (br t, J=6.3 Hz, 2H), 2.59 (q, J=7.1 Hz, 4H), 1.47 (br s, 4H), 1.00 (t, J=7.0 Hz, 6H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](OCC)=[O:12])[CH:6]=[CH:7][CH:8]=1.O.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]([NH:19][NH2:20])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: CCOC(=O)CCc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1cccc(C(F)(F)F)c1
Yield: 80.9 %

Procedure:
A solution of ethyl 3-[3-(trifluoromethyl)phenyl]propionate (9.85 g, 40.0 mmol) and hydrazine monohydrate (9.70 mL, 200 mmol) in ethanol (50 mL) was heated under reflux overnight. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (7.51 g, yield 81%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15]C(=O)OC(C)(C)C)[CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:24]=2)[CH:3]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]([S:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:24]=2)[CH:3]=1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(NC3CCCC(NC(=O)OC(C)(C)C)C3)c1)cn2S(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2c(c1)c(-c1cc(Cl)nc(NC3CCCC(N)C3)c1)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of Example 261b (1.76 g, 2.88 mmol) in CH2Cl2 (30 mL) was treated with trifluoroacetic acid (3.32 mL, 43.1 mmol). The mixture is stirred at room temperature for 3 hours and concentrated to give 2.34 of the title compound as trifluoroacetic acid salts.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.C=O.[BH3-][C:21]#N.[Na+].CC(O)=O>CO>[CH3:7][C:4]1[N:3]([C:8]2[CH:17]=[C:11]3[CH:12]([CH3:16])[N:13]([CH3:21])[CH2:14][CH2:15][N:10]3[N:9]=2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C)n1-c1cc2n(n1)CCNC2C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(C)n1-c1cc2n(n1)CCN(C)C2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 287g (1.54 g, 1.0 eq., 6.70 mmol), formaldehyde (37% in water) (1.09 g, 2.0 eq., 13.4 mmol), NaBH3CN (2.11 g, 5.0 eq., 33.5 mmol), HOAc (3 mL), and methanol (30 mL). The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was partitioned between water (50 mL) and dichloromethane (50 mL). The water phase was extracted with dichloromethane (3×50 mL). The combined organic layer was concentrated under reduced pressure to afford crude 287h, which was used in the next step without further purification. MS-ESI: [M+H]+ 245.0
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:29])[NH:17][C:18]2([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:22][CH2:21][NH:20][CH2:19]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:30]=O>C(O)=O>[CH3:30][N:20]1[CH2:21][CH2:22][C:18]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])([NH:17][C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)=[O:29])[CH2:19]1
Reactant: C=O
Reactant: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCNC2)cc1
Solvent: O=CO
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Temperature: 110 °C
Yield: 35 %

Procedure:
To a solution of ethyl 2-(3-(3-(4-octylphenyl)ureido)pyrrolidin-3-yl)acetate (84 mg, 0.2 mmol) in formic acid (2 mL) was added formalin (15 μL, 0.16 mL). The solution was heated to 110° C. for 2 h. The mixture was concentrated and dissolved into CH2Cl2 (25 mL) and washed with sat. bicarbonate (2×5 mL), H2O (5 mL), dried over MgSO4 and concentrated to dryness to give the title compound as a brown oil (29 mg, 35%) MS ESI 418.4 [M+H]+, calcd for [C24H39N3O3+H] 418.30.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[C:33](Cl)(=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:33](=[O:38])[CH2:34][CH:35]([CH3:37])[CH3:36])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CC(C)C)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, isovaleryl chloride (24 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 20×50 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (22.4 mg, 68% of theory).
Reaction SMILES: [F:1][C:2]1([F:43])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18](CC3C=CC(OC)=CC=3OC)[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[CH:10]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:43][C:2]1([F:1])[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)(=[O:17])=[O:16])=[C:11]([F:36])[CH:10]=2)[C@@H:4]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC(F)(F)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CC(F)(F)CC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 98.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (79.7 mg, 0.13 mmol) prepared in Example 130a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (60 mg, 99%) as a colorless solid.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[O:9][C:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[C:14](=[O:23])[NH:13][C:12](=[O:24])[C:11]=1[CH:25]([CH3:27])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.CC(C)=O>[CH:25]([C:11]1[C:12](=[O:24])[NH:13][C:14](=[O:23])[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[C:10]=1[O:9][C:8]1[CH:7]=[C:6]([CH:30]=[C:29]([CH3:31])[CH:28]=1)[CH:2]=[O:1])([CH3:27])[CH3:26]
Reactant: Cc1cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccncc2)cc(C2OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C=O)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccncc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A mixture of 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-5-isopropyl-1-pyridin-4-ylmethyl-1H-pyrimidine-2,4-dione (1.2 g, 2.83 mmol), p-toluenesulfonic acid monohydrate (538 mg, 2.83 mmol), and water (15 drops) in acetone (20 ml) was heated under reflux for 3 hr. After cooling to room temperature, excess sodium bicarbonate was added and the mixture was stirred for 1 hr. Then the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA:hexane (9:1)) to afford 978 mg (91%) of 3-(5-Isopropyl-2,6-dioxo-3-pyridin-4-ylmethyl-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzaldehyde as a white solid. 1H NMR (200 MHz, CDCl3) δ 1.12 (6H, d, J=7.0 Hz), 2.40 (3H, s), 2.70 (1H, m), 4.92 (2H, s), 6.90 (1H, s), 7.08 (1H, s), 7.11 (1H, s), 7.14 (1H, s), 7.43 (1H, s), 8.50 (2H, d, J=6.2 Hz), 9.73 (1H, s), 9.91 (1H, s). 6.85-6.89 (3H, m), 7.09 (1H, s), 7.21-7.27 (2H, m), 7.40 (1H, s), 8.98 (1H, s), 9.89 (1H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.O.C([NH:44][C@H:45]([C:50](O)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])(OC(C)(C)C)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCOC(C)=O.CN(C=O)C>[NH2:44][C@@H:45]([CH2:46][CH:47]([CH3:49])[CH3:48])[C:50]([N:19]1[CH2:20][CH2:21][CH:16]([N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH2:17][CH2:18]1)=[O:51]
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](N)CC(C)C)CC1
Reaction time: 4.5 h
Yield: 85.8 %

Procedure:
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (Ic, 1.03 g, 2.94 mmol) was dissolved DMF (15 mL) and treated with Hunig's base (1.3 mL, 7.4 mmol), Boc-L-leucine hydrate (0.74 g, 2.94 mmol), and HBTU (1.11 g, 2.94 mmol). The reaction was stirred for 4.5 hours, then diluted with EtOAc (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The crude material was chromatographed on silica gel eluting with 5% (MeOH/CH2Cl2) to give 1.17 g (71%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9].[OH-].[Na+].[H][H]>[Ni].O>[CH3:1][O:2][C:3]1[CH2:4][CH:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([OH:10])=[O:9]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1=CC=CC(C=CC(=O)O)C1
Yield: 89.8 %

Procedure:
A mixture of m-methoxycinnamic acid (100 g, 0.56 mole), water (1 L), and NaOH (22.4 g, 0.56 mole), in the presence of Raney nickel catalyst (20 g, #30), was hydrogenated under 3 atmospheres H2 pressure until the theoretical uptake of hydrogen was observed. The solution was filtered, cooled to 0°, and concentrated HCl was added until acidic pH was achieved. The solid was filtered, washed with water, dried (in-vacuo) to yield 90.6 g white solid, (90%); M+ 180.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:23]=1[N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]1[CH2:20][CH2:19][CH2:18][C:17](=[O:32])[C:16]2=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:23]=1[N:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:32])[C:16]2=1
Reactant: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1cccc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Temperature: 75 °C
Reaction time: 5.5 h
Yield: 72 %

Procedure:
Pyridinium bromide perbromide (0.1988 g, 0.62 mmol) is added to a solution of 8-chloro-9-(4-fluorobenzyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one in THF (0.7 mL) and DMF (0.5 mL) and the mixture is heated to 75° C. After stirring for 5.5 h, THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium sulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. A mixture of the resulting residue, lithium bromide (0.0976 g, 0.0011 mol), lithium carbonate (0.0762 g, 0.0010 mol) and DMF (2 mL) is heated at 120° C. for two hours. The DMF is then removed under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (80 mL) using 15% ethyl acetate in heptane/dichloromethane (6:1) to give 0.1199 g (72%) of the title compound; mp 142-145° C.; MS (ESI−) for C19H13ClFNO m/z 324.1 (M−H)−; IR (drift) 3521, 1591, 1508, 1457, 1416, 1351, 1337, 1311, 1269, 1226, 1218, 1110, 852, 791, 736 cm−1; 1H NMR (CDCl3) δ5.38, 5.94, 6.60, 6.93, 7.06, 7.18, 7.26, 7.36, 8.29. Anal. Calcd for C19H13ClFNO: C, 70.05; H, 4.02; N, 4.30. Found: C, 69.26; H, 4.05; N, 4.20.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](OC)(OC)OC.Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:20]3[N:21]=[CH:22]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)OC
Reactant: Nc1cccnc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Product: c1ccc(CN2CCC(n3cnc4cccnc43)CC2)cc1

Procedure:
The title compound was prepared from 153 mg of 2-N-(1-benzyl-piperidin-4-yl)-pyridine-2,3-diamine (from Step B), 6 mL of trimethyl orthoformate, and) 0.2 mL of concentrated HCl, using a procedure analogous to that described in Example 95, Step B to provide 139 mg of the title compound as a yellow solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1([F:37])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([NH:35]N)[C:28]=2[O:27]1.N([O-])=O.[Na+].[Sn](Cl)Cl>>[F:37][C:26]1([F:25])[O:30][C:29]2[CH:31]=[CH:32][CH:33]=[C:34]([N:35]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:2]3)[C:28]=2[O:27]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: NNc1cccc2c1OC(F)(F)O2
Agent: Cl[Sn]Cl
Agent: O=N[O-]
Agent: [Na+]
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4c3OC(F)(F)O4)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and 2,2-difluoro-benzo[1,3]dioxol-4-yl-hydrazine (prepared from the corresponding amino derivative using sodium nitrite and tin(II) chloride as described in J. Med. Chem. 2003, 46, 4676-4686) according to the method described for example 91. MS: M=473.2 (M+H)+
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:29])[C@@H:7]1[CH2:11][CH:10]([CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][N:8]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[C:25]([O:24][C:22]([N:8]1[CH2:9][CH:10]([CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:7]1[C:6]([OH:29])=[O:5])=[O:23])([CH3:27])([CH3:28])[CH3:26]
Reactant: COC(=O)[C@@H]1CC(CCNC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.1 %

Procedure:
Lithium hydroxide monohydrate (7 mg) was added to a solution of N-tert-butoxycarbonyl-4-[2-(tert-butoxycarbonylamino)ethyl]-L-proline methyl ester (E, 50 mg) in tetrahydrofuran (0.5 mL)-methanol (0.5 mL)-water (0.5 mL). After stirring at room temperature for 4 hr, the reaction mixture was acidified with 10% citric acid and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the title compound (52 mg).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: CCOC(=O)c1sc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)nc1C

Procedure:
This compound was prepared from ethyl 2-amino-4-methylthiazole-5-carboxylate and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described for EXAMPLE 30. Yield 254 mg, 62%: 1H NMR (DMSO) δ 7.64 (d, 1H), 7.53 (d, 1H), 4.22 (q, 2H), 2.67 (s, 3H), 2.41 (s, 3H), 1.25 (t, 3H); MS-ES (neg) In/z 407.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]([NH2:14])=O)=[N:7]1.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]#[N:14])=[N:7]1
Reactant: Cc1nc(C(N)=O)nn1Cc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1nc(C#N)nn1Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a suspension of 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carboxamide (50 mg, 0.17 mmol) and Et3N (47 μL, 0.34 mmol) in DCM (2 mL) was slowly added a solution of trifluoroacetic anhydride (29 μL, 0.20 mmol) in DCM (2 mL) at 0° C. The reaction was stirred at 0° C. for 2 h, and was then warmed to RT while stirring overnight. The reaction was then quenched with H2O (3 mL) and washed with NaOH (1N, 5 mL) and brine (2×5 mL) before being concentrated under reduced pressure. The crude product was purified on a Biotage pre-packed silica gel column with a gradient of 12% to 80% EtOAc:Hexanes to afford 1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazole-3-carbonitrile (39 mg, 83%) as a viscous oil. MS (ES+) C11H9BrN4 requires: 276, 278 found: 277, 279 [M+H]+(1:1).
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].CCN(CC)CC.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)Cl>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:4][CH2:1][C:2]#[CH:3])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCNS(=O)(=O)c1ccc(C)cc1

Procedure:
To solution of propargyl amine (2.00 g, 36.29 mmol) and Et3N (7.30 g, 72.59 mmol) in CH2Cl2 was added in small portions p-toluenesulfonyl chloride (6.90 g, 36.29 mmol) (J. T. Baker) at 0° C. After 5 min the mixture was filtered and the filtrate was concentrated to a residue that upon direct application on a silica gel column with a 0-40% EtOAc in hexanes gradient yielded 4-Methyl-N-(prop-2-ynyl)-benzenesulfonamide. (Yield 7.30 g, 96%).
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5(O)[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]5)=[CH:19][C:18]=4[O:31][CH3:32])=[N:11][C:10]=3[C:9]([CH3:33])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([C:23]5[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH:24]=5)=[CH:19][C:18]=4[O:31][CH3:32])=[N:11][C:10]=3[C:9]([CH3:33])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C2(O)CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C2=CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 51.4 %

Procedure:
To a 10 ml toluene solution of 160 mg (0.35 mmol) of the compound obtained in Example 122, 135 mg (0.71 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 22 hours with the use of a Dean-Stark dehydrator. The reaction mixture was returned to room temperature, and washed with a saturated aqueous solution of sodium hydrogen carbonate. The system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) to obtain 78 mg (51%) of the captioned compound.