Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:21][C:22]([F:32])([F:33])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])=[CH:26][CH:25]=1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(Cc2ccc(OC(F)(F)F)cc2)c(=O)[nH]c1=O
Yield: 63.8 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 4-trifluoromethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (285 mg, yield: 63.8%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[C:18]1[N:19]=[CH:20][N:21]([CH3:30])[C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>>[C:1]1([NH:7][C:8]([C:20]2[N:21]([CH3:30])[C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:18]([C:12]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=3[Cl:10])[N:19]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: Cn1c(C(=O)Nc2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 36, Method A, but using phenyl isocyanate (0.023 mL, 0.21 mmol), 4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-1-methylimidazole (35 mg, 0.10 mmol) was converted to the title compound after purification by Prep TLC (25% ethyl acetate in hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][N:38]([CH3:45])[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40].C(NC(C)C)(C)C.CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:44]#[C:43][CH2:42][NH:41][C:39](=[O:40])[N:38]([CH3:45])[CH3:37])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[C:31](=[O:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: C#CCNC(=O)N(C)C
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1CCN(C)C(=O)C1
Reaction time: 6 h
Yield: 65.7 %

Procedure:
4-[3-({4-[(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl}oxy)propyl]-1-methylpiperazin-2-one (250 mg, 0.40 mmol) and N,N-dimethyl-N′-prop-2-yn-1-ylurea (60 mg, 0.48 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamine (81 mg, 0.80 mmol). The reaction was stirred 6 hr then DMF (3 ml) added and reaction heated at 60° for 3 hr. A further 60 mg N,N-dimethyl-N′-prop-2-yn-1-ylurea was added and heating continued for 3 hr. The mixture was then evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with brine, dried over magnesium sulphate and evaporated to an orange oil. This was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent to give the title compound (164 mg, 66%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.99 (quintet, 2H), 2.54 (t, 2H), 2.66 (t, 2H), 2.81 (s, 9H), 3.00 (s, 2H), 3.28 (t, 2H), 3.93 (s, 3H), 4.10 (d, 2H), 4.20 (t, 2H), 6.14 (s, 2H), 6.82 (t, 1H), 7.07 (s, 1H), 7.23 (s(broad), 1H), 7.85 (s, 1H), 8.40 (s(br), 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 624/626.
Reaction SMILES: [C:1]([S:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.C[O-].[Na+].[N+:23](C1C=CC(F)=CC=1)([O-:25])=[O:24].O>CO.C(Cl)(Cl)Cl>[N+:23]([C:6]1[CH:7]=[CH:2][C:1]([S:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:4][CH:5]=1)([O-:25])=[O:24]
Reactant: O=C(Sc1cccc2cnccc12)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Sc2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
5-Benzoylsulfanylisoquinoline 1.41 g (5.3 mmol) was dissolved in a mixture solution of methanol (50 ml) and chloroform (5 ml), sodium methoxide 500 mg (9.3 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, the resulting residue was dissolved in DMF 50 ml, 4-nitrofluorobenzene 0.75 g (5.3 mmol) was added, and the mixture was heated and stirred at 100° C. for 3.5 hours. After cooling, water was added to the reaction mixture, the resulting precipitate was collected and washed with water to obtain 5-(4-nitrophenylsulfanyl)isoquinoline 1.36 g (90.9%).
Reaction SMILES: Br[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[CH3:12].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][C:3]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][O:6][C:2]=1[CH:13]=[CH2:14]
Reactant: CCOC(=O)c1noc(Br)c1C
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1onc(C(=O)OCC)c1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (15 g, 64.1 mmol) and tributyl(vinyl)stannane (22.48 mL, 77 mmol) were stirred in dry dioxane (250 mL) and purged with nitrogen for 90 minutes at room temperature. Tetrakis(triphenylphosphine)palladium (3.70 g, 3.20 mmol) was added and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was partitioned in ethyl acetate (250 mL) and water (250 mL) and separated. To the organic layer was added sodium fluoride solution (˜1M, 250 ml) and the resulting suspension was filtered through Celite®. The layers were separated and the organics were washed with water, brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-30% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: CO.[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([C:27](O)=[O:28])[CH2:16]1)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].[BH4-].[Li+].O>O1CCCC1>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:17]([CH2:27][OH:28])[CH2:16]1)=[O:13])=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Yield: 97.8 %

Procedure:
Methanol (8 mL) was added over a period of 1 hr to a refluxed mixture of trans-4-N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline methyl ester (Compound D103 (B), 1.39 g) and lithium borohydride (328 mg) in tetrahydrofuran (30 mL). After being cooled, water was added to the mixture and the product was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, then evaporated in vacuo and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5, v/v) to give title compound (1.31 g): 1H NMR (400 MHz, CDCl3) δ 1.46 (s, 9H), 1.47 (s, 9H), 1.89 (m, 1H), 1.98 (m, 1H), 3.34 (dd, J=11.7, 3.9 Hz, 1H), 3.60 (d, J=5.9 Hz, 1H), 3.64 (d, J=5.9 Hz, 1H), 3.69 (m, 1H), 3.75 (d, J=5.9 Hz, 1H), 4.04 (m, 1H), 4.42 (m, 1H), 4.55 (m, 1H), 5.15 (m, 1H), and 6.44 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:24])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][C:20]([F:23])([F:22])[F:21])[CH2:8][CH2:7]1)C.[OH-].[Na+]>CCO.O>[F:22][C:20]([F:21])([F:23])[O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]([CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:25])=[O:3])[CH2:7][CH2:8]1)=[O:24]
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCC(C(=O)c2ccccc2OC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of [4-(2-trifluoromethoxy-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (0.36 g, 1 mmol, 1 eq.) in 5 mL of EtOH was added a solution of NaOH (0.08 g, 2 mmol, 2 eq.) in 5 mL of H2O. The resulting mixture was stirred at room temperature overnight. After 18 h, the reaction mixture was concentrated and treated with 1 N HCl to pH 5. The resulting mixture was freeze dried using a lyophilizer to remove H2O. The resulting yellow solids were washed with dichloromethane/methanol and filtered off NaCl. The filtrate was concentrated to give the title compound as a white solid (0.33 g, 99%). Exact mass calculated for C15H19F3N1O4332.1. MS (ESI) m/z 332.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC1(C)[O:54][CH2:53][CH:52]([CH2:55]O)[CH2:51][O:50]1.CCOC(/N=N/C(OCC)=O)=O.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:55][CH:52]([CH2:53][OH:54])[CH2:51][OH:50])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:7]=1[CH3:8]
Reactant: CC1(C)OCC(CO)CO1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3cccnc3)ccnc2cc1OCC(CO)CO
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
4-(5,6-Dimethyl-[2,3′]bipyridin-3-yloxy)-6-methoxy-quinolin-7-ol (compound 345) (80 mg) was dissolved in tetrahydrofuran (2 ml) to prepare a solution. Triphenylphosphine (112 mg), (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (38 mg), and diethylazodicarboxylate (0.078 ml) were added to the solution, and the mixture was stirred at room temperature for 6 hr. Further, 1 N sulfuric acid (4 ml) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (54 mg, yield 56%).
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11]Cl)[CH2:5][CH2:4]1)=[O:2].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=1.[I-].[Na+].[OH-].[Na+]>O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:13][C:14]2[CH:22]=[CH:21][C:17]([CH2:18][C:19]#[N:20])=[CH:16][CH:15]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: N#CCc1ccc(N)cc1
Reactant: O=CN1CCN(CCCCl)CC1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCc1ccc(NCCCN2CCN(C=O)CC2)cc1

Procedure:
A mixture of 1-formyl-4-(3-chloropropyl)piperazine (1.0 g, 5.2 mmol) prepared according to step a) above, 4-aminobenzylcyanide (0.66 g, 5 mmol) and sodium iodide (0.15 g, 1 mmol) was heated at 100°-105° C. for 2 hours. After cooling the mixture was dissolved in 40 ml of water and treated with decolorizing carbon. The filtered solution was made alkaline with 2N aqueous NaOH and extracted with chloroform (3×20 ml). The organic extracts were washed with water, dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column eluting with a 2:1 mixture of ethyl acetate and methanol to give the title compound. Yield: 0.55 g, 38.5%. Mp. after trituration with ether: 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Cl:1][C:2]1[C:3](=[O:9])[N:4]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][O:10]2)[N:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1=COCCC1
Reactant: Oc1nncc(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Temperature: 25 °C

Procedure:
A mixture of 4,5-dichloropyridazin-3-ol (42 g, 250 mmol), 3,4-dihydro-2H-pyran (168 g, 2.00 mol) and p-toluenesulfonic acid (8.8 g, 51 mmol) in tetrahydrofuran (2 L) was heated at reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated in vacuo and purified by silica gel chromatography (Gradient: 3% to 5% ethyl acetate in petroleum ether). The product was obtained as a white solid. Yield: 42 g, 170 mmol, 68%. 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 6.01 (br d, J=11 Hz, 1H), 4.10-4.16 (m, 1H), 3.70-3.79 (m, 1H), 1.99-2.19 (m, 2H), 1.50-1.80 (m, 4H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:21]=[CH:20][C:14]3[S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][C:13]=3[CH:12]=2)[C:8]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc2c(c1)CCS2(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)c2ccc3c(c2)CCS3(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
A solution of 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-propionic acid (114 mg, 0.37 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 212 μL, 0.43 mmol) which produced gas evolution and it was stirred at 0° C. for 15 min and it was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to ˜1.5 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 63 mg, 0.41 mmol), 2,6-lutidine (61 μL, 0.55 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture was diluted with methylene chloride (10 mL) and washed with a saturated aqueous sodium bicarbonate solution (15 mL). The aqueous layer was then extracted with methylene chloride (2×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification using reverse phase HPLC afforded 3-cyclopentyl-2-(1,1-dioxo-2,3-dihydro-benzo[b]thiophen-5-yl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (103 mg, 63%) as a white foam (as a racemic mixture): ES-HRMS m/e calcd for C23H31N3O4S (M+H)+ 446.2108, observed 446.2109; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.03 (s, 3H, CH3), 1.04 (s, 3 H, CH3), 1.10 (m, 2H, CH2), 1.38-1.79 (m, 8H, 4×CH2), 2.07 (m, 1H, CH), 3.33 (t, J=6.8 Hz, 2H, ArCH2), 3.56 (t, J=6.8 Hz, 2H, SO2CH2), 3.86 (s, 2 H, NCH2), 3.91 (m, 1 H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.51 (m, 3H, Ar), 7.69 (d, Jo=8.5 Hz, 1H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([NH2:44])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:44][C:35]([CH3:37])([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH3:36])=[O:7]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Yield: 97.6 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-chloro-4-methoxybenzoic acid (1.00 g, 5.36 mmol) was dissolved in DMF (20 mL), and the solution was treated with EDCI (2.06 g, 10.7 mmol), HOBT monohydrate (724 mg, 5.36 mmol) and cumylamine (1.54 mL, 10.7 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 3-chloro-4-methoxy-N-(1-methyl-1-phenylethyl)benzamide (1.59 g, yield 97%).
Reaction SMILES: [F:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[F:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:4][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCC[C@H](F)CO
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC[C@H](F)COS(=O)(=O)c1ccc(C)cc1
Yield: 98 %

Procedure:
Three grams of the obtained (S)-2-fluorooctane-1-ol, 4.5 g of p-toluenesulfonyl chloride and 50 ml of pyridine were stirred at room temperature. 100 ml of water and 200 ml of toluene were added to the solution. The organic layer was separated and washed with an acid solution, with an alkali solution and with water, dried over magnesium sulfate, and concentrated. 6.0 g of (S)-2-fluoro-1-p-toluenesulfonyloxyoctane was obtained.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2C(=O)c1ccccc1
Yield: 20.9 %

Procedure:
The same procedures used in Example 11 were repeated except for using 725 mg of indole-4-carbaldehyde and 773 mg of benzoyl chloride instead of phenylacetyl chloride to give 260 mg of 1-benzoylindole-4-carbaldehyde as colorless crystals. The yield thereof was found to be 21%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:30]([O:32]C)=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.O.[NH2:35][NH2:36]>O1CCOCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:18]3)(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[N:4][C:3]=1[C:30]([NH:35][NH2:36])=[O:32]
Reactant: NN
Reactant: COC(=O)c1nc(-c2ccc(S(=O)(=O)C3CCCN(C(=O)OC(C)(C)C)C3)cc2)cnc1N
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(S(=O)(=O)c2ccc(-c3cnc(N)c(C(=O)NN)n3)cc2)C1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 94.5 %

Procedure:
methyl 3-amino-6-[4-[(1-tert-butoxycarbonyl-3-piperidyl)sulfonyl]phenyl]pyrazine-2-carboxylate (1.65 g, 3.462 mmol) in dioxane (16.50 mL) was treated with hydrazine hydrate (866.5 mg, 842.1 μL, 17.31 mmol) and stirred at 65° C. for 2.5 hours. The reaction mixture was concentrated in vacuo. The residue was treated with water and stirred for 1 hour, filtered and washed with water, and dried overnight under high vacuum giving tert-butyl 3-[4-[5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl]phenyl]sulfonylpiperidine-1-carboxylate (1.572 g, 3.272 mmol, 93.77%) as a pale yellow powder. LC/MS m/z 421.1 [M−56+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>C(Cl)Cl>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])=[O:30])=[CH:9][C:8]=1[C:14]1[N:15]([CH3:19])[N:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1ccccc1F
Reactant: CN(C)CCCOc1ccc(N)cc1-c1ccnn1C
Solvent: ClCCl
Product: CN(C)CCCOc1ccc(NC(=O)Nc2ccccc2F)cc1-c1ccnn1C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (60.6 mg, 0.221 mmol) in CH2Cl2 (2 mL) was added 2-fluorophenyl isocyanate (0.27 μL, 0.240 mmol) and stirred for two hours. The resulting material was purified by solid phase extraction (SCX, 1 gram cartridge), eluting with methanol (30 mL) followed by 2M NH3 in methanol (30 mL). The NH3 containing fractions were dried in vacuo to afford Compound 138 as a colorless solid (85.5 mg, 91%). LCMS m/z (%)=412 (MH+) (100), 1H NMR (400 MHz, DMSO-d6) δ: 9.36 (bs, 1H), 8.25 (bs, 1H), 8.15 (dd, J=8.34, 1.52 Hz, 1H), 7.47-7.42 (m, 3H), 7.40 (d, J=2.78 Hz, 1H), 7.31-7.26 (m, 1H), 7.11 (d, J=9.09 Hz, 1H), 7.05-6.99 (m, 1H), 6.25 (d, J=2.02 Hz, 1H), 3.98 (t, J=6.32 Hz, 2H), 3.66 (s, 3H), 2.19 (t, J=7.07 Hz, 2H), 2.07 (s, 6H), 1.77-1.69 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7].O.N>C(O)C.S([O-])([O-])(=O)=O.[Fe+2]>[Br:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][O:5][C:6]2=[O:7]
Reactant: O=C1OCc2c1ccc([N+](=O)[O-])c2Br
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1Br)COC2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
6.6 g of 4-bromo-5-nitrophthalide is dissolved in 45 ml of ethanol and added in drops to a mixture of 65 g of iron(II) sulfate, 220 ml of water and 65 ml of ammonia (33%) that is heated to 60° C. and stirred well. After 2 hours at 60° C., the mixture is absorptively precipitated five times with 200 ml of diethyl ether. The diethyl ether phases are concentrated by evaporation. As a residue, 4.1 g of 4-bromo-5-aminophthalide is obtained, melting point 176-180° C.