Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:18](I)=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:1]([NH:8][C:9]1[C:10]2[C:18]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[CH:17][N:16]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:11]=2[N:12]=[C:13]([Cl:15])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NCc4ccccc4)nc(Cl)nc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 9.9 %

Procedure:
To a mixture of N-benzyl-2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (300 mg, 0.557 mmol), pyridine-4-boronic acid (137 mg, 1.11 mmol) and Pd(Ph3P)2Cl2 (40 mg, 0.042 mmol) in dioxane (3 mL), aq. Na2CO3 (120 mg, 1.13 mmol) (1.0 mL) was added. The mixture was stirred at 100° C. for 4 h. It was concentrated in vacuo. The residue was purified by HPLC to give N-benzyl-2-chloro-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (27 mg).
Reaction SMILES: CN(OC)[C:3](=[O:13])[CH2:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH:16]([Mg]Cl)([CH3:18])[CH3:17].Cl>O1CCCC1.C(OCC)C>[C:9]([O:8][C:6]([NH:5][CH2:4][C:3](=[O:13])[CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)[Mg]Cl
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)C(=O)CNC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
A solution of 10.9 g of N-tert.-butoxycarbonylglycine N-methyl-N-methoxyamide in 300 ml of anhydrous tetrahydrofuran and 100 ml of anhydrous diethyl ether was cooled at 0-5° C. while 100 ml of a 2M solution of isopropyl magnesium chloride in tetrahydrofuran was added slowly. The mixture was stirred at 0-5° C. for 4 h then poured into 1.5 liter of 1M hydrochloric acid. The product was extracted with three portions of 500 ml diethyl ether. Combined extracts were washed with 500 ml brine then dried over anhydrous magnesium sulphate, filtered and evaporated to give 8.38 g of 4-tert.-butoxycarbonylamino-2-methyl-3-butanone as a colourless oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C:8]=32)=[N:3]1>CO.[C].[Pd]>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C:8]=32)=[N:3]1
Reactant: CCC(=O)NCC=C1CCc2ccc3nn(C)cc3c21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NCCC1CCc2ccc3nn(C)cc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.9 %

Procedure:
To a solution of N-[2-(2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethyl]propanamide (83 mg, 0.225 mmol) in methanol (2 mL) was added palladium-carbon powder (8 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography (methanol/ethyl acetate=10/90) to give the title compound (45.1 mg, yield 74%).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCSCC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 142 %

Procedure:
To a solution of 4.1 g (0.015 mole) of tetrahydro-4H-thiopyran-4-ol in 40 mL of pyridine, cooled in an ice bath, was added 2.90 g (0.15 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into a mixture of ice and water, and the whole extracted with diethyl ether. The organic phase was washed with water then with a 10% aqueous solution of sodium hydroxide, dried, and concentrated to give 5.8 g of product as an oil.
Reaction SMILES: Cl.[NH:2]1[C:6]([CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:5][N:4]=[CH:3]1.[NH2:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)=[O:15]>>[NH:2]1[C:6]([CH2:7][CH2:8][C:9]([NH:12][C@@H:13]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[CH:21][CH:22]=2)=[O:15])=[O:11])=[CH:5][N:4]=[CH:3]1
Reactant: O=C(O)CCc1cnc[nH]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CCc1cnc[nH]1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 5 %

Procedure:
Proceeding as in Example 1, but substituting 3-(1H-imidazol-5-yl)propanoic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 207, (S)-2-(3-(1H-imidazol-5-yl)propanamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (18.4 mg, 5%). 1H-NMR (400 MHz, DMSO-D6): σ 10.19 (s, 1H), 8.29 (d, 1H), 7.60 (d, 2H), 7.46 (s, 1H), 7.29-7.16 (m, 6H), 7.01-6.94 (m, 4H), 6.73 (s, 1H), 4.70-4.64 (m, 1H), 4.50 (s, 2H), 2.73-2.67 (m, 2H), 2.48-2.43 (m, 4H). MS (EI) for C28H27FN4O4. found 503.2 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:36])=[O:35]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4c(Cl)cccc4Cl)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,6-dichlorobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH:40]([CH3:42])[CH3:41])[CH2:28][CH:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH:40]([CH3:41])[CH3:42])[C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:34][CH:35]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
To a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (41 mg, 0.13 mmol) and 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (46 mg, 0.13 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (51 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate-DCM/MeOH (20:1) to give tert-butyl 2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (58 mg, 78%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (s, 1H), 7.30-7.22 (m, 4H), 5.11 (m, 1H), 3.80-3.40 (m, 13H), 2.20-2.10 (m, 2H), 1.48 (s, 9H), 1.14 (m, 3H), 1.03 (m, 3H), 0.68 (m, 3H). MS (APCI+) [M+H] +559.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:11][CH2:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:18].[Na+]>CO>[CH:9]1([CH:7]([NH2:18])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11][CH2:10]1
Reactant: O=C(c1ccccc1)C1CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC(c1ccccc1)C1CC1
Reaction time: 96 h
Yield: 76 %

Procedure:
100 g of cyclopropyl phenyl ketone are stirred in 2,000 ml of methanol with 500 g of pre-dried ammonium acetate and 50 g of sodium cyanoborohydride, in the presence of 4 A molecular sieves, under argon for 4 days at 50° C. After cooling, the molecular sieves are filtered off and hydrochloric acid is added to bring the pH to 2. The methanol is evaporated to dryness under vacuum and the residue is taken up in diethyl ether. The aqueous phase is washed with ethyl ether and basified by addition of concentrated potassium hydroxide solution so that the pH is above 10. The mixture is extracted twice with methylene chloride and the extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulphate and then concentrated under vacuum to give α-cyclopropylbenzylamine.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[N:16][C:17]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C=Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution containing 1-Boc-piperidine-4-carboxaldehyde (3.0 g, ca. 14 mmol), 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (3.7 g, 14 mmol), and pyridinium p-toluene-sulfonate (0.3 g, 1.4 mmol) in benzene (250 mL) was heated at reflux for 24 h with azeotropic removal of water. The solution was allowed to cool to room temperature; then the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (300 mL) and water (150 mL). The organic phase was separated and washed again with water (150 mL) and then brine (150 mL); then dried with MgSO4, filtered and concentrated in vacuo to give 6.0 g (93%) of the title compound as an orange foam which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[CH:12]=2)[NH:7][C:6]1=[O:18])[CH:2]=[CH2:3].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[CH:12]=2)[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]1=[O:18])[CH:2]=[CH2:3]
Reactant: C=CCOn1c(=O)[nH]c2cc(F)c(F)cc2c1=O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOn1c(=O)c2cc(F)c(F)cc2n(Cc2ccccc2)c1=O
Reaction time: 0.5 h
Yield: 107.9 %

Procedure:
A solution of 3-allyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example Z-3, 0.7 g, 2.8 mmol) in 20 mL of DMF was added to a suspension of sodium hydride (0.12 g, 3.0 mmol) in 15 mL of DMF and stirred for 30 minutes. Benzyl bromide (0.65 mL, 5.5 mmol) was added, and the mixture was stirred at 25° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform washed with water and brine and dried over magnesium sulfate. The solution was concentrated to give 1.04 g of the title compound as a solid, mp 130-132° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Product: CCCCCCCOc1ccc(C=O)cc1
Yield: 80.5 %

Procedure:
General procedure K was used to convert 4-hydroxybenzaldehyde (8.2 mmols) and 1-bromoheptane (12.3 mmols) to 6.6 mmols (80%) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 9.87 (s, 1H), 7.82 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.03 (t, J=6.5 Hz, 2H), 1.81 (quin., J=6 Hz, 1H), 1.24-1.53 (m, 8H), 0.89 (t, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 191.0, 164.4, 132.13, 129.8, 114.9, 68.6, 31.9, 29.18, 29.1, 26.1, 22.7, 14.2.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:40](Cl)(=[O:42])[CH3:41].C(=O)([O-])O.[Na+]>C1COCC1>[C:40]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18](=[O:19])[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:22][CH2:23]1)(=[O:42])[CH3:41]
Reactant: CC(=O)Cl
Reactant: O=C(NC1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Reaction time: 1 h
Yield: 69 %

Procedure:
The compound obtained in Example 13 (435 mg, 1.00 mmol), triethylamine (0.335 ml) were dissolved in THF (10 ml), and under ice cooling, to the solution was added acetyl chloride (0.142 ml). The mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were collected by filtration. The filtrate was concentrated under reduced pressure. To the concentrate was added diethyl ether, and the resulting precipitates were collected by filtration. The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (331 mg, 0.69 mmol, Yield 69%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:44])[N:14]([CH2:25][C:26]([NH:28][CH:29]([CH:41]([CH3:43])[CH3:42])[CH:30]([OH:40])[C:31]([F:39])([F:38])[C:32](=[O:37])[NH:33][CH2:34][CH2:35][CH3:36])=[O:27])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:45](N)[CH2:46][C:47]1C=CC=[CH:49][CH:48]=1.Cl>O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:44])[N:14]([CH2:25][C:26]([NH:28][CH:29]([CH:41]([CH3:43])[CH3:42])[CH:30]([OH:40])[C:31]([F:38])([F:39])[C:32](=[O:37])[NH:33][CH2:34][CH2:35][C:36]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:27])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCNC(=O)C(F)(F)C(O)C(NC(=O)Cn1c(-c2ccccc2Cl)ccc(NC(=O)OCc2ccccc2)c1=O)C(C)C
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2Cl)ccc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)C(=O)NCCc1ccccc1

Procedure:
2-[3-Benzyloxycarbonylamino-6-(2-chlorophenyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-[3,3-difluoro-2-hydroxy-1-isopropyl-3-(N-propylcarbamoyl)propyl]acetamide was treated with phenethylamine using a method similar to that described in Example 1.h. except that the reaction mixture was diluted with water, and the pH was adjusted to 6-7 with 10% hydrochloric acid; the mixture was evaporated; and the residue was partitioned between ethyl acetate and water. The organic phase was washed (10% hydrochloric acid, brine), dried and evaporated. Purification by trituration from ether afforded the amide; TLC: Rf =0.34, chloroform:methanol (40:1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:5](=[O:12])[CH2:4][S:3]1.[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:35])([F:34])[F:33])[CH:15]=1.C(CN)O>>[Cl:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:4]4/[C:5](=[O:12])[N:6]([NH:7][S:8]([CH3:11])(=[O:10])=[O:9])[C:2](=[O:1])[S:3]/4)=[CH:25][CH:26]=3)[CH:21]=[N:20]2)=[C:16]([C:32]([F:33])([F:35])[F:34])[CH:15]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CS(=O)(=O)NN1C(=O)CSC1=O
Solvent: NCCO
Product: CS(=O)(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methanesulfonamide was prepared from N-(2,4-dioxo-thiazolidin-3-yl)-methanesulfonamide (from Example 360) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure E. The compound was made as an ethanolamine salt following General Procedure T.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1.BrC1N=C(C[N:37]2[CH2:47][CH2:46][C:40]3([NH:44][C:43](=[O:45])[O:42][CH2:41]3)[CH2:39][CH2:38]2)C=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:12]1[S:16][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:37]3[CH2:38][CH2:39][C:40]4([NH:44][C:43](=[O:45])[O:42][CH2:41]4)[CH2:46][CH2:47]3)[N:19]=2)=[C:14]([C:26]([NH2:28])=[O:27])[CH:13]=1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C=O)n3)s2)c(F)c1
Reactant: O=C1NC2(CCN(Cc3cccc(Br)n3)CC2)CO1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCC5(CC4)COC(=O)N5)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to Example 106 Step 2 using 5-(2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl)-2-((6-formyl-2-pyridinyl)amino)-3-thiophenecarboxamide (19.5 mg, 0.05 mmol) and 8-[(6-bromopyridin-2-yl)methyl]-3-oxa-1,8-diazaspiro[4.5]decan-2-one (7.6 mg, 0.05 mmol) as the starting materials.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1.[F-].[Cs+]>COCCOC.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>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([Cl:10])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)c1
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1cc(Cl)cc(Cl)n1
Yield: 32.1 %

Procedure:
To a mixture of 2,4,6-trichloropyridine (50 mg, 0.27 mmol), 5-chloro-2-methoxy-phenylboronic acid (54 mg, 0.28 mmol), cesium fluoride (100 mg, 0.66 mmol) in ethylene glycol dimethyl ether (10 ml), degassed with argon, was added tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The mixture was heated under reflux for 2 hours and filtered through a pad of celite under suction. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate-hexane (1:9) to provide 2,4-dichloro-6-(5-chloro-2-methoxy-phenyl)-pyridine (25 mg, 32% yield). 1H NMR (acetone-d6) δ 3.95 (s, 3H, CH3), 7.24 (d, 1H, J=8.9 Hz, Ar), 7.49 (dd, 1H, J=8.9 Hz, J=2.8 Hz, Ar), 7.56 (d, 1H, J=2.8 Hz, Ar), 7.94 (d, 1H, J=2.8 Hz, Ar), 8.10 (d, 1H, J=1.6 Hz, Ar).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[NH3:17]>>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=2[Cl:15])=[N:6][CH:5]=[C:4]([NH2:17])[N:3]=1
Reactant: Nc1nc(Cl)cnc1-c1cccc(Cl)c1Cl
Reactant: N
Product: Nc1cnc(-c2cccc(Cl)c2Cl)c(N)n1

Procedure:
This compound was prepared in an analogous manner to Example 1 Route A, from 2-amino-6-chloro-3-(2,3-dichlorophenyl)pyrazine, by reaction with 0.880 ammonia. Yield 0.195 g, M.p. 169-170° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18](=O)[CH2:19]Br)=[C:13]([CH3:22])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:23][C:24]([NH2:26])=[S:25]>CCO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[C:15]([CH3:17])[C:14]([C:18]4[N:23]=[C:24]([NH2:26])[S:25][CH:19]=4)=[C:13]([CH3:22])[CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2ccc3c(c2)OCO3)cc(C)c1-c1csc(N)n1
Yield: 95.6 %

Procedure:
A mixture of 1-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)-2-bromoethanone (6.13 g, 16.9 mmol) and thiourea (1.29 g, 16.9 mmol) in 95% EtOH (24.1 mL) was heated at reflux for 90 min. The solution was concentrated and added with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(4-(benzo[d][1,3]dioxol-5-yloxy)-2,6-dimethylphenyl)thiazol-2-amine (5.50 g) as yellow solids in 96% yield: 1H NMR (500 MHz, CDCl3) δ 6.75 (d, J=8.5 Hz, 1H), 6.66 (s, 2H), 6.58 (m, 1H), 6.49 (m, 1H), 6.28 (s, 1H), 5.98 (s, 2H), 5.05 (bs, 2H), 2.13 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])=[CH:4][CH:3]=1.[NH2-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([CH2:23][CH:22]=[CH2:21])([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: N#CC(CCc1ccc(F)cc1)c1cccnc1
Reactant: C=CCBr
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(C#N)(CCc1ccc(F)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A solution of α-[2-(4-fluorophenyl)ethyl]-3-pyridineacetonitrile (4 g) in tetrahydrofuran (30 ml) was added dropwise, under nitrogen atmosphere, to a stirred suspension of sodium amide (0.8 g) at 0° C. After complete addition (~20 minutes) the resultant mixture was stirred at 0° C. for 1 hour followed by 1 hour at room temperature. The mixture was then cooled to -40° C. and treated with dropwise addition of a solution of allyl bromide (2 g) in tetrahydrofuran (30 ml) to produce a reaction mixture. The reaction mixture was allowed to warm up to room temperature overnight, then neutralized with 10% hydrochloric acid and worked up by extraction with methylene chloride to produce a crude reaction product. The crude reaction product was then chromatographed on a silica gel column and eluted with 25% ethyl acetate in hexanes to give 3.7 g of 4-fluoro-α-(2-propenyl)-α-(3-pyridinyl)benzene-butanenitrile. The structure was confirmed by NMR spectroscopy.