Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23]2[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]=2[CH3:31])[CH:16]=1)[C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[CH3:13][C:3]([CH3:14])([C:2](=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](/[CH:21]=[CH:22]/[C:23]2[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][CH2:25][C:24]=2[CH3:31])[CH:16]=1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:10])[CH3:11]
Reactant: CC1=C(/C=C/c2cccc(C(O)C(C)(C)CNC(=O)OC(C)(C)C)c2)C(C)(C)CCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CC1=C(/C=C/c2cccc(C(=O)C(C)(C)CNC(=O)OC(C)(C)C)c2)C(C)(C)CCC1
Reaction time: 0.25 h

Procedure:
(E)-Tert-butyl 3-hydroxy-2,2-dimethyl-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propylcarbamate (0.0809 g, 0.19 mmol) was reacted with pyridinium chlorochromate according to the method used in Example 56 except that the reaction time was 2 h, 15 min. Purification by flash chromatography (10 to 40% EtOAc-hexanes gradient) gave (E)-tert-butyl 2,2-dimethyl-3-oxo-3-(3-(2-(2,6,6-trimethylcyclohex-1-enyl)vinyl)phenyl)propylcarbamate as an oil. 1H NMR (400 MHz, CD3OD) δ 7.72 (s, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 6.72 (dd, J=16.0, 0.8 Hz, 1H), 6.33 (d, J=16.0 Hz, 1H), 5.05 (t, J=6.0 Hz, 1H), 3.38 (d, J=6.8 Hz, 2H), 2.04 (t, J=6.4 Hz, 2H), 1.76 (s, 3H), 1.61-1.67 (m, 2H), 1.48-1.50 (m, 2H), 1.36-1.42 (m, 15H), 1.06 (s, 6H).
Reaction SMILES: [NH:1]([C:21]([O:23]CC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]>O1CCCC1>[NH:6]([CH2:5][CH2:4][CH2:3][C@@H:2]1[NH:1][C:21](=[O:23])[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:10]1=[O:11])[C:7]([NH2:8])=[NH:9]
Reactant: CC(C)(C)OC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: N=C(N)NCCC[C@@H]1NC(=O)N(CC(=O)O)C1=O

Procedure:
67.5 g of Z-Arg-Gly-OtBu are suspended in 800 ml of absolute tetrahydrofuran and refluxed for 2 hours. The mixture is then concentrated and the residue is triturated with methyl tert.-butyl ether. The precipitate is filtered off with suction and dried. Yield 54.2 g.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(CC)CC)C.[C:15]([C:17](=[N:28]OS(C1C=CC(C)=CC=1)(=O)=O)[C:18]1[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=1)[C:23]#[N:24])#[N:16]>C(O)C>[NH2:16][C:15]1[C:17]([C:18]2[CH:19]=[CH:20][C:21]([O:26][CH3:27])=[C:22]([C:23]#[N:24])[CH:25]=2)=[N:28][S:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: COc1ccc(C(C#N)=NOS(=O)(=O)c2ccc(C)cc2)cc1C#N
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1snc(-c2ccc(OC)c(C#N)c2)c1N
Reaction time: 5 h

Procedure:
Ethyl sulfanylacetate and triethylamine were dissolved in an ethanol solution of 5-[cyano({[(4-methylphenyl)sulfonyl]oxy}imino)methyl]-2-methoxybenzonitrile, followed by stirring for 5 hours under ice-cooling to obtain ethyl 4-amino-3-(3-cyano-4-methoxyphenyl)isothiazole-5-carboxylate. AP: 378.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:18][CH2:19][CH2:20][CH2:21][C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: BrCCCOC1CCCCO1
Reactant: CCOC(=O)C1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CCCOC2CCCCO2)CCCC1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2.0 g (12.8 mmol) ethyl 2-oxocyclopentanecarboxylate, 5.71 g (25.6 mmol) 1-(tetrahydropyranyl- oxy)-3-bromopropane, 7.08 g (57.2 mmol) powdered potassium carbonate and 60 mL acetone is heated to 60° C. under nitrogen with stirring for 8 hours. The reaction mixture is cooled to room temperature, filtered and evaporated to give a yellow orange liquid which is purified by flash chromatograhy using 1:9 ethyl acetate, hexane to yield 2-[3-(tetrahydropyranyloxy)propyl]-2-carbethoxycyclopentanone; IR (neat): 1750 cm-1 1724 cm-1.
Reaction SMILES: O.[NH2:2][NH2:3].Cl.[NH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15](=O)[CH2:16][CH2:17][C:18]([O:20]C)=O)[CH:12]=2)[CH2:7]1>C(O)(=O)C>[NH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]3[CH2:16][CH2:17][C:18](=[O:20])[NH:2][N:3]=3)[CH:12]=2)[CH2:7]1
Reactant: COC(=O)CCC(=O)c1ccc2c(c1)CC(N)C2
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 0.5 h

Procedure:
8.5 g (0.17 mol) of 99% hydrazine hydrate are added to 10.0 g (0.035 mol) of methyl 4-(2-amino-indan-5-yl)-4-oxobutyrate hydrochloride in glacial acetic acid and the mixture is boiled for 30 minutes. The mixture is evaporated in vacuo, the residue is dissolved in water and the reaction product is precipitated by neutralisation with sodium hydroxide.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=2[C:6]=1[CH:7]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[O:42][CH2:41][CH2:40][CH2:39]3)O1>C1(C)C=CC=CC=1.O.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:14]([O:13][CH:7]([C:6]1[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[O:3][C:2]=1[C:36]1[CH:45]=[CH:44][C:43]2[O:42][CH2:41][CH2:40][CH2:39][C:38]=2[CH:37]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(Br)oc2ccccc12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)oc2ccccc12
Temperature: 95 °C
Yield: 53.6 %

Procedure:
A mixture of ethyl 2-(2-bromo-1-benzofuran-3-yl)-2-(tert-butoxy)acetate (20c) (100 mg, 0.28 mmol), sodium carbonate (120 mg, 1.13 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (132 mg, 0.51 mmol) and palladium tetrakis(triphenylphosphine) (16 mg, 0.01 mmol) in toluene (1.26 mL), water (0.50 mL) and ethanol (0.60 mL) was heated at 95° C. for 24 hours. After cooling to room temperature, the mixture was poured into water (2 mL). The aqueous layer was extracted with toluene (2×5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide the desired product (20d) (61 mg, 0.15 mmol, 53%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][C:14]([F:18])=[CH:13][C:12]=3[C:11]3[CH2:19][N:20]4[CH2:25][CH2:24][CH:23]([C:10]2=3)[CH2:22][CH2:21]4)=[CH:4][CH:3]=1.[OH:26][C@@H:27]([C@H:31]([OH:35])[C:32]([OH:34])=[O:33])[C:28]([OH:30])=[O:29]>C(OCC)(=O)C.C(O)C.CO>[C:28]([CH:27]([CH:31]([C:32]([OH:34])=[O:33])[OH:35])[OH:26])([OH:30])=[O:29].[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[CH:16]=[CH:15][C:14]([F:18])=[CH:13][C:12]=3[C:11]3[CH2:19][N:20]4[CH2:21][CH2:22][CH:23]([C:10]2=3)[CH2:24][CH2:25]4)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: Fc1ccc2c(c1)c1c(n2Cc2ccc(Cl)nc2)C2CCN(CC2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
The salt was prepared by dissolving the starting material from Example 164C (275. mg, 0.775 mmol) in ethyl acetate (5.0 mL) and ethanol (1.0 mL) then adding (2S,3S)-2,3-dihydroxysuccinic acid (128 mg, 0.852 mmol, dissolved in a minimal amount of methanol) slowly and stirring rapidly over night. The material precipitated to give a white solid. The solid was collected by filtration and dried under vacuum to give the titled compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.97-2.13 (m, 2H) 2.19-2.37 (m, 2H) 3.38-3.51 (m, 3H) 3.51-3.69 (m, 2H) 4.41 (s, 2H) 4.70 (s, 2H) 5.54 (s, 2H) 6.89-7.05 (m, 1H) 7.18 (dd, J=9.32, 2.58 Hz, 1H) 7.32-7.50 (m, 3H) 8.05 (s, 1H); MS (DCI/NH3) m/z 356 (M+H)+. Anal. Calcd. for C20H19ClFN3.C4H6O6: C, 56.98; H, 4.97; 8.31. Found: C, 56.71; H, 4.88; N, 8.20.
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][CH:2]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:21][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:16])[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Reactant: C1COCCN1
Product: CCCCCCC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1

Procedure:
Prepared from the product of Example 14 and morpholine.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([NH:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:27])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:34]4[CH:35]=[C:30]([CH:31]=[CH:32][CH:33]=4)[CH2:29][NH:28][C:25](=[O:27])[CH3:26])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CC(=O)NCc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)NCc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 10.6 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(acetamidomethyl)phenylboronic acid (19.3 mg, 0.1 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro-[chroman-4,4′-imidazole]-6-yl)benzyl)acetamide (2.5 mg, 11%). 1H-NMR (MeOD): 2.01 (s, 3H), 2.16 (d, 1H), 2.32 (t, 1H), 3.17 (s, 3H), 4.40 (s, 2H), 5.92 (d, 1H), 7.03 (d, 1H), 7.23 (d, 2H), 7.36 (m, 2H), 7.41 (t, 4H), 7.48 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[N:29]=[C:14]2[C:15]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[CH:16][CH:17]=[CH:18][N:13]2[N:12]=1>>[CH3:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:15]1[C:14]2[N:13]([N:12]=[C:11]([NH:1][C:2]3[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=3)[N:29]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: COc1ccc(N)cn1
Product: COc1ccc(Nc2nc3c(NCc4ccccc4OC)cccn3n2)cn1

Procedure:
N(8)-(2-Methoxy-benzyl)-N(2)-(6-methoxy-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from 5-amino-2-methoxypyridine (96.31 mg, 0.7758 mmol) and (2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methoxy-benzyl)-amine (200.00 mg, 0.69268 mmol) in a manner analogous to Example 2d. Product isolated as a red foam (41.05 mg, 16%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.31 (s, 1H), 8.58 (s, 1H), 8.04 (d, J=9.3 Hz, 1H), 7.93 (d, J=6.8 Hz, 1H), 7.24 (m, 2H), 7.02 (d, J=8.4 Hz, 1H), 6.87 (t, J=14.9, 7.2 Hz, 1H), 6.78 (d, J=9.4 Hz, 1H), 6.72 (t, J=14.9, 7.2 Hz, 1H), 6.29 (m, 2H), 4.45 (d, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H). MS=377 (MH)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.F[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=1>CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[O:18])=[CH:9][CH:8]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=Cc1ccc(F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(-n2cncn2)c2ccccc12
Reaction time: 3 h
Yield: 68.8 %

Procedure:
1,2,4-triazole (248 mg) is added to a solution of 4-fluoro-naphthalene-1-carbaldehyde (522 mg) and potassium carbonate (4 mg) in DMF (4 ml): After 3 hours a room temperature, the reaction is quenched with water (40 ml) and ethyl acetate (50 ml). The organic phase is separated and the aqueous phase is extracted two times with ethyl acetate. The organic phases are combined, extracted with water and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield 4-[1,2,4]triazol-1-yl-naphthalene-1-carbaldehyde (460 mg) as beige crystals. MS (HPLC/MS): 224 (MH+). Retention time: 2.97 min.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[CH3:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][C:18]=1[CH:26]=O.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:18]1[NH:19][C:20]2[C:25]([C:17]=1[CH3:16])=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:5])=[O:4]
Reactant: Cc1c(C=O)[nH]c2ccccc12
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]c3ccccc3c1C)C(=O)N2
Temperature: 90 °C
Yield: 69.6 %

Procedure:
A mixture of 5-methylaminosulfonyl-2-oxindole (90 mg), 3-methylindole-2-carbaldehyde (56 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (30 mg) in ethanol (1 mL) was heated in a sealed tube at 90° C. for overnight. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in oven for overnight to give 90 mg (70% yield) of 3-(3-methyl-1H-indol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (mixture of isomers).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([C:8](O)=[O:9])=[N:4]1)[CH3:2].[N+](=C[Si](C)(C)C)=[N-].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1C=CC=CC=1.CO>[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[N:4]1)[CH3:2]
Reactant: CCn1ccc(C(=O)O)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Solvent: c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: CCn1ccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To 1-ethyl-1H-pyrazole-3-carboxylic acid (5.01 g, 35.7 mmol) in benzene/MeOH (45 mL/10 mL) at 0° C. was added dropwise (diazomethyl)trimethylsilane (19.7 mL, 39.3 mmol) in hexanes (2M). The cold bath was removed and the reaction mixture was stirred at ambient temperature for one hour. The reaction was quenched with the addition of acetic acid (0.25 mL). The mixture was concentrated under reduced pressure to give crude product, to which was added THF (50 mL) and the solution was cooled to 0° C. Lithium aluminum hydride (1.36 g, 35.7 mmol) was added cautiously to the solution. The cold bath was removed once the addition was complete. The mixture was stirred at ambient temperature for 2 hours and the reaction was quenched by careful addition of sodium sulfate decahydrate. The mixture was filtered through Celite, and the filter pad was washed with EtOAc (200 mL). The filtrate was concentrated under reduced pressure to give the product (4.41 g).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.Br[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[N:32][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:43][C:44]([CH3:46])=[O:45]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:34][C:31]1[N:32]=[CH:33][C:28]([CH2:43][C:44](=[O:45])[CH3:46])=[CH:29][CH:30]=1
Reactant: CC(C)=O
Reactant: Fc1ccc(Br)cn1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Cc1ccc(F)nc1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
Anhydrous, de-gassed THF (20 mL) was added to 2-(dicyclohexylphosphino)-2′-methylbiphenyl (1.2 g, 3.2 mmol) and tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (1.4 g, 1.4 mmol), and the resulting solution was warmed to 45° C. and sparged with N2. After 20 min, the reaction mixture was allowed to cool to RT, then added to a stirring, degassed mixture of 5-bromo-2-fluoropyridine (4.8 g, 27 mmol), finely ground potassium phosphate tribasic (14 g, 68 mmol), and acetone (100 mL, 1400 mmol) at RT, and the resulting mixture was sparged with N2. After 20 min, the reaction mixture was heated at reflux for 24 h, the reaction mixture was allowed to cool to room temperature, filtered through a 0.45 μm Teflon filter, and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (gradient elution; 4:1→2:1 hexane-ethyl acetate) to give 2.3 g (55%) of 1-(6-fluoropyridin-3-yl)propan-2-one as a brown oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](O)=[O:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13]([N:21]3[CH2:22][CH2:23][N:24]([C:38]([C:34]4[S:33][CH:37]=[CH:36][CH:35]=4)=[O:39])[CH2:25][CH2:26]3)[C:12]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCNCC3)c2-c2ccccc2)cc1
Reactant: O=C(O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCN(C(=O)c4cccs4)CC3)c2-c2ccccc2)cc1
Temperature: 37 °C
Yield: 48.6 %

Procedure:
To a solution of 6-[4-(methylsulfonyl)phenyl]-5-phenyl-4-piperazin-1-yl-2-(trifluoromethyl)pyrimidine (0.2 g, 0.43 mmol, prepared according to the procedure described in preparation 2) in dimethylformamide (20 ml) was added thiophene-2-carboxylic acid (0.149 g, 0.78 mmol) under stirring at 37° C., and then after 10 minutes EDCI (0.149 g, 0.78 mmol), and HOBt (0.023 g, 0.173 mmol) were added. Further TEA (0.179 ml, 2.9 mmol) was added to the resultant clear solution and it was stirred for 18 hours. Subsequently the reaction mixture was diluted with ethyl acetate (50 ml) and the organic layer was washed successively with water, 10% sodium bi carbonate solution (100 ml), and brine (100 ml) respectively and dried over anhydrous sodium sulphate. Evaporation of the solvent and purification by column chromatography (0.4% MeOH:DCM) gave the title compound (0.12 g, yield 48.6%); m.p. 189-194° C. 1H-NMR (CDCl3) δ: 2.98 (s, 3H), 3.4-3.41 (t, 4H), 3.66-3.68 (t, 4H), 7.02-7.77 (m, 12H). MS m/z: 573.2 (M++1).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[N:27][OH:28])=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[CH3:10][C:11]1[N:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=4)[O:28][N:27]=3)=[CH:21][CH:20]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc(OCc2ccc(CC(Cl)=NO)cc2)n1
Reactant: C#Cc1cccnc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(OCc2ccc(Cc3cc(-c4cccnc4N)on3)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of 3-ethynyl-pyridin-2-ylamine (30 mg, 0.25 mmol) described in Manufacturing Example 1-2-3 in anhydrous tetrahydrofuran (5 mL) was added (4-(6-methyl-pyridin-2-yloxymethyl)-phenyl)-acetohydroximoyl chloride (222 mg, 0.76 mmol) described in Manufacturing Example 3-1-5 at room temperature. Triethylamine (142 μL, 1.0 mmol) was added dropwise to the reaction solution, and stirred overnight at room temperature. The reaction mixture was partitioned into water and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3 then 1:1) to obtain the title compound (10.5 mg, 11%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:13])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][CH3:38])[CH:31]=2)[CH2:26][CH2:25]1)=[O:23].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:13][C:3]1[C:2]([Br:1])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]([CH2:21][C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][CH3:38])[CH:31]=3)[CH2:28][CH2:29]2)=[O:23])[N:4]=1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: Nc1n[nH]c(-c2ccccc2)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(N)c(Br)c3-c3ccccc3)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Bromo-5-phenyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 7.78-7.84 (d, 2H), 7.32-7.42 (m, 3H), 7.18-7.22 (d, 1H), 6.44-6.48 (d, 1H), 6.36-6.42 (dd, 1H), 4.94 (s, 2H), 4.28 (s, 2H), 3.88 (s, 3H), 3.76-3.86 (m, 4H), 3.12-3.18 (m, 4H). 13C NMR (400 MHz, CDCl3): 164.6, 154.8, 150.2, 144.6, 130, 128.2, 128, 126.4, 109.2, 102, 56, 51, 50, 49.6, 45.6, 42.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]([CH3:30])([CH3:29])[CH2:5][NH:6][C:7]([C:9]1[N:10]=[C:11]([C:27]#[N:28])[C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]=2)=[O:8].[OH-].[Na+].Cl>CO>[C:27]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([S:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:13]=2)[C:18]([OH:19])=[C:9]([C:7]([NH:6][CH2:5][C:4]([CH3:30])([CH3:29])[C:3]([OH:31])=[O:2])=[O:8])[N:10]=1)#[N:28]
Reactant: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Sc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A mixture of 3-[(1-cyano-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid methyl ester (46 mg, 0.11 mmol), 2 M NaOH (2 mL) and MeOH (2 mL) was stirred at r.t. for 3 h. 1 M HCl was added until pH was ˜2, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-25% EtOAc/hexanes+2% AcOH) to give 29 mg of the title compound. MS: (−) m/z 420.09 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>N1C=CC=CC=1>[NH:11]([C:2]1[C:7]([I:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: Cc1ccnc(Cl)c1I
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccnc(NN)c1I
Reaction time: 24 h
Yield: 86.9 %

Procedure:
A mixture of 2-chloro-3-iodo-4-methylpyridine (preparation 28a, 2.0 g, 7.9 mmol) and hydrazine hydrate (1.2 mL, 24.2 mmol) in pyridine (12 mL) under an argon atmosphere was stirred and heated to reflux. After 24 hours, the mixture was cooled and evaporated to dryness. The crude mixture was triturated with water and the solid was filtered and washed with water to give the title compound (1.71 g, 87%) which was used without further purification in the next reaction.