Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[F:60][C:61]([F:73])([F:72])[O:62][C:63]1[CH:71]=[CH:70][C:66]([C:67](Cl)=[O:68])=[CH:65][CH:64]=1>>[O:50]=[C:47]1[C:48]2[C:44](=[CH:43][CH:42]=[C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:67](=[O:68])[C:66]4[CH:70]=[CH:71][C:63]([O:62][C:61]([F:60])([F:72])[F:73])=[CH:64][CH:65]=4)=[CH:40][CH:39]=3)[CH:49]=2)[CH2:45][N:46]1[C:51]1([C:56]([O:58][CH3:59])=[O:57])[CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCCC1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(OC(F)(F)F)cc5)cc4)cc3C2=O)CCCC1
Yield: 77 %

Procedure:
The compound of example 534 was prepared analogous to compound of example 97 by reaction of compound of example 527 with 4-trifluoromethoxy benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][OH:16].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:42]1[CH:43]=[C:44]([CH:59]=[CH:60][CH:61]=1)[CH2:45][O:46][C:47]([NH:49][CH2:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])=[O:48].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(OCC)(=O)C.CO>[OH:16][CH2:15][CH2:14][CH2:13][C:12]([N:7]1[C:8]2[C:3](=[C:2]([C:42]3[CH:43]=[C:44]([CH:59]=[CH:60][CH:61]=3)[CH2:45][O:46][C:47]([NH:49][CH2:50][CH2:51][C:52]([O:54][C:55]([CH3:57])([CH3:58])[CH3:56])=[O:53])=[O:48])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH2:6]1)=[O:17]
Reactant: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(Br)c1
Reactant: O=C(CCCO)N1CCCc2c(Br)cccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNC(=O)OCc1cccc(-c2cccc3c2CCCN3C(=O)CCCO)c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 69.2 %

Procedure:
To a degassed mixture of 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxybutan-1-one (0.208 g, 0.698 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.532 g, 2.094 mmol), and potassium acetate (0.411 g, 4.19 mmol) in DMF (10 mL) was added PdCl2(dppf)-CH2Cl2 (0.057 g, 0.070 mmol). The vial was purged with argon, sealed, and stirred at 90° C. for 2 d. tert-Butyl 3-((3-bromobenzyloxy)carbonylamino)propanoate (0.5 g, 1.396 mmol), PdCl2(dppf)-CH2Cl2 (0.057 g, 0.070 mmol), and 2 M Na2CO3 (2 mL, 1.396 mmol) were added. The reaction mixture was purged with argon and stirred at 95° C. overnight. At the conclusion of this period, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic extract was dried, concentrated, and purified by flash chromatography (0-100% ethyl acetate:hexanes then 10% CH3OH:ethyl acetate) to afford the title compound (0.24 g, 69% yield) as a dark brown oil. LCMS, [M+H]+=497.4.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:24][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(N)c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: COc1cccc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 3-methoxyaniline as the starting materials.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1.[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:26]=1[NH2:27]>CCO>[CH3:23][O:24][C:25]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:26]=1[NH:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][N:3]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: COc1ccc(OC)c(N)c1
Solvent: CCO
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2cc(OC)ccc2OC)ncc1[N+](=O)[O-]
Temperature: 78 °C

Procedure:
To a solution of 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide (100 mg, 0.29 mmol) in EtOH (3 mL), 2,5-dimethoxyaniline (49 mg, 0.32 mmol) is added at room temperature. The mixture is heated at 78° C. for 5 h. The solvent is evaporated, and the mixture is purified by reverse phase HPLC to give the title product in.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[CH:10]=[O:11].BrCCC.OC1C=CC(C=O)=CC=1>>[CH2:2]([O:15][C:14]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[Cl:6])[CH2:3][CH2:4][CH3:5]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: CCCCBr
Agent: O=Cc1ccc(O)cc1
Solvent: CCCBr
Product: CCCCOc1ccc(C=O)cc1Cl
Yield: 86 %

Procedure:
When the 1-bromobutane and 3-chloro-4-hydroxybenzaldehyde was substituted for 1-bromopropane and 4-hydroxybenzaldehyde in Example 50, Step A, the identical process afforded the title compound in 86% yield, as light yellow oil. 1H-NMR (CDCl3) 0.98 (tr, 3H); 1.56-1.58 (m, 2H); 1.78-1.88 (m, 2H); 4.1 (tr, 2H, J=6.3 Hz); 6.98 (d, 1H, J=7.17 Hz); 7.71 (dd, 1H, J=2.1, 8., Hz); 7.87 (d, 1H, J=2.1 Hz); 9.81 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13]>O>[N:1]1[N:2]([CH:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: c1ccc2[nH]ncc2c1
Reactant: CC(C)CC(Br)C(=O)O
Solvent: O
Product: CC(C)CC(C(=O)O)n1cc2ccccc2n1
Temperature: 160 °C

Procedure:
Referring to Scheme 1, a mixture of indazole (450 mg, 3.86 mmol) and 2-bromo-4-methylpentanoic acid (1.5 eq.) was heated to 160° C. for 4 hours. The mixture was cooled, diluted with water, extracted by EtOAc, and dried over MgSO4. The solvent was then removed to give the crude product, which was used for the next step without further purification. [M+H] calc'd for C14H16N2O4, 233; found, 233.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])[CH3:3].[CH3:14][S:15][C:16](SC)=[CH:17][N+]([O-])=O.C(N(CC)CC)C>C(O)C>[CH3:14][S:15][C:16]1[CH:17]=[C:13]2[N:8]([C:7]=1[C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH:9]=[CH:10][CH:11]=[CH:12]2
Reactant: CCOC(=O)C[n+]1ccccc1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(SC)cc2ccccn12
Yield: 91.8 %

Procedure:
A solution of 1-ethoxycarbonylmethylpyridinium bromide 5 (6.15 g, 25 mmol), 1,1-bis(methylsulphanyl)-2-nitroethylene (8.2 g, 50 mmol) and 25 g of triethylamine in 150 ml of ethanol was heated at reflux for 12 h. Following evaporation of the solvents and of the excess triethylamine, 150 ml of water were added to the residue, and the organic phase was extracted with petroleum ether (75 ml×3). The combined extracts were dried over anhydrous magnesium sulphate, filtered and then concentrated under vacuum. The residual oil was chromatographed on a neutral alumina column, with hexane as the eluting solvent, to give ethyl 2-(methylsulphanyl)-3-indolizinecarboxylate 9 (5.4 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C[Si](C)(C)[CH2:21][CH2:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=1)=[O:25].C([O-])(O)=O.[Na+].ClCCl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CCO.C1(C)C=CC=CC=1>[CH2:22]([O:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32]([C:33]1[CH:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)=[CH:35][CH:34]=1)=[O:40])=[O:25])[CH3:21]
Reactant: C[Si](C)(C)CCOC(=O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1CCCCC1C(=O)c1ccc(-c2ccc(Nc3nc4cc(C)ccc4o3)cc2)cc1
Temperature: 90 °C
Yield: 57.7 %

Procedure:
N-(4-Bromophenyl)-5-methyl-1,3-benzoxazol-2-amine (76.70 mg, 0.25 mmol) and trans-2-(trimethylsilyl)ethyl-2-(4-bromobenzoyl)cyclohexanecarboxylate (105.45 mg, 0.23 mmol) were combined in a clean dry flask under argon. Toluene (25 mL), EtOH (8 mL), and saturated aqueous NaHCO3 (5 mL) were added, and the resulting solution was degassed by bubbling with argon for 30 minutes. Then, [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1 complex with dichloromethane (18.78 mg, 0.02 mmol) was added, and the resulting mixture was heated at 90° C. for 16 h. The reaction mixture was then diluted with EtOAc and passed through a Celite® pad, and the solvent was removed by rotary evaporation. Silica gel chromatography (Biotage cartridge), eluting with 25% EtOAc in hexane gave trans-2-trimethylsilyl)ethyl-2-({4′-[(5-methyl-1,3-benzoxazol-2-yl)amino]biphenyl-4-yl}carbonyl)cyclohexanecarboxylate (64 mg, 50%). 1H NMR (400 MHz, CD2Cl2) δ-0.013 (s, 9H), 0.88 (m, 2H), 1.41 (m, 3H), 1.71˜2.15 (m, 5H), 2.44 (s, 3H), 2.73 (m, 1H), 3.88 (m, 1H), 4.08 (m, 2H), 7.08 (d, 1H), 7.21 (s, 1H), 7.33 (d, 1H), 7.67 (m, 2H), 7.69 (m, 2H), 7.73 (m, 2H), 7.89 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[C:15]([NH2:17])=[O:16])=O.[OH-:18].[Na+]>>[OH:18][CH2:2][C:3]1[N:17]=[C:15]([OH:16])[C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]=2[N:5]=1
Reactant: NC(=O)c1c(NC(=O)CCl)sc2c1CCCC2
Reactant: [OH-]
Agent: [Na+]
Product: OCc1nc(O)c2c3c(sc2n1)CCCC3
Yield: 25 %

Procedure:
The 2-(2-chloro-acetylamino)-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid amide (20 g, 0.073 mol) in 150 ml of 1.5M-NaOH solution was refluxed for 4 h. The reaction mixture was cooled and filtered. The filtrate was acidified (pH=5) with dilute hydrochloric acid to give solid material. The solid was filtered, washed with water, and dried to provide 2-hydroxymethyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-ol (4.5 g, 25%) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.70-1.80 (m, 4H), 2.68-2.75 (m, 2H), 2.80-2.88 (m, 2H), 4.35 (d, 2H), 5.61 (t, 1H), 11.95 (s, 1H); LC-MS: [M+H]=237.2 m/z.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>CC(C)=O.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][N:39]2[CH2:38][CH2:37][N:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[O:29][CH3:28])[CH2:41][CH2:40]2)=[C:4]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[CH:3]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccccc1N1CCN(CC(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)CC1
Yield: 89.9 %

Procedure:
To a compound of N1-[4-chloro-2-(2-chlorobenzoyl)phenyl]-2-chloroacetamide (600 mg, 1.74 mmol) in dry acetone (20 mL) was added anhydrous potassium carbonate (1.21 g, 8.78 mmol) and 1-(2-methoxyphenyl)piperazine (336 mg, 1.98 mmol). The reaction mixture was refluxed for 24 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. The potassium carbonate was then removed by suction filtration and the solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product 6c (780 mg, 89% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:14])[F:13])(=[O:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>OS(O)(=O)=O>[C:1]([NH:4][C:5]1[C:10]([N+:16]([O-:18])=[O:17])=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[C:12]([F:15])([F:13])[F:14])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(F)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 2-acetamido-5-fluorobenzotrifluoride (1.369 g, 6.19 mmol) in concentrated H2SO4 (6 mL) at 0° C. was added dropwise 70% HNO3 (0.8 mL, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 3 h and it was poured into ice water (25 g). The precipitate was collected by filtration, affording 2.1 g of crude 2-acetamido-5-fluoro-3-nitrobenzotrifluoride. It was crystallized from EtOH/H2O to afford 1.50 g of pure compound as yellow needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:25][C:24]([CH:31]=O)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([N:22]1[C:26]([CH2:27][CH:28]([CH3:29])[CH3:30])=[CH:25][C:24]([CH2:31][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:23]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: COc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(C(C)(C)C)n3)CC2)cc1
Yield: 35.2 %

Procedure:
Compound 40 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:19]>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:6]=[C:5]2[Cl:19]
Reactant: O=C1NC(C(Cl)(Cl)Cl)Nc2ccc(I)cc21
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1nc(C(Cl)(Cl)Cl)nc2ccc(I)cc12

Procedure:
A suspension of 6-iodo-2-trichloromethyl-1,2-dihydro-quinazolin-4-one (38.9 g=100 mmol) in POCl3 (500 mL) was heated to reflux for 12 hours. The homogeneous solution was cooled and excess POCl3 was distilled under vacuum. Viscous oil obtained was poured over crushed ice and triturated vigorously to give grey solid, which was dissolved in toluene (200 mL), filtered and evaporated under vacuo to give off-white crystalline solid. Mp 154°-155° C. Elemental Analysis: Calculated for C9H3Cl4IN2, C: 26.50, H, 0.74, N: 6.87; Found: C: 26.15, H: 0.79, N. 6.68.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]([NH:21][NH2:22])=[O:20].[C:23](=S)=[S:24]>CO>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[O:20][C:23](=[S:24])[NH:22][N:21]=1
Reactant: NNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: S=c1[nH]nc(Cc2ccccc2Nc2c(Cl)cccc2Cl)o1
Yield: 69.1 %

Procedure:
Potassium hydroxide (363.0 mg, 5.50 mmol) is added to a 0° C. suspension of 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid, hydrazide (1.556 g, 5.01 mmol) and carbon disulfide (700 μl, 11.87 mmol) in 30 ml of methanol. The mixture is heated at reflux overnight under an atmosphere of nitrogen. The solution is concentrated in vacuo and the residue dissolved in water. The resulting aqueous solution is acidified with 1N hydrochloric acid and the resulting solids extracted into a 1:1 mixture of ether and ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is chromatographed, eluting with hexane:ethyl acetate (1:1), providing a white solid. Drying in vacuo at 65° C. for five days gives 1.22 g (65%) of product, mp 168°-170° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[S:13](Cl)(=[O:15])=[O:14].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[F:27])[NH:23][C:22](=[O:28])[C:21]2([C:45]1[C:46]([O:51][CH2:52][CH3:53])=[N:47][CH:48]=[CH:49][CH:50]=1)[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)=[O:31].ClCCl.CO>CN(C)C=O.C(OCC)(=O)C.O>[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[F:27])[N:23]([S:13]([C:6]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=1[O:4][CH3:3])(=[O:15])=[O:14])[C:22](=[O:28])[C:21]2([C:45]1[C:46]([O:51][CH2:52][CH3:53])=[N:47][CH:48]=[CH:49][CH:50]=1)[CH2:29][C:30]([N:32]1[CH2:33][CH2:34][N:35]([CH:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH2:36][CH2:37]1)=[O:31]
Reactant: CCOc1ncccc1C1(CC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2cc(F)c(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOc1ncccc1C1(CC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2cc(F)c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
16.3 mg (0.41 mmol, 60% w/w) of sodium hydride and, after 10 minutes, 96 mg (0.41 mmol) of 2,4-dimethoxyphenylsulfonyl chloride were added to a solution, cooled to 0° C., of 180 mg (0.34 mmol) of 5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-3-{2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-ethyl}-1,3-dihydroindol-2-one in 2 ml of dimethylformamide. The reaction mixture was allowed to warm to room temperature and was stirred for a further 50 minutes. The progress of the reaction was followed by thin-layer chromatography (silica gel, dichloromethane/methanol 15:5). Water and ethyl acetate were added to the reaction mixture. The two phases were then separated and the aqueous phase was extracted once more with ethyl acetate (1×). The combined organic phase was washed with water (1×) and saturated sodium chloride solution (1×), dried over magnesium sulfate and filtered, and the solvent was evaporated in vacuo. The residue was purified by preparative HPLC (RP, eluents acetonitrile/water, 0.01% TFA). 116 mg (0.16 mmol, 46%, 99% purity) of the title compound were obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([O:18]CC)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:21]1([CH:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(C(O)=O)(F)(F)F.Cl.O.C(Cl)Cl>[C:21]1([CH:27]([NH:29][C:16]([CH2:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:14][CH2:13]2)=[O:18])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(N)c1ccccc1
Reactant: CCOC(=O)CC1CCN(Cc2ccc(F)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(NC(=O)CC1CCN(Cc2ccc(F)cc2)CC1)c1ccccc1
Yield: 50 %

Procedure:
1-[(4-fluorophenyl)methyl]-4-[(ethoxycarbonyl)methyl]piperidine (0.55 g, 1.97 mmol) was refluxed in CF3CO2H/HCl/H2O (1:1:1) 10 ml to give the corresponding acid, which was then reacted with 1-phenylethylamine (0.29 g, 2.40 mmol), EDCI (0.56 g, 2.97 mmol) and HOBT (0.40 g, 2.96 mmol) in CH2Cl2 (10 ml) to produce a solid, 0.33 g (50% yield)(procedure D). 1H NMR (CD3Cl) δ 7.35-7.23 (7H, m, Ar—H), 7.00-6.94 (2H, t, J=8.4 Hz, Ar—H), 5.83-5.80 (1H, bd, J=7.5 Hz, NH), 5.15-5.10 (m, 1H, PhCHMe), 3.42 (s, 2H, p-PhCH2N), 2.83-2.78 (m, 2H, N(CH)2), 2.07-2.05 (2H, d, J=7.2 Hz, CH2CO), 1.99-1.89 (2H, m), 1.86-1.78 (1H, m), 1.71-1.61 (2H, t, J=15 Hz), 1.48-1.45 (3H, d, J=6.9 Hz, Me), 1.33-1.21 (2H, m).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:11][C@@H:9]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1)[CH3:10]
Reactant: COc1cccc([C@@H](C)N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@@H](N)c1cccc(O)c1
Temperature: 25 °C
Yield: 112.3 %

Procedure:
To the solution of (R)-1-(3-Methoxy-phenyl)-ethylamine (0.5 g, 3.31 mmol) in DCM (25 mL) at −78° C. was added 1.0M BBr3 solution in DCM (6.6 mL, 6.62 mmol) dropwise. The solution was warmed to room temperature and the reaction mixture was quenched with methanol (100 mL) and then concentrated in vacuo. This process was repeated until no white fumes were observed upon addition of methanol to afford 3-((R)-1-Amino-ethyl)-phenol as a pale yellow oil (0.51 g) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=2)=[O:13])[N:6]=1)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([NH:22][NH2:23])=[O:2])[N:6]=2)=[O:13])[CH:19]=1
Reactant: NN
Reactant: COC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(NC(=O)c2cc(Cl)ccn2)n1
Yield: 92 %

Procedure:
The crude 6-[(4-chloro-pyridine-2-carbonyl)-amino]-pyridine-2-carboxylic acid methyl ester from the previous step (25.3 g, 87.8 mmol) was suspended in ethanol (200 mL), and hydrazine hydrate (21.3 mL, 439 mmol) was added. The reaction mixture was refluxed for 4 hours, solvent removed under reduced pressure, and the residue suspended in acetonitrile and collected by filtration. The solids were washed with acetonitrile (2×100 mL) and diethylether (2×100 mL), and dried under reduced pressure to afford 25.3 g (92% yield) of 4-chloro-N-(6-(hydrazinecarbonyl)pyridin-2-yl)picolinamide as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH2:20][CH2:21][O:22][Si](C(C)(C)C)(C)C)[N:18]=[C:17]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=3)[C:16]=2[C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC>C1COCC1.CCOCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH2:20][CH2:21][OH:22])[N:18]=[C:17]([O:30][CH2:31][CH2:32][O:33][C:34]3[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=3)[C:16]=2[C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(CCO[Si](C)(C)C(C)(C)C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(CCO)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A solution of 4-(tert-butyl)-N-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(2-[{5-chloro-2-pyrimidinyl}oxy]ethoxy)-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 27) (90 mg) and tetrabutylammonium fluoride (1.0M in THF, 0.13 ml) in anhydrous THF (2 ml) was stirred for 3 hours at room temperature. After this period, tlc analysis (2:1 ethyl acetate:hexane) showed that little reaction had occurred. A second aliquot of 1.0M tetrabutylammonium fluoride in THF (0.13 ml) was added to the reaction solution and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether (30 ml) and then extracted with 1.0M citric acid (20 ml) and water (20 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a Biotage Flash 12i cartridge at 10 psi using 60% ethyl acetate/hexane as eluent to give the title compound as a colourless oil (56 mg).