Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:22](COCC[Si](C)(C)C)[C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][C:41](N)=[O:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:22][C:21]([O:31][C@H:32]3[C@H:36]4[O:37][CH2:38][CH:39]([CH2:40][CH2:41][OH:42])[C@H:35]4[O:34][CH2:33]3)=[N:20][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@@H]3C(CC(N)=O)CO[C@@H]32)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCCC1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1

Procedure:
2-[(3aR,6R,6aS)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]acetamide (84.6 mg, 0.139 mmol) was dissolved in TFA (0.5 mL) and DCM (1.0 mL) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was then evaporated to an oil, dissolved in methanol (0.5 mL) and purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-80% acetonitrile/water+0.05% TFA gradient. The desired fractions were lyophilized to give the title compound as a solid. Major isomer LC-MS: calculated for C26H24ClN3O4 477.15 observed m/e: 478.26 (M+H)+ (Rt 1.10/2 min); 1H NMR δ (ppm) (CD3OD): 7.87 (s, 1H), 7.75 (ABq, 4H), 7.71 (d, 2H), 7.48 (dd, 2H), 7.38 (dd, 1H), 5.56 (qt, 1H), 4.98 (t, 1H), 4.53 (t, 1H), 4.10 (dd, 1H), 4.04-3.96 (m, 3H), 3.63 (t, 2H), 3.54 (dd, 1H), 2.34 (m, 2H), 1.95 (m, 2H) and 1.77 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[C:15]([Br:22])[N:14]=2)=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[C:15]([Br:22])[N:14]=2)=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:25])[CH3:24]
Reactant: Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(=O)c2nc(Br)c3ccccn23)cc1C(=O)O

Procedure:
0.92 g (2.56 mmol) of 2-amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid in 30 ml of acetic anhydride are refluxed for 5.5 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and then filtered and dried under reduced pressure overnight at 40° C. 1.1 g of a yellow solid are obtained.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccccc1Cl
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccccc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-phenyl)-acrylic acid.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:8][OH:9].O1[CH2:15][CH2:14]OCC1>>[CH2:2]1[C:15]2([CH2:14][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:6][CH2:5][C:4](=[N:8][OH:9])[CH2:3]1
Reactant: C1COCCO1
Reactant: NO
Reactant: c1ccncc1
Agent: Cl
Product: ON=C1CCC2(CCCCC2)CC1

Procedure:
70 ml of pyridine and 3.45 g of hydroxylamine hydrochloride are added to 39 mmol of the compound obtained in the above Step in solution in dioxane. The reaction mixture is then heated at reflux overnight and subsequently concentrated to dryness to yield an oil, which crystallises and which is washed with water to yield the expected product in the form of a powder after filtration and drying.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([O:18]C)[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:5].[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:5]
Reactant: COc1ccc(C(=O)c2ccccc2C)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1ccccc1C(=O)c1ccc(O)c(Cl)c1Cl

Procedure:
The procedure of Example 24b is repeated except that 38 g of 2,3-dichloro-4-methoxy-2'-methylbenzophenone is combined with 34.6 g of AlCl3 in 300 ml of benzene. The resultant product is recrystallized from toluene to yield 2,3-dichloro-4-hydroxy-2'-methylbenzophenone.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[CH3:8]CCCCC.[C:14]1([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][C:22]([C:30]([OH:32])=[O:31])([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CO>[C:14]1([C:20]23[CH2:29][CH:24]4[CH2:25][CH:26]([CH2:28][C:22]([C:30]([O:32][CH3:8])=[O:31])([CH2:23]4)[CH2:21]2)[CH2:27]3)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCC
Reactant: O=C(O)C12CC3CC(C1)CC(c1ccccc1)(C3)C2
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C12CC3CC(C1)CC(c1ccccc1)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Trimethylsilyldiazomethane 2M solution in hexane (8.15 mL, 16.31 mmol) was added dropwise to a stirred solution of 3-phenyl-1-adamantanecarboxylic acid (2.09 g, 8.15 mmol, CAS 37589-22-3) in toluene (20 mL) and methanol (10 mL) over a period of 2 minutes. The resulting solution was stirred at ambient temperature for 60 minutes. The reaction mixture was evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (2.140 g, 97%) as a colourless oil.
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]3[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH2:20])[C:14]=3[N+:21]([O-])=O)[CH2:9][CH2:8]2)=[N:2]1.[CH3:24][N:25]1[CH:29]=[C:28]([CH:30]=O)[C:27]([CH3:32])=[N:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Cl:19][C:18]1[C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:3]3[N:4]=[CH:5][O:1][N:2]=3)[CH2:8][CH2:9]2)=[C:14]2[N:21]=[C:30]([C:28]3[C:27]([CH3:32])=[N:26][N:25]([CH3:24])[CH:29]=3)[NH:20][C:15]2=[N:16][CH:17]=1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ncon3)CC2)c1[N+](=O)[O-]
Reactant: Cc1nn(C)cc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)cc1-c1nc2c(N3CCN(Cc4ncon4)CC3)c(Cl)cnc2[nH]1
Temperature: 80 °C
Reaction time: 15 h
Yield: 42.7 %

Procedure:
To a solution of 4-(4-((1,2,4-oxadiazol-3-yl)methyl)piperazin-1-yl)-5-chloro-3-nitropyridin-2-amine (50.0 mg, 0.147 mmol) and 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (19.2 mg, 0.155 mmol) in EtOH (3.4 mL) was added 1M Na2S2O4 (0.588 mL, 0.588 mmol, freshly prepared) and the solution was heated to 80° C. and stirred for 15 h whilst being open to air. Once cooled, the reaction was evaporated in vacuo and the residue dry loaded onto silica. Purification was accomplished by flash chromatography on silica gel (2×14) eluting with MeOH/CH2Cl2 (5-7.5%) to yield the title compound (26 mg, 43%) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:32][C:33]1([CH3:41])[O:37][CH:36]([CH2:38][O:39][NH2:40])[CH2:35][O:34]1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:40][O:39][CH2:38][C@H:36]1[CH2:35][O:34][C:33]([CH3:41])([CH3:32])[O:37]1)=[O:7]
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Reactant: CC1(C)OCC(CON)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](CONC(=O)c2cc(Br)ncc2Nc2ccc(I)cc2F)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide was synthesized as described in General Method 3: to a solution of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (145.0 mg, 0.33 mmol) in DMF (1.5 ml) was added 1,1′-carbonylbis(1H-imidazole) (60 mg, 0.36 mmol). The reaction mixture was stirred at room temperature under argon for 6 hrs. Then, O-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]hydroxylamine (125 mg, 0.83 mmol) was added, and stirred overnight. The reaction mixture was poured into water (10 ml). Extracted with EtOAc (3×15 ml), the combined organic layer was washed with brine (2×15 ml), and dried over MgSO4. The solvent was evaporated, and the residue was purified on silica gel column (Hex:EtOAc=3:1) to obtain 104 mg (55%) of 2-bromo-N-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-5-[(2-fluoro-4-iodophenyl)-amino]isonicotinamide. LC/MS:10.43 min, 566, 568.
Reaction SMILES: [CH2:1]([P:8](=[O:11])(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CN(C=O)C>ClCCl>[CH2:1]([P:8]1(=[O:11])[CH2:6][CH2:7][CH2:2][CH2:3][CH2:4]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=P(O)(O)Cc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=P1(Cc2ccccc2)CCCCC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 89.1 %

Procedure:
Under nitrogen atmosphere, to a mixture of magnesium (3.2 g) and a piece of iodine in diethylether (20 ml) was dropwise added to a solution of 1,5-dibromopentane (13.21 g) and 1,2-dibromoethane (1.21 ml) in diethylether (80 ml) at 40° C. for 1 hour. The mixture was refluxed for 1 hour, cooled to room temperature and allowed to stand for 2 hours. The upper layer of diethylether was removed through cannula, to obtain the di-Grignard reagent, which was dissolved in dichloromethane (250 ml). The resulting di-Grignard reagent as it is was used for the following reaction. To benzylphosphonic acid (10.0 g) was added thionyl chloride (30 ml) and then a drop of DMF, and the mixture was refluxed for 3 hours and concentrated under reduced pressure. The residue was dissolved in dichloromethane (210 ml), and the mixture was cooled to 0° C. To the mixture was dropwise added a solution of the above di-Grignard reagent in dichloromethane, which was cooled to 0° C., through cannula for 1 hour, and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added 10% ammonium chloride solution (100 ml) and saturated sodium chloride solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3→1:2) to give 1-benzylphosphorinane-1-oxide (5.39 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:25][C:26]([CH3:32])=[CH:27][C:28]=1[C:29]([OH:31])=O)(=[O:12])=[O:11].[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH2:38])[CH3:34]>>[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37][NH:38][C:29]([C:28]1[CH:27]=[C:26]([CH3:32])[NH:25][C:24]=1/[CH:23]=[C:16]1\[C:17](=[O:22])[NH:18][C:19]2[C:15]\1=[CH:14][C:13]([S:10]([CH2:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=2)=[O:31])[CH3:34]
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)[nH]1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)c1cc(C)[nH]c1/C=C1\C(=O)Nc2ccc(S(=O)(=O)Cc3c(Cl)cccc3Cl)cc21

Procedure:
2-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid was coupled with N,N-diethylethylenediamine to give the titled compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([CH3:39])[C:8]([CH2:10][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:17]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]2[C:25]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)=[N:18]1)=[O:9])=[O:5])C.[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1.O>[C:4]([CH2:6][N:7]([CH3:39])[C:8]([CH2:10][C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=1[N:17]1[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]2[C:25]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=23)=[N:18]1)=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)CN(C)C(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(=O)O)C(=O)CC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.6 %

Procedure:
To a solution of 3-[2-{2-(N-ethoxycarbonylmethyl-N-methylcarbamoyl)methyl-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (710 mg) in a mixture of dioxane (7 ml) and water (4 ml) was added 1N-aqueous sodium hydroxide solution (3.4 ml), which was stirred for two hours at room temperature. The reaction mixture was poured into ethyl acetate (100 ml) and aqueous layer was collected, which was adjusted to pH 1.5 with 6N-aqueous hydrochloric acid and extracted with ethyl acetate (100 ml×2). Organic layers were combined, washed in turn with water (50 ml×3) and brine (50 mil×2), and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (80 ml) eluting in turn with dichloromethane, 5%, 10%, 15% methanol in dichloromethane. Fractions containing desired product were collected. Evaporation of the solvent gave a residue, which was recrystallized from a mixture of dichloromethane and n-hexane to give 3-[2-{2-(N-carboxymethyl-N-methylcarbamoyl)methyl-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (300 mg).
Reaction SMILES: [F:1][C:2]([F:25])([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:3]1[N:7]2[N:8]=[C:9]([C:12](=O)[CH3:13])[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[NH2:26][O:27][CH2:28][CH2:29][OH:30]>CO>[OH:30][CH2:29][CH2:28][O:27]/[N:26]=[C:12](/[C:9]1[CH:10]=[CH:11][C:6]2[N:7]([C:3]([C:2]([F:25])([F:1])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:4][N:5]=2)[N:8]=1)\[CH3:13]
Reactant: CC(=O)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Reactant: NOCCO
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(C(F)(F)c3ccc4ncccc4c3)n2n1
Yield: 55.3 %

Procedure:
A solution of 1-(3-(difluoro(quinolin-6-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (54 mg, 0.159 mmol) and 2-(aminooxy)ethanol (intermediate S) (36.1 mg, 0.318 mmol) in 8 mL of MeOH was stirred at it overnight. Solvent was evaporated and the residue was partitioned between water and EtOAc. Aqueous layer was extracted with EtOAc twice. Organic layers were combined, washed with brine and dried over Na2SO4. Solvent was evaporated and the crude was purified by HPLC (basic with 0.05% NH4OH) to give 35 mg (55%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.98 (d, 1H), 8.52 (d, 1H), 8.43 (s, 1H), 8.23 (d, 1H), 8.19 (d, 1H), 8.06 (d, 1H), 8.04 (d, 1H), 7.66 (m, 1H), 4.36 (m, 2H), 3.84 (m, 2H), 2.18 (s, 3H). LCMS (method B): [MH]+=398.9, IR=2.29 min.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1>C1COCC1>[CH3:25][N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (65.27 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified over silica (5% MeOH/CHCl3) providing the title compound in 53% yield (81 mg, 0.163 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([S:23][CH3:24])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:24][S:23][C:18]1[C:17]2[C:21](=[CH:22][C:14]([C:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH:12]=3)=[CH:15][CH:16]=2)[N:20]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[N:19]=1
Reactant: CSc1n[nH]c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc12
Reactant: Cc1ccc(B(O)O)cc1
Product: CSc1nn(-c2ccc(C)cc2)c2cc(C3=CCNCC3)ccc12

Procedure:
The title compound was prepared as a white solid by coupling 4-(3-methylsulfanyl-1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester and 4-methyl-phenyl boronic acid to yield an intermediate, which was de-protected to remove the N-Boc.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Br:17])=[CH:12][C:11]=2[Br:18])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:19](OC(=O)C)(=[O:21])[CH3:20].O>C(O)(=O)C>[C:7]([C:6]1[C:5]([CH3:9])=[CH:4][N:3]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Br:17])=[CH:12][C:11]=2[Br:18])[C:2]=1[NH:1][C:19](=[O:21])[CH3:20])#[N:8]
Reactant: Cc1cn(-c2c(Cl)cc(Br)cc2Br)c(N)c1C#N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(C#N)c(C)cn1-c1c(Cl)cc(Br)cc1Br

Procedure:
In 5 ml of acetic acid, 1.9 g of 2-amino-4-methyl-1-(2,4-dibromo-6-chlorophenyl)pyrrole-3-carbonitrile and 1.48 g of acetic anhydride were dissolved. The reaction mixture was heated under reflux for 30 minutes. Water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. Subsequently, the extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure to yield crude N-[3-cyano-4-methyl-1-(2,4-dibromo-6-chlorophenyl)-1H-pyrrol-2-yl]acetamide. To the obtained crude N-[3-cyano-4-methyl-1-(2,4-dibromo-6-chlorophenyl)-1H-pyrrol-2-yl]acetamide, 8 ml of 85% phosphoric acid were added. The reaction mixture was heated for 0.5 hours at 130° C., and subsequently, water was added thereto. The reaction mixture was extracted with chloroform, and subsequently, the extract was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) and was allowed to stand for crystallization. The precipitated crystals were washed with ethyl acetate to yield 1.1 g of 2,5-dimethyl-7-(2,4-dibromo-6-chlorophenyl)-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH3:12][NH:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:22]=[CH:21][CH:20]=[C:19]2Cl)=[O:15].C(OCC)(=O)C>CS(C)=O.O>[CH3:12][NH:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:22]=[CH:21][CH:20]=[C:19]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Cl:9])[CH:4]=1)=[O:15]
Reactant: CNC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
After dissolving 4-amino-3-chlorophenol (624 mg, 4.35 mmol) in dimethylsulfoxide (15 ml), sodium hydride (174 mg, 4.35 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. N6-Methyl-7-(benzyloxy)-4-chloro-6-quinolinecarboxamide (947 mg, 2.90 mmol) was added, and the mixture was heated at 100° C. while stirring for 2 hours. After cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out and blow-dried to obtain the title compound (1.098 g, 2.53 mmol, 87.3%) as light brown crystals.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([O:10][C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:19]=1[C:20]#N)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(O)C.[OH2:34]>>[CH2:3]([O:10][C@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[NH:17][C:18]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:19]=1[C:20]([OH:34])=[O:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N[C@H]1CCCC[C@@H]1OCc1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1ccc(C(F)(F)F)cc1N[C@H]1CCCC[C@@H]1OCc1ccccc1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Potassium hydroxide aqueous solution was added to an ethanol-water mixed solution of 2-{[(1S,2S)-2-(benzyloxy)cyclohexyl]amino}-4-(trifluoromethyl)benzonitrile. This was stirred at 100° C. for 5 hours and then spontaneously cooled. After neutralizing with 1 M hydrochloric acid, the organic layer was extracted with chloroform. By concentrating the organic layer under a reduced pressure, 2-{[(1S,2S)-2-(benzyloxy)cyclohexyl]amino}-4-(trifluoromethyl)benzoic acid was obtained.
Reaction SMILES: ClC1C(C[N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=NC=CN=1.[NH2:20]N.CO>C(Cl)Cl>[C:10]1(=[O:19])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[NH:9][NH:20]1
Reactant: NN
Reactant: O=C1c2ccccc2C(=O)N1Cc1nccnc1Cl
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH][nH]c(=O)c2ccccc12
Reaction time: 2.5 h

Procedure:
A solution of 2-(3-chloropyrazin-2-ylmethyl)-isoindole-1,3-dione (10.0 g, 36.5mmol) in anhydrous CH2Cl2 (200 mL) was charged with hydrazine (2.87 mL, 2.93 g, 91.3 mmol, 2.5 eq.) at rt, under N2 atmosphere. After 2.5 h, MeOH (300 mL) was added and the reaction was heated until the solution was homogenous. The reaction mixture was allowed to stir for 19 h. The white ppt that had formed (2,3-dihydrophthalazine-1,4-dione byproduct), was filtered off and washed several times with ether. The clear filtrate was concentrated in vacuo and the concentrate was dissolved in EtOAc and filtered again to remove white ppt. All solvent was removed, giving a yellow oil, which was dissolved into EtOAc and ether and charged with HCl (g). The title compound, a pale yellow solid, instantly precipitated. The title compound was dried in a 40° C. oven for 72 h, affording the title compound, as a dark yellow solid; 1H NMR (400 MHz, CD3OD) δ 4.55 (2H, s), 8.27 (1H, d, J=2.52 Hz), 8.54 (1H, d, J=2.56 Hz); MS (ES+): m/z 143.96/145.96 (100/60) [MH+]; HPLC: tR=0.41 min (OpenLynx, polar—7 min).
Reaction SMILES: [CH:1]1([CH:4]([N:11]([CH2:15][CH2:16][CH3:17])[C:12]([NH2:14])=[S:13])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.Br[CH:19]([CH3:30])[C:20]([C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[Cl:29])=O>>[Cl:29][C:23]1[CH:24]=[C:25]([I:28])[CH:26]=[CH:27][C:22]=1[C:20]1[N:14]=[C:12]([N:11]([CH:4]([CH:1]2[CH2:2][CH2:3]2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH3:17])[S:13][C:19]=1[CH3:30]
Reactant: CC(Br)C(=O)c1ccc(I)cc1Cl
Reactant: CCCN(C(N)=S)C(c1ccccc1)C1CC1
Product: CCCN(c1nc(-c2ccc(I)cc2Cl)c(C)s1)C(c1ccccc1)C1CC1

Procedure:
This compound was prepared from N-(α-cyclopropylbenzyl)-N-propylthiourea (Compound 75) and 2-bromo-1-(2-chloro-4-iodophenyl)-1-propanone (Compound 18) according to the process described in Example 1.