Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: Cc1ccc(Cl)c(Cl)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Clc1ccc(CBr)c(Cl)c1Cl
Yield: 85.5 %

Procedure:
2,3,4-Trichlorotoluene (2.00 g) was dissolved in carbon tetrachloride (20 ml), and 2,2′-azobis(2,4-dimethyl-4-methoxyvaleronitrile) (158 mg) and N-bromosuccinimide (2.00 g) were added thereto. The mixture was refluxed under heating for 2 hr, and hexane was added, which was followed by stirring under cooling for 30 min. The mixture was filtrated and an insoluble matter on a filter paper was washed with small amounts of hexane. The filtrates were combined and concentrated under reduced pressure. Diisopropyl ether was added to the residue and the mixture was washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure to give a mixture (2.40 g) of the objective compound and 2,3,4-trichlorotoluene as brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][CH2:16][CH:17]1[O:19][CH2:18]1>CN(C)C=O>[Br:15][CH2:16][CH:17]([OH:19])[CH2:18][N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Cl)cn1CC(O)CBr
Temperature: 80 °C

Procedure:
A stirred suspension of 5-chloropyrimidin-2-one (2.610 g), potassium carbonate (55 mg) and 1-bromo-2,3-epoxypropane (3.42 ml) in dry N,N-dimethylformamide (40 ml) was heated at 80° C. After 23/4 h the reaction mixture was evaporated and the residue was subjected to column chromatography on silica developing and eluting with chloroform-ethanol, 19:1. This gave an off white solid which was triturated with ethyl acetate to give white crystals of the title pyrimidinone (1.483 g), m.p. 166°-170° C., λmax (EtOH) 227 nm (ε 9,740).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)C=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.7 %

Procedure:
4-Fluorobenzaldehyde (1r, 0.75 ml, 7.0 mmol) and acetone (19, 0.26 ml, 3.5 mmol) were combined in ethanol (30 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.50 g, 12.5 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol to afford 0.82 g (86%) of a yellow solid: mp 150-152° C. [expected mp 152-154° C.]; 1H NMR: δ 6.97 (d, 2H, J=15.9 Hz), 7.09 (m, 4H), 7.58 (m, 4H), 7.68 (d, 2H, J=15.9 Hz); 13C NMR: δ 116.1, 1125.1, 130.2, 130.9, 142.0, 164.0, 188.3.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21]([S:23][CH3:24])[C:20]([CH2:25]C)=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.N1C(NC(C2C(=O)N3C(SC4C=C(SC)C(OC)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(SC)C(OCCC)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(SC)C(Cl)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(SC)C(F)=CC=43)=NC=2)=O)=NN=N1.N1C(NC(C2C(=O)N3C(SC4C=C(SC)C(C(F)(F)F)=CC=43)=NC=2)=O)=NN=N1>>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[C:21]([S:23][CH3:24])[C:20]([CH3:25])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1
Reactant: CCc1cc2c(cc1SC)sc1ncc(C(=O)Nc3nnn[nH]3)c(=O)n12
Agent: CCCOc1cc2c(cc1SC)sc1ncc(C(=O)Nc3nnn[nH]3)c(=O)n12
Agent: COc1cc2c(cc1SC)sc1ncc(C(=O)Nc3nnn[nH]3)c(=O)n12
Agent: CSc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1C(F)(F)F
Product: CSc1cc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2cc1C

Procedure:
N-(5-tetrazolyl)-7-ethyl-8-methylthio-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-methoxy-8-methylthio-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-n-propoxy-8-methylthio-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-chloro-8-methylthio-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; N-(5-tetrazolyl)-7-fluoro-8-methylthio-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide; and N-(5-tetrazolyl)-7-trifluoromethyl-8-methylthio-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][C:8]=1[CH2:16][CH3:17])(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:16]([C:8]1[CH:9]=[C:10]([CH2:13][C:14]#[N:15])[CH:11]=[CH:12][C:7]=1[C:25]1[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=1)[CH3:17]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CCc1cc(CC#N)ccc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCc1cc(CC#N)ccc1-c1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
After toluene (150 ml), ethanol (30 ml) and distilled water (30 ml) were added to 4-(cyanomethyl)-2-ethylphenyl trifluoromethanesulfonate (9.7 g, 33 mmol) obtained in Example (26-2), 4-methoxyphenylboronic acid (5.3 g, 35 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (2.7 g, 3.3 mol) and sodium carbonate (10.0 g, 94 mmol), the mixture was stirred at 80° C. for 4 hours. After the reaction mixture was cooled to room temperature, the insolubles were removed by filtration. The obtained filtrate was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=7/1-6/1) to give (2-ethyl-4′-methoxy-1,1′-biphenyl-4-yl)acetonitrile as an oil (5.5 g, yield: 66%).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:31])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:15][CH2:14]3)=[N:11][N:12]=[C:5]2[CH2:4]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:31][C:3]1([CH2:2][OH:1])[S:9][CH2:8][CH2:7][N:6]2[C:10]([C:13]3([C:16]4[CH:21]=[CH:20][C:19]([C:22]5[CH:30]=[CH:29][C:25]([C:26]([N:32]6[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]6)=[O:27])=[CH:24][N:23]=5)=[CH:18][CH:17]=4)[CH2:14][CH2:15]3)=[N:11][N:12]=[C:5]2[CH2:4]1
Reactant: C1CCNCC1
Reactant: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)O)cn5)cc4)CC3)n2CCS1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(=O)N6CCCCC6)cn5)cc4)CC3)n2CCS1
Yield: 11.3 %

Procedure:
A solution of the compound (200 mg, 0.458 mmol) obtained in Example 66, piperidine (210 μL, 2.29 mmol), N,N-dimethylaminopyridine (6 mg, 46 μmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (264 mg, 1.37 mmol) in N,N-dimethylformamide (4.00 mL) was stirred at room temperature for 6 h. Saturated aqueous sodium hydrogencarbonate (100 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane/2-propanol (4/1), and the organic layer was washed with water and dried with anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1 to 4:1) to obtain the title compound (26 mg, 11%) as a white solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][CH:11]1[NH:16][CH2:15][CH2:14][NH:13][C:12]1=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:39]([C:41]1[C:57]([F:58])=[CH:56][C:44]([O:45][C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][C:47]=2[F:55])=[C:43]([O:59]C)[CH:42]=1)[CH3:40]>ClCCl.O>[CH2:39]([C:41]1[C:57]([F:58])=[CH:56][C:44]([O:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([N:16]3[CH2:15][CH2:14][NH:13][C:12](=[O:17])[CH:11]3[CH3:10])=[O:51])=[CH:48][C:47]=2[F:55])=[C:43]([OH:59])[CH:42]=1)[CH3:40]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)O)cc2F)cc1F
Reactant: CC1NCCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCNC(=O)C3C)cc2F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N-Diisopropylethylamine (74 μL, 0.42 mmol), 3-methylpiperazin-2-one (23.3 mg, 0.20 mmol), EDCI (39.1 mg, 0.20 mmol) and HOBt (27.6 g, 0.20 mmol) were successively added to a suspension of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 50 mg, 0.17 mmol) in dichloromethane (0.55 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (10 mL) and water (10 mL). After separation, the organic layer was washed with water (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (98:2 to 95:5) as eluent. The title product was obtained as a white solid (24 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[S:27]>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:26]([NH:25][C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[Cl:17])=[S:27])[C:3]=1[NH:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCNc1c(N)cccc1N
Solvent: C1CCOC1
Product: CCOC(=O)CCNc1c(N)cccc1NC(=S)Nc1ccc(Cl)cc1Cl
Yield: 55.8 %

Procedure:
To a solution of ethyl N-(2,6-diaminophenyl)-beta-alaninate (Reference Example 25; 500 mg, 2.24 mmol) in tetrahydrofuran (22 mL) was added 2,4-dichlorophenyl isothiocyanate (503 mg, 2.46 mmol) at room temperature. The resultant mixture was stirred at room temperature for 1 hr and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and NH-silica gel eluting with a 10-90% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (533 mg, 1.25 mmol, 56%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6](O)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=1)[CH:10]=[CH:9][CH:8]=2)[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.CS(Cl)(=O)=O.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16][CH:15]=1)[CH:10]=[CH:9][CH:8]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1=Cc2c(-c3cccc4ccccc34)cccc2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC1=Cc2c(cccc2-c2cccc3ccccc23)C1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
A 200-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 4.54 g (14.4 mmol) of 2-i-butyl-1-hydroxy-4-(1-naphthyl)indene, 5.13 g (50.8 mmol) of triethylamine, 0.10 g (0.82 mmol) of 4-dimethylaminopyridine and 57.7 ml of methylene chloride. To the mixture was added dropwise a solution containing 3.87 ml (33.8 mmol) of methanesulfonyl chloride dissolved in 7.7 ml of methylene chloride under a nitrogen atmosphere while cooling with ice bath. After the addition was completed, the temperature was elevated to room temperature and the mixture was further stirred for 3 hours. The reaction mixture was poured onto 100 ml of water Thereafter, the organic phase was separated, and the aqueous phase was extracted with 50 ml of methylene chloride. The extracted organic phases were combined and washed with a saturated NaCl aq., followed by dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was separated and purified with silica gel chromatography (eluting with hexane/ethyl acetate (20/1 parts by volume)) to obtain 3.98 g of the desired product (mixture of two isomers) as a pale yellow pasty liquid (yield: 93%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:11]([N:18]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:11]([N:18]1[C:31]2[C:26](=[CH:27][C:28]([CH2:2][CH:3]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:29][CH:30]=2)[C:20]2([CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:19]1=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1N(Cc2ccccc2)c2ccccc2C12CCNCC2
Reactant: BrCC1CCCCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)c2ccc(CC3CCCCCCC3)cc2C12CCNCC2
Temperature: 55 °C
Reaction time: 18 h

Procedure:
1-Bromomethyl-cyclooctane (0.087 g, 0.424 mmol) and 1-benzyl-spiro[indoline-3,4′-piperidin]-2-one (0.030 g, 0.141 mmol) were dissolved in dry N,N-dimethylformamide (3 mL). Potassium carbonate (0.078 g, 0.565 mmol) and a catalytic amount of potassium iodide were added. The reaction mixture was then stirred at 55° C. under nitrogen atmosphere for 18 hours. The reaction mixture was partitioned with water and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (50% ethyl acetate/hexanes) to yield the title compound as an oil.
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([NH2:8])=[O:7].Br[CH2:16][C:17]([O:19]CC)=[O:18]>C(O)C>[C:6]([C:5]1[C:4]([I:14])=[C:3]([C:11]([I:12])=[CH:10][C:9]=1[I:13])[O:2][CH2:16][C:17]([OH:19])=[O:18])(=[O:7])[NH2:8]
Reactant: CCOC(=O)CBr
Reactant: NC(=O)c1c(I)cc(I)c(O)c1I
Agent: [Na]
Solvent: CCO
Product: NC(=O)c1c(I)cc(I)c(OCC(=O)O)c1I
Yield: 93.7 %

Procedure:
0.436 g (19 mmol) of sodium is dissolved in 20 ml of ethanol. Then 9.78 g (19 mmol) of 3-hydroxy-2,4,6-triiodobenzamide and subsequently 3.5 g (21 mmol) of ethyl bromoacetate are added thereto. The mixture is heated for one hour to reflux and, after several hours of stirring in an ice bath, the resultant 3-carbamoyl-2,4,6-triiodophenoxyacetic acid ethyl ester is vacuum-filtered, washed with a small amount of ice-cold ethanol, and suspended in 80 ml of water. The mixture is brought to pH 12 by adding concentrated sodium hydroxide solution, stirred for 30 minutes at α° C., the solution is treated with 1 g of active carbon, filtered, and brought to pH 1 by the dropwise addition of dilute hydrochloric acid. After several hours of stirring in an ice bath, the thus-formed precipitate is vacuum-filtered, washed with water, and dried, thus obtaining 10.2 g (89% of theory) of 3-carbamoyl-2,4,6-triiodophenoxyacetic acid as a white powder, mp 211°-213° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([C:16](OC)=[O:17])=[CH:15][C:4]=2[N:3]=1.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)nc(N)c1ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2cc(CO)ccc2c2cccnc12
Temperature: 80 °C

Procedure:
To a solution of methyl 5-aminobenzo[f][1,7]naphthyridine-8-carboxylate (from the previous step) (1.0 eq.) in EtOH (0.03M) was added NaBH4 (10 eq.) at 25° C. The solution was heated to 80° C. for 5 hours. After cooling to ambient temperature, the reaction mixture was concentrated en vacuo. The residue was portionized between saturated NaHCO3 and EtOAc. The layers were separated and aqueous layer was extracted with EtOAc twice. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH/DCM to give (5-aminobenzo[f][1,7]naphthyridin-8-yl)methanol as an off white solid: 1H NMR (methanol-d4): δ 8.82 (dd, 1H), 8.77 (dd, 1H), 7.26 (d, 1H), 7.70 (dd, 1H), 7.50 (d, 1H), 7.27 (dd, 1H), 4.66 (s, 2H). LRMS [M+H]=226.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].[C:25]([C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)#[N:26]>N1C=CC=CC=1>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:30]4[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=4)(=[O:35])=[O:34])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A mixture of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.026 g, 0.08 mmol), 4-cyanobenzenesulfonyl chloride (0.019 g, 0.10 mmol) and pyridine (0.40 ml) was stirred at room temperature overnight. Most of pyridine was removed under reduced pressure and the residue was purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 A, 25 cm; 25%-100% acetonitrile-0.1M ammonium acetate over 25 min, 21 ml/min) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxy-phenyl]-4-cyano-1-benzenesulfonamide as yellow solids (0.018 g, 0.04 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 9.91 (s, 1H), 8.13 (s, 1H), 8.05 (d, 2H), 7.89 (d, 2H), 7.44 (s, 1H), 7.27 (d, 1H), 7.00 (dd, 1H), 6.98 (d, 1H), 6.07 (broad, 2H), 5.07 (m, 1H), 3.49 (s, 3H), 2.11 (m, 2H), 1.88 (m, 4H), 1.69 (m, 2H); MH+489; TLC (ethyl acetate/methanol=9:1) Rf 0.49; RP-HPLC (Hypersil C18, 5 μm, 200 A, 25 cm; 25%-100% acetonitrile-0.1M ammonium acetate over 25 min, 1 ml/min) Rt 14.65 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])#[N:33]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([C:32]#[N:33])[CH:35]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (40 mg, 0.118 mmol) (from Example 5 supra) and Et3N (33 μL , 0.237 mmol) in 3 mL of chloroform was treated with 3-cyanobenzoyl chloride (22 mg, 0.130 mmol) (Aldrich), and the resulting reaction mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo to remove chloroform. The yellow residue was suspended in distilled water, and the resulting solid was collected by suction filtration to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-3-cyanobenzamide (yield: 41 mg, 81%) as a yellow solid (mp 250-251° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]([C:13]([O:15]C)=[O:14])[C:9](OC)=[O:10])=[C:5]([N+:19]([O-])=O)[CH:4]=1.[H][H]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([CH2:7][CH:8]([C:13]([OH:15])=[O:14])[C:9](=[O:10])[NH:19]2)=[CH:17][CH:18]=1
Reactant: COC(=O)C(Cc1ccc(OC)cc1[N+](=O)[O-])C(=O)OC
Reactant: [H][H]
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Temperature: 80 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
A solution of dimethyl (4-methoxy-2-nitrobenzyl)malonate (19 g) in ethanol (200 ml) was hydrogenated in the presence of 10% palladium-C (2.0 g) at room temperature under one atmosphere of hydrogen for 24 hr. The reaction mixture was further stirred at 80° C. for 24 hr and the catalyst was removed by filtration. The filtrate was concentrated. The residue was dissolved in the combined solvent of THF (250 ml) and methanol (250 ml) and 1 N aqueous sodium hydroxide (126 ml) was added in an ice bath. The reaction mixture was stirred at room temperature for 72 hr and concentrated. The residue was made acidic by adding 1 N aqueous hydrochloric acid and the precipitate was collected by filtration. The crude crystals were washed with acetone to obtain the titled compound (11.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccc(OC)cc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3cc(OC)ccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodobenzene (commercially available) and 3-{[(4-methoxy-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.49 (s, 3H), 3.91 (s, 3H), 4.92 (s, 2H), 6.10 (dd, 1H), 6.51 (d, 1H), 6.62 (dd, 1H), 7.25-7.50 (m, 1H), 7.93 (d, 1H), 7.99 (s, 1H).
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:44]=[CH:43][C:14]([C:15]([N:17]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34](=[O:42])[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[CH2:30][CH2:29]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[O:16])=[CH:13][CH:12]=1)C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]([CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:15](=[O:16])[C:14]3[CH:43]=[CH:44][C:11]([CH2:10][NH:8][CH3:6])=[CH:12][CH:13]=3)[CH2:29][CH2:30]2)=[O:42])=[CH:36][CH:37]=1
Reactant: COc1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(C(=O)N(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2ccccc2OC)cc1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
4-(N-tert-Butoxycarbonyl-N-methylamino)methyl-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxyphenyl)benzamide (144 mg, 0.239 mmol) was dissolved in methylene chloride (4 ml) to which was subsequently added dropwise trifluoroacetic acid (0.4 ml) while cooling in an ice bath. After 2 hours of stirring at the same temperature, the solvent was removed by evaporation, and the resulting residue was diluted with methylene chloride (10 ml), washed with saturated sodium bicarbonate aqueous solution and saturated brine, and then dried on anhydrous sodium carbonate. Thereafter, the solvent was removed by evaporation to obtain 119 mg (98.9%) of the title compound in a colorless amorphous form.