Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=3)[NH2:19])[C:10]=2[CH:9]=[CH:8]1.CCN(C(C)C)C(C)C.[CH3:34][C:35](=[CH2:39])[C:36](Cl)=[O:37]>ClCCl>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[C:18]([NH:19][C:36](=[O:37])[C:35]([CH3:39])=[CH2:34])[CH:20]=[CH:21][CH:22]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cccc(N)c3)ncnc21
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline (10.0 g, 29.4 mmol) in dichloromethane (200 mL), was added DIPEA (12.0 g, 92.9 mmol) followed by dropwise addition of a solution of 2-methylprop-2-enoyl chloride (4.60 g, 44.0 mmol) in dichloromethane (50 mL) at −5 to 0° C. The reaction was stirred overnight at room temperature, quenched by addition of water (150 mL), and extracted with dichloromethane (×3). The organic layers were combined, washed with water and HCl solution (0.5 M in water), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was then purified by chromatography using silica gel, eluting with 0-33% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a yellow oil. LRMS (ESI) calc'd for C22H29N4O2Si [M+H]+: 409, found 409.
Reaction SMILES: CO[N:3]=[CH:4][CH:5]1[CH:11]([CH:12]=NOC)[CH:10]2[CH2:16][CH:6]1[CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9]2.F[C:25](F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:18]1([CH2:17][N:8]2[CH2:7][CH:6]3[CH2:16][CH:10]([C:11]4[C:5]3=[CH:4][N:3]=[CH:25][CH:12]=4)[CH2:9]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CON=CC1C2CC(CN(Cc3ccccc3)C2)C1C=NOC
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CC3CC(C2)c2cnccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(phenylmethyl)-3-azabicyclo[3.2.1]octane-6,7-dicarbaldehye bis (O-methyloxime) (Preparation 33, 5.0 g, 15.2 mmol) in dichloroethane (150 ml) was added trifluoroacetic acid (17 ml) and the reaction mixture was stirred under nitrogen at room temperature for 20 min. The reaction mixture was heated under reflux for 2 h and then concentrated to give a brown oil. Ethyl acetate (100 ml) was added and the solution was treated with saturated sodium carbonate solution (70 ml) the layers were separated and the organic layer washed with brine and dried (Na2SO4) and concentrated to give an oil (4.0 g). The crude oil was purified by flash chromatography using silica gel eluting with ethyl acetate to give the title compound as an orange oil (1.93 g, 51%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>>[CH:25]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)([CH3:27])[CH3:26]
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(C(F)(F)F)c3nn2C(C)C)cc1
Yield: 23.8 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (1.0 g, 3.4 mmol), sodium hydride (60% in oil, 0.136 g, 3.4 mmol) and 2-iodopropane (0.34 mL, 3.4 mmol) to give the title compound (0.27 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([OH:26])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[CH2:35]([N:37](CC)CC)C.CN>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24](=[O:26])[NH:37][CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(=O)O)CC1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: ClCCl
Product: CNC(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carboxynitrobenzene (3.3 g) in dichloromethane (50 ml) were added isobutyl chloroformate (1.4 ml) and triethylamine (1.4 ml) in an ice bath and the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 40% aqueous methylamine (1.1 ml) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (3.5 g, yield quantitative) as a yellow amorphous solid.
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].N1C=CC=CC=1.[C:31]1([CH2:37][C:38](Cl)=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1(CS(Cl)(=O)=O)C=CC=CC=1>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:38](=[O:39])[CH2:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[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: O=C(Cl)Cc1ccccc1
Agent: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)Cc1ccccc1
Reaction time: 8 h
Yield: 18.4 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (28 mg, 0.086 mmol) was dissolved in dichloromethane (1 mL). Pyridine (1 mL) was added followed by 2-phenylethanoyl chloride (14 uL, 0.105 mmol). After stirring overnight, another 14 uL of phenylmethanesulfonyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatogram eluted with dichlormethane/methanol (95:5) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-phenylacetamide (7 mg, 0.0158 mmol). 1H NMR (DMSO-d6) δ 1.89 (m, 6H), 2.25 (m, 2H), 3.77 (s, 3H), 3.79 (s, 2H), 5.21 (m, 1H), 5.56 (bs, 2H), 6.89 (s, 1H), 6.99 (s, 1H), 7.05 (d, J=8.22, 1H), 7.36 (m, 5H), 7.81 (s, 1H), 8.27 (s, 1H), 8.43 (d, J=8.23 Hz, 1H). LC/MS MH+=442.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[C:10](=N/[S@@](C(C)(C)C)=O)/[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:19]([O:22][CH3:23])(=[O:21])[CH3:20]>>[CH3:23][O:22][C:19](=[O:21])[CH2:20][CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:11]
Reactant: C/C(=N\[S@](=O)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Reactant: COC(C)=O
Product: COC(=O)CC(C)c1cccc([N+](=O)[O-])c1

Procedure:
Starting from (R)-2-methyl-propane-2-sulfinic acid [1-(3-nitro-phenyl)-(E)-ethylidene]-amide and methyl acetate, the product (S)-3-(R)-2-methyl-propane-2-sulfinylamino)-3-(3-nitro-phenyl)-butyric acid methyl ester was obtained as a pale yellow oil. MS (ESI): m/z=343.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[C:1]1([CH:11]=[CH:13][C:14](=[O:15])[CH:16]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccc2ccccc12)C=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
1-Naphthaldehyde (22, 1.36 ml, 10.0 mmol) and acetone (19, 0.37 ml, 5.0 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethyl acetate to give 0.63 g (38%) of a yellow solid: mp 132-133° C. [expected mp 128° C.]; 1H NMR: δ 7.24 (d, 2H, J=15.7 Hz), 7.57 (m, 6H), 7.92 (m, 6H), 8.28 (d, 2H, J=8.0 Hz), 8.65 (d, 2H, J=15.5 Hz); 13C NMR: δ 123.4, 125.1, 125.4, 126.2, 126.9, 128.1, 128.7, 130.7, 131.7, 132.2, 133.7, 140.3, 188.5.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[C:22]([NH:33][CH2:34][CH3:35])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.ClCC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][CH3:35])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCNc1nc2ccc(OC)cc2cc1Cc1c(O)nc(CC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (308 mg, 1.07 mmol) followed by 2N aq. LiOH solution (1.07 ml, 2.14 mmol) and the mixture was stirred for 1.5 h at 150° C. under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a new purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 29 mg of 1-ethyl-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol as a brown solid. This product was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.55 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 40 as a yellow solid (20 mg, 4% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10](Br)=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1.[C-:16]#[N:17].[Na]>CN(C)C=O.O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:6]=2[NH:5][C:4](=[O:15])[CH2:3]1
Reactant: CN1CC(=O)Nc2cccc(Br)c2C1=O
Reactant: [C-]#N
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)Nc2cccc(C#N)c2C1=O
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 42.4 %

Procedure:
2.3 g of 3,4-dihydro-4-methyl-6-bromo-2H-1,4-benzodiazepine-2,5(1H)-dione (U.S. Pat. No. 4,352,817 ex.9) and 1.26 g of cupro cyanide was dissolved in 5 ml dimethyl formamide. This mixture was heated to 110° C. for 30 minutes. This mixture was then cooled to 50° C. and 2.4 g sodium in 6 ml water was added. The resulting mixture was then stirred for 10 minutes, whereafter 30 ml water was added. This mixture was extracted two times with 25 ml ethyl acetate. The organic phase was dryed with calcium chloride. After filtration the organic solution was evaporated in vacuo to give 0.78 g of the title compound. M.p. 261°-69° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+].ClCCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23][NH:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[CH2:17][OH:18])[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1ccc(C=O)cc1Cl
Reactant: CCOC(=O)c1sc(N2CCCC2CO)nc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-amino-5-ethoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolodinyl)thiazole (prepared in the above (2)) 177 mg, 3-chloro-4-methoxybenzaldehyde 111 mg, acetic acid 78 mg and 1,2-dichloroethane 8 ml is added sodium triacetoxyborohydride 415 mg, and the mixture is stirred at room temperature for 6 hours. Further 3-chloro-2 5 4-methoxybenzaldehyde 111 mg and sodium triacetoxyborohydride 415 mg are added thereto, and the mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and the organic layer is washed, dried and concentrated in vacuo. The residue is separated with reversed phase column chromatography and preparative thin-layer chromatography, and then triturated with ether to give 4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonyl-2-(2-hydroxymethyl-1-pyrrolodinyl)thiazole as crystals, 171 mg. mp 103.5-104.5° C.
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=3)[NH:7][C:6]=2[C:5]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[C:4]2[NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][C:28]=3[C:3]=12.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][O:16][C:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][C:11]([F:15])=[CH:10][CH:9]=3)[C:14]=2[C:2]([C:30]#[N:31])=[C:3]2[C:28]3[CH:27]=[C:26]([F:29])[CH:25]=[CH:24][C:23]=3[NH:22][C:4]=12
Reactant: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(Br)c2c1[nH]c1ccc(F)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CN(C)CCOc1c2[nH]c3ccc(F)cc3c2c(C#N)c2c1[nH]c1ccc(F)cc12
Temperature: 160 °C
Yield: 46 %

Procedure:
A mixture of 2-(12-bromo-2,10-difluoro-5,7-dihydroindolo[2,3-b]carbazol-6-yloxy)-N,N-dimethylethanamine (97.8 mg, 0.1991 mmol), zinc cyanide (233.7 mg, 1.9910 mmol) and tetrakis(triphenylphosphine)palladium (0) (23.0 mg, 0.01991 mmol) in anhydrous DMF was purged with high-purity Ar for five minutes, sealed with Teflon cap and heated to 160° C. for 12 hours. The reaction mixture was cooled down and filtered. The solvent was removed via vacuum pump. The residue was purified via flash chromatography to provide the title compound (37.3 mg, 46%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 2 H), 8.39 (dd, J=10.2, 2.8 Hz, 2 H), 7.55 (dd, 8.8, 4.4 Hz, 2 H), 7.31 (td, J=8.8, 2.4 Hz, 2 H), 4.33 (t, J=4.2 Hz, 2 H), 2.74 (t, J=4.2 Hz, 2 H), 2.35 (s, 6 H); MS (ESI) m/z 403.1 (M−H)−; MS (ESI) m/z 405.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:16][C:17]1[C:26]2[C:21](=[CH:22][C:23](OCCCCl)=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[C:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])[CH3:35].[I-].[Na+]>COCCO.ClCCl>[C:34]([N:37]1[CH2:42][CH2:41][N:40]([CH2:3][CH2:4][CH2:5][O:6][C:19]2[N:18]=[C:17]([NH:16][C:3]3[C:4]4[O:8][CH2:7][O:6][C:5]=4[C:9]([C:11]#[C:12][CH2:13][O:14][CH3:15])=[CH:10][C:2]=3[Cl:1])[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=2)[CH2:39][CH2:38]1)(=[O:36])[CH3:35]
Reactant: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: CC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCO
Product: COCC#Cc1cc(Cl)c(Nc2nc(OCCCN3CCN(C(C)=O)CC3)nc3ccc(OC)cc23)c2c1OCO2
Temperature: 105 °C
Yield: 145 %

Procedure:
N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.158 g) was dissolved in 2-methoxyethanol (5 ml) and then N-acetylpiperazine (0.600 g) was added and the mixture heated to 105° C. A small amount of sodium iodide was added to the reaction mixture, and heating continued for a total of 2½ hours. The reaction mixture was cooled to room temperature and then diluted with dichloromethane. The mixture was washed with a water/brine (5/1) mixture followed by brine and then dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of dichloromethane and methanol as eluent. There was thus obtained the title compound (0.136 g) as a pale yellow foam. NMR Spectrum: (CDCl3) 2.10 (quin, 2H), 2.43 (m, 2H), 2.47 (m, 2H), 2.57 (t, 2H), 3.46 (s, 3H), 3.47 (m, 2H), 3.49 (s, 3H), 3.62 (t, 3H), 3.98 (s, 3H), 4.25 (t, 2H), 4.35 (s, 2H), 6.08 (s, 2H), 7.06 (s, 1H), 7.20 (s, 1H), 7.28 (s, 2H), 8.62 (s, 1H); Mass Spectrum: M+H+ 582/584.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:37][C:38]1C2=CC=C3C(OC(C4C=CC=CC=4)=C(I)C3=O)=[C:41]2[N:40](C)[N:39]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21]([O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]3[N:40]([CH3:41])[N:39]=[C:38]([Cl:37])[C:23]3=[CH:24][CH:25]=4)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: Cn1nc(Cl)c2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Product: Cn1nc(Cl)c2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c21

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-chloro-7-iodo-1-methyl-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a pale yellow gum (34 mg). LCMS (Method H): RT=4.76 min, [M+H]+=556/558.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[C:31]#[N:32])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:24]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[C:31]#[N:32])=[CH:23][C:22](=[O:33])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1sccc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccsc1C1=CC(=O)Nc2cc(-c3ccccc3F)ccc2N1

Procedure:
Prepared from {3-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K55) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (258 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[CH2:11][CH2:10]3)=[CH:5][CH:4]=[C:3]1[C:17]#[N:18].[I-].[Sm+3].[I-].[I-].[C:23](Cl)(=[O:25])[CH3:24].Cl>C(#N)C>[C:23]([C:5]1[CH:4]=[C:3]([C:17]#[N:18])[N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10]2)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc2c(c1)CCC2=O
Agent: Cl
Agent: [I-]
Agent: [Sm+3]
Solvent: CC#N
Product: CC(=O)c1cc(C#N)n(C)c1-c1ccc2c(c1)CCC2=O
Temperature: 120 °C
Yield: 9 %

Procedure:
To a stirred solution of 1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile (0.25 g, 1.0 mmol) in acetonitrile (25 mL) was added samarium iodide (0.5 g, 1.2 mmol) and acetyl chloride (1.75 mL, 24.6 mmol). The reaction mixture was heated in microwave to 120° C. for 10 minutes. The mixture was treated with a 10% aqueous HCl solution (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (30% ethyl acetate in hexane) to give 4-acetyl-1-methyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)-1H-pyrrole-2-carbonitrile as a tan solid (0.025 g, 8%). MS (ESI) m/z 279; HRMS: calcd for C17H14N2O2+H+, 279.1128; found (ESI, [M+H]+), 279.1125.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:5]=1[OH:14].C1N2CN3CN(C2)CN1C3.Cl.[OH:26]C(C)=O.O>O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[O:26])=[C:5]([OH:14])[CH:6]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)O
Reactant: CC(C)(C)c1ccc(CN)c(O)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: CC(C)(C)c1ccc(C=O)c(O)c1
Temperature: 130 °C

Procedure:
To a solution of 1.5 g (6.9 mmol) of the product of Example 1 in 15 mL of HOAc-H2O (11:3) was added 1.17 g (8.3 mmol) of hexamethylenetetramine dissolved in 3 mL water. The reaction mixture was magnetically stirred and heated at 130° C. for 3 h at which point 13.5 mL of a 2:1 solution of conc. hydrochloric acid and water was added. The reaction mixture was heated for an additional 10 min at 130° C., then cooled to room temperature and the acetic acid was removed on a rotary evaporator. The residue was partitioned between EtOAc and water, then extracted and the organic layers were combined and dried (Na2SO4). The filtrate was passed through a layer of Celite filter aid mixed with silica gel to remove polar impurities, then evaporated. The residual oil was dried in vacuo and subsequently used in the next step without further purification.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:13])=[NH:12])[CH2:6][CH2:5][CH2:4][CH2:3]1.CC[O-].[Na+].[CH3:21][S:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29]N)=O)=[CH:25][CH:24]=1.Cl.CCOCC>C(O)C>[ClH:1].[CH3:21][S:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]2[NH:29][N:13]=[C:11]([C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[CH:9]=3)[N:12]=2)=[CH:25][CH:24]=1
Reactant: CSc1ccc(C(=O)NN)cc1
Reactant: N=C(N)c1cccc(CN2CCCC2)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CSc1ccc(-c2nc(-c3cccc(CN4CCCC4)c3)n[nH]2)cc1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
To a stirred ethanolic suspension of 3-pyrrolidin-1-ylmethyl-benzamidine hydrochloride salt (1:2) (414 mg, 1.5 mmol, 1.5 eq.) in 15 ml ethanol was added over 3 minutes 1.2N NaOEt in ethanol (3.4 ml, 4 eq.) and stirring was continued for 30 min. at r.t. 4-Methylsulfanyl-benzoic acid hydrazide (182 mg, 1 mmol) in ethanol at 20° C. was then added and the mixture heated to reflux for 50 hrs. Upon cooling the product mixture was filtered, solvent evaporated and residue chromatographed over 20 g SiO2 (Merck 230-400 mesh) with CH2Cl2-MeOH (2M NH3) 96:4, affording a foam after solvent evaporation. This material was dissolved in ethanol at r.t. and an excess 2N HCl/ether solution (1.0 ml, 2 mmol) was added. After 30 min. the solvent was evaporated and the residue was dried overnight under high vacuum at 30° C. affording the title compound (200 mg, 52% yield) as a yellow foam. MS: m/e=351.5 (M+H+).