Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:26])=[C:11]([F:25])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:33](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:33][N:17]1[C:18]2[C:13](=[CH:12][C:11]([F:25])=[C:10]([F:26])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14](=[O:24])[C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:16]1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cnc2c(OCc3ccccc3)c(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2c(OCc3ccccc3)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
After a mixture of ethyl 8-benzyloxy-6,7-difluoro-4-hydroxy-3-quinolinecarboxylate (410 mg) and anhydrous potassium carbonate (315 mg) in dry dimethylformamide (10 ml) was stirred at room temperature for 3 hours, O-(2,4-dinitrophenyl)hydroxylamine (260 mg) was added. The mixture was stirred at room temperature for further 6.5 hours. After removal of the solvent under reduced pressure, water (12 ml) was added to the residue, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and washed with cold water and then with ether to give 405 mg of ethyl 1-amino-8-benzyloxy-6,7-difluoro-4-oxo-1,4-dihydro -3-quinolinecarboxylate. An analytical sample, mp 143°-144° C.; MS m/z 374 (M+), was prepared by recrystallization from methanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:4][C:3]=1[C:18](=[O:26])[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.[CH3:27][O:28][CH2:29][CH2:30][NH:31][CH3:32]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](=[O:14])[N:31]([CH2:30][CH2:29][O:28][CH3:27])[CH3:32])=[C:10]([F:17])[CH:9]=2)=[CH:4][C:3]=1[C:18]([NH:19][C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)=[O:26]
Reactant: CNCCOC
Reactant: Nc1ncc(-c2ccc(C(=O)O)c(F)c2)cc1C(=O)Nc1ccncc1
Product: COCCN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)cc1F

Procedure:
Reaction of 4-[6-amino-5-(pyridin-4-ylcarbamoyl)-pyridin-3-yl]-2-fluoro-benzoic acid with N-(methoxyethyl)-methylamine gives “A102”; method 1: HPLC/MS: 1.34 min, [M+H]=424;
Reaction SMILES: [Br:1]Br.[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:7]=1)([O-:5])=[O:4].O>C(O)(=O)C>[Br:1][C:10]1[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[C:8]([C:13]([F:14])([F:15])[F:16])[C:9]=1[NH2:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Br)cc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 120 °C
Yield: 91 %

Procedure:
Bromine (0.60 mL) dissolved in acetic acid (11 mL) was added dropwise to a solution of 4-nitro-2-trifluoromethyl-phenylamine (2.4 g) in acetic acid (12 mL). The reaction mixture was heated to 120° C. for 2½ hours, poured into water (400 mL) and filtered. The collected solid was washed with water (200 mL) and dried in vacuo to furnish 3.03 g (91% yield) of the title compound as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 7.08 (s, 2H), 8.23 (d, 1H), 8.51 (d, 1H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1>CN(C)C=O>[C:1]1([S:7][CH2:12][CH:11]([OH:10])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cncc(CCC2CO2)c1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)CSc1ccccc1
Yield: 76.7 %

Procedure:
Prepared according to the method described in Example 1a) from thiophenol (0.142 g), sodium hydride (0.062 g) and 3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide at room temperature to give the title compound as an oil (0.200 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: Clc1ncccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1Oc1ncccn1
Temperature: 120 °C
Yield: 25 %

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (4 g, 25.6 mmol), 2-chloro-pyrimidine (5.4 g, 48 mmol), t-BuOK (3.5 g, 29 mmol) were mixed in DMF (20 mL). Then the mixture was heated for 2 hour at 120° C. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N NaOH. Then the organic layer was dried over anhydrous Na2SO4 and concentrated to give title compound as a white solid (Yield: 1.5 g, 25%).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]1=O)(=O)[CH3:2].O.[NH2:15][NH2:16]>C(O)C>[CH3:2][C:1]1[C:4]2[C:9](=[O:10])[CH2:8][C:7]([CH3:12])([CH3:11])[CH2:6][C:5]=2[NH:16][N:15]=1
Reactant: NN
Reactant: CC(=O)C1C(=O)CC(C)(C)CC1=O
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-acetyl-5,5-dimethyl-cyclohexane-1,3-dione (2 g, 11.04 mmol), prepared as described in example 2, and hydrazine hydrate (1.66 ml, 33.13 mmol) in ethanol (25 ml) was stirred at room temperature for about 3 hours and then the solvent was evaporated. The residue was dissolved in dichloromethane, washed with water and brine, dried over sodium sulfate and evaporated. The title compound was obtained after chromatography on silica gel (dichloromethane:methanol=95:5) as a colourless solid (0.8 g, 45%): m.p. 103-104° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10]C2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:17])=[C:8]([NH:10][S:19]([CH3:18])(=[O:21])=[O:20])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(Cl)c(Nc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1ccc(Cl)c(NS(C)(=O)=O)c1
Temperature: 0 °C
Yield: 56.6 %

Procedure:
To a stirred solution of 5-acetyl-2-chloro-phenylaniline (which was obtained in Example 22) (7.40 g, 43.5 mmol) in CH2Cl2 (200 mL) and pyridine (40 mL) at 0˜5° C. was added dropwise methanesulfonyl chloride (5.0 g, 43.6 mmol) in 50 mL of CH2Cl2. After 1 hour at 0° C. the mixture was warmed to room temperature and stirred at room temperature for another hour. The solvents were removed and the residue was dissolved in CH2Cl2(500 mL). The reaction mixture was washed with water and the organic layer was dried (MgSO4) and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (6.1 g, 57%); 1H NMR (300 MHz, DMSO-d6) δ 2.58 (s, 3H), 3.08 (s, 3H), 7.69 (d, J=8.3 Hz, 1H), 7.83 (dd, J=8.3, 2.1 Hz, 1H), 7.94 (d, J=2.1 Hz, 1H), 9.69 (s, 1H); MS (ES) m/z: 245.9 ((M−H)−, 100%); HRMS Calcd. for C9H11ClNO3S(MH+): 248.0148. Found: 248.0135.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12]>>[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH:12][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc[nH]1
Product: Cc1cccc(C)c1NC(=O)c1ccc[nH]1
Yield: 23.3 %

Procedure:
The title compound was prepared from 1H-pyrrole-2-carboxylic acid (2 g, 18 mmol) and 2,6-dimethylaniline (2.75 g, 22.7 mmol) following the experimental procedure described in Preparation 44a. 900 mg (23% yield) of the desired compound were obtained.
Reaction SMILES: N1CCCCC1.[N:7]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)=[N+:8]=[N-:9].[CH2:21]([C:24]#[N:25])[C:22]#[N:23]>C(O)C>[N:7]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[C:21]([C:24]#[N:25])[C:22]#[N:23])=[CH:15][CH:14]=1)=[N+:8]=[N-:9]
Reactant: N#CCC#N
Reactant: [N-]=[N+]=NCCOc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(C#N)=Cc1ccc(OCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
47 μl (0.47 mmol) of piperidine are added dropwise to a solution of 3.02 g (15.79 mmol) of the compound from Example 36A and 1.09 g (16.42 mmol) of malonodinitrile in 100 ml of ethanol, and the reaction mixture is stirred at +78° C. for 3.5 h. During this time, the colour of the solution changes to orange-red. After cooling to RT, the solution is allowed to stand without stirring for 20 h. A colourless precipitate is formed. Using a rotary evaporator, the crude suspension is concentrated to half of its original volume, and the crystallization is completed with cooling in an ice bath. The resulting precipitate is filtered off with suction and washed twice with in each case 20 ml of ethanol and twice with in each case 20 ml of methyl tert-butyl ether.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.[Br:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[Br:21][C:22]1[N:23]=[CH:24][N:25]([C:2]2[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[N:3]=2)[CH:26]=1
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Brc1c[nH]cn1
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-isopropyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.43) (0.4 g, 1.33 mmol) and commercially available 4-bromo-imidazole (0.29 g, 2.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.5 g, 91%). MS (ISP) 413.1 [(M+H)+]; mp 185° C.
Reaction SMILES: [OH:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[CH2:3][NH:4]C(=O)OC(C)(C)C.ClS([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:27](=[O:28])([O:1][CH:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:19])([F:20])[F:21])[CH2:3][NH2:4])[NH2:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NCC(OC(N)=O)c1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A solution of 420 mg (1.38 mmol) of the compound of Example 36A in 100 ml of acetonitrile was cooled to −15° C., and a solution of 168 μl (1.93 mmol) of chlorosulphonyl isocyanate in 10 ml of acetonitrile was added dropwise. After 5 min, 50 ml of water were added and the reaction mixture was stirred further at 60° C. overnight. After cooling to RT, 50 ml of a saturated aqueous sodium bicarbonate solution were added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and freed from the solvent on a rotary evaporator. The residue (321 mg, about 90% pure, 85% of theory) corresponded to the title compound and was reacted further without additional purification.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][C:3](=[O:8])[CH2:2]1.C([O-])(=O)C.[Na+].BrBr.[NH2:17][C:18]([NH2:20])=[S:19]>C(O)(=O)C>[NH2:20][C:18]1[S:19][C:2]2[C:3](=[O:8])[CH2:4][CH2:5][CH2:6][CH2:7][C:1]=2[N:17]=1
Reactant: O=C1CCCCC(=O)C1
Reactant: NC(N)=S
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2c(s1)C(=O)CCCC2
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
Cycloheptane-1,3-dione (20.0 g, 159 mmol) [prepared according to Organic Process Research & Development 1998, 2, 379] is taken up in 200 mL acetic acid and sodium acetate (14.3 g, 174 mmol) is added. The reaction mixture is stirred for 10 min, cooled to 10° C. and than bromine (8.99 mL, 174 mmol) is added dropwise over a period of 20 min. The reaction mixture is allowed to come to RT and stirred for 2 h. Thiourea (13.2 g, 174 mmol) is added and the reaction mixture is heated to 85° C. and stirred for 1 h. The reaction mixture is stirred overnight at RT, filtered and the solids are washed with 200 mL petroleum ether. The solids are taken up in water, filtered and the filtrate is basified to pH 8 with aqueous ammonia. The precipitated solids are filtered off and dried in vacuo. Yield: 10.0 g. HPLC-MS: tR=0.14 min, (M+H)+=183. 1H NMR (DMSO-d6): δ 7.81 (s, 2H), 2.84 (t, 2H), 2.58 (t, 2H), 1.81 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[N:9]=[C:8]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)[C:7]=1[N+:28]([O-])=O)=[O:5])[CH3:2]>C(O)C.[Pd]>[NH2:28][C:7]1[C:8]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=2)=[N:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[N:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1nc(Nc2cccc(O)c2)nc(Nc2cccc(O)c2)c1N

Procedure:
A suspension of 6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-5-nitro-2,4-pyrimidinediamine and 10% Pd/C (10% by weight) in ethanol was prepared and reacted in a Parr bottle under hydrogen gas (20 PSI) for 1 h. The reaction mixture was filtered through Celite. Purification by column chromatography gave 5-amino-6-ethoxycarbonyl-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.30 (bs, 1H), 7.18-7.10 (m, 3H), 7.00 (t, 2H, J=8.1 Hz), 6.59-6.54 (m, 1H), 6.33 (dd, 1H, J=2.1 and 11.1 Hz), 4.39 (q, 2H, J=6.9 Hz), 1.43 (t, 3H, J=6.9 Hz); LCMS: ret. time: 19.24 min.; purity: 100%; MS (m/e): 382 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:35]=[C:34]([CH3:36])[C:7]([O:8][C:9]2[C:10]3[N:26](CC4C=CC=CC=4)[CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[N:14]=2)=[C:6]([CH3:37])[CH:5]=1)(=[O:3])[CH3:2].[Al+3].[Cl-].[Cl-].[Cl-].C(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH3:37])[C:7]([O:8][C:9]2[C:10]3[NH:26][CH:25]=[CH:24][C:11]=3[N:12]=[C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)[N:14]=2)=[C:34]([CH3:36])[CH:35]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CC(=O)c1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3cc[nH]c23)c(C)c1
Temperature: 160 °C
Yield: 79.4 %

Procedure:
To a suspension of 4-(4-(4-acetyl-2,6-dimethylphenoxy)-5-benzyl-5H-pyrrolo[3,2-d]pyrimidin-2-ylamino)benzonitrile (65 mg, 0.13 mmol) in 1,2-dichlorobenzene (5.3 mL) was added AlCl3 (178 mg, 1.3 mmol). The reaction mixture was heated at 160° C. for 1.5 h, after which time the reaction mixture became dark and homogeneous. Upon completion of the reaction, the reaction mixture was cooled, CHCl3 was added, and the mixture was washed with NH4Cl. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes:ethyl acetate (3:1), to give the product as a brown solid (41 mg, 77%).
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[S:6][C:7]([Cl:12])=[CH:8][C:9]=1[CH:10]=O.[CH3:13][C:14]([CH3:16])=[O:15]>>[Cl:4][C:5]1[S:6][C:7]([Cl:12])=[CH:8][C:9]=1[CH:10]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: O=Cc1cc(Cl)sc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)sc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2,5-dichlorothiophene (100.0 g) and dichloromethylmethylether (165.3 g) in dichloromethane (800 ml) was added dropwise a solution of titanium tetrachloride (272.7 g) in dichloromethane (160 ml) at −10 to −15° C. taking 50 minutes, and at the same temperature, the mixture was stirred for 30 minutes. The reaction solution was poured into ice, and the organic layer was washed with water, sodium hydrogen carbonate solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 2,5-dichloro-3-formylthiophene (115.0 g) as oil. To a mixture of acetone (1000 ml), sodium hydroxide (28.6 g) and water (1200 ml) was added at 0° C. a solution of 2,5-dichloro-3-formylthiophene (58.6 g) in acetone (200 ml) for 1.5 hours, and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the crystals were filtered, washed with water and dried to give 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g). To a solution of 20% sodium ethoxide in ethanol (211 g) was added diethyl malonate (99.3 g) at room temperature, and then 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g) little by little. The mixture was stirred at room temperature for 30 minutes, heated for 2 hours while stirring, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, to which was added 2M sodium hydroxide (340 ml). The mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (340 ml) for 15 minutes, and the mixture was stirred at 100° C. for 1.5 hours. The mixture was cooled, and precipitated crystals were filtered and washed with ethyl acetate-isopropylether (1:4) and isopropylether to give 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (78.9 g) as colorless crystals.
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:25]C(=O)C)=[C:18]([O:21]C(=O)C)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)#[CH:3].N>CO>[ClH:1].[C:2]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:25])=[C:18]([OH:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)#[CH:3]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC(C)=O)c(OC(C)=O)cc23)c1
Agent: Cl
Agent: N
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3cc(O)c(O)cc23)c1
Reaction time: 4 h
Yield: 82.3 %

Procedure:
To the hydrochloride salt, 14 (4.2 g, 11.62 mmol) in methanol (30 ml) was added 25% aqueous ammonia (4.73 ml) and the solution was stirred for 4 h. The reaction mass was filtered and the solid was washed with water to give the N-(3-ethynylphenyl)-6,7-dihydroxy-4-quinazolinamine hydrochloride, 15 (3.0 g, 93%) as a brownish yellow solid. 1H NMR (400 MHz, DMSO-d6): 4.2 (s, 1H), 7.10 (s, 1H), 7.17-7.19 (m, 2H), 7.34-7.39 (t, 1H), 7.79 (s, 1H), 7.87-7.89 (d, 1H), 8.05 (s, 1H), 8.45 (s, 1H), 9.4-9.6 (bs. s, 1H). MS (ESI): 278.
Reaction SMILES: C[Si](C)(C)C[CH2:4][O:5]COC[Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[CH3:29][NH:30][C@H:31]([C:41]([NH:43][C@H:44]([C:49]([N:51]([C@@H:53]([CH:63]([CH3:65])[CH3:64])/[CH:54]=[C:55](\[CH3:62])/[C:56](N(OC)C)=[O:57])[CH3:52])=[O:50])[C:45]([CH3:48])([CH3:47])[CH3:46])=[O:42])[C:32]([CH3:40])([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[OH:5][CH2:4][C:56](=[O:57])[C:55]([CH3:62])=[CH:54][CH:53]([N:51]([CH3:52])[C:49]([CH:44]([NH:43][C:41](=[O:42])[CH:31]([NH:30][CH3:29])[C:32]([CH3:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:40])[C:45]([CH3:46])([CH3:48])[CH3:47])=[O:50])[CH:63]([CH3:65])[CH3:64]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOCC[Si](C)(C)C
Reactant: CN[C@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)N(C)OC)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(C(=O)NC(C(=O)N(C)C(C=C(C)C(=O)CO)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 21.3 %

Procedure:
To a solution of trimethyl-(2-tributylstannanylmethoxymethoxy-ethyl)-silane (933 mg, 2.07 mmole, E. Fernandez-Megia and S. V. Ley; Synlett 2000, 4, 455-8) in 6 mL tetrahydrofuran at −78° C. is added dropwise 1.6 M n-butyllithium solution in hexanes (1.25 mL, 2.0 mmole). The resulting yellow solution is stirred for 10 mins at −78° C. Then a solution of N,β,β-trimethyl-L-phenylalanyl-N1 {(1S,2E)-1-isopropyl-4-[methoxy(methyl)amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamide (258 mg, 0.5 mmole, Example 52) in tetrahydrofuan (5 mL) at −78° C. is added dropwise and the reaction mixture stirred at −78° C. for 15 mins and then at −60° C. for 45 mins. The reaction is quenched with a saturated aqueous solution of ammonium chloride (2 mL), warmed to room temperature and partioned between ethyl acetate (50 mL) and saturated aqueous solution of ammonium chloride (50 mL). The aqueous layer is extracted with ethyl acetate (30 mL) and the combined organic layer is washed with water, brine, dried over sodium sulfate, filtered and the residue treated with a mixture of trifluoroacetic acid (10 mL) and dichloromethane (5 mL) at 0° C. and stirred for 1 hour, evaporated and then purified by HPLC to give 52 mg of an off-white solid, MS (ES): m/z 488.4 (M+H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH:5]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:11]1([CH:5]2[CH:6]=[C:7]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:8][CH2:9][N:4]2[C:1](=[O:3])[CH3:2])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CCNC1
Reactant: CC(=O)N1CCC(=O)CC1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(N2CCCC2)=CC1c1ccccc1

Procedure:
To a mixture of 1-acetyl-2-phenylpiperidin-4-one (3.364 mmol, 1.0 eq.) and pyrrolidine (3.7 mmol, 1.1 eq.) in toluene (16 ml) was added PTSA (0.336 mmol, 0.1 eq.) and the reaction mixture was heated to reflux for 5 h using a Dean-Stark apparatus. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:23](=[O:24])[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[C:16]1=[O:25].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36](Cl)=[O:37]>O1CCOCC1>[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[C:36]([NH:1][C:2]1[C:7]2[N:8]([CH3:13])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=[C:4]([F:14])[C:3]=1[N:15]1[C:16](=[O:25])[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[C:23]1=[O:24])=[O:37]
Reactant: CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c(N)c21
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Product: CN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)c(NC(=O)c3ccc4ccccc4c3)c21
Yield: 34.6 %

Procedure:
2-[5-Amino-7-fluoro-4-methyl-2H-1,4-benzoxazine-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.3 g) and 2-naphthoyl chloride (0.19 g) were dissolved in anhydrous dioxane (10 ml) and the solution refluxed for 2 hr. Solvent was evaporated and the residue subjected to column chromatography on silica gel in hexane-ethyl acetate (6:4) to furnish the title compound (0.15 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Li+].[CH3:11]C([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH3:11])[N:3]=1
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 2,4-dichloro-6-methylpyrimidine (4.0 g) in 90 mL THF was cooled to −78 C and treated dropwise with LDA (2 M, 14.7 mL). After 35 min, iodomethane (1.55 mL) was added and the reaction was stirred for 3 more hours at −78 C. The reaction was allowed to slowly warm to room temperature, then quenched with 0.5 mL of water. The mixture was dissolved in water and extracted with ethyl acetate. Chromatography (30% ethyl acetate in hexanes) provided 1.64 g of 2,4-Dichloro-6-ethylpyrimidine.