Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[N:37]=[CH:38][S:39][CH:40]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[N:37]=[CH:38][S:39][CH:40]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cscn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 62 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.22 mmol), 4-tributylstannanyl-thiazole (121 mg, 0.32 mmol) and PdCl2(PPh3)2 (30 mg, 0.043 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified twice by silica gel chromatography (0-40% EtOAc/CH2Cl2, then 5-30% EtOAc/hexanes+1% AcOH) to give 64 mg of the title compound. MS: (+) m/z 470.33 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=2[CH:11]=[C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.O>[CH3:19][N:17]([CH3:18])[CH2:16][CH2:15][O:14][C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[CH:8][N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(OCCN(C)C)cc2c1ccn2C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ccc2c(C(=O)O)cc(OCCN(C)C)cc21
Yield: 84 %

Procedure:
To a solution of 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.64 mmol) in THF (5 mL) was added LiOH.H2O (200 mg, 4.93 mmol) in water (5 mL). the reaction was heated at reflux for 5 h, at which time the THF was removed under reduced pressure. The remaining mixture was acidified with 1 N HCl (pH˜6) and extracted with 10% MeOH in chloroform (4×30 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to yield 6-(2-dimethylamino-ethoxy)-1-isopropyl-1H-indole-4-carboxylic acid (400 mg), which was used in the next stage without further purification. LCMS (ES+): m/z=291.30 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:18]1C=CC=C[CH:19]=1.N.O>CN(C=O)C>[C:19]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:18]
Reactant: O=C(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: c1ccncc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Reaction time: 8 h

Procedure:
The compound (840 mg) obtained in the above (2) is dissolved in DMF (7 ml), and thereto are added pyridine (10 μl) and cuprous cyanide (I) (410 mg), and the mixture is refluxed with stirring for 8 hours. To the mixture is further added cuprous cyanide (I) (410 mg), and the mixture is refluxed with stirring for 7.5 hours. After cooling, to the mixture is added a mixture of conc. aqueous ammonia (5 ml) and water (60 ml), and the precipitates are removed by filtration. The filtrate is concentrated under reduced pressure, and the pH value of the residue is adjusted to pH 11 with 1N aqueous sodium hydroxide solution, and washed twice with ether. The pH value of the residue is adjusted to pH 1 with conc. hydrochloric acid, and extracted three times with ethyl acetate. The organic layer is washed with a saturated brine, and dried over anhydrous magnesium sulfate. The desiccant is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (654 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I-].C[N+]1C=CN([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])C=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:23])[O:13][C:14]3[C:19]([C:20]=2[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH:15]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2c(C)c3ccc(O)cc3oc2=O)cc1OC
Reactant: C[n+]1ccn(C(=O)N2CCOCC2)c1
Agent: [I-]
Product: COc1ccc(-c2c(C)c3ccc(OC(=O)N4CCOCC4)cc3oc2=O)cc1OC
Yield: 56.4 %

Procedure:
The title compound (120 mg, 56% yield) was prepared from 3-(3,4-dimethoxy-phenyl)-7-hydroxy-4-methyl-chromen-2-one (156 mg, 0.50 mmol) and 1-methyl-3-(morpholine-4-carbonyl)-3H-imidazol-1-ium iodide (165 mg, 0.51 mmol).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH2:12]Cl)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.O>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:14]=[C:15]([NH2:17])[S:16][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOC)C(=O)CCl
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(=NOC)c1csc(N)n1
Reaction time: 0.58 h
Yield: 68.5 %

Procedure:
Ethyl 2-methoxyimino-4-chloroacetoacetate (syn isomer) (50 g.) was added over 3 minutes with stirring at ambient temperature to a solution of thiourea (18.4 g.) and sodium acetate (19.8 g.) in a mixture of methanol (250 ml.) and water (250 ml.). After stirring for 35 minutes at 40° to 45° C., the reaction mixture was cooled with ice and adjusted to pH 6.3 with a saturated aqueous solution of sodium bicarbonate. After stirring for 30 minutes at the same temperature, precipitates were collected by filtration, washed with water (200 ml.) and then with diisopropyl ether (100 ml.), and dried to give colorless crystals of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (37.8 g.), m.p. 161° to 162° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10][C:11](SC)=[C:12]([C:15]#[N:16])[C:13]#[N:14].CS>C(OCC)(=O)C>[CH2:1]([NH:8][C:11]([S:10][CH3:9])=[C:12]([C:15]#[N:16])[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(SC)=C(C#N)C#N
Reactant: NCc1ccccc1
Agent: CS
Solvent: CCOC(C)=O
Product: CSC(NCc1ccccc1)=C(C#N)C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
43.6 ml (400 mmol) of benzylamine are added to a suspension of 68.4 g (400 mmol) of 3,3-bis(methylsulfanyl)-2-cyano-acrylonitrile (Maybridge) in 400 ml of ethyl acetate. The clear solution is slowly heated to 70° C. (→evolution of MeSH!), stirred at that temperature for 1.5 hours, cooled to RT and concentrated by evaporation, yielding crystalline 3-benzylamino-3-methylsulfanyl-2-cyano-acrylonitrile; 1H-NMR: (CD3OD) 7.36 (m, 5H), 4.77 (s, 2H), 2.59 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:15](=[O:17])=[O:16]>C1COCC1>[C:1]([C:5]1[O:6][C:7]([C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CC(C)(C)c1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 2-tert-butylfuran (4.5 g, 36 mmol) in anh. THF (60 mL) at −78° C. under N2 was added n-butyllithium (1.6M in hexane, 25 mL, 40 mmol, 1.1 equiv) dropwise. After 30 min, the cooling bath was replaced with an ice bath and the mixture was stirred at 0° C. for 1 h. Dry CO2, generated from dry ice and dried over an anhydrous Na2SO4 tower, was bubbled into the reaction mixture over 20 min at −78° C. and then at 0° C. The reaction mixture was acidified to pH 1 with a 1M HCl solution, then extracted with EtOAc. The organic layer was washed with a concentrated NaCl solution, dried (NaSO4) and concentrated under reduced pressure to give 5-tert-butylfuran-2-carboxylic acid as a pale yellow solid (4.2 g, 69%): 1H NMR (CDCl3) δ1.29 (s, 9H), 6.11 (d 1H, J=3.3 Hz), 7.19 (d, 1H, J=3.3 Hz), 11.0 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[CH:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].Br[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25](C(OC(C)(C)C)=O)[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[CH:17][N:16]([CH2:22][C:23]4[C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[NH:25][N:24]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]cnc23)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2ncn3Cc2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a suspension of 3-chloro-5-[(5-chloro-1H-benzimidazol-4-yl)oxy]benzonitrile (101 mg, 0.332 mmol) and tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (104 mg, 0.332 mmol) in DMF (1 mL) was added cesium carbonate (216 mg, 0.664 mmol) and the suspension was stirred at room temperature for 2.25 hours. This mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×12 mL). The combined extracts were washed with water, dried over MgSO4, filtered and evaporated in vacuo. This residue was purified on silica gel (40 g) column eluting with 0-100% ethyl acetate/methylene chloride. The fractions corresponding to the desired Boc protected product were combined and the solvent removed in vacuo. This residue was redissolved in TFA (3 mL) and allowed to stand at room temperature for 10 minutes. The solvent was removed in vacuo and the residue was purified on silica gel (4 g) column eluting with 0-10% methanol/methylene chloride gradient. The pure fractions were combined, treated with 1N hydrochloric acid and the solvent removed in vacuo to provide title compound. 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.58 (s, 1H), 8.52 (d, 1H, J=4.4 Hz), 8.16 (d, 1H, 8.0 Hz), 7.74 (dd, 1H, J=1.5 Hz), 7.63 (d, 1H, J=8.8 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H, J=1.5 Hz), 7.29 (dd, 1H, J=2 Hz), 7.19 (dd, 1H, J=4.5 and 8.1 Hz) and 5.92 (s, 2H) ppm. LRMS (M+1)=434.7
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH2:17](Cl)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[C:20]1([CH:19]=[CH:18][CH2:17][O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(OCC=Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Tert-butyl 4-hydroxypiperidine-1-carboxylate (0.396 g, 1.97 mmol) was dissolved in DMF (5 ml), to which sodium hydride (0.086 g, 2.16 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Cinnamyl chloride (0.300 g, 1.97 mmol) was added to the mixture while cooling in an ice-bath, and the resulting mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and brine. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=6/1) to afford tert-butyl 4-(3-phenyl-2-propenyloxy)piperidine-1-carboxylate (0.314 g, yield 50%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH2:40][O:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH2:40][O:41][CH3:42])[CH:36]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: COCc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and 3-[3-(3-methoxymethyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K9) according to the general procedure M. Obtained as a yellow solid (205 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:29][C@@H:30]1[O:32][CH2:31]1)(=O)=O.CN(C=O)C>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[O:18][CH2:29][C@H:30]1[CH2:31][O:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OC[C@H]2CO2)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
A 500 mL round bottomed flask equipped with a nitrogen inlet and a magnetic stir bar is charged with: 2-(benzyloxy)-4-nitrophenol (10.00 g, 40.8 mmol), potassium carbonate (7.05 g, 51.0 mmol), (R)-(−)-glycidyl tosylate (10.00 g, 43.8 mmol) and DMF (65 mL). The mixture is immersed in an oil bath heated to 60° C. and stirred for 18 h. The solution is allowed to cool to rt, then water (200 mL) is slowly added. The resulting suspension is stirred for 2 h, the precipitate is collected by vacuum filtration and the filter cake is washed with water (25 mL). The cake is dried under suction to yield 10.70 g (87%) of the title compound as a light yellow powder. LCMS (Standard Method): 2.74 min, 302 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.48-7.34 (m, 5H), 6.98 (d, J=8.8 Hz, 1H), 5.19 (s, 2H), 4.43 (dd, J=2.7, 11.5 Hz, 1H), 4.08 (dd, J=5.8, 11.5 Hz, 1H), 3.43-3.39 (m, 1H), 2.95-2.91 (m, 1H), 2.81-2.78 (m, 1H).
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])=[O:5].[Br:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>O1CCCC1>[Br:21][C:22]1[CH:23]=[C:24]([NH:25][C:30](=[O:32])[NH:2][CH2:3][C:4]([NH:6][C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[O:5])[CH:26]=[CH:27][CH:28]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)Nc1cccc(Br)c1)Nc1ccccc1C(=O)c1ccccc1
Yield: 186.4 %

Procedure:
A solution of the compound 3a (1.341 g, 4 mmol) prepared in Preparation 3 in tetrahydrofuran (10 ml) is added under ice cooling to a solution of m-bromoisocyanate which is prepared according to the method described in EP-508796-A1 from a solution of m-bromoaniline (846 mg, 4.92 mmol), triphosgene (551 mg, 1.72 mmol) and triethylamine (960 μl, 6.9 mmol) in tetrahydrofuran (50 ml). In addition, triethylamine (558 μl, 4 mmol) is added and treated in a manner similar to that described in Preparation 5 to prepare the compound 6v (1.45 g, yield 68%).
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:17]CN[CH2:14][CH2:13]2)=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:18](=[O:27])[N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=[C:5]3[C:4]=2[CH:3]=1.FC1C(F)=CC2C3C(C(=O)N(C4C=CC=CC=4)N=3)=CNC=2C=1.[CH3:50][N:51]([CH3:58])[CH:52]1CCNC[CH2:53]1>>[CH3:50][N:51]([CH3:58])[CH:52]1[CH2:14][CH2:13][N:12]([C:11]2[C:2]([F:1])=[CH:3][C:4]3[C:5]4[C:6]([C:18](=[O:27])[N:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:20]=4)=[CH:7][NH:8][C:9]=3[CH:10]=2)[CH2:17][CH2:53]1
Reactant: CN(C)C1CCNCC1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)c(F)cc3c-2nn1-c1ccccc1
Agent: O=c1c2c[nH]c3cc(F)c(F)cc3c-2nn1-c1ccccc1
Product: CN(C)C1CCN(c2cc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3cc2F)CC1

Procedure:
The title compound was prepared following the procedure described in the synthesis of 28a using 27a and 4-dimethylaminopiperidine. 1H-NMR (DMSO-d6) δ (ppm): 1.56 (2H, brm), 1.89 (2H, brm), 2.22 (6H, s), 2.74 (2H, brm), 3.13 (1H, brm), 3.52 (2H, brm), 7.10 (1H, m), 7.22 (1H, d, J=7.96 Hz), 7.40 (2H, t, J=7.42 Hz), 7.76 (2H, d, J=2.91 Hz), 8.20 (2H, m), 8.64 (1H, s). m/z 406.4 (MH+).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:18]=[C:17]2[C:12]([C:13](NC3C=CC(Cl)=CC=3F)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C.O>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Reactant: COCCO
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1cc2ncncc2cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), the mixture stirred for 15 minutes to give a complete solution and the volatiles removed by evaporation. The residue was dissolved in DMSO (5 ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazoline hydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred at ambient temperature for 18 hours then diluted with a solution of acetic acid (1 ml) in water (20 ml). The resulting precipitate was collected by filtration, washed with water, dried and purified by column chromatography eluting with methylene chloride/methanol (96/4). The purified product was recrystallised from methylene chloride/isohexane to give 4-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as a yellow solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH:17]1[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:31]([F:34])([F:33])[F:32])[CH:26]=3)[NH:21][C:20]=2[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[N:39]=1>CN(C=O)C.CCOC(C)=O>[CH2:7]([O:14][C:15](=[O:35])[NH:16][CH:17]1[CH2:29][C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][C:31]([F:34])([F:32])[F:33])[CH:26]=3)[N:21]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[N:39]=3)[C:20]=2[CH2:19][CH2:18]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1cccc(CBr)n1
Reactant: O=C(NC1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1CCc2c(c3cc(OC(F)(F)F)ccc3n2Cc2cccc(F)n2)C1)OCc1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
Add Cs2CO3 (6.44 g, 19.8 mmol) to a solution of (6-trifluoromethoxy-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid benzyl ester (Preparation 43) (4.00 g, 9.88 mmol) and 2-bromomethyl-6-fluoropyridine (Preparation 44) (3.11 g, 13.8 mmol) in DMF (40 mL). Heat the resulting mixture to 50° C. for 18 h and then dilute with EtOAc (120 mL). Wash the organics with water (3×40 mL), dry (MgSO4), filter, and concentrate to give the crude product (5.40 g) as a brown oil. Purify the crude product on silica gel (120 g) eluting with 2545% EtOAc/hexanes to afford 2.85 g (56%) of the title compound as a tan oil. MS (ES): m/z 514 (M+1); HPLC (Method A): Rt=4.54 min (95%).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]3[NH:27][CH2:26][CH2:25][C:24]([C:28]([O:30][CH3:31])=[O:29])=[CH:23][C:22]=3[CH:32]=2)=[CH:14][CH:13]=1)[CH2:9][CH3:10].C(OC=O)=O>C1COCC1>[CH:1]([N:27]1[C:21]2[CH:20]=[CH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:8][CH2:9][CH3:10])=[CH:17][CH:16]=3)=[CH:32][C:22]=2[CH:23]=[C:24]([C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:26]1)=[O:3]
Reactant: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC(=O)O
Agent: O=COC=O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.65 ml) was added formic acid (0.32 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, air-cooled and diluted with THF (10 ml). In THF (10 ml) was dissolved methyl 7-(4 propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (520 mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0° C. The mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-formyl-7-(4-propoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (563 mg) as white crystals.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([CH3:24])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([CH3:24])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:4]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][C:10]2[C:9](=[O:18])[NH:8][CH:7]=[N:6][C:5]1=2)[CH:2]=[CH2:3].[CH2:19](I)[CH2:20][CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([N:4]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][C:10]2[C:9](=[O:18])[N:8]([CH2:19][CH2:20][CH3:21])[CH:7]=[N:6][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2cccs2)nc2c(=O)[nH]cnc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(-c2cccs2)nc2c(=O)n(CCC)cnc21
Temperature: 27 °C
Reaction time: 20 h
Yield: 85.4 %

Procedure:
A mixture of 9-Allyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 0.39 mmol), n-propyl iodide (0.04 ml, 0.4 mmol) and Cs2CO3 (0.192 g, 0.59 mmol) were taken in DMF (1 ml) and stirred for 20 hours at 27° C. The reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was washed with brine (2×15 ml), dried over Na2SO4. Solvent was removed to get 9-allyl-1-propyl-8-thiophen-2-yl-1,9-dihydro-purin-6-one (0.100 g, 86%).