Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])O.[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[C:16]([C:22]#[N:23])[N:15]=1.O>C(#N)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:16]([C:22]#[N:23])[N:15]=1
Reactant: N#Cc1nc(Cl)ccc1CCl
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1nc(Cl)ccc1COc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
A solution (10 ml) of 1.50 g (5.70 mmol) of the resulting N-oxide substance in phosphorus oxychloride was stirred at 80° C. for 1 hour. The reaction solution was concentrated in vacuo, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue followed by extracting with chloroform and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous saline solution. After drying and concentrating, the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1) to give 625 mg (yield: 58%) of 2-chloro-5-chloromethyl-6-cyanopyridine as a white solid. Phenol (30 mg; 0.32 mmol) and 44 mg (0.32 mmol) of sodium hydrogen carbonate were added to a solution (5 ml) of 50 mg (0.27 mmol) of 2-chloro-5-chloromethyl-6-cyanopyridine in acetonitrile followed by stirring at room temperature for 8 hours and 30 minutes. Water was added to the reaction solution followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, dried and concentrated in vacuo and the resulting residue was purified by a thin-layer column chromatography (hexane:ethyl acetate=6:1) to give 61 mg (yield: 93%) of 2-chloro-6-cyano-5-phenoxymethylpyridine as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[C:12]([C:13](O)=[O:14])=[C:11]([NH:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([Cl:24])=[CH:19][C:18]=2[CH3:25])[N:10]=[C:9]([CH3:26])[CH:8]=1)[CH2:4][CH3:5])[CH3:2].CSC>C1COCC1>[Cl:24][C:20]1[CH:19]=[C:18]([CH3:25])[C:17]([NH:16][C:11]2[C:12]([CH2:13][OH:14])=[C:7]([O:6][CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:8]=[C:9]([CH3:26])[N:10]=2)=[C:22]([CH3:23])[CH:21]=1
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(Cl)cc2C)c1C(=O)O
Solvent: CSC
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(Cl)cc2C)c1CO
Reaction time: 0.5 h

Procedure:
To a solution of 4-(1-ethyl-propoxy)-6-methyl-2-(4-chloro-2,6-dimethyl-phenylamino)nicotinic acid in dry THF was added BH3.DMS. The resulting mixture was heated at reflux overnight. The mixture was quenched with dilute HCl and stirred for 30 minutes, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a brown oil. After silica gel column chromatography, the title compound was obtained as a green oil. 1H NMR(CDCl3) d 7.02(s,2H), 6.83(brs,1H), 4.78(s,2H), 4.14(m,1H), 2.2(s,3H), 2.13(s,6H), 1.66(m,4H), 0.93(9t,6H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[C:4]2[O:8][C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[N:6][C:5]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16].F[B-](F)(F)F.[H+].[CH3:26][Si](C=[N+]=[N-])(C)C.O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:19])=[C:4]2[O:8][C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH3:26])=[N:6][C:5]2=[C:14]([C:17]#[N:18])[C:15]=1[CH3:16]
Reactant: Cc1c(Br)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC(C)(C)c1nc2c(C#N)c(C)c(Br)c(F)c2o1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 106.1 %

Procedure:
6-Bromo-7-fluoro-2-(2-hydroxy-1,1-dimethylethyl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-108) (912.6 mg, 2.79 mmol) and (514 mg, 1.57 mmol) were separately dissolved in methylene chloride (9 ml and 5 ml), and aqueous 42% tetrafluoroboric acid solution (420 μl, 2.79 mmol) and (240 μl, 1.57 mmol) were individually added to each, then with cooling with ice, trimethylsilyldiazomethane (2 M hexane solution, 2.8 ml, 5.58 mmol) and (1.6 ml, 3.14 mmol) were dropwise added, followed by stirring at 0° C. for 40 minutes; but since the reaction did not finish, the same amount of aqueous 42% tetrafluoroboric acid solution and trimethylsilyldiazomethane were added, followed by stirring for 19 hours with heating up to room temperature. After the reaction, the two reaction solutions were combined, water was added, followed by extraction with ethyl acetate and washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane/ethyl acetate (10:1, v/v) to obtain the entitled compound (1.01 g, 68%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][C@H:32]([C:36](O)=[O:37])[CH:33]([CH3:35])[CH3:34])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:3]1.C[Si](C)(C)[O:41][NH2:42].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[OH:41][NH:42][C:36]([CH:32]([NH:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:4]3[NH:3][C:2](=[O:1])[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)=[O:13])[CH:17]=2)=[CH:23][CH:24]=1)(=[O:29])=[O:30])[CH:33]([CH3:34])[CH3:35])=[O:37]
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)O
Reactant: C[Si](C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2cccc(CNC(=O)c3nc4ccccc4c(=O)[nH]3)c2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
A suspension of N-{[3′-({[(4-oxo-3,4-dihydroquinazolin-2-yl)carbonyl]amino}methyl)biphenyl-4-yl]sulfonyl}valine obtained in Example 77 (0.080 g, 0.150 mmol), O-(trimethylsilyl)hydroxylamine (0.055 mL, 0.449 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl-carbodiimide hydrochloride (0.086 g, 0.449 mmol) and 1-hydroxybenzotriazole (0.061 g, 0.449 mmol) in DMF (5 mL) was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate, and washed successively with 0.05N hydrochloric acid, aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from methanol-diethyl ether to give the title compound as a white powder (0.058 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[NH2:25])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1.C1N=C[N:29]([C:32]([N:34]2C=NC=C2)=[O:33])C=1.CCN(C(C)C)C(C)C>C1COCC1>[NH2:29][C:32]([NH2:34])=[O:33].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[NH2:25])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Nc1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ccccc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(N)=O

Procedure:
N*4*-[2-(5-Chloro-2-fluoro-phenyl)-quinolin-4-yl]-pyridine-3,4-diamine (cf. Example 7) was treated in THF with CDI and DIPEA over night at ambient temperature. After work up the urea derivative was isolated with correct mass M+H+ 391 and Rt˜1.78 min in LC-MS system 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:17])=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([O-])=O.[CH:18](OC)(OC)OC.FC(F)(F)C(O)=O>[Ni].CO>[O:14]1[CH2:15][CH2:16][CH:11]([N:10]2[C:9]3=[N:8][C:7]([OH:17])=[CH:6][CH:5]=[C:4]3[N:1]=[CH:18]2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(O)nc1NC1CCOCC1
Reactant: COC(OC)OC
Agent: [Ni]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2ncn(C3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
5-Nitro-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-ol (0.173 g, 0.723 mmol) and methanol (160 mL) were stirred at 25° C. for 4 h with excess Raney nickel and under an atmosphere of hydrogen. After 4 h the solution was filtered by vacuum filtration through Celite® and the solvent was removed under reduced pressure. The intermediate 5-amino-6-(tetrahydro-2H-pyran-4-ylamino)pyridin-2-ol was then taken up in trimethyl orthoformate (20.0 mL, 183 mmol), and trifluoroacetic acid (0.05 ml, 0.649 mmol) was added. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (0.0246 g). LCMS m/z=220.0 [M+H]+; 1H NMR (400 MHz, acetonitrile-d3) δ ppm 2.10-2.20 (m, 2H), 2.31 (qd, J1=12.4 Hz, J2=4.7 Hz, 2H), 3.59 (td, J1=12.0 Hz, J2=1.9 Hz, 2H), 4.11 (dd, J1=11.8 Hz, J2=4.5 Hz, 2H), 4.80-4.90 (m, 1H), 6.98 (d, J=8.9 Hz, 1H), 8.18 (d, J=8.9 Hz, 1H), 8.56 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59][C:60](=[O:70])[CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([NH2:69])=[CH:65][N:64]=1)[CH3:58]>CN(C)C=O>[CH2:57]([O:59][C:60](=[O:70])[CH2:61][CH2:62][C:63]1[CH:68]=[CH:67][C:66]([NH:69][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:65][N:64]=1)[CH3:58]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CCc1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCc1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.1 %

Procedure:
A solution of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (0.7 g, Reference Example 31) in anhydrous dimethylformamide (25 ml) was treated sequentially with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.85 g), diisopropylethylamine (0.54 g) and a solution of 3-(5-amino-pyrid-2-yl)propanoic acid ethyl ester [0.42 g, Reference Example 4(a)] in dimethylformamide (5 ml). After stirring at room temperature for 5 hours and standing over night the reaction mixture was evaporated. The residue was treated with ethyl acetate and the resulting solution was washed three times with water, then with brine and then evaporated. The residue was subjected to flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (97:3, v/v) to give the title compound (0.68 g) as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](S(C)(=O)=O)=[N:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[N:10]2)=[N:7][CH:8]=1.[OH:22][C:23]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:22][C:23]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][CH:24]=2)=[N:5][C:6]([N:9]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: Oc1csc(C(F)(F)F)c1
Reactant: COc1cnc(-n2cc(C(F)(F)F)cn2)nc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(-n2cc(C(F)(F)F)cn2)nc1Oc1csc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
A mixture of 0.4 g (1.24 mmol) of 5-methoxy-4-methylsulfonyl-2-(4-trifluoromethyl-1H-1-pyrazolyl)pyrimidine, 0.27 g (1.60 mmol) of 3-hydroxy-5-trifluoromethyl-thiophene and 0.34 g (2.47 mmol) of K2CO3 in 10 ml of DMF is stirred at 60° C. for 6 h and then at RT for 48 h. It is subsequently poured into 20 ml of water and extracted with four times 15 ml of CH2Cl2. The combined organic phase is dried over Na2SO4, filtered and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 0.3 g of 5-methoxy-2-(4-trifluoromethyl-1H-1-pyrazolyl)-4-(5-trifluoromethyl-3-thienyloxy)pyrimidine as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.[H-].[Na+].Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH2:18][C:19]2[N:23]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]3=[N:21][C:20]=2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:12]=1>C1COCC1.C(OCC)(=O)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]2[N:23]([C:19]([CH2:18][NH:17][C:13]3[N:14]=[C:15]([O:7][C@@H:4]4[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]4)[CH:16]=[CH:11][N:12]=3)=[C:20]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[N:21]=2)[CH:24]=1
Reactant: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nccc(Cl)n2)cc1
Reactant: CN1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-1-methylpyrrolidin-3-ol (66 mg, 0.65 mmol) in THF (3 ml) was added NaH (25 mg, 65% in mineral oil). The mixture was stirred for 30 min and 4-chloro-N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine (50 mg, 0.13 mmol) was added. The mixture was heated from 65 to 95° C. until the reaction was completed. The mixture was diluted with ethyl acetate and the resulting mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated by evaporation. The crude product was purified by silica gel chromatography (methanol/methylene chloride gradient) to obtain the desired product. 1H-NMR (CDCl3, 400 MHz, δ) 8.23 (s, 1H), 7.69 (m, 2H), 7.52 (d, J=9.5 Hz, 1H), 7.12 (m, 3H), 5.97 (s, 1H), 5.36 (s, 1H), 4.96 (d, J=4.7 Hz, 2H), 2.80 (m, 3H), 2.68 (m, 1H), 2.34 (s, 3H), 2.25 (m, 2H), 1.96 (m, 1H) ppm; m/e 453 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2.Cl.Cl[CH2:26][C:27]1[N:28]=[CH:29][S:30][CH:31]=1>>[NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]3[N:28]=[CH:29][S:30][CH:31]=3)=[C:18]([Cl:23])[CH:17]=1)=[N:8][CH:9]=[N:10]2
Reactant: ClCc1cscn1
Reactant: NCCOc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: Cl
Product: NCCOc1cccc2ncnc(Nc3ccc(OCc4cscn4)c(Cl)c3)c12
Yield: 91 %

Procedure:
The procedure described in Example 65 (preparation of starting materials) was repeated using 4-{[5-(2-aminoethoxy)quinazolin-4-yl]amino}-2-chlorophenol and 4-(chloromethyl)-1,3-thiazole hydrochloride to give 5-(2-aminoethoxy)-N-[3-chloro-4-(1,3-thiazol-4-ylmethoxy)phenyl]quinazolin-4-amine in 91% yield; NMR spectrum (DMSO-d6 400 MHz) 3.02-3.19 (bs, 2H), 4.22-4.36 (m, 2H), 5.33 (s, 2H), 7.14 (d, 1H), 7.27-7.40 (m, 2H), 7.67-7.86 (m, 3H), 8.23 (s, 1H), 8.52 (s, 1H), 9.15 (s, 1H) (3 exchangeables); Mass spectrum MH+ 427.9.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[S:3]([N:6]1[CH:10]=[C:9]([CH3:11])[CH:8]=[N:7]1)(=[O:5])=[O:4].[O:13]1[CH2:15][CH2:14]1>C1COCC1>[OH:13][CH2:14][CH2:15][C:8]1[C:9]([CH3:11])=[CH:10][N:6]([S:3]([N:2]([CH3:12])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: C1CO1
Reactant: Cc1cnn(S(=O)(=O)N(C)C)c1
Solvent: C1CCOC1
Product: Cc1cn(S(=O)(=O)N(C)C)nc1CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
Into a 50-mL three-neck round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N,N,4-trimethyl-1H-pyrazole-1-sulfonamide (compound 305.1, 1.19 g, 6.26 mmol) in THF (24 mL) n-BuLi (3 mL, 7.5 mmol, 2.5 M in hexanes) was added to the reaction dropwise at −78° C. The resulting mixture was stirred for 30 min at −78° C. This was followed by the addition of a solution of oxirane (5.6 mL, 113.51 mmol) in THF (4 mL) at −78° C. The reaction mixture was then brought to room temperature and stirred for 3 h. The reaction was quenched with 10 mL of NH4Cl (sat.) and the aqueous phase was extracted with 3×50 mL of EtOAc. The combined organic layers were dried over Na2SO4. The solvent was removed to give the crude product which was purified by silica gel chromatography with hexanes/EtOAc (3:1) as the eluent to furnish 636 mg (44%) of the title compound as light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[C:4](=[O:13])[C:5](=[O:12])[NH:6]2.[OH2:14]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[Cl:1][C:2]1[C:3]2[C:4](=[O:13])[O:12][C:5](=[O:14])[NH:6][C:7]=2[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2c(=O)o1

Procedure:
To a suspension of 4,6-dichloroindolin-2,3-dione (5.95 g) in acetic acid (95 ml) was added chromium trioxide (16 g) over a period of 15 minutes at 60° C. with stirring and the mixture was stirred at 70°-75° C. for 1 hour. After cooling, the reaction mixture was poured into water (360 ml) and the resulting precipitates were collected by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent gave a residue, which was combined with the precipitates. Recrystallization from isopropyl ether gave 5,7-dichloro-2H-3,1-benzoxazine-2,4(1H)-dione (2.85 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1cccc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Reactant: CN
Solvent: CCO
Product: CNc1cc2ncnc(Nc3cccc(C)c3)c2cc1[N+](=O)[O-]

Procedure:
After repetition of the previous steps, a mixture of 7-chloro-4-(3'-methylanilino)-6-nitroquinazoline (10.5 g), an ethanolic solution of methylamine (30% weight/volume; 100 ml) and ethanol (100 ml) was stirred at ambient temperature for 16 hours. The mixture was evaporated to give 7-methylamino-4-(3'-methylanilino)-6-nitroquinazoline which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl.[OH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]([C:32]([O:34][CH3:35])=[O:33])[NH:27][CH2:26][CH2:25]2.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(O)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[OH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]([C:32]([O:34][CH3:35])=[O:33])[N:27]([S:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:9][CH:10]=1)(=[O:16])=[O:15])[CH2:26][CH2:25]2
Reactant: COc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: COC(=O)C1NCCc2cc(O)ccc21
Agent: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(OC)cc2)cc1

Procedure:
4-(4-Methoxyphenoxy)benzenesulfonyl chloride is reacted with methyl 6-hydroxytetra-hydroisoquinoline-1-carboxylate hydrochloride in analogy to the method described in 3B to give the desired sulfonamide.
Reaction SMILES: [K+].[N:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=[O:29]>C1COCC1>[O:29]=[C:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:23]1[CH2:22][O:19][C:18]([C:10]1[NH:11][C:12]2[C:17]([C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20]
Reactant: O=C1CCCCN1CCl
Reactant: O=C([O-])c1[nH]c2ccccc2c1Nc1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(OCN1CCCCC1=O)c1[nH]c2ccccc2c1Nc1ccncc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
Heat at 50° C. a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid potassium salt (1.6 g, 5.49 mmol) in anhydrous THF (30 mL) in an oil bath for 20 min. Add a solution of N-(chloromethyl)-2-piperidone (850 mg, 5.76 mmol) in anhydrous THF (5 mL) dropwise. After 30 min, cool the reaction to ambient temperature. Add water (100 mL), and extract with ethyl acetate (3×100 mL). Combine the organic layers, wash with NaHCO3 (sat), water, brine, dry with MgSO4 and then concentrate. Purify the residue on an ISCO RediSep 35 gram silicagel cartridge, eluting with 5% methanol in ethyl acetate then 20% methanol in ethyl acetate. Combined product containing fractions and, concentrate to give the title compound as a white solid (520 mg, 26%): MS 365 (M+H), TLC (silica gel, MeOH/EtOAc 25:75) Rf=0.18, 1H NMR (DMSO-d6) δ 11.77 (1H, s), 8.46 (1H, s), 8.08 (2H, d, J=5.7 Hz), 7.50 (3H, m), 7.09 (1H, m), 6.58 (2H, d, J=6 Hz), 5.54 (2H, s), 3.27 (2H, br2), 2.23 (2H, brs), 1.66 (4H, brs). 13C NMR (DMSO-d6) δ 170.00, 160.43, 152.25, 149.44, 135.54, 125.60, 122.96, 121.84, 120.22, 119.87, 118.99, 113.00, 108.59, 70.99, 47.00, 31.99, 22.39, 20.60.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.ClCCl>[Br:17][CH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1
Reactant: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Temperature: 100 °C

Procedure:
A mixture of ethyl 6-methyl-2-(trifluoromethyl)pyrimidine-4-carboxylate (1.1 g, 4.5 mmol, prepared as described in WO 2007/090748), N-bromosuccinimide (2.86 g, 16.1 mmol) and benzoyl peroxide (0.21 g, 0.9 mmol) in carbon tetrachloride (9 mL) was heated in a sealed vessel to 100° C. overnight. The mixture was diluted with dichloromethane (DCM), filtered and the solvent was removed in vacuo. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded the product, which on removal of solvent, was an oil.
Reaction SMILES: [C:1](OC(N1CCN(CC(C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)CC1)=O)(C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:47][CH:46]=2)[CH2:38][N:39]2[CH2:44][CH2:43]N[CH2:41][CH2:40]2)=[CH:33][CH:32]=1.C(N1CCNCC1)(OC(C)(C)C)=O>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:52]=[N:53][NH:54][CH:55]=3)=[CH:47][CH:46]=2)[CH2:38][N:39]2[CH2:40][CH2:41][CH2:1][CH2:43][CH2:44]2)=[CH:33][CH:32]=1
Reactant: Clc1ccc(C(CN2CCNCC2)c2ccc(-c3cn[nH]c3)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: Clc1ccc(C(CN2CCCCC2)c2ccc(-c3cn[nH]c3)cc2)cc1

Procedure:
By following the procedure described in Example 33A, 33B and 33D but substituting piperidine for N-BOC-piperazine, the title compound was obtained. LC/MS: (PS-A2) Rt 2.21 [M+H]+ 366.09. 1H NMR (Me-d3-OD) δ 1.44 (2H, m), 1.53 (4H, m), 2.39-2.57 (4H, m), 2.94-3.09 (2H, m), 4.26 (1H, t), 7.22-7.35 (6H, m), 7.50 (2H, d), 7.91 (2H, s).