Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C>C(O)CO>[N:32]1[CH:33]=[CH:34][N:35]=[CH:36][C:31]=1[N:23]1[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]2[CH:26]=[CH:27][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)[CH2:21][CH2:22]1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: Clc1cnccn1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(c2cnccn2)CC1
Yield: 38.5 %

Procedure:
A mixture of 2.00 g (0.005 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine [U.S. Pat. No. 4,025,629] 0.57 g (0.005 mol) of 2-chloropyrazine, and 0.505 g (0.005 mol) of triethylamine is heated in 20 ml of ethylene glycol at 75° C. for 24 hours and at 95° C. for 24 hours. The mixture is partitioned with 1 N toluenesulfonic acid in water and methylene chloride. The aqueous phase is made basic and extracted with methylene chloride. The organic phase is dried with anhydrous sodium sulfate and concentrated. The residue is chromatographed (4% methanol/1/2% ammonium hydroxide/methylene chloride) to yield 0.92 g (38%) of 1-(2-pyrazinyl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine. This is re-crystallized from methylene chloride to give 0.48 g of the pure product of melting point 260°-261° C. The IR spectrum is consistent with the named structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[H-].[K+].[CH2:22]1OCCOCCOCCOCCOCCO[CH2:23]1.ICC>C1COCC1>[CH2:22]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:10]=2[CH3:12])[C:6]([CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)=[CH:7]1)[CH3:23]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: COc1cc(C)c2[nH]cc(C3CCN(C)CC3)c2c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCn1cc(C2CCN(C)CC2)c2cc(OC)cc(C)c21
Yield: 704.3 %

Procedure:
By a method similar to Preparation 26, using 5-methoxy-7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole (5.81 mmole, 1.5 g) in THF (100 mL), 35% potassium hydride (5.81 mmole, 0.665 g), 18-crown-6 (0.58 mmole, 0.153 g), and iodoethane (5.81 mmole, 0.906 g, 0.464 mL) afforded 1.17 g (70%) of the title compound: mass spectrum (ion spray): m/z=287 (M+1); Calculated for C18H26N2O-0.1 H2O: C, 75.01; H, 9.16; N, 9.72. Found: C, 75.10; H, 9.01; N, 9.79.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:21][CH2:20][C:19]2[S:22][C:23]([NH:25][C:26](=[O:28])[CH3:27])=[N:24][C:18]=2[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[S:22]1[C:19]2[CH2:20][CH2:21][NH:15][CH2:16][CH2:17][C:18]=2[N:24]=[C:23]1[NH:25][C:26](=[O:28])[CH3:27]
Reactant: CC(=O)Nc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
35 ml trifluoroacetic acid was added to 2.4 g 2-acetylamino-4,5,7,8-tetrahydro-thiazolo[4,5-d]-azepine-6-carboxylic acid tert-butyl ester in 80 mL chloroform. The reaction was stirred 3 h at RT and concentrated. The residue was dissolved in 75 mL chloroform and basified with 2.5 M potassiumcarbonate solution. The chloroform layer was separated and concentrated to give 1.3 g of the desired product., (M+H)+=212
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[NH:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24].[C:28]([Si:30]([CH3:33])([CH3:32])[CH3:31])#[CH:29]>O1CCOCC1.[Cu](I)I.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:19]=[C:14]1[C:13]2[NH:20][CH:21]=[CH:22][C:12]=2[C:11]2[CH:10]=[C:9]([C:29]#[C:28][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:18]=[CH:17][C:16]=2[NH:15]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1[nH]c2ccc(I)cc2c2cc[nH]c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
224 mg (1.2 mmol) of copper iodide, 309 mg (3 mmol) of triethylamine and 165 mg (0.23 mmol) of dichlorobis(triphenylphosphine)-palladium (11) are added to a suspension of 898 mg (2.35 mmol) of 8-iodo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 30 ml of anhydrous dioxan then this mixture is degassed under argon. After 15 minutes, 346 mg (3.52 mmol) of ethynyl-trimethyl-silane is added and the reaction mixture is heated at 100° C. for 3 hours. The raw reaction product is filtered on celite, then the filtrate is evaporated to dryness and the residue is purified on silica (eluent ethyl acetate) to give 400 mg (48%) of 4-oxo-8-trimethylsilanylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a yellow solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCCCC1
Temperature: 60 °C
Yield: 17.1 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea from Example 79A (225 mg, 0.426 mmol) in DMF (3 mL) was added piperidine (0.126 mL, 1.278 mmol) followed by diisopropyl ethylamine (0.222 mL, 1.278 mmol) and tetrabutyl ammonium iodide (157.35 mg, 0.426 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(piperidin-1-yl)ethoxy)quinazolin-4-ylthio)phenyl)urea (42 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.22 (m, 5H), 6.45 (s, 1H), 4.30 (m, 2H), 3.95 (s, 3H), 2.85-2.30 (m, 6H), 1.70-1.30 (m, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33](Cl)[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:19]3[C:27]4[C:22](=[CH:23][C:24]([O:28][C:29]5[CH:34]=[C:33]([N:36]=[N+:37]=[N-:38])[N:32]=[CH:31][N:30]=5)=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(Cl)ncn5)ccc43)cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(Cc2ccc(NC(=O)N3CCc4cc(Oc5cc(N=[N+]=[N-])ncn5)ccc43)cc2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of 218 mg (0.44 mMol) 5-(6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole-1-carboxylic acid [4-(4-ethyl-piperazin-1-ylmethyl)-phenyl]-amide in 2.5 ml DMF, 57 mg (0.88 mMol) NaN3 are added at rt. After 2.5 h at 68° C., the resulting red solution is poured into water and extracted three times with EtOAc. The organic layers are washed twice with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: MS: [M+1]+=500; HPLC: AtRet=10.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](O)=[C:23]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[CH:30]=3)[C:24](=[O:28])[NH:25]2)=[CH:20][C:19]=1[N+:38]([O-:40])=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:22]1[C:21]2[C:26](=[CH:27][C:18]([Cl:17])=[C:19]([N+:38]([O-:40])=[O:39])[CH:20]=2)[NH:25][C:24](=[O:28])[C:23]=1[C:29]1[CH:30]=[C:31]([CH3:36])[CH:32]=[C:33]([CH3:35])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCO
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 74.5 %

Procedure:
To a solution of 2-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.864 g in 38 mL dry tetrahydrofuran) was added 1.56 g of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro- 1H-quinolin-2-one followed by 1.19 g of triphenylphosphine and the mixture stirred at room temperature. To this was added 0.72 mL of diethyl azodicarboxylate (DEAD) and stirring was continued for 64 hours. At this time the solvents were removed in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 6:4) to give the title compound (1.56 g).
Reaction SMILES: OC(C(F)(F)F)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH2:27])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([NH:35][CH2:36][C:37](O)=[O:38])=[O:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:26][CH:25]([NH:27][C:37]([CH2:36][NH:35][C:33](=[O:34])[C:32]5[CH:40]=[CH:41][CH:42]=[C:30]([C:29]([F:44])([F:28])[F:43])[CH:31]=5)=[O:38])[CH2:24]4)[CH2:19][CH:18]=3)=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CC=C(c3ccc4c(c3)OCO4)CC2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1-(4-benzo[1,3]dioxol-5-yl-cyclohex-3-enyl)-azetidin-3-ylamine TFA salt (as prepared in the previous step, 550 mg, 1.10 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet, 272 mg, 1.10 mmol) in DCM (10 mL) was treated with TEA (770 μL, 5.5 mmol) at room temperature. The mixture was treated with EDCI (Aldrich, 252 mg, 1.32 mmol), HOBT (Aldrich 149 mg, 1.10 mmol), and the reaction was stirred at room temperature for additional 6 hours. The reaction was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.[CH2:19]([OH:22])[CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][O:22][CH2:2][C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1
Reactant: OCCO
Reactant: O=C1c2ccccc2C(=O)c2cc(CCl)ccc21
Product: O=C1c2ccccc2C(=O)c2cc(COCCO)ccc21
Yield: 80.92 %

Procedure:
10 g (0.039 mol) of 2-chloromethylanthraquinone (prepared in accordance with the instructions of G. Izoret, Ann. Chim. 7, 151 (1962)) in 200 ml of ethylene glycol are refluxed for 3 hours, with stirring and with exclusion of moisture. The product which has crystallised out on cooling is washed with water and recrystallised from ethanol. 8.9 g (80.92% of theory) of 2-(2-hydroxyethoxymethyl)anthraquinone are obtained. 8 g (0.03 mol) of 2-(2-hydroxyethoxymethyl)-anthraquinone are dissolved in 180 ml of tetrahydrofuran, 4.34 ml (0.05 mol) of triethylamine are added and the mixture is cooled to 5° C. 3 ml (0.03 mol) of methacryloyl chloride in 10 ml of tetrahydrofuran are then added dropwise, with stirring and under an inert gas, such that the temperature does not exceed 5° C. When the dropwise addition has ended, stirring is continued at room temperature for 5 hours. The solvent is then stripped off on a rotary evaporator and the solid product is washed several times with 1% citric acid and water and dried in vacuo. 7.76 g of (2-anthraquinonyl)-7-oxa-4-oxa-3-oxo-2-methyloct-1-ene are obtained, and 7.48 g (71.17% of theory) after recrystallisation from ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[NH:30][CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2].[CH:37](=O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:35])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:29][C@@H:28]3[CH3:34])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)NC[C@@H]3C)c2)CC1
Reactant: O=Cc1ccccc1
Product: CCOC(=O)CN1CCN(C(=O)c2cccc([C@H](c3cccc(O)c3)N3C[C@@H](C)N(Cc4ccccc4)C[C@@H]3C)c2)CC1
Yield: 34.4 %

Procedure:
The title compound was made by a procedure identical to that of Example 66 with 1.50 g of (4-{3-[(R)-((2S,5R)-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperazin-1-yl)-acetic acid ethyl ester (3.03 mmol) and 0.64 g of benzaldehyde (6.07 mmol) to give 0.61 g (34%) of the desired compound as a light yellow solid. 1H NMR (300 MHz, d6-DMSO): □ 1.00-1.02 (d, J=4.7 Hz, 6H); 1.15-1.19 (t, 3H), 1.87-2.00 (m, 2H); 2.48-2.65 (m, 8H); 3.25 (s, 2H); 3.36-3.57 (m, 5H); 3.73-3.77 (dd, 1H); 4.03-4.10 (q, 2H); 4.96 (s, 1H); 6.62-6.69 (m, 3H); 7.08-7.42 (m, 10H); 9.35 (s, 1H). Calculated for C35H44N4O4.0.16 CH2Cl2: C, 70.58; H, 7.47; N, 9.36. Found: C, 70.57; H, 7.52; N, 9.39.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1.COC1C=CC(C[NH:34][C:35]2[N:36]=[CH:37][S:38][CH:39]=2)=CC=1.CN1C=CN=C1.C(O)(C(F)(F)F)=O>CC#N>[F:1][CH:2]([F:26])[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:34][C:35]4[N:36]=[CH:37][S:38][CH:39]=4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Reactant: COc1ccc(CNc2cscn2)cc1
Agent: Cn1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(C(F)F)c(F)cc1-c1ncnc2cc(S(=O)(=O)Nc3cscn3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
A solution of 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)quinazoline-7-sulfonyl chloride (0.300 g, 0.745 mmol) and N-(4-methoxybenzyl)thiazol-4-amine (Intermediate PPPPP; 0.492 g, 2.234 mmol) in 6 mL MeCN was placed under argon and was treated with 1-methylimidazole (0.073 ml, 0.745 mmol). After stirring for 3 hours at room temperature, LC/MS showed mostly product, so the reaction mixture was concentrated. The crude residue was dissolved in TFA (2.295 ml, 29.8 mmol) and was heated to 100° C. for 2 hours. LC/MS showed mostly product, so the reaction mixture was concentrated. Purification of the crude residue by reverse phase column chromatography [Puriflash C18 30μ, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 4-(4-(difluoromethyl)-5-fluoro-2-methoxyphenyl)-N-(thiazol-4-yl)quinazoline-7-sulfonamide (0.141 g, 0.302 mmol, 40.6% yield). 1H NMR (MeCN-d3) δ: 9.43 (s, 1H), 8.61 (s, 1H), 8.51 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.79-7.86 (m, 1H), 7.37 (d, J=5.4 Hz, 1H), 7.32 (d, J=9.9 Hz, 1H), 6.92-7.25 (m, 2H), 3.71 (s, 3H). (M+H)+=467.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[C:27]([NH2:45])=[CH:28][C:29]2[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH2:32][CH2:31][C:30]=2[CH:44]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:45][C:27]2[C:26]([O:25][CH3:24])=[CH:44][C:30]3[CH2:31][CH2:32][N:33]([CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[CH2:34][CH2:35][C:29]=3[CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCN1CCOCC1)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CCN1CCOCC1)CC2
Yield: 22 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 8-Methoxy-3-(2-morpholin-4-yl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamine. Product isolated as an off-white foam (23 mg, 22%). MS (ESI+): 624 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.29 (d, J=9 Hz, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 6.65 (s, 1H), 6.57 (s, 1H), 6.53 (d, J=9 Hz, 1H), 3.94 (s, 4H), 3.91 (m, 2H), 3.88 (s, 4H), 3.73 (t, J=5 Hz, 4H), 3.17 (t, J=4 Hz, 4H), 2.88 (m, 4H), 2.70 (m, 6H), 2.56-2.51 (m, 6H).
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.N1C=CC=CC=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=CC(O)OC1
Solvent: c1ccncc1
Product: CC(=O)OC1C=CC(=O)CO1
Temperature: 0 °C

Procedure:
24.0 g of 6-hydroxy-2H-pyran-3(6H)-one was dissolved in 80 ml of acetic anhydride. After cooling the solution to 0° C., 30 ml of pyridine was dropwise added thereto.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Si](N=C=S)(N=C=S)(N=C=S)[N:18]=[C:19]=[S:20].Cl>C1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:19](=[S:20])[NH2:18])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: S=C=N[Si](N=C=S)(N=C=S)N=C=S
Reactant: Cc1cnc2c(c1)CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (1.43 g, 0.01 mole) in benzene (20 ml) was treated with n-butyl-lithium (15% w/w, 4.5 ml, 0.01 mole) and the solution was allowed to stand at room temperature for 0.5 h. The solution was then treated with a suspension of silicon tetraisothiocyanate (1.3 g, 0.005 mole) in benzene (5 ml) at 0° C. After 10 min., water (50 ml) was added and the mixture was stirred for 0.5 h at room temperature and then acidified with conc. HCl. The aqueous layer was separated, washed with ethyl acetate and the pH was adjusted to 10 with solid Na2CO3. The basic mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with n-hexane to give 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.2 g, 10%).
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[I:16]CI.N(OCCC(C)C)=O>C(#N)C.CCCCCC>[C:7]([C:6]1[C:2]([I:16])=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:4][C:5]=1[S:9][CH3:10])#[N:8]
Reactant: ICI
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1N
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCCCCC
Product: CCOC(=O)c1sc(SC)c(C#N)c1I
Temperature: 40 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (10 g, 41.3 mmol) was dissolved in acetonitrile (50 mL) under an atmosphere of argon. Diiodomethane (11.6 mL, 0.144 mol) was added and the mixture was heated at 40° C. Isoamyl nitrite (12.1 g, 0.103 mol) was added and the reaction was allowed to cool to room temperature and stirred for 2 hours. Mixture was cooled down at 0° C., diluted with hexane (50 mL) and the precipitate was filtered off, washed with 10:1 hexane-acetonitrile mixture (10 mL), 3:1 hexane-ether (10 mL) and hexane (10 mL). The precipitate was dried to afford ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (6.90 g, 45%). LCMS: (FA) ES+ 354. 1H NMR (400 MHz, d1-chloroform) δ: 4.38 (q, 2H), 2.70 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3F)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[O:28]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30][CH2:29]1.Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3[O:34][CH:31]2[CH2:32][CH2:33][O:28][CH2:29][CH2:30]2)=[O:11])=[CH:4][CH:3]=1
Reactant: OC1CCOCC1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(OC3CCOCC3)c(F)c(F)cc2c1O
Temperature: 140 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example No. 15 and sodium hydride (60% dispersion, 40 mg) are dissolved in DMF (10 mL) and to the mixture is added tetrahydro-2H-pyran-4-ol (114 μL). Additional sodium hydride (60 mg) is added and the mixture is heated at 140° C. for 1 h. The reaction mixture is allowed to cool to rt, poured into water (30 mL), acidified with 1 N hydrochloric acid (20 mL), and extracted with ethyl acetate (3×25 mL). The organic layer is washed with brine (10 mL), dried (MgSO4), and concentrated. The resulting solid is triturated with heptane (10 mL) and filtered to afford 153 mg of the title compound as a white solid.