Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][CH:13]([OH:24])[CH2:14][S:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].CO.[OH-].[Na+]>O>[OH:1][CH:2]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[O:11][CH2:12][CH:13]([OH:24])[CH2:14][S:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC(O)c1cccc(OCC(O)CSCCCC(=O)OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCC(O)c1cccc(OCC(O)CSCCCC(=O)O)c1

Procedure:
10.0 g. Ethyl S-[3-(3-{1-hydroxyhexyl}-phenoxy)-2-hydroxypropyl]-4-mercaptobutyrate are stirred for 2 hours at 50° C. with 50 ml. methanol and 50 ml. 2M aqueous sodium hydroxide solution. The solvent is subsequently stripped off and the residue is taken up in water and extracted three times with ethyl acetate. The aqueous phase is acidified with 2M hydrochloric acid and extracted three times with ethyl acetate. The organic phase is washed natural, dried and evaporated. There are obtained 7.4 g. (80% of theory) of the title compound in the form of an oil.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4[S:33]([CH3:32])(=[O:35])=[O:34])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:31])[NH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1S(C)(=O)=O
Yield: 58.3 %

Procedure:
Using an analogous procedure to that described for the preparation of Example 22, 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (150 mg, 0.36 mmol), (prepared as described for the starting material in Example 12), was reacted with methanesulphonyl chloride (33 μl, 0.43 mmol). The product was purified by column chromatography, eluting with methanol/methylene chloride (2/98) to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-([(2S)-1-(methylsulfonyl)pyrrolidin-2-yl]methoxy)quinazoline (105 mg, 59%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([NH2:10])[C:4]=1[NH2:11].CO[C:14]1C(OC)=C[C:17]2[NH:18][C:19](CCCNC)=N[C:16]=2[CH:15]=1>>[CH3:1][O:2][C:3]1[C:4]2[NH:11][C:14]([CH2:15][CH2:16][CH2:17][NH:18][CH3:19])=[N:10][C:5]=2[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: COc1ccc(C)c(N)c1N
Product: CNCCCc1nc2c(C)ccc(OC)c2[nH]1

Procedure:
Prepared from 3-methoxy-6-methyl-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+:17]>CO>[NH2:17][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)c1ccccc1
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C=C(N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of 40.00 g (0.2245 mol) of methyl benzoylacetate in 400 ml of methanol, 70.30 g (1.115 mol) of ammonium formate was added and the mixture was refluxed for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was distilled away under reduced pressure. To the residue, 200 ml of ethyl acetate and 150 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layer and the extract were combined, washed with water and a brine successively and dried with sodium sulfate. The solvent was removed under reduced pressure, and the residue was then distilled to give the objective methyl 3-amino-3-phenylacrylate (32.44 g, a colorless oil). The yield was 81.6%.
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:19][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[C:24]([CH2:28][C:29](O)=[O:30])[CH:25]=[CH:26][CH:27]=1.O.N1(O)C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]=[C:2]([C:4]1[N:5]=[CH:6][C:7]([O:10][C@H:11]2[CH2:19][N:14]3[CH2:15][CH2:16][N:17]([C:29](=[O:30])[CH2:28][C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:32])([F:20])[F:33])[CH:23]=4)[CH2:18][C@@H:13]3[CH2:12]2)=[N:8][CH:9]=1)[CH3:3]
Reactant: C=C(C)c1cnc(O[C@@H]2C[C@H]3CNCCN3C2)cn1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C=C(C)c1cnc(O[C@@H]2C[C@H]3CN(C(=O)Cc4cccc(C(F)(F)F)c4)CCN3C2)cn1
Reaction time: 0.08 h
Yield: 57.7 %

Procedure:
The product from Example 152C (102 mg, 0.392 mmol) was dissolved in dichloromethane (1 mL) followed by addition of 3-trifluoromethylphenylacetic acid (88 mg, 0.431 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (66.0 mg, 0.431 mmol). The mixture was stirred for 5 minutes and then N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (76 μL, 0.431 mmol) was added. After stirring for 18 hours at ambient temperature, the mixture was partitioned between water and dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on a 24 g silica gel column, eluting with 2.5% methanol (containing 2 N ammonia) in dichloromethane for 3 minutes and then a gradient to 10% methanol (2 N ammonia) in dichloromethane to afford the title compound as a viscous colorless oil (101 mg, 57.7%). 1H NMR (300 MHz, CDCl3) δ ppm 1.76-2.15 (m, 2H), 2.18 (s, 3H), 2.19-2.37 (m, 2H), 2.37-2.53 (m, 1H), 2.69-2.91 (m, 1H), 2.91-3.05 (m, 1H), 3.14-3.29 (m, 1H), 3.65-3.78 (m, 1H), 3.80 (d, J=3.3 Hz, 2H), 3.93 (dd, J=12.5, 2.0 Hz, 1H), 4.64 (ddd, J=10.3, 5.9, 4.5 Hz, 1H), 4.74-4.83 (m, 1H), 5.23 (d, J=1.4 Hz, 1H), 5.39 (tdd, J=7.2, 5.2, 1.9 Hz, 1H), 5.80 (s, 1H), 7.49 (ddd, J=16.3, 4.6, 2.8 Hz, 3H), 8.14 (t, J=1.4 Hz, 1H), 8.18-8.23 (m, 1H); MS (ESI) m/z 447 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31]>>[Cl:24][C:25]1[CH:26]=[C:27]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccc(Cl)c(Cl)c4)c(C(=O)O)s3)c2cc1OC
Yield: 35.3 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-dichlorophenylboronic acid (28.6 mg, 0.15 mmol) gave 4-(3,4-Dichloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (15.9 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.81 (br.s., 1 H); 8.85 (s, 1 H); 8.25 (d, 1 H); 7.97 (dd, 1 H); 7.81 (s, 1 H); 7.79 (d, 1 H); 7.39 (s, 1 H); 3.85 (s, 3 H); 3.87 (s, 3 H). MS m/z 450 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:10].C(C1C=C(C=C(C)C=1O)[C:16]#[N:17])C>>[OH:1][C:2]1[C:3]([CH3:10])=[CH:4][C:5]([C:16]#[N:17])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cccc(C)c1O
Reactant: CCc1cc(C#N)cc(C)c1O
Product: COc1cc(C#N)cc(C)c1O

Procedure:
The title compound is prepared from commercially available 2-hydroxy-3-methoxy-toluene in analogy to literature procedures (see 3-ethyl-4-hydroxy-5-methyl-benzonitrile). LC-MS: tR=0.84 min. 1H NMR (CDCl3): δ 2.27 (s, 3H), 3.93 (s, 3H), 6.24 (s, 1H), 6.97 (d, J=1.3 Hz, 1H), 7.12 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[CH:13][N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12.C([Li])CCC.CN(C)[CH:25]=[O:26]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:12]=[C:13]([CH:25]=[O:26])[N:14]([CH2:16][CH3:17])[CH:15]=3)[S:10][C:3]=12
Reactant: CCn1cnc(-c2cc3nccc(Cl)c3s2)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1cc(-c2cc3nccc(Cl)c3s2)nc1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.1 %

Procedure:
To a solution of 7-chloro-2-(1-ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (13, scheme 4) (1.50 g, 5.69 mmol) in tetrahydrofuran at −78° C. (1.3 mL) was added n-Butyllithium (3.4 mL, 8.53 mmol) and the reaction mixture was stirred for about 15 minutes. Dimethylformamide (0.66 mL, 8.53 mmol) was added slowly and the reaction mixture was stirred at −78° C. until completion of the reaction. The mixture was warmed to room temperature and quenched with water. The precipitate was removed by filteration, washed with water and dried well. The crude product was purified by trituration with dichloromethane, filtered, washed with additional dichloromethane and dried to afford the title compound 111 as a yellow solid (682 mg, 41% yield). MS (m/z): 291.9 (M+H).
Reaction SMILES: ClCCCC([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=O.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>>[CH3:18][C:19]1[N:23]2[CH2:9][CH2:8][CH:7]=[C:12]([C:11]3[CH:12]=[CH:7][C:8]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:9][CH:10]=3)[C:22]2=[CH:21][N:20]=1
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)CCCCl
Reactant: Cc1ncc[nH]1
Product: Cc1ncc2n1CCC=C2c1ccc(NS(C)(=O)=O)cc1

Procedure:
Combine 100 g (0.36 mol) of N-[(4-chloro-1-oxobutyl)phenyl]methanesulfonamide with 400 g (4.88 mol) of 2-methylimidazole and heat to 175° C. for 22 hr under argon. Crystallization from methylene chloride provides the title compound.
Reaction SMILES: Br[CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1.[F:8][C:9]([F:29])([C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][OH:12].[H-].[Na+]>CN(C)C=O>[F:8][C:9]([F:29])([C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][O:12][CH2:2][C:3]1([CH3:7])[CH2:6][O:5][CH2:4]1
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC1(CBr)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)COC1
Yield: 66 %

Procedure:
In a manner similar to that described above, 12.0 grams of 3-bromomethyl-3-methyloxetane (73 mmol) was reacted with 26.5 grams of 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol (72.7 mmol) in 300 milliliters of dimethylformamide in the presence of 3.9 grams of a 50 weight percent dispersion of sodium hydride (81 mmol) in mineral oil at 85° C. for 24 hours to give 21.5 grams (70% yield) of 3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyloxymethyl)-3-methyloxetane, a colorless oil with a boiling point of 66-68° C./2-2.5 mm-Hg; 1H NMR (CDCl3) δ 4.50 and 4.36 (AB, J=5.5 Hz, 4 H), 3.78 (t, J=6.6 Hz, 2 H), 3.53 (s, 2 H), 2.42 (triplet of triplets, J=6.6 and 18 Hz, 2 H), and 1.31 (s, 3 H); 13C NMR (CDCl3) δ 79.89, 78.30, 63.31, 39.9, 31.64 (t), and 21.1 (signals due to carbons bearing fluorines are not included due to the complex splitting patterns and low peak intensities); 19F NMR δ −81.4 (3 F), −113.8 (2 F), −118.2 (2 F), −112.3 (2 F), −124.1 (2 F) and −126.7 (2 F). The elemental analysis was: Calculated for C13H13F13O2: C, 34.8; H, 2.9; F, 55.1. Found: C, 35.1; H, 3.0; F, 54.7.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:32][CH:33]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(C(C)=O)cn2)cc1
Yield: 35.3 %

Procedure:
A mixture of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (1.05 g; 2.57 mmol), 2-chloro-5-acetyl-pyridine (0.40 g; 2.57 mmol) and DIEA (0.36 g; 2.83 mmol) was heated in a pressure tube at 180C for 5 hr. Upon cooling, the residue was chromatographed using 20% ethyl acetate-hexane mixtures to afford ethyl 2-[4-(2-{(5-acetylpyridin-2-yl)[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (0.48 g; 35% yield).
Reaction SMILES: CN([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[O:8][C:7]([CH3:13])([CH3:12])[C:6]1=O)C.C(O)(=O)C.[NH2:19][C:20]([NH2:22])=[NH:21].C[O-].[Na+]>C(O)C>[CH3:10][C:9]1([CH3:11])[C:5]2[CH:4]=[N:19][C:20]([NH2:22])=[N:21][C:6]=2[C:7]([CH3:13])([CH3:12])[O:8]1
Reactant: N=C(N)N
Reactant: CN(C)C=C1C(=O)C(C)(C)OC1(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)OC(C)(C)c2nc(N)ncc21
Temperature: 100 °C
Yield: 67.3 %

Procedure:
To a solution of 4-dimethylaminomethylene-2,2,5,5-tetramethyl-dihydro-furan-3-one (1.97 g, 10.0 mmol, 1.0 equiv) and guanidine acetate (1.19 g, 10.0 mmol, 1.0 equiv) in ethanol (40 mL) was added sodium methylate (0.54 g, 10.0 mmol, 1.0 equiv) and the reaction mixture heated to 100° C. for 3 h. The solvent was removed under reduced pressure and the reaction product purified by crystallization from a mixture of hot heptane/ethyl acetate to yield 1.3 g (67% yield) of the title compound. MS (EI): 193 [M]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[CH3:29])[C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)[CH3:5].Cl.[CH3:31][C:32]1[N:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:33]=1[C:34](O)=[O:35]>>[C:17]([C:16]1[CH:20]=[CH:21][C:13]([N:12]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:28]=2[CH3:29])[CH:9]2[CH2:10][CH2:11][N:6]([CH:4]([CH3:5])[CH2:3][CH2:2][NH:1][C:34](=[O:35])[C:33]3[C:37]([CH3:41])=[CH:38][CH:39]=[N:40][C:32]=3[CH3:31])[CH2:7][CH2:8]2)=[CH:14][CH:15]=1)(=[O:18])[NH2:19]
Reactant: Cc1ccncc1CN(c1ccc(C(N)=O)cc1)C1CCN(C(C)CCN)CC1
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: Cl
Product: Cc1ccncc1CN(c1ccc(C(N)=O)cc1)C1CCN(C(C)CCNC(=O)c2c(C)ccnc2C)CC1
Yield: 84.6 %

Procedure:
Using general procedure E, 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-methyl-pyridin-3-ylmethyl)-amino]-benzamide (see EXAMPLE 355) (21.8 mg, 0.055 mmol) and 2,4-dimethylnicotinic acid hydrochloride (15 mg, 0.080 mmol) gave COMPOUND 366 as an off-white solid (24.6 mg, 84%). 1H NMR (CDCl3) δ 1.03 (d, 3H, J=6.6 Hz), 1.09-1.38 (m, 2H), 1.53-1.63 (m, 1H), 1.72-1.90 (m, 3H), 2.24 (t, 1H, J=11.0 Hz), 2.29 (s, 3H), 2.39 (s, 3H), 2.53 (s, 3H), 2.59 (t, 1H, J=11.0 Hz), 2.74-2.93 (m, 3H), 3.31-3.42 (m, 1H), 3.71-3.84 (m, 2H), 4.12 (s, 2H), 5.64 (br s, 2H), 6.53 (d, 2H, J=8.9 Hz), 6.84 (d, 1H, J=5.0 Hz), 7.12 (d, 1H, J=4.9 Hz), 7.61 (d, 2H, J=8.9 Hz), 7.65 (br s, 1H), 8.18 (s, 1H), 8.18 (d, 1H, J=5.0 Hz), 8.37 (d, 1H, J=4.9 Hz). 13C NMR (CDCl3) δ 13.44, 18.65, 18.72, 22.26, 29.28, 30.17, 31.72, 39.11, 44.05, 44.86, 51.61, 56.13, 59.29, 112.07, 121.24, 122.44, 125.08, 129.13, 131.84, 133.50, 143.83, 144.19, 147.41, 148.19, 148.63, 150.95, 154.03, 168.20, 169.02. ESI-MS m/z 529 (MH)+. Anal. Calcd. for C31H40N6O2.0.6CH2Cl2: C, 65.48; H, 7.16; N, 14.50. Found: C, 65.26; H, 7.46; N, 14.25.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[S:4][N:3]=1.Cl[C:15]1[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[N:16]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C:17]2[N:16]=[C:15]([NH:13][CH:10]3[CH2:9][CH2:8][N:7]([C:5]4[S:4][N:3]=[C:2]([CH3:1])[N:6]=4)[CH2:12][CH2:11]3)[N:20]=[C:19]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Product: Cc1nsc(N2CCC(Nc3nc(Cc4ccc(Cl)cc4)cc(C(C)(C)O)n3)CC2)n1
Yield: 36.3 %

Procedure:
In analogy to example 29, 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine (65 mg, 0.33 mmol) was reacted with 2-[2-chloro-6-(4-chloro-benzyl)-pyrimidin-4-yl]-propan-2-ol (98 mg, 0.33 mmol) to give the title compound (55 mg, 36%) as yellow foam.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[N:32]=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:29]3[C:38]4[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=4)[N:32]=[CH:31][N:30]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:12])[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cc(O)ccc2F)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC
Temperature: 35 °C
Reaction time: 15 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-hydroxyphenyl)urea (217 mg, 0.59 mmol) and 4-chloro-6,7-dimethoxyquinazoline (132 mg, 0.59 mmol) in DMF (4 mL) at rt, was added potassium carbonate (163 mg, 1.18 mmol). The reaction mixture was stirred at 35° C. for 15 h. The mixture was poured into water, and the resulting brown solid was filtrated, washed with water, and dried to afford the crude product. Purification via reverse-phase preparative HPLC afforded 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (19 mg, 6%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (brs, 1H), 8.89 (brs, 1H), 8.57 (s, 1H), 8.16 (m, 1H), 7.53-7.59 (m, 5H), 7.37-7.46 (m, 3H), 7.15 (m, 1H), 6.43 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 557 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[N:19]=[C:20]=S.[NH2:22][C:23]1[CH:24]=[C:25]([CH:36]=[CH:37][C:38]=1[NH:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:27].CC(C)N=C=NC(C)C>CN(C=O)C>[Br:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:25]2[CH:36]=[CH:37][C:38]3[N:39]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:20]([NH:19][C:3]4[CH:4]=[C:5]([CH2:6][NH:7][C:8]([C:10]5([C:13]([F:16])([F:15])[F:14])[CH2:12][CH2:11]5)=[O:9])[CH:17]=[CH:18][C:2]=4[Cl:1])=[N:22][C:23]=3[CH:24]=2)=[O:27])=[CH:30][CH:31]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: CN(C)CCNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(C)CCn1c(Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)ccc21

Procedure:
The title compound was prepared in accordance with the procedure in Example 72, step (a) using N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide ((222 mg; 0.66 mmol) see Example 59, step (c)), 3-amino-N-(4-bromophenyl)-4-(2-(dimethylamino)ethylamino)benzamide (250 mg; 0.66 mmol), DIC (83 mg; 0.66 mmol) and DMF (4 mL). Yield: 151 mg (34%). 400 MHz 1H-NMR (DMSO-d6, ppm) 10.37 (1H, s) 10.22 (1H, s) 8.39 (1H, t, J=5.8 Hz) 8.10 (1H, d, J=1.8 Hz) 8.06 (1H, d, J=1.6 Hz) 7.82-7.71 (3H, m) 7.53-7.46 (3H, m) 7.40 (1H, d, J=8.2 Hz) 6.86 (1H, dd, J=8.2, 1.8 Hz) 4.32-4.21 (4H, m) 2.74-2.68 (2H, m) 2.29 (6H, s) 1.37-1.32 (2H, m) 1.23-1.19 (2H, m).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([O:13][CH2:14][CH3:15])(=[O:12])[C:7]([O:9]CC)=O.Cl>C(OCC)C>[O:9]=[C:7]([CH:1]([CH3:3])[CH3:2])[C:6]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)[Mg]Cl
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C)C
Temperature: -70 °C

Procedure:
Isopropylmagnesium chloride (2.0M in ether, 200 mmol) was added to a solution of diethyl oxalate (29.23 g, 20.0 mmol) in dry diethyl ether (100 ml) at −70° C. over a period of one hour. The mixture was stirred at −70° C. for a further half an hour and then poured immediately into a vigorously stirred suspension of ice (80 g), diethyl ether (100 ml) and concentrated HCl (18 ml). The aqueous phase was separated out and the organic phase washed with water (100 ml) and then dried (MgSO4) and the solvent was removed in order to leave the desired product in the form of a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:7][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: O=S1(=O)CCCO1
Reactant: COc1ccc(CN)cc1OC
Solvent: CC(C)=O
Product: COc1ccc(CNCCCS(=O)(=O)O)cc1OC
Temperature: 25 °C
Yield: 42.4 %

Procedure:
To a solution of 3,4-dimethoxybenzylamine (2.2 mL, 15.0 mmol) in acetone (20 mL) was added 1,3-propane sultone (1.97 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid material was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The crude product was suspended in 90% acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec., the solid material was collected by filtration, and dried in vacuo. Compound S (1.84 g, 43%) was isolated as a white solid. 1H NMR (D2O, 500 MHz) δ ppm 6.96 (m, 3H), 4.06 (s, 2H), 3.74 (s, 6H), 3.07 (t, 1H, J=7.8 Hz), 2.86 (t, 1H, J=7.8 Hz), 2.01 (m, 2H). 13C NMR (D2O, 125 MHz) δ ppm 149.23, 148.50, 123.63, 123.37, 55.90, 55.86, 50.96, 48.06, 45.62, 21.39. ES-MS 290 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:22][CH:23]([OH:25])[CH3:24])=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[NH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].N1C=CN=C1.[C:31]([Si:35]([CH3:38])([CH3:37])Cl)([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[F:1][C:2]1[C:3]([CH2:22][CH:23]([O:25][Si:35]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:38])[CH3:37])[CH3:24])=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[NH:5][CH:6]=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1CC(C)O)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1CC(C)O[Si](C)(C)C(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
14.2 g (40 mmol) of the compound (151) and 3.27 g (48 mmol) of imidazole were added to 100 ml of methylene chloride, and 20 ml of methylene chloride containing 7.23 g (48 mmol) of t-butyldimethylchlorosilane was dropped to the solution through 30 minutes. After the solution was stirred for 2.5 hours at room temperature, it was heated at reflux for 2 hours. 3.27 g of imidazole and 7.23 g of t-butyldimethylchlorosilane were supplemented to the solution, and the solution was heated at reflux for 11 hours. The solution was washed 100 ml of water, 50 ml of aqueous citric acid solution and 50 ml of saturated aqueous sodium hydrogen carbonate solution in this order, and after drying over magnesium sulfate, the solvent was removed by distillation. The solid matter was separated by column chromatography (silica gel 600 g, eluent solvent; chloroform:n-hexane=1:1) to obtain 14.2 g of an oily subject compound (152) in a 76% yield.