Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C(N(CC)CC)C.C[Si](C)(C)Cl>CS(C)=O>[C:21]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:24])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C:26]4[N:35]=[C:34]5[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]5[CH:36]5[CH2:38][CH2:37]5)=[CH:28][C:27]=4[F:43])[CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N[C@@H]3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
A suspension of 119 mg N-{(5S)-3-[3-fluoro-4-(pyrrolidin-3-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.35 mmol), 100 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 148 μl triethylamine (, 1.05 mmol) and 89 μl trimethylchlorosilane (0.70 mmol) in 2 ml DMSO was stirred in a microwave oven at 150° C. for 10 min. The DMSO was evaporated, the residue digested in water and the solid filtrated. The solid was purified by chromatography using a 95/5 dichloromethane/methanol mixture.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCN(CC)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
To a solution of 1-ethylpiperazine (1 g, 8.771 mmol, 1.0 eq) in DMF were added K2CO3 (3 g, 21.927 mmol, 2.5 eq.) and ethyl 2-bromoacetate (2.19 g, 13.156 mmol, 1.5 eq.). The mixture was stirred at RT for 16 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to afford the product in 76.4% yield (1.3 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[F:17][C:18]([F:34])([F:33])[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:30](=[O:31])[CH2:29][CH2:28][C:27]#[C:26][C:23]3[CH:24]=[CH:25][C:20]([O:19][C:18]([F:33])([F:34])[F:17])=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: O=C(O)CCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cn1ccc2ccc(N)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)Cn1ccc2ccc(NC(=O)CCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described in example 8 c], (6-amino-indol-1-yl)-acetic acid ethyl ester (WO 2003041714 A1) was reacted with 5-(4-trifluoromethoxy-phenyl)-pent-4-ynoic acid in the presence of 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride and 4-(dimethylamino)pyridine to give the title compound as brown crystals.
Reaction SMILES: Br[C:2]1[CH:13]=[C:12]([O:14][C@@H:15]([C@H:17]2[CH2:21][NH:20][C:19](=[O:22])[CH2:18]2)[CH3:16])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[F:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[N:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1.C1(N2C3C(O[C@@H]([C@@H]4CC(=O)NC4)C)=NC(C4C=CC(N5CCN(C(OC(C)(C)C)=O)CC5)=C(F)C=4)=CC=3N=C2)CC1>>[CH:9]1([N:6]2[C:5]3[C:12]([O:14][C@@H:15]([C@@H:17]4[CH2:18][C:19](=[O:22])[NH:20][CH2:21]4)[CH3:16])=[CH:13][C:2]([C:28]4[CH:27]=[CH:26][C:25]([N:39]5[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:41][CH2:40]5)=[C:24]([F:23])[CH:29]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[CH2:11][CH2:10]1
Reactant: C[C@@H](Oc1cc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Agent: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Product: C[C@@H](Oc1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1

Procedure:
Following the procedure described for intermediate from Step-3 in Example 3.100, starting from combined (R)-4-((R)-1-((5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one (250 mg, 0.69 mmol) and tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (348.59 mg, 0.86 mmol) (B11), 250 mg tert-butyl 4-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-2-fluorophenyl)piperazine-1-carboxylate was synthesized.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C@:8]([CH3:12])([OH:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@@:8]2([CH3:12])[CH2:9][O:10][C:15]([CH3:20])([CH3:16])[O:11]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C[C@@](O)(CO)COc1ccc(Br)cc1
Solvent: CC(C)=O
Product: CC1(C)OC[C@](C)(COc2ccc(Br)cc2)O1
Yield: 1729.3 %

Procedure:
(R)-3-(4-Bromophenoxy)-2-methylpropane-1,2-diol (25 g, 0.1 mol) and p-toluenesulfonic acid (0.91 g, 4.8 mmol) were dissolved in acetone (300 g), followed by stirring under reflux for 5.5 hours. The progress of reaction was monitored by TLC. The generated water was removed by azeotropic distillation with 300 g of solvent under atmospheric pressure, and 300 g of acetone was added during the reaction. After the reaction was completed, the solvent was removed under a reduced pressure and the resulting concentrated residue was dissolved in isopropyl acetate (250 mL). The organic layer thus obtained was washed with a 1 M sodium hydroxide aqueous solution (100 mL). Thereafter, the organic layer was concentrated and dried, obtaining 25 g of (S)-4-(4-bromophenoxy)methyl-2,2,4-trimethyl-1,3-dioxolane (yield: 82%).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:27])([F:26])[F:28])[CH:13]=[N:12]2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Cc2ccccc2C(F)(F)F)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Cc3ccccc3C(F)(F)F)cc2=O)n1
Yield: 61 %

Procedure:
Using the method described in Example 17, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionic acid (Intermediate 63) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethyl-benzyl)-6H-pyridazin-1-yl]-propionamide as an off-white solid (77 mg, 61%); ES+-HRMS m/e calcd for C27H32N5O3F3 [M+H+] 532.2530, found 532.2530. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.04 (s, 3H), 1.06 (s, 3H), 1.08 (m, 1H), 1.21-1.74 (m, 8H), 1.90 (m, 1H), 2.26 (m, 1H), 3.88 (s, 2H), 4.09 (s, 2H), 4.66 (s, 1H), 5.46 (dd, J=3.9, J=10.6 Hz, 1H), 6.29-6.42 (m, 2H), 7.38-7.59 (m, 3H), 7.70 (t, J=7.4 Hz, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.92 (d, J=2.1 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=1.CC1C=CC(C(C)C)=CC=1>[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([OH:18])=[CH:13][CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2cc(-c3ccc(O)cc3)ccc21
Agent: [Pd]
Solvent: Cc1ccc(C(C)C)cc1
Product: Oc1ccc(-c2ccc3c(O)cccc3c2)cc1
Yield: 51.9 %

Procedure:
To a 25 mL flask was added 6-(4-hydroxyphenyl)-1-tetralone (500 mg, 2.12 mmol), palladium on carbon (510 mg) and p-cymene (15 mL). The mixture was heated to reflux for 24 h, cooled, filtered through celite and extracted with 1 M NaOH (2×25 mL). The aqueous layer was then acidified, extracted with ether (3×), and passed through a silica plug. Concentration under reduced pressure afforded 260 mg (53%) product as a brown solid: mp above 200° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 6.82 (1H, d, J=7.5 Hz), 6.87 (2H, d, J=8.1 Hz), 7.29 (1H, t, J=7.5 Hz), 7.38 (1H, d, J=7.5 Hz), 7.63 (2H, d, J=8.2 Hz), 7.70 (1H, d, J=8.5 Hz), 7.99 (1H, s) 8.14 (1H, d, J=8.5 Hz), 9.59 (1H, s), 10.09 (1H, s); MS m/z 235 (M−H+).
Reaction SMILES: C([N:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([OH:14])=[O:13])[S:5][C:4]1=[O:15])C.[OH-].[Li+]>C1COCC1.O>[O:15]=[C:4]1[NH:3][C:7]([C:8]([F:11])([F:9])[F:10])=[C:6]([C:12]([OH:14])=[O:13])[S:5]1
Reactant: CCn1c(C(F)(F)F)c(C(=O)O)sc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1sc(=O)[nH]c1C(F)(F)F
Temperature: 50 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 2,3-dihydro-2-oxo-4-(trifluoromethyl)-5-thiazolecarboxylic acid (Bionet Research, 2.0 g) in THF (20 mL) was added a solution of lithium hydroxide (0.696 g) in water (20 mL). The mixture was stirred at 50° C. for 72 h, cooled to room temperature and filtered. The filtrate was washed with ethyl acetate (10 mL), acidified to pH 3 using dilute hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined organic extractions were washed with water (2×50 mL), saturated brine solution, dried (Na2SO4), filtered and concentrated in vacuo to give the subtitle compound as a colourless solid (1.583 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([O:22]C)=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2ccc(C(=O)CCC(=O)O)cc2)cc1
Yield: 76.3 %

Procedure:
In a manner similar to Example 17, Step (b), 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (0.43 g, 0.0013 mol) was allowed to react with 1.0 M aqueous sodium hydroxide (2.0 mL, 0.002 mol) in THF-methanol (5 mL each) to give 0.308 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid as a white solid; mp 172.0-173.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3C=N[C:20]4[CH:23]=[CH:24][CH:25]=C[C:19]=4[S:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CI.O.[CH3:32][N:33]([CH3:36])[CH:34]=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:34](=[O:35])[N:33]([CH3:36])[C:32]4[CH:25]=[CH:24][CH:23]=[CH:20][C:19]=4[S:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(N2CCN(CCCC3C=Nc4ccccc4S3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CN1C(=O)C(CCCN2CCN(c3ccc(F)cc3)CC2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 193 mg of 2-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-2H-1,4-benzothiazine in 2 ml of dimethylformamide was added 20 mg of 60% sodium hydride in oil. The mixture was stirred at room temperature for 30 minutes and cooled with ice. To the resultant was added 0.07 ml of methyl iodide, and the mixture was stirred for further one hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to give 2-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate and hexane gave prisms, m.p. 103°-104° C. The yield was 84 mg (42%). IR and NMR spectra of this product was in agreement with those of the compound obtained in Example 34.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1ccnc(-c2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-phenyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)=[CH:11][C:10]([C:23]([F:26])([F:25])[F:24])=[N:9]2)=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([NH:45][C:14]([NH:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[C:10]([C:23]([F:24])([F:25])[F:26])[CH:11]=2)=[O:22])[CH:46]=[CH:47][CH:48]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)Oc1ccccc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(F)cc4)c3)c2cc1OC
Yield: 89 %

Procedure:
The title compound was prepared as described in Example 162B, using phenyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 171B (0.146 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-[3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-3-[1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.203 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.79 (s, 1H), 8.55 (d, 1H), 7.68 (m, 2H), 7.55 (m, 2H), 7.41 (m, 4H), 7.20 (d, 1H), 6.96 (d, 1H), 6.85 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H); LC-MS (ESI) m/z 569 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:16][N:14]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:4]([OH:3])=[O:5])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cccnc2[nH]1
Product: O=C(O)c1cc2cccnc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (Adams, David Reginald et al., PCT Int. Appl. (2000), WO2000044753) was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 301.3 ([M−H]−)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>CC#N.CCOCC.C([O-])([O-])=O.[Na+].[Na+]>[Br:14][C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)c1ccncc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C(C)(Br)c1ccncc1
Reaction time: 2 h

Procedure:
The above compounds were prepared according to the procedure reported in the literature: see D. Yang, J. Org. Chem. 2002, 67, 7429. MS: 258, 260 (M+1). To a solution of ethyl 2-(pyridin-4-yl)propanoate (5.3 g, 30 mmol), Mg(ClO4)2 (Aldrich, 2.0 g, 9.0 mmol) in CH3CN (60 mL) was added N-bromosuccinimide (Aldrich, 5.9 g, 33 mmol) at room temperature. After 2 h, the reaction mixture was diluted with ether (200 mL), and 10% Na2CO3. The organic phase was separated, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography. Mass Spec. m/z+ion 258, 260 (M+1).
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([OH:14])[CH:6]=1.C(=O)=O.[ClH:18].[H][H]>C(O)C.O1CCCC1.[Pd]>[ClH:18].[ClH:18].[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:3])=[CH:6][C:7]=1[OH:14]
Reactant: [H][H]
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Agent: Cl
Agent: O=C=O
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ccc(N)c(O)c1
Yield: 97 %

Procedure:
A solution of 3-hydroxy-4-nitrobenzaldehyde O-methyloxime (5.9 g, 30 mmol) in ethanol (100 mL) and tetrahydrofuran (100 mL) is degassed with solid carbon dioxide, then charged with 10% palladium on carbon (500 mg) and concentrated hydrochloric acid (5.5 mL). The mixture is shaken under 50 psi hydrogen gas until consumption of hydrogen had ceased. The mixture is then filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 2-amino-5-(aminomethyl)phenol dihydrochloride (6.1 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([O:11][C:12](=[O:27])[NH:13][C:14]1[C:15]([CH3:26])=[N:16][O:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)[CH3:10].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:22]2[CH:23]=[CH:24][C:19]([C:18]3[O:17][N:16]=[C:15]([CH3:26])[C:14]=3[NH:13][C:12]([O:11][CH:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])[CH3:10])=[O:27])=[CH:20][CH:21]=2)=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)c1cc(F)ccc1F
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3cc(F)ccc3F)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-(2,5-difluoro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{4-[1-(2,5-difluoro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)=[CH2:10])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[CH3:10])[CH3:2]
Reactant: [H][H]
Reactant: C=C(c1ccco1)c1ccccc1CC
Agent: [Pd]
Solvent: CCO
Product: CCc1ccccc1C(C)c1ccco1
Yield: 87.6 %

Procedure:
A solution of 1-(2-ethylphenyl)-1-(2-furyl)ethylene (27 g.) in ethanol (150 ml.) in the presence of 10% palladium on charcoal (0.5 g.) was treated with hydrogen at room temperature for 3 hours. The mixture was filtered and evaporated to give a clear oil which was distilled to give (±) 2-[1-(2-ethylphenyl)ethyl]-furan (23.9 g.), b.p. 130°-150° C./20 mm.Hg, in the form of a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:15]([O:17]CC)=[O:16])=[C:4]([CH3:14])[N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:20][O-:21].[Na+].Cl>CO.[Cu]I>[CH3:20][O:21][C:2]1[C:3]([C:15]([OH:17])=[O:16])=[C:4]([CH3:14])[N:5]([CH3:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1c(Br)c(-c2ccccc2)n(C)c1C
Reactant: C[O-]
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1c(C(=O)O)c(C)n(C)c1-c1ccccc1
Yield: 105 %

Procedure:
The mixture of the 4-bromo-1,2-dimethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (2.91 g, 9.91 mmol), NaOMe (11.3 mL, 25% wt in MeOH) and CuI (566 mg, 2.97 mmol) in MeOH (35 mL) was refluxed overnight. The reaction mixture was poured into 1M HCl solution (100 mL) and extracted with ethyl acetate (200 mL). The organic phase was dried over MgSO4 and evaporated under vacuum to provide the title compound (2.56 g, 10.4 mmol, 105%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[NH:12][C:13](=[O:15])[NH:14][C:7]=23)[CH:3]=1)=[O:27])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)c1
Yield: 54 %

Procedure:
Method H was used Method H was used with 7-(3-Aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 3-tert-butylbenzoyl chloride to afford the title compound as a light pink solid (90 mg, 54%). 1H-NMR (δ, ppm, DMSO-d6): 1.32 (s, 9H, tBu), 6.49 (d, 1H, HPy,5, J=5.9 Hz), 6.91 (d, 1H, Harom, J=6.7 Hz), 7.41-7.46 (m, 2H, Harom), 7.62-7.66 (m, 3H, Harom), 7.75 (d, 1H, Harom, J=7.6 Hz), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 7.89 (s, 1H, Harom,), 10.35 (s, 1H, NHamide), 11.26 (s, 1H, NHurea), 11.44 (s, 1H, NHurea). 13C-NMR (δ, ppm, DMSO-d6): 30.98 (C(CH3)3), 34.55 (C(CH3)3), 106.41, 110.83, 113.60, 114.40, 116.31, 124.30, 124.78, 128.09, 128.67, 130.11, 134.42, 140.84, 141.31, 144.67, 147.06, 150.90, 154.17, 154.58, 166.06. HRMS (EI): m/z [M+H] calculated for C23H22N4O3: 403.1765; found: 403.1762.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[C:19]1[N:20]=[CH:21][N:22]([C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26](O)=[O:27])[CH:23]=1>>[CH:1]1([NH:6][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[N:22]2[CH:23]=[C:19]([C:9]3[C:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:11][O:12][C:8]=3[CH3:7])[N:20]=[CH:21]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)O)cn1
Reactant: NC1CCCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2C(=O)NC2CCCC2)cn1
Yield: 40 %

Procedure:
As described for Example 71, cyclopentylamine was converted, using 2-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (48 mg, 40%) which was obtained as an off-white solid. MS: m/e=413.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:12]([OH:17])(=[O:16])/[CH:13]=[CH:14]/[CH3:15].O.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:3](=[C:2]([NH:1][CH:14]([CH3:15])[CH2:13][C:12]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccc2ncccc12
Reactant: C/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CC(=O)O)Nc1cccc2ncccc12
Yield: 51 %

Procedure:
A mixture of 5-aminoquinoline (9.9 g, 0.069 mol) and crotonic acid (8.9 g, 0.103 mol) in toluene (35 ml) was stirred at reflux for 48 h. The reaction mixture was allowed to cool to ambient, added to water (500 ml) and the pH adjusted to 9 to 10 by the addition of 2N sodium hydroxide. The reaction mixture was screened and the filtrate extracted with diethyl ether (3×100 ml). The pH of the aqueous layer was first adjusted to pH2 with concentrated HCl and then to pH7 with calcium hydroxide. The precipitate which formed was collected by filtration, washed first with water (200 ml) and then with acetone (200 ml) before being dried to give 8.1 g of a cream solid.