Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[SH:10].CN(C=O)C.[H-].[Na+].Cl[CH2:19][C:20]([N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1)=[O:21]>C1COCC1.CCOC(C)=O.O.C(Cl)Cl.CCOC(C)=O>[N:22]1([C:20](=[O:21])[CH2:19][S:10][C:2]2[S:1][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: Sc1nc2cnccc2s1
Reactant: O=C(CCl)N1CCCc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CSc1nc2cnccc2s1)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
Compound 68 (0.5 g, 3.0 mmol) was mixed with 20 mL of dry THF and 20 mL of dry DMF under N2 and the suspension was stirred for 30 min at RT and then cooled to 0° C. NaH (0.15 g 60% in mineral oil, 3.7 mmol) was added to the ice-cold suspension which became a greenish solution upon stirring for several minutes at 0° C. The reaction mixture was stirred for another 30 min at 0° C. and then 2-chloro-1-(3,4-dihydroquinolin-1(2H)-yl)ethanone (0.63 g, 3.0 mmol) dissolved in 5 ml of dry THF was added. After the reaction mixture was stirred for 16 h at RT (monitored by TLC (CH2Cl2/EtOAc=1:1 and MS), it was diluted with 100 mL of EtOAc followed by addition of 50 mL of H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined washed with water, brine, dried over Na2SO4 and concentrated giving 1.1 g of crude which was purified by flash chromatography (CH2Cl2/EtOAc) to yield compound 69 (0.5 g, 49%). MS: m/z+ 342.1 [M+H]+; Anal. Calcd (found) for C17H15N3OS2: C, 59.80 (59.89); H, 4.43 (4.51); N, 12.31 (12.12); S, 18.78 (18.53).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[C:14]([NH:23][NH2:24])(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]>>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[N:24][NH:23][C:14](=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[OH:17]
Reactant: NNC(=O)c1ccccc1O
Reactant: O=Cc1c(O)ccc2ccccc12
Product: O=C(NN=Cc1c(O)ccc2ccccc12)c1ccccc1O
Yield: 74 %

Procedure:
Following the general procedure of Example 1, condensation of 2-hydroxy-1-naphthaldehyde and salicylic hydrazide yielded a pale yellow solid (74%): mp 265° C.; 1H NMR d 12.32 (s, 1 H), 11.65 (br s, 1 H), 11.36 (br s, 1 H), 9.09 (s, 1 H), 7.84 (d, 1 H, J=7.5 Hz), 7.43 (m, 3 H), 7.13 (t, 1 H, J=6.0 Hz), 7.01 (t, 1 H, J=6.6 Hz), 6.83 (t, 1H, J=6.9 Hz), 6.77 (d, 1H, J=8.4 Hz), 6.57 (m, 2 H); 13C NMR d 163.72, 158.58, 157.88, 147.40, 133.75, 132.63, 131.42, 128.64, 128.49, 127.53, 127.44, 123.27, 120.65, 118.87, 118.61, 117.04, 115.35, 108.32; HRMS Calcd for C18H14N2O3 :306.1004, found 306.0985; Anal. (C18H14N2O3) C, H, N.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:4]([C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[O:1][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:5]
Reactant: CC(C)(C)OC(=O)n1ncc2c(CCl)cccc21
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccc3c2cnn3C(=O)OC(C)(C)C)c(C=O)c1
Temperature: 80 °C
Yield: 76.7 %

Procedure:
A mixture of 2-hydroxy-5-methoxybenzaldehyde (46 mg, 0.3 mmol), tert-butyl 4-(chloromethyl)-1H-indazole-1-carboxylate (80 mg, 0.3 mmol), and K2CO3 (166 mg, 1.2 mmol) in DMF (1.0 mL) was heated at 80° C. for 2 h. The mixture was filtered and the solid was washed with DCM. The filtrate was concentrated and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give tert-butyl 4-((2-formyl-4-methoxyphenoxy)methyl)-1H-indazole-1-carboxylate (88 mg, 77%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Cl[C:18]1[C:19]([N+:47]([O-:49])=[O:48])=[C:20]([CH:30]=[CH:31][C:32]2[C:37]([N+:38]([O-:40])=[O:39])=[CH:36][C:35]([N+:41]([O-:43])=[O:42])=[CH:34][C:33]=2[N+:44]([O-:46])=[O:45])[C:21]([N+:27]([O-:29])=[O:28])=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25].C(#N)C>CO>[N+:8]([C:7]1[CH:6]=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[CH2:1][C:22]1[C:21]([N+:27]([O-:29])=[O:28])=[C:20]([CH:30]=[CH:31][C:32]2[C:33]([N+:44]([O-:46])=[O:45])=[CH:34][C:35]([N+:41]([O-:43])=[O:42])=[CH:36][C:37]=2[N+:38]([O-:40])=[O:39])[C:19]([N+:47]([O-:49])=[O:48])=[CH:18][C:23]=1[N+:24]([O-:26])=[O:25])([O-:10])=[O:9]
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(C=Cc2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cl)c2[N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CO
Solvent: CC#N
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(C=Cc2c([N+](=O)[O-])cc([N+](=O)[O-])c(Cc3c([N+](=O)[O-])cc([N+](=O)[O-])cc3[N+](=O)[O-])c2[N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
The reaction of 4.5 g (0.02 mole) of TNT with 4.6 g (0.01 mole) of 3-chloro-2,2',4,4',6,6'-hexanitrostilbene was carried out as in the above reactions. The crude reaction product, after extraction with methanol was a brittle mass which was dissolved in 50 mol of acetonitrile, diluted with an equal volume of methanol and heated on a hot plate with magnetic stirring. Light yellow crystals separated and were filtered off, washed well with methanol and dried. This material weighed 4.8 g, 71% of the theoretical yield, melted at 168°-170° (dec), and elemental analysis showed that it contained a mole of acetonitrile. Calcd for C23H12N10O18 : N, 19.6. Found: N, 19.7, 19.4. Recrystallized from 50 ml of THF with 50 ml of methanol added to the hot THF solution after filtering, the product separated in very fine, almost colorless crystals, mp 210°-211°C. Anal. Calcd for C21H9N9O18 : C, 37.2; H, 1.3; N, 18.8. Found: C, 37.5, 37.7; H, 1.6, 1.5; N, 19.0, 18.4.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:17]2[CH:18]=[CH:13][CH:14]=[C:15]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)[CH:16]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: Clc1cccc(-c2ccncc2)c1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2cccc(-c3ccncc3)c2)cc1
Temperature: 80 °C
Yield: 48 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 4-(3-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 4-(4′-vinyl-biphenyl-3-yl)pyridine was isolated. The yield was 48%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:29])[C:16]([NH:18][C:19]([CH3:28])([CH3:27])[CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:17])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[CH:30]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:30]1([CH2:36][N:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[C:15]([NH:14][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][CH:12]=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:29])([CH3:27])[CH3:28])[CH2:26][CH2:25]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=CC1CCCCC1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN2CCNCC2)ccc1-c1cnco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CN2CCN(CC3CCCCC3)CC2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 48 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(1-piperazinyl)ethyl]oxalamide (1.2 mmol) and 13 mg of cyclohexanecarboxaldehyde (1.2 mmol) in 1 ml of a 5% acetic acid/dichloromethane mixture was treated with a solution of 38 mg of sodium triacetoxyborohydride (1.8 mmol) in 1 ml of a 5% acetic acid/dichloromethane mixture. After stirring overnight at room temperature the reaction mixture was diluted with 10 ml of dichloromethane and washed with 8 ml of a sodium bicarbonate solution followed by 8 ml of water. The organic layer was then evaporated and purified using flash chromatography on a silica gel column eluting with 5% methanol/dichloromethane to give after evaporation of the fractions 14.3 mg (0.3 mmol, 25%) of N-[2-[4-(cyclohexylmethyl)-1-piperazinyl-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide in the form of a white solid. MS: m/e 498.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:31][C:32]([CH3:34])=O.[BH4-].[Na+]>C(O)(=O)C.O>[CH:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:9]=2)=[CH:4][CH:3]=1)([CH3:34])[CH3:31]
Reactant: CCOC(=O)CCCCCOc1cc(-c2ccc(N)cc2)cc(-c2ccccc2)n1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCOc1cc(-c2ccc(NC(C)C)cc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 6-{[4-(4-aminophenyl)-6-phenyl-2-pyridyl]oxy}hexanoate (3 g) and acetone (0.54 cc) in acetic acid (45 cc), brought to 15° C., is slowly added sodium borohydride (1.14 g) so as to maintain the temperature below 22° C. The mixture is then stirred at room temperature for 4 hours. The reaction mixture is then poured in distilled water (150 cc) and extracted with ethyl ether (2×100 cc). The combined organic phases are washed with distilled water until neutrality, dried over sodium sulphate and concentrated to dryness at 40° C. under reduced pressure. The oily residue obtained is purified by chromatography under pressure on silica gel (30-60 mm; eluent: n-hexane-ethyl acetate 9-1 as a yellow oil)
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]=[CH:33][C:34]([O:36]C)=[O:35])[CH:25]=1.[H-].[Na+].Cl>C1COCC1>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:24]2[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]=[CH:33][C:34]([OH:36])=[O:35])[CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20]
Reactant: COC(=O)C=Cc1cc(Cl)nc(OC)n1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(OC)n3)nc2CC(C)(C)C)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
To a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (480 mg) and methyl 3-(6-chloro-2-methoxypyrimidin-4-yl)acrylate (360 mg) in THF (8.0 mL) was added 60% sodium hydride (128 mg) at 0° C., and the mixture was stirred at 50° C. for 2 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (520 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:47]1[CH:52]=[C:51]([O:53][C@@H:54]([C@@H:56]2[CH2:60][O:59][C:58]([CH3:62])([CH3:61])[O:57]2)[CH3:55])[N:50]=[C:49]([S:63][CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[C:67]([F:71])[C:66]=2[F:72])[N:48]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:72][C:66]1[C:67]([F:71])=[CH:68][CH:69]=[CH:70][C:65]=1[CH2:64][S:63][C:49]1[N:48]=[C:47]([CH2:1][S:2]([NH2:5])(=[O:4])=[O:3])[CH:52]=[C:51]([O:53][C@@H:54]([C@@H:56]2[CH2:60][O:59][C:58]([CH3:61])([CH3:62])[O:57]2)[CH3:55])[N:50]=1
Reactant: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H](Oc1cc(CS(N)(=O)=O)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of methane sulfonamide (0.25 g), tris(dibenzylideneacetone)dipalladium (0) (55 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (29 mg), cesium carbonate (0.30 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-{(1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethoxy}pyrimidine (the product of Example 47, step i) (0.25 g) in dioxane (5 ml). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent to give the subtitle compound as a yellow oil. Yield: 0.25 g.
Reaction SMILES: [CH:1]1([CH:13]=[O:14])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH:15]([Mg]Cl)([CH3:17])[CH3:16]>C1COCC1>[CH:1]1([CH:13]([OH:14])[CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: O=CC1CCC=CCCC=CCCC1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)C1CCC=CCCC=CCCC1
Yield: 65.2 %

Procedure:
4,8-Cyclododecadiene carboxaldehyde (QRM 2185) [14.0 g; 0.072 mol] was dissolved in THF (50 ml), and isopropylmagnesium chloride [36 ml; 2.0 M in Et2O, 0.072 mol] was added dropwise with stirring under N2. The reaction mixture was stirred for 30 minutes, most solvent was removed in vacuo, and the residue quenched with saturated ammonium chloride solution, then partitioned (Et2O/H2O). The organic layer was separated, washed and dried over MgSO4. The solvent was removed in vacuo, and the residue was chromatographed [silica: Et2O 50%, hexane 50%] to give 1-(4,8-cyclododecadienyl)-2-methyl-1-propanol (11.1 g, 65%) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(C(F)(F)F)cc3s1)n2C
Yield: 68.1 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (78 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-methoxy-ethylamine (21 mg), HBTU (116 mg), and DIEA (67 uL). LC/MS: m/z 450.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.45 (bs, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.78 (s, 2H), 7.67 (d, 1H), 7.48 (d, 1H), 3.66 (bs, 3H), 3.51-3.39 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:34])=[C:7]2[C:12](=[C:13]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 43 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (76 mg, 0.14 mmol), 3-tributylstannanyl-pyridine (0.068 mL, 0.21 mmol) and PdCl2(PPh3)2 (20 mg, 0.029 mmol) in 4 mL of DMF was heated at 120° C. for 2.5 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-100% EtOAc/hexanes+1% AcOH) to give 32 mg of the title compound as a tan solid. MS: (+) m/z 532.30 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C(#N)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]4[C:27]3=[O:36])[CH2:12][CH2:13]2)[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1ccc(Cl)cc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cl)cc1N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A mixture of 28.6 g of 1-(5-chloro-2-methoxyphenyl)piperazine, 44.6 g of anhydrous potassium carbonate, 33.6 g of N-(3-bromopropyl)phthalimide and 250 mL of acetonitrile was stirred at reflux temperature for 8 hours. After cooling to room temperature, 800 mL of water was added to the mixture and the formed precipitate was collected by filtration and crystallized from methanol to give 46.5 g of the title compound, m.p. 131°-133° C.
Reaction SMILES: C(=O)(O)N.[F:5][C:6]1[CH:7]=[C:8]([NH:16][C:17](=[O:19])O)[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH2:34][O:35][CH3:36])[N:28]=[CH:27][N:26]=[C:25]2[O:37][C:38]1[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=1)[NH2:41].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[F:5][C:6]1[CH:7]=[C:8]([NH:16][C:17]([NH:41][C:40]2[CH:42]=[CH:43][CH:44]=[C:38]([O:37][C:25]3[C:24]4[C:29](=[CH:30][C:31]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[C:22]([O:21][CH3:20])[CH:23]=4)[N:28]=[CH:27][N:26]=3)[CH:39]=2)=[O:19])[CH:9]=[CH:10][C:11]=1[C:12]([F:13])([F:14])[F:15]
Reactant: O=C(O)Nc1ccc(C(F)(F)F)c(F)c1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Agent: NC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(F)(F)F)c(F)c4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used reacting 3-fluoro-4-(trifluoromethyl)phenylcarbamate carbamate as described in Example 150 (135 mg, 0.45 mmol) with amine 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (102 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.46 mmol) and DMAP (4.0 mg, 0.03 mmol). The reaction was concentrated to dryness and triturated with dichloromethane to give 126 mg of 1-(3-fluoro-4-(trifluoromethyl)phenyl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea. 1H (DMSO-d6) 9.50 (s, 1H), 9.15 (s, 1H), 8.60 (s, 1H), 7.70 (m, 2H), 7.60 (s, 2H), 7.35 (m, 2H), 7.30 (m, 2H), 7.00 (m, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 3.84 (m, 2H), 3.40 (s, 3H). LCMS (ESI) m/z 547 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:5].[C:35](OC(=O)C)(=[O:37])[CH3:36].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:3]=1[C:4]([N:6]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1)=[O:5])(=[O:37])[CH3:36]
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)ccc2N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
2-Amino-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (140 mg, 0.286 mmol) was dissolved in methylene chloride (2 ml). Acetic acid anhydride (32 mg, 0.315 mmol) and ethyl-diisopropylamine (41 mg, 0.315 mmol) were added and the reaction was stirred over night at RT. Further acetic acid anhydride (30 μl) was added and the reaction was stirred for another night at RT. The reaction was extracted with ethyl acetate, the combined organic layers were concentrated in vacuo and the residue was purified by flash column chromatography (heptane/ethyl acetate:7/3) to yield the desired product (110 mg, 72%) as an off-white solid. MS (ISP) 529.2 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:39][CH2:40][N:42]([CH3:46])[CH2:43][CH2:44][CH3:45])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCCN(C)C(=O)CCl
Product: CCCN(C)CCOc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 49.2 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N-propyl acetamide (8.7 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.4 mg) was obtained.