Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH2:24])[CH2:23][O:22][CH2:21]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1.[N:32]1[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[N:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C@@H:13]([NH:17][C:18]([C:20]2([NH:24][C:38]([C:36]4[CH:37]=[N:32][CH:33]=[N:34][CH:35]=4)=[O:39])[CH2:21][O:22][CH2:23]2)=[O:19])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: O=C(O)c1cncnc1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(N)COC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)CC[C@@H]3NC(=O)C2(NC(=O)c3cncnc3)COC2)no1

Procedure:
In analogy to the procedures described for the preparation of intermediate A-1 [B], 3-amino-oxetane-3-carboxylic acid{(S)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-indan-1-yl}-amide (example 49) was coupled with pyrimidine-5-carboxylic acid to yield the title compound as light yellow solid. MS: 549.1 (MH+, 1Cl).
Reaction SMILES: [Br:1][CH:2]([Br:15])[C:3]1[N:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[C:16]([NH:7][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=[N:11][C:3]=1[CH:2]([Br:1])[Br:15])(=[O:18])[CH3:17]
Reactant: NC(=O)c1cc([N+](=O)[O-])cnc1C(Br)Br
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)NC(=O)c1cc([N+](=O)[O-])cnc1C(Br)Br
Temperature: 0 °C

Procedure:
A mixture of 0.48 g of 2-dibromomethyl-5-nitronicotinamide and acetic anhydride was stirred with 3 drops of conc. sulfuric acid at room temperature for 1 hour. The reaction mixture was poured into ice-water, made alkaline with 5% sodium bicarbonate and extracted with ethyl acetate. The extract was dried and the solvent was distilled off to give 0.35 g of crystalline substance, which was then recrystallized from ethyl acetate-n-hexane to give the desired product as yellow needles. mp 168° C. (with decomp.)
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]2[O:22][CH2:23][C:24](=O)[C:16]=12>>[CH3:1][O:2][N:3]=[C:24]1[C:16]2[C:17](=[N:18][C:19]([CH3:21])=[CH:20][C:15]=2[O:14][CH3:13])[O:22][CH2:23]1
Reactant: COc1cc(C)nc2c1C(=O)CO2
Reactant: CON=C1COc2nnccc21
Product: CON=C1COc2nc(C)cc(OC)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-methoxy-6-methylfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as white solid;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[NH:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1)=[O:25].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[NH:23][C:24]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=23)=[CH:31][CH:32]=1)=[O:25]
Reactant: COC(=O)c1cc2nccc(Br)c2s1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc2nccc(-c3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Temperature: 70 °C

Procedure:
To a mixture of methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate (68 mg, 0.25 mmol) and 1-(2-fluoro-5-methylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (102 mg, 0.28 mmol) in 8 ml of 1,4-dioxane, was added PdCl2(PPh3)2 (10 mg, 0.014 mmol) and 1M Na2CO3 aqueous solution (0.25 ml, 0.5 mmol). The mixture was heated at 70° C. under N2 for 1 hour, cooled to room temperature and poured into 100 ml of water. The brown precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography, eluting with 2-3% MeOH/CHCl3 to give methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thieno[3,2-b]pyridine-2-carboxylate as light yellow solid. Yield: 30 mg, 28%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](Cl)=[N:6][OH:7].[CH3:12][CH:13]([OH:16])[C:14]#[CH:15].C(N(CC)CC)C>C1C=CC=CC=1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[CH:15]=[C:14]([CH:13]([OH:16])[CH3:12])[O:7][N:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: C#CC(C)O
Reactant: ON=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(O)c1cc(-c2cccc(Cl)c2)no1
Temperature: 0 °C

Procedure:
3-Chloro-benzohydroximoyl chloride (e.g. Kim, Jae Nyoung; Ryu, Eung K; J. Org. Chem. (1992), 57(24), 6649-50) (2.84 g, 14.8 mmol) was suspended in benzene (50 ml) and cooled to 0° C. 3-Butyn-2-ol (2.10 g, 29.9 mmol) and triethylamine (1.89 ml, 26.7 mmol) were added. The mixture was heated to 60° C. for 1.5 houes, cooled and diluted with benzene and 1N aqueous hydrochloric acid. After stirring, the separated benzene layer was evaporated to dryness and the crude purified via flash chromatography over silica using heptane/ethyl acetate=5/1 giving after drying in vacuo the title compound (0.49 g, 15%). 1H NMR (CDCl3), δ (ppm): 1.64 (d, 3 H), 5.07 (dq, 1 H), 6.50 (s, 1 H), 7.40 (m, 2 H), 7.68 (m, 1 H), 7.79 (m, 1 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[N:13]1[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:15]=[CH:14]1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClC1C=CC=CC=1Cl>[CH2:22]([O:21][C:19]([C:16]1[N:15]=[C:14]2[C:24](=[O:25])[NH:1][C:2]3[C:3](=[CH:4][C:5]([N:8]4[CH:12]=[CH:11][N:10]=[CH:9]4)=[CH:6][CH:7]=3)[N:13]2[C:17]=1[CH3:18])=[O:20])[CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)c1ncn(-c2cc(-n3ccnc3)ccc2N)c1C
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc2c(=O)[nH]c3ccc(-n4ccnc4)cc3n2c1C
Temperature: 180 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
A mixture of 1-(2-amino-5-(1-imidazolyl)phenyl)-4-ethoxycarbonyl-5-methyl-1H-imidazole (1.0 g, 3.2 mmol), 1,1'-carbonyldiimidazole (2.6 g, 16.0 mmol) in 1,2-dichlorobenzene (50 ml) was stirred at 180° C. for 16 h under N2. The precipitate was filtered off and submitted to flash chromatography on silica gel 60 eluting with dichloromethane/methanol (4:1) to give 400 mg (37%) of the title compound. M.p. >250° C.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH:11]=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([O:3]C)=[O:2].C([O-])([O-])=O.[K+].[K+]>CO>[O:12]1[C:13]2[C:5]([C:1]([OH:3])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[CH:10]=[CH:11]1
Reactant: COC(=O)c1cccc2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)c1cccc2ccoc12
Reaction time: 24 h
Yield: 93.4 %

Procedure:
A mixture of 0.25 g (0.99 mmol) of 7-Carbomethoxybenzofuran and 0.1 mL of K2CO3 (1N in water) in 6 mL of methanol was stirred at it for 24 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes: ethyl acetate, 4:1, then ethyl acetate: methanol, 9:1) to give 0.15 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[CH3:23][CH:22]([CH3:24])[CH2:21][CH2:20][C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: CC(C)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 8.6 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.1 g of 1-bromo-3-methylbutane were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 2-(3-methylbutyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (77)).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH3:12])=[CH:4][CH:3]=1>CO.[Ni]>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][CH2:9][N:8]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CN1CCCC1=Cc1ccc(Cl)cc1
Agent: [Ni]
Solvent: CO
Product: CN1CCCC1Cc1ccc(Cl)cc1
Yield: 80.3 %

Procedure:
Dissolve 28 g of 2-(p-chlorobenzylidene)-1-methylpyrrolidine in 250 ml of methanol and hydrogenate the thus-obtained solution with Raney nickel as catalyst. Filter the catalyst from the hydrogenated product and then concentrate the filtrate to obtain 22.7 g of the title compound having a boiling point of 75° at 0.005 millimeters (mm) of Hg (yield: 81% of theory). The picrate (from ethanol) melts at 149°.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:41]=[CH:40][CH:39]=[CH:38][C:7]=1[CH2:8][N:9]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:4])([CH3:3])[CH3:2].BrCCCCCCN(CC1C=CC=CC=1OC(C)(C)C)CCN[C:53](=O)[O:54]C(C)(C)C.COC1CC(C2C=CC=CC=2)CCN1.C([O-])([O-])=O.[K+].[K+]>>[C:15]([O:14][C:13](=[O:19])[NH:12][CH2:11][CH2:10][N:9]([CH2:8][C:7]1[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=1[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:37]=2[O:54][CH3:53])[CH2:28][CH2:27]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCBr)Cc1ccccc1OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCN(CCCCCCN1CCC(c2ccccc2)CC1)Cc1ccccc1OC(C)(C)C
Agent: COC1CC(c2ccccc2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccccc1C1CCN(CCCCCCN(CCNC(=O)OC(C)(C)C)Cc2ccccc2OC(C)(C)C)CC1
Yield: 63.4 %

Procedure:
The same procedure as described for compound 16 was applied to starting material 15 (1.9 g, 4.66 mmol), 2-methoxy-4-phenylpiperidin (1.338 g, 6.99 mmol) and K2CO3 (0.644 g, 4.66 mmol). Purification was carried out on a silica gel TLC plate that was developed in with a 3% methanolic NH3 (7 M NH3 in methanol/97% CH2Cl2. The product was isolated as pale yellow oil (63.4%). Mass Spec.=596.44 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:36])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>C(O)C>[Cl:36][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:37])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:17]=[CH:18][C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:34])([F:33])[F:35])(=[O:24])=[O:25])=[CH:20][CH:21]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
To a solution of {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (125 mg, 0.23 mmol) in ethanol (10 mL) was added a solution of sodium hydroxide solution (684 uL, 1.0 N) at room temperature. The resulting clear solution was stirred overnight. Then, the solvents were removed under vacuum and the residue was diluted with water (10 mL), acidified with 1.0 N hydrochloric acid and extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum provided the desired {6-chloro-3-methyl-4-[4-(2-trifluoromethyl-benzenesulfonylamino)-phenyl]-naphthalen-2-yl}-acetic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.47 (br. s, 1 H), 10.80 (br. s, 1 H), 8.02-8.23 (m, 1 H), 7.97-8.07 (m, 1 H), 7.85-7.95 (m, 3 H), 7.83 (s, 1 H), 7.44 (dd, J=8.8, 1.6 Hz, 1 H), 7.24 (d, J=8.5 Hz, 2 H), 7.13 (d, J=8.5 Hz, 2 H), 6.94 (d, J=1.6 Hz, 1 H), 3.81 (s, 2 H), 2.00 (s, 3 H). HRMS calcd. for C26H18ClF3NO4S [(M−H)−] 532.0602, obsd. 532.0602.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([O:16]C)=O)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1>CCOCC>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH2:26][C:14](=[O:16])[CH2:13][C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH3:3])[CH:6]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(CC(=O)CC(=O)c2ccc(Br)cc2)cc1OC
Yield: 50.1 %

Procedure:
Sodium hydride (60% dispersion, 3.80 g, 95.1 mmol) was added portionwise to methyl 2-(3,4-dimethoxyphenyl)acetate (10 g, 47.6 mmol) in Et2O (100 ml) at 0° C. A solution of 4′-bromoacetophenone (9.48 g, 47.6 mmol) in Et2O (50 ml) was added dropwise over 1 h. The mixture was heated at reflux for 16 h, cooled, poured into ice/HCl (2 M), extracted with Et2O (3×100 ml), dried (MgSO4) and the solvent removed under reduced pressure. The residue was crystallized from MeOH to give the title compound (9 g, 50%) as a tan powder.
Reaction SMILES: [Cl:1][C:2]1[S:13][C:5]2=[N:6][C:7]([CH2:11][Cl:12])=[CH:8][C:9](=[O:10])[N:4]2[CH:3]=1.S(Cl)([Cl:17])(=O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[S:13][C:5]2=[N:6][C:7]([CH2:11][Cl:12])=[C:8]([Cl:17])[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(CCl)nc2sc(Cl)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=c1c(Cl)c(CCl)nc2sc(Cl)cn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, (6.07 g), prepared according to Example 5, was reacted with sulfuryl chloride (3.8 g) in dichloroethane (150 ml) under stirring at room temperature for 4 hours. The reaction mixture was treated with 5% aqueous NaHCO3 solution then the organic phase was separated and evaporated in vacuo to dryness. Crystallization from methanol gave 5.6 g of 2,6-dichloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 117°-119° C. dec., which was reacted with triphenylphosphine (5.95 g) in acetonitrile (115 ml) at the reflux temperature for 20 hours. The solution was evaporated in vacuo to dryness and the residue was purified with isopropyl ether to give 10.4 g of [2,6-dichloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl]-methyl-triphenylphosphonium chloride, which was suspended in dimethylsulfoxide (50 ml) and treated with potassium tert-butoxide (2.41 g) dissolved in dimethylsulfoxide (45 ml) at room temperature.
Reaction SMILES: C(Cl)CCl.Cl.[CH3:6][C:7]1([CH3:24])[C:13](=[O:14])[NH:12][C:11]2[N:15]=[CH:16][C:17](/[CH:19]=[CH:20]/[C:21]([OH:23])=O)=[CH:18][C:10]=2[CH2:9][O:8]1.C1C=CC2N(O)N=NC=2C=1.[CH3:35][O:36][C:37]1[C:38]([O:47][CH2:48][CH2:49][CH3:50])=[C:39]([C@H:43]([NH:45][CH3:46])[CH3:44])[CH:40]=[CH:41][CH:42]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.O>[CH3:24][C:7]1([CH3:6])[C:13](=[O:14])[NH:12][C:11]2[N:15]=[CH:16][C:17](/[CH:19]=[CH:20]/[C:21]([N:45]([C@@H:43]([C:39]3[CH:40]=[CH:41][CH:42]=[C:37]([O:36][CH3:35])[C:38]=3[O:47][CH2:48][CH2:49][CH3:50])[CH3:44])[CH3:46])=[O:23])=[CH:18][C:10]=2[CH2:9][O:8]1
Reactant: CCCOc1c(OC)cccc1[C@@H](C)NC
Reactant: CC1(C)OCc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(OC)cccc1[C@@H](C)N(C)C(=O)/C=C/c1cnc2c(c1)COC(C)(C)C(=O)N2
Temperature: 35 °C
Reaction time: 8 h

Procedure:
EDC (0.14 g, 0.73 mmol) was added to a suspension of (E)-3-(3,3-dimethyl-2-oxo-1,2,3,5-tetrahydropyrido[2,3-e][1,4]oxazepin-7-yl)acrylic acid hydrochloride (0.16 g, 0.61 mmol), HOBt (0.091 g, 0.67 mmol), (R)-1-(3-methoxy-2-propoxyphenyl)-N-methylethanamine (0.15 g, 0.67 mmol) and (i-Pr)2EtN (0.62 mL, 3.7 mmol) in DMF (5 mL). The mixture was allowed to stir overnight at 35° C. The mixture was cooled to 0° C. and diluted with H2O (30 mL) with rapid stirring. The resulting precipitate was filtered, washed with H2O (20 mL) then dried under high vacuum. The solid was then triturated with Et2O, and the resultant solid was collected, to yield 125 mg (44%); 1H NMR (300 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.25 (s, 1H), 7.92 and 7.86 (2×s, 1H), 7.47-6.97 (m, 5H), 6.01 and 5.77 (2×s, 1H), 4.07 (s, 2H), 3.83 and 3.73 (2×m, 2H), 3.78 (s, 3H), 2.81 and 2.58 (2×s, 3H), 1.65-1.38 (m, 5H), 1.19 (s, 6H), 0.86 and 0.77 (2×m, 3H); ESI MS m/z 468 [C26H33N3O5+H]+
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[C:10]([O:15][CH3:16])(=[O:14])[C:11]([CH3:13])=[CH2:12].C1(C(N)C2CCCCC2)CCCCC1>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].C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCOCC1>[CH3:16][O:15][C:10](=[O:14])/[C:11](/[CH3:13])=[CH:12]/[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: C=C(C)C(=O)OC
Reactant: Cc1cccc(C)c1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: Cc1ccc([B-](c2ccc(C)cc2)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: C1COCCO1
Product: COC(=O)/C(C)=C/c1c(C)cccc1C
Yield: 75.9 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.703 g (5 mmol) of 2-chloro-meta-xylene, 1.001 g (10 mmol) of methyl methacrylate, 0.034 g (0.038 mmol) of tris(dibenzylideneacetone)dipalladium (0), 1.074 g (5.5 mmol) of dicyclohexylmethylamine and 5 ml of 1,4-dioxane were weighed in the flask, followed by stirring. Further, 0.087 g (0.15 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 120° C. for 37 hours. After the completion of the reaction, 5 ml of toluene and 10 ml of saturated sodium chloride solution were added, followed by separation. The organic phase was purified by column chromatography to afford 0.775 g of (E)-3-(2,6-dimethylphenyl)-2-methylacrylic acid methyl ester (yield: 76 mol % based on 2-chloro-meta-xylene). The identification of the product was made by 1H-NMR and 13C-NMR.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].C(N(C(C)C)C(C)C)C.[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44](Cl)=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1>O1CCCC1>[F:31][C:32]([F:50])([F:49])[C:33]1[CH:34]=[C:35]([C:43]([CH3:48])([CH3:47])[C:44]([N:2]([CH3:1])[C:3]2[CH:4]=[N:5][C:6]([N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)=[CH:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:45])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnc(N2CCSCC2)cc1-c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(N2CCSCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of 2.32 g (7.7 mmol) methyl-(6-thiomorpholin-4-yl-4-o-tolyl-pyridin-3-yl)-amine and 1.50 g (11.6 mmol) N-ethyldiisopropylamine in 20 ml tetrahydrofuran was cooled in an ice bath and 2.72 g (8.5 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride were added dropwise. The reaction mixture was stirred at room temperature overnight and evaporated in vacuo. The residue was suspended in 200 ml 1 N sodium carbonate solution and extracted three times with 200-ml portions of ethyl acetate. The combined organic layers were dried (sodium sulfate) and evaporated. The residue was crystallized from ethanol to give 3.60 g (80%) of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c(Cl)c1

Procedure:
A solution of 3-chloro-4-methylbenzoic acid (5.0 g, 29 mmol), N-bromosuccinimide (5.7 g, 32 mmol), benzoyl peroxide (710 mg, 2.9 mmol) in CCl4 (300 mL) was heated at reflux for 2.5 h. The mixture was concentrated under reduced pressure and dissolved in MTBE. The organic mixture was washed with 1N NaOH (3×25 mL). The aqueous mixture was acidified with 1N HCl to pH 2 and extracted with CH2Cl2 (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to afford 4-(bromomethyl)-3-chlorobenzoic acid.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:7][CH:6]=1.[F:25]C1C=C(C=CC=1OCC1C=CC2C(=CC=CC=2)N=1)C(O)=O>>[F:25][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[C:4]([N:3]([O:2][CH3:1])[CH3:24])=[O:23]
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1
Reactant: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)c(F)c1

Procedure:
Following the procedure for the preparation of N-Methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide but substituting 3-Fluoro-4-(quinolin-2-ylmethoxy)-benzoic acid provided the title compound. MS: (M+H m/z=341.2).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[O:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1ccc(OC)c(Br)c1
Product: CCSc1ncc(C(=O)c2cc(OC)ccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, (Example 1), and 2-bromo-4-methoxyanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,5-dimethoxy-phenyl)-methanone as a white solid. MS (M+H)+, 320.