Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=1)[C:9](Cl)=[O:10])(=[O:3])[CH3:2].[NH2:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][CH3:15])=[C:8]([CH:12]=1)[C:9]([NH:16][C:17]1[C:18]([CH2:26][CH2:27][CH3:28])=[N:19][N:20]([CH3:25])[C:21]=1[C:22]([NH2:24])=[O:23])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)Cl
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1cc(C(C)=O)ccc1OCC

Procedure:
The title compound was prepared form 5-acetyl-2-ethoxybenzoyl chloride and 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide following the procedure of Preparation 6, and was obtained as a white solid (60%), m.p. 225°-227° C. Found: C,61.35; H,6.25; N,15.07. C19H24N4O4 requires C,61.28; H,6.50; N,15.04%
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C:35]([O:37]CC(=O)C1C=CC=CC=1)=[O:36])=[O:28])[NH:16][C:17]([C:19]1[N:20]([CH3:26])[C:21]([CH3:25])=[C:22]([CH3:24])[CH:23]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(O)(=O)C>[Zn].C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:27]([NH:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C:35]([OH:37])=[O:36])=[O:28])[NH:16][C:17]([C:19]1[N:20]([CH3:26])[C:21]([CH3:25])=[C:22]([CH3:24])[CH:23]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OCC(=O)c2ccccc2)n(C)c1C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)O)n(C)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.9 %

Procedure:
To a mixture of 2-oxo-2-phenylethyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,4,5-trimethyl-1H-pyrrol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.30 g) and DMF (3.0 ml) were added zinc (0.61 g) and acetic acid (3.0 ml) under ice-cooling, followed by stirring at room temperature for 6 hours. To the reaction mixture was added ethyl acetate and the insolubles were separated by filtration through Celite. The filtrate was concentrated under reduced pressure, and a 1 M aqueous sodium hydroxide solution was added to the residue, followed by washing with diethyl ether. Citric acid was added thereto under ice-cooling, and the solid precipitated was collected by filtration and washed with water to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1,4,5-trimethyl-1H-pyrrol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (0.19 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:18]([CH3:22])[C:19](=[O:21])[CH3:20]>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:18]([CH3:22])[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)C(C)Cl
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)C(C)Oc1ccccc1Br
Temperature: 80 °C
Yield: 89 %

Procedure:
60 g (347 mmol) of 2-bromophenol, 57.43 g (416 mmol) of potassium carbonate, 57 g (347 mmol) of potassium iodide, 600 ml of dimethylformamide and 4.34 g (416 mmol) of 3-chloro-2-butanone are introduced into a 1 liter three-necked flask equipped with a reflux condenser. The mixture is heated to 80° C. for 16 hours. 1500 ml of water are added and then extraction is carried out with ethyl acetate (3×400 ml). The organic phases are combined, washed with a molar sodium hydroxide solution (2×500 ml), dried over magnesium sulphate and concentrated. The residue is purified by silica column chromatography (elution solvent, 9/1 cyclohexane/ethyl acetate). 75.07 g (yield: 89%) of 3-(2-bromophenoxy)-2-butanone are obtained (yellow oil).
Reaction SMILES: [CH2:1](O)[CH3:2].[Br:4][C:5](=[CH:9][OH:10])[C:6](=[O:8])[CH3:7]>C1(C)C=CC=CC=1>[Br:4][C:5](=[CH:9][O:10][CH2:1][CH3:2])[C:6](=[O:8])[CH3:7]
Reactant: CCO
Reactant: CC(=O)C(Br)=CO
Solvent: Cc1ccccc1
Product: CCOC=C(Br)C(C)=O
Yield: 100 %

Procedure:
A mixture of 400 ml absolute ethanol and 60 ml toluene was heated to reflux and 20 ml of azeotrope was removed via a Dean Stark trap. To the ethanol-toluene solution was added 33.0 g (0.2 mol) of 3-bromo-4-hydroxy-3-buten-2-one and reflux was continued for 2 hours during which period three aliquots of 20 ml of ethanol-toluene were removed via the trap. The solution was concentrated in vacuo to give 38.6 g (100%) of 3-bromo-4-ethoxy-3-buten-2-one as a mobile oil. nmr (DMSOd-6) (δ): 8.21 (s, 1H); 4.23 (q, 2H); 2.33 (s, 3H); 1.31 (s, 3H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH3:16])=[C:12]([CH2:14]O)[N:13]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[ClH:2].[Cl:19][CH2:14][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[NH:10][C:11]=1[CH3:16]
Reactant: Cc1[nH]c(-c2ccc(Cl)cc2)nc1CO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(-c2ccc(Cl)cc2)nc1CCl
Temperature: 25 °C
Yield: 98 %

Procedure:
To a stirred slurry of 10.4 g (0.04 mole) of 2-p-chlorophenyl-4-hydroxymethyl-5-methyl-imidazole hydrochloride in 250 ml of chloroform is added 10 g (0.08 mole) of thionyl chloride in CHCl3. The reaction mixture is warmed to reflux for 6 hours with stirring and then cooled to room temperature. White crystals of 4-chloromethyl-2-p-chlorophenyl-5-methylimidazole hydrochloride in 98% yield, m.p., 224°-226° C (dec.) are obtained. This material is collected and dissolved in 50 ml of warm DMSO and added to a solution of 10 g (0.2 mole) of sodium cyanide in 150 ml of hot DMSO. The mixture is warmed to 60° C for 16 hours and then stirred at room temperature for 16 hours. The reaction mixture is poured over 1 liter of ice and stirred. The tan solid that forms is filtered, collected and air-dried. The crude solid is taken up in 2 liters of ether, charcoaled and filtered. Concentration on a steam bath with hexane addition yields pale green crystals of product. Additional recrystallizations from ether-hexane and methylene chloridehexane gives about 4.5 g (49%) of pale yellow crystals of 2-(p-chlorophenyl)-4-cyanomethyl-5-methyl-imidazole, m.p., 163° - 165° C. Treatment with a mineral acid, e.g., hydrochloric, nitric, sulfuric and the like, affords the corresponding acid addition salts.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH:57]([CH3:68])[CH2:58][NH:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:67][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][N:59]2[CH2:58][CH:57]([CH3:68])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:66][CH:65]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(C)CNCc1ccc(F)cc1
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1CN(Cc2ccc(F)cc2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.109 g, 0.308 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.129 g, 0.339 mmol) and 4-methylmorpholine (0.068 mL, 0.618 mmol) were added sequentially to a solution of rac-3-(4-fluoro-benzylamino)-2-methyl-propionic acid ethyl ester (0.074 g, 0.309 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (4 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.400 mL, 1.23 mmol) was added and the reaction mixture was heated to 60° C. for 4 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 60-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-5-methyl-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.040 g, 0.076 mmol, 25%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.08 (3H, d, J=7.3 Hz), 2.84-2.86 (1H, m), 2.96 (3H, s), 3.17 (1H, dd, J1=13.0 Hz, J2=7.2 Hz), 3.55 (1H, dd, J1=5.7 Hz, J2=12.7 Hz), 4.24 (2H, d, J=5.4 Hz), 4.54 (1H, d, J=14.9 Hz), 4.69 (1H, d, J=14.8 Hz), 7.14-7.18 (2H, m), 7.26 (1H, s), 7.37 (2H, d, J=14.0 Hz), 7.65 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C20H21FN4O6S3 528.06. found 529.2 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][CH2:8]2)=[O:4].[O:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[NH:17]1>>[S:11]1[C:12]2[C:7](=[CH:6][C:5]([CH:3]([OH:4])[CH2:2][N:24]3[CH2:23][CH2:22][CH:21]([N:20]4[C:19]5[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=5[NH:17][C:16]4=[O:15])[CH2:26][CH2:25]3)=[CH:14][CH:13]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(CBr)c1ccc2c(c1)CCCS2
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Product: O=c1[nH]c2ccccc2n1C1CCN(CC(O)c2ccc3c(c2)CCCS3)CC1
Yield: 38 %

Procedure:
By the procedure of Example 29, and starting from 6-(alpha-bromoacetyl)-thiochromane and 4-(2-oxo-1-benzimidazolinyl)-piperidine, the corresponding aminoketone is obtained in 38% yield (MG 16413), m.p. 184°-186° C., which is then reduced with NaBH4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][NH:6][C:7](=[O:17])[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)O1.[C:42](=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:42][N:6]([CH2:5][C:4]1[CH:3]=[C:2]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][CH:30]=2)[CH:20]=[CH:19][CH:18]=1)[C:7](=[O:17])[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCc1cccc(Br)c1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CN(Cc1cccc(-c2ccc(N3CCOCC3)cc2)c1)C(=O)CNC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 10 h
Yield: 80.4 %

Procedure:
tert-Butyl {2-[(3-bromobenzyl)amino]-2-oxoethyl}carbamate (274 mg), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]morpholine (222 mg), sodium carbonate (81 mg), tetrakis(triphenylphosphine)palladium (88 mg), DME (5 ml), and water (2.5 ml) were put into a 50-ml recovery flask, followed by stirring at 80° C. for 10 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The obtained residue was subjected to liquid separation with CHCl3 and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl (2-{methyl[(4′-morpholin-4-ylbiphenyl-3-yl)methyl]amino}-2-oxoethyl)carbamate (270 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH:9][CH:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1]
Reactant: COC(CBr)OC
Reactant: CC(N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(CNC(C)c1ccccc1)OC

Procedure:
A solution of α-methylbenzylamine (8.37 g, 0.07 mol) and bromoacetaldehyde dimethylacetal (11.67 g, 0.07 mol) in acetonitrile (150 ml) containing potassium carbonate (12.39 g, 0.09 mol) was heated at reflux for 2d and cooled. The solid was filtered off and the filtrate was concentrated under reduced pressure to leave an oil. Chromatography on silica gel eluting with ethyl acetate afforded the title compound as an oil.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]([F:26])([F:25])[C:9]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14]C=1C(O)=O.CN(C=O)C>CCOCC>[F:7][C:8]([F:25])([F:26])[C:9]1[CH:17]=[C:16]([NH:18][C:19](=[O:24])[C:20]([CH3:21])([CH3:23])[CH3:22])[CH:15]=[CH:14][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: CC(C)(C)C(=O)Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1ccc(C(=O)Cl)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 115.3 %

Procedure:
Oxalyl chloride (0.64 g) in dry ether (7 ml) was added dropwise with stirring to 2-trifluoromethyl-4-(2',2'-dimethylpropionamido)-benzoic acid (0.926 g) in dry ether (40 ml) at room temperature. A drop of DMF was added during the addition. After two hours further oxalyl chloride (0.257 g) was added and the reaction stirred for a further two hours. The organic solution was then decanted from a precipitate, and evaporated to yield 2-trifluoromethyl-4-(2',2'-dimethylpropionamido)-benzoyl chloride as a liquid (1.136 g), which was used without purification.
Reaction SMILES: [OH-].[Na+].[NH2:3][NH:4][C:5]([NH:7][NH2:8])=[S:6].[CH2:9]([OH:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CCCC.[C:20](O)(=O)C>O>[NH2:3][N:4]1[C:9](=[O:19])[CH:10]([CH:11]([CH:12]2[CH2:13][CH2:14]2)[CH3:20])[NH:8][NH:7][C:5]1=[S:6]
Reactant: CCCCCCCCCCO
Reactant: CC(=O)O
Reactant: NNC(=S)NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C1CC1)C1NNC(=S)N(N)C1=O
Temperature: 70 °C

Procedure:
882 g (4.14 mols) of 4-(cyclopropyl-methyl-methylene)-N-methylrhodanine (as an E/Z mixture) are introduced into a solution of 712 g (17.8 mols) of sodium hydroxide in 4.4 l of water. After the addition of 7 ml of alkylaryl polyglycol ether, the mixture is stirred at 70° C. until complete dissolution occurs (about 16 hours). 438 g (4.14 mols) of thiocarbohydrazide and 115 ml of 1-decanol are then added, the mixture is stirred for one hour at 70° C., and 1525 ml of acetic acid are rapidly added dropwise, causing the reaction product to precipitate. The mixture is stirred at 80° C. for a further 2 hours, allowed to cool to room temperature and the precipitate is filtered off with suction, washed several times with water and also with petroleum ether and dried at 70° C. 725 g (82.6% of theory) of the above compound of melting point 142°-143° C. are obtained.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.[O:9]([C:16]1[CH:17]=[C:18]([N:22]([CH2:30][C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34](OC)=[O:35])[CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN([Al]CCl)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:2][N:3]([CH3:4])[C:34](=[O:35])[C:33]1[CH:38]=[CH:39][CH:40]=[C:31]([CH2:30][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=2)[CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[CH:32]=1
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Reactant: CNC
Agent: CN(C)[Al]CCl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of N,N-dimethylamine hydrochloride (525 mg, 0.0064 mol) in 3.0 mL of toluene at −40° C. was added dropwise a 2.0 M solution of trimethylaluminum in toluene (3.2 mL, 0.0064 mol) over 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (209 mg, 0.00047 mol) from EX-612B in 2.5 mL of toluene at −10° C. was slowly added the (N,N-dimethylamino)chloromethylaluminum reagent (850 μL, 0.00085 mol). The reaction mixture was warmed to room temperature then heated at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and quenched with 10% aqueous potassium hydrogen phosphate. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate in hexane to afford 195 mg (91%) of the desired N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-benzamide product as a pale yellow solid. Anal. calcd. for C25H25F3N2O3. 0.5 H2O: C, 64.23; H, 5.61; N, 5.99. Found: C, 64.49; H, 5.77; N, 5.85. HRMS calcd. 459.1896 [M+H]+, found: 458.1887. 1H NMR (C6D6) δ 7.01-6.95 (m, 3H), 6.92-6.87 (m, 5H), 6.79 (t, 1H), 6.46 (s, 1H), 6.37 (t, 2H), 4.91 (bs, 1H), 4.26 (s, 2H), 4.10 (bq, 1H), 3.84 (dd, 1H), 3.38 (dd, 1H), 2.53 (bs, 3H), 2.14 (bs, 3H). 19F NMR (C6D6) δ −78.69 (d, 3F).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[CH2:35]([SH:38])[CH:36]=[CH2:37]>>[CH2:35]([S:38][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[C:29]([O:30][CH3:31])[CH:28]=3)[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:36]=[CH2:37]
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: C=CCS
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccc(OC)c(OC)c3)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 3,4-dimethoxyphenylboronic acid. Bromination and coupling reaction with allyl mercaptan gave 10 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1.[CH:21](=O)[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:21]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][O:7][C:8]2=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][C:12]2=[O:20])=[CH:4][CH:3]=1)[CH3:22]
Reactant: Nc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCNc1ccc2c(c1)C(=C1C(=O)Nc3ccccc31)OC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.1 %

Procedure:
A mixture of 3-(6-Amino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (50.0 mg, 0.189 mmol), acetaldehyde (10.0 mg, 0.227 mmol), and sodium triacetoxyborohydride (52.1 mg, 0.246 mmol) was stirred at room temperature for 2.5 h. The reaction was then partitioned between EtOAc and H2O. The organic phase was washed with H2O, brine and then dried with Na2SO4. The solvent was removed in vacuo and the residue recrystallized from EtOAc/hexanes to afford the title compound (21.6 mg, 39%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[C:10](CN)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].CO[C:27](=[O:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1.[CH:38]([N:41](C(C)C)CC)(C)C.[Cl-].[CH3:48]OC(=O)C1C=CC(C(O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:48][C:30]1[CH:29]=[C:28]([C:27]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=4)[N:11]=[C:10]([NH:41][CH3:38])[N:9]=3)[CH:3]=2)=[O:37])[CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]
Reactant: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)c(C)c3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Subsequently, a suspension of 9.50 g (30.00 mmol) of [4-(3-aminophenyl)-6,7-dimethoxyquinazolin-2-yl]methylamine in 380 mL of tetrahydrofuran was stirred, while it was cooled at 0° C. To the suspension was added dropwise over 1 hour, 80.71 g of the above mixed solution consisting of [terephthalic acid monomethyl ester chloride/diisopropylethylamine] (the content of terephthalic acid monomethyl ester chloride: 6.55 g; 33.00 mmol). The mixture was then stirred at 0° C. for 11 hours. Thereafter, 190 mL of ethyl acetate was added to the reaction mixture at 0° C., and 380 g of a 5% sodium hydrogencarbonate solution was then added dropwise. The reaction mixture was transferred into a separatory funnel, and 190 mL of ethyl acetate was added. After extraction, the organic layer was separated, and washed with 190 g of a 5% sodium chloride solution and 190 mL of water (twice) in this order. The organic layer was concentrated under reduced pressure at 40° C. To the residue was added 143 mL of methanol, and the mixture was stirred while heating to 40° C. Thirty-three minutes after initiation of stirring, the temperature of an oil bath was set at 75° C. Thereafter, 30 minutes after the internal temperature had exceeded 60° C., the oil bath was set at 50° C. When the internal temperature was decreased to 55° C., 143 mL of 2-propanol was added dropwise. Subsequently, the internal temperature was gradually cooled to 27.3° C., and the mixture was then stirred at 20° C. for 17 hours. The precipitated crystals were filtered, and rinsed with a mixed solution of 14.3 mL of methanol and 14.3 mL of 2-propanol to yield 15.72 g of a crude target product (wet body; the content of the target compound: 13.31 g) as pale yellow crystals (yield: 93.9%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[N:14]1([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH2:28])=[S:27])=[CH:21][C:20]=2[O:29][CH3:30])[CH:18]=[CH:17][N:16]=[CH:15]1>>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([C:3]2[N:28]=[C:26]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([N:14]4[CH:18]=[CH:17][N:16]=[CH:15]4)=[C:20]([O:29][CH3:30])[CH:21]=3)[S:27][CH:2]=2)[CH:10]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1ccnc1
Reactant: COc1ccc(Br)cc1C(=O)CBr
Product: COc1ccc(Br)cc1-c1csc(Nc2ccc(-n3ccnc3)c(OC)c2)n1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 232 mg (0.75 mmol) 2-bromo-1-(5-bromo-2-methoxyphenyl)ethanone and 170 mg (0.68 mmol) (4-imidazol-1-yl-3-methoxy-phenyl)-thiourea yielding 130 mg (41%) [4-(5-bromo-2-methoxy-phenyl)-thiazol-2-yl]-(4-imidazol-1-yl-3-methoxy-phenyl)-amine as a light yellow solid. MS ISP (m/e): 457.1/459.3 (100/90) (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:14]=[C:15](F)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CN1Cc2occc2C(O)C1
Product: CN1Cc2occc2C(Oc2ccc(Cl)c(Cl)c2)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.