Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]O)[CH:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]([F:43])([F:42])[C:35]1[C:39]([CH2:40][OH:41])=[CH:38][NH:37][N:36]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C@@H:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:37]3[CH:38]=[C:39]([CH2:40][OH:41])[C:35]([C:34]([F:33])([F:42])[F:43])=[N:36]3)[CH:17]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1Cc2ccc(CO)cc2C1)OCc1ccccc1
Reactant: OCc1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1)OCc1ccccc1
Temperature: 60 °C
Yield: 84.1 %

Procedure:
(S)-benzyl-5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-ylcarbamate (7.13 mmol, 2.12 g) was dissolved in DCM (20 mL), thionyl chloride (14.26 mmol, 1.040 mL, 1.696 g) added and the resultant solution stirred at room temperature for 45 min. The sample was concentrated and azeotroped with dichloromethane (×4). Potassium carbonate (21.39 mmol, 2.96 g) was added followed by DMF (20 mL) and (3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (7.13 mmol, 1.184 g) and the mixture heated to 60° C. for 1 h. The mixture was concentrated and partitioned between ethylacetate/water. The aqueous layer was twice extracted with ethylacetate and combined organics dried, filtered and concentrated to give a yellow oil which was purified on silica eluting with 0-1% MeOH/DCM to give (S)-benzyl-5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-ylcarbamate as a light coloured oil (2.67 g, 84%). 1H NMR (400 MHz, CDCl3) δ 1.83 (t, 1H) 2.79 (m, 2H) 3.27 (m, 2H) 4.51 (bs, 1H) 4.63 (d, 2H) 4.98 (bs, 1H) 5.08 (bs, 2H) 5.24 (s, 2H) 7.05-7.11 (m, 2H) 7.18 (m, 1H) 7.26-7.39 (m, 6H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.[CH:21]([NH:24][C:25]1[C:26]2[N:27]([C:37]([O:40][CH3:41])=[N:38][N:39]=2)[C:28]2[C:33]([N:34]=1)=[CH:32][C:31]([CH:35]=O)=[CH:30][CH:29]=2)([CH3:23])[CH3:22].CC(O)=O>ClCCCl>[CH:21]([NH:24][C:25]1[C:26]2[N:27]([C:37]([O:40][CH3:41])=[N:38][N:39]=2)[C:28]2[C:33]([N:34]=1)=[CH:32][C:31]([CH2:35][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH:30][CH:29]=2)([CH3:22])[CH3:23]
Reactant: C1COCCN1
Reactant: COc1nnc2c(NC(C)C)nc3cc(C=O)ccc3n12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1nnc2c(NC(C)C)nc3cc(CN4CCOCC4)ccc3n12
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
Solid sodium triacetoxyborohydride (59 mg) and morpholine (15 μL) were added to a solution of 4-isopropylamino-1-methoxy-[1,2,4]triazolo[4,3-a]quinoxaline-7-carbaldehyde (50 mg) in 1,2-dichloroethane (1.0 mL). The resulting suspension was stirred at 23° C. for 2.5 hrs., and then a portion of AcOH (10 μL) was added. After an additional 2.5 hrs., the reaction mixture was concentrated. The residue was partitioned between methylene chloride and a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. Silica gel chromatography afforded isopropyl-(1-methoxy-7-morpholin-4-ylmethyl-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl)-amine as a white solid. MS (M+H)+=357.5.
Reaction SMILES: CC(O)CNCC(O)C.C(OC(OCC)[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)C.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][C:45](=[C:48]3[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH2:52][CH2:51][N:50]4[C:59]([CH:62]=[O:63])=[CH:60][N:61]=[C:49]34)[CH2:44][CH2:43]2)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(O)(=O)C>[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:62]([C:59]1[N:50]2[C:49]([C:48](=[C:45]3[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][C:37]4[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:23]5[CH:24]=[CH:25][C:26]6[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=6)[N:22]=5)=[CH:35][CH:36]=4)[CH2:47][CH2:46]3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[CH2:52][CH2:51]2)=[N:61][CH:60]=1)[OH:63]
Reactant: CCOC(OCC)n1ccnc1
Reactant: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: CC(O)CNCC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC(c1ncc[nH]1)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: -78 °C
Yield: 98.1 %

Procedure:
A mixture of diisopropanolamine (1.13 g) in THF was stirred under nitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was added portionwise at −70° C. and the mixture was stirred for 15 minutes. 1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. The mixture was brought till room temperature and it was stirred at room temperature overnight. Acetic acid (5 ml) was added and the mixture was stirred at room temperature for 20 minutes. K2CO3 (5 g) was added and the mixture was evaporated. The residue was taken up in water and DCM and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered off and the solvent was evaporated, yielding 6.1 g (97%) of 6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol (compound 46).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si](O)(O)(O)O.[Cl:40]OC(C)(C)C>C(Cl)(Cl)(Cl)Cl.O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:34])=[C:22]([N:27]2[CH:31]=[C:30]([Cl:40])[CH:29]=[C:28]2[C:32]#[N:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OCl
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Agent: O[Si](O)(O)O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cc(Cl)cc2C#N)c1Cl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
To a mixture of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-cyanopyrrole (900 mg) and silicic acid (100 mg) in carbon tetrachloride (15 ml) was added a solution of tert-butyl hypochlorite (222 mg) in carbon tetrachloride (10 ml) in water bath, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of n-hexane and ethyl acetate (15:1, V/V) to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-4-chloro-2-cyanopyrrole (290 mg) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[C@H:10]([F:26])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:26][C@H:10]1[C@H:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2C(F)(F)F)[C@H](F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: F[C@@H]1CNCC[C@H]1NCc1ccccc1C(F)(F)F
Yield: 96.9 %

Procedure:
Using a similar procedure to that described in Example 1, step 4, trans-1-tert-butoxycarbonyl-3-fluoro-4-[2-(trifluoromethyl)benzylamino]piperidine (0.4615 g, 1.23 mmol) was reacted with trifluoroacetic acid (1.5 mL) in dichloromethane (3 mL) to give 0.3292 g (97%) of the title compound as a colourless oil. δH (360 MHz, CDCl3) 1.35 (1H, m), 2.02 (1H, m), 2.55-2.69 (2H, m), 2.82 (1H, m), 2.99 (1H, m), 3.31 (1H, m), 4.02 (2H, m), 4.34 (1H, two m), 7.35 (1H, t, J=7.6 Hz), 7.53 (1H, t, J=7.6 Hz), 7.63-7.67 (2H, m). m/e (ES+) 277 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3ncc(Cl)cc32)cc1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of 6-chloro-1H-pyrrolo[3,2-b]pyridine (5.0 g, 32.8 mmol) in THF (150 mL) in an ice bath was added NaH (1.57 g, 60% in mineral oil, 39.3 mmol). After stirring in an ice bath for 30 min, 4-toluenesulfonyl chloride (6.87 g, 36.1 mmol) was added. The mixture was stirred at RT overnight. The reaction mixture was quenched with water (50 mL) at 0° C. and extracted with EtOAc (300 mL). The extract was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by SiO2 chromatography eluting with petroleum ether/EtOAc gradient (8:1 to 2:1) to afford 6-chloro-1-tosyl-1H-pyrrolo[3,2-b]pyridine as a yellow solid (8.5 g, 84%). MS (ESI): m/z=307.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[CH:14]([C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[C:17]=1[C:24]([F:27])([F:26])[F:25])[OH:15]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[C:5]([CH3:13])[C:4]=1[C:14]([C:16]1[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[C:17]=1[C:24]([F:27])([F:26])[F:25])=[O:15]
Reactant: COc1cc(C)c(C(O)c2c(Cl)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(Cl)cnc(Cl)c2C(F)(F)F)c(OC)c1OC
Yield: 89 %

Procedure:
14 g of manganese dioxide was added to a solution having 3.5 g (8.2 mmol) of (2,3,4-trimethoxy-6-methylphenyl)(2,915 5-dichloro-3-trifluoromethyl-4-pyridyl)methanol obtained in step (b) dissolved in 100 ml of toluene, followed by stirring under reflux by heating for 6 hours. The mixture was cooled and then subjected to filtration, and toluene was distilled off under reduced pressure. The crude product thus obtained was purified by silica gel column chromatography to obtain 3.1 g (yield 89%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl-2,5-dichloro-3-trifluoromethylpyridine (compound No. 90; m.p. 106-109° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15](O)=[O:16])=[CH:9]2)=[CH:5][CH:4]=1.ClC(OCC(C)C)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[BH4-].[Na+]>ClCCl>[OH:16][CH2:15][C:10]1[CH:11]=[CH:12][C:13](=[O:14])[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)ccc2=O)cc1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(CO)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of crude 1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (55.3 mg, 0.226 mmol, 1 eq) in anhydrous dichloromethane (10 mL) was added isobutyl chloroformate (29.6 μL, 30 mg, 0.226 mmol, 1 eq) and triethylamine (47 μL, 34 mg, 0.338 mmol, 1.5 eq). The mixture was stirred at rt for 4 h. Carbonate resin (3 mmol/g, 150 mg, 0.451 mmol, 2 eq) was added and the reaction is stirred for another 2 h. The mixture was then cooled down to 0° C. and sodium borohydride (25 mg, 0.677 mmol, 3 eq) was added and the mixture stirred at rt for 16 h. After this time, the reaction was filtered, and the filtrate was diluted with dichloromethane then washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 95:5 dichloromethane/methanol to give 5-hydroxymethyl-1-(4-methoxy-benzyl)-1H-pyridin-2-one. Mass Spec m/z=232 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[CH3:24][N:25](C=O)C.C(O)=O>C(N)=O.C(O)(C)C>[C:12]1([C:4]2[NH:3][C:2]3[N:1]=[CH:24][N:25]=[C:7]([OH:9])[C:6]=3[CH:5]=2)[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc(-c2ccc(-c3ccccc3)cc2)[nH]c1N
Solvent: NC=O
Solvent: CC(C)O
Solvent: O=CO
Product: Oc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12

Procedure:
766 mg (2.5 mmol) of 2-amino-3-ethoxycarbonyl-5-(biphen-4-yl)-1H-pyrrole are stirred in 5 ml of formamide, 2.5 ml of DMF and 1.25 ml of formic acid for 20 h at 150° C. The reaction mixture is diluted with isopropanol and filtered. Washing with isopropanol and hexane yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =288.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[CH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25](O)=[O:26])=[C:16]([C:29]([O:31]C)=[O:30])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:28])[CH2:22][O:23][CH2:24][C:25]([NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:6]([C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:7]=2)=[O:26])=[C:16]([CH:15]=1)[C:29]([OH:31])=[O:30]
Reactant: Nc1cccc(-c2ccoc2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccoc2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(furan-3-yl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-3-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 89%).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:2][C:3]1[N:7]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1
Reactant: N#CCCCn1c(CO)nc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#CCCCn1c(CCl)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 4-(2-hydroxymethyl-benzoimidazol-1-yl)-butyronitrile, 68, (22 g, 102.2 mmol) suspended in CH2Cl2 (100 mL), thionyl chloride (15.81 g, 132.9 mmol) was slowly added with ice-water bath cooling. The ice bath was removed. The solution was stirred at room temperature for 1 hour and then evaporated. The residue was triturated with EtOAc to give a nearly quantitative yield of 4-(2-chloromethyl-benzoimidazol-1-yl)-butyronitrile, 69, as light gray powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14](O)=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(N(C)C)=C(C)C.C(N(CC)C(C)C)(C)C.[C:41]([O:45][C:46](=[O:49])[CH2:47][NH2:48])([CH3:44])([CH3:43])[CH3:42]>ClCCl>[C:41]([O:45][C:46](=[O:49])[CH2:47][NH:48][C:14]([C:13]1[CH:12]=[N:11][C:10]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:17]=1)=[O:15])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNC(=O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a suspension of 3.66 g 5-(3,4-dichloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid in 40 ml dichloromethane was added 1.469 g Ghosez's reagent ((1-chloro-2-methyl-propenyl)-dimethyl-amine)) and the mixture was stirred at ambient temperature for 30 min. To the resulting solution was added 3.224 g N,N-diisopropylethylamine and 1.44 g glycine-t-butylester and the mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched by addition of 10% aqueous citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to 1:1 to yield 4.10 g of the title compound as white foam. MS (EI): 477.0608 (M−H).
Reaction SMILES: [C:1]([CH:9](Br)[CH2:10][CH2:11][Cl:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][NH:15][C:16](=[S:20])[O:17]CC>O1CCOCC1>[CH3:14][N:15]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]([CH2:10][CH2:11][Cl:12])[S:20][C:16]1=[O:17]
Reactant: O=C(c1ccccc1)C(Br)CCCl
Reactant: CCOC(=S)NC
Solvent: C1COCCO1
Product: Cn1c(-c2ccccc2)c(CCCl)sc1=O

Procedure:
The 3-methyl-4-phenyl-5-β-chloroethyl-4-thiazolin-2-one is prepared in the following manner. A solution of 21.9 g of 1-benzoyl-1-bromo-3-chloropropane and 5 g of ethyl N-methyl-thiocarbamate in 50 cc of dioxan is heated under reflux for 10 hours, and then evaporated to dryness under reduced pressure, M.P. = 88°-90° C (from hexane).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: [H][H]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2nc(N)sc2c1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
2-Amino-6-nitrobenzothiazole (500 mg, 2.56 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon (50 mg) was added as a slurry in methanol (1 mL). The atmosphere was replaced with hydrogen and the suspension was stirred overnight. The catalyst was removed by suction filtration and the solvent evaporated to afford 2,6-diaminobenzothiazole (420 mg, 99%) as a pale yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([CH2:13][C:14]1[C:15]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[N:16][O:17][C:18]=1[C:19](OCC)=[O:20])[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].CC(C)([O-])C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[OH:20][C:19]1[C:18]2[O:17][N:16]=[C:15]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)[C:14]=2[CH:13]=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1c(-c2cccs2)noc1C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ncc2c(-c3cccs3)noc2c1O
Temperature: -78 °C
Reaction time: 14 h
Yield: 67.2 %

Procedure:
Ethyl 4-(((2,4-dimethoxybenzyl)(2-ethoxy-2-oxoethyl)amino)methyl)-3-(thiophen-2-yl)isoxazole-5-carboxylate (2.2 g, 4.51 mmol) was dissolved in 40 mL of THF and cooled to −78° C. Potassium tert-butoxide solution (9 mL, 9.02 mmol, 1M in THF) was added dropwise, and the mixture was stirred for 14 hours, the cold bath allowed to evaporate spontaneously. The reaction mixture was quenched with 8 mL of 1M HCl and 50 mL of saturated ammonium chloride solution. The product was extracted with EtOAc and the organic layer was dried over MgSO4 and concentrated to give 2.0 g of crude oil. The crude intermediate was dissolved in 25 mL of CH2Cl2. Thionyl chloride (0.49 mL, 6.79 mmol) was added and the reaction mixture was stirred for 3 h. The mixture was filtered through a medium porosity funnel. The solid was rinsed three times with cold CH2Cl2 and dried under vacuum to give 0.88 g of the title compound. MS: (+) m/z 291.34 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CC(C)=O>[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH:26][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 44 h
Yield: 33.8 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and 3-hexyloxypropylamine (1.75 g, 0.011 mole) was heated at 140° C. for 6 hours. After standing at ambient temperature for 44 hours, the reaction mixture was dissolved in acetone (10 ml) and the solution poured into water (150 ml). The light brown oil which separated from solution solidified on standing for 1 hour. The solid was collected and dried on absorbent paper for 18 hours. The solid was then triturated in isooctane (soluble) and the solution chilled to obtain a solid which was collected, washed with cold isooctane, and dried under ambient conditions to obtain 1.20 g (34%) of the product, m.p. 67°-69° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1B(O)O.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.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>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:35]=[C:34]3[C:29]([CH:30]=[CH:31][CH:32]=[N:33]3)=[CH:28][CH:27]=2)[CH:20]=1
Reactant: COCOc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Clc1cc(Oc2ccc3cccnc3c2)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 140 °C

Procedure:
To a suspension of 2-methoxymethoxy-4-trifluoromethylphenyl-boronic acid, (Example 135(b)), (220 mg, 0.87 mmol) and 7-(6-chloro-pyrimidin-4-yloxy)-quinoline, (Example 102(a)), (150 mg, 0.58 mmol) in toluene/EtOH (1:4, 3.8 mL) was added 2 M K2CO3 (1.2 mL, 2.3 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol, Strem). The reaction mixture was stirred and heated by microwave synthesizer at 140° C. for 10 min. The mixture was partitioned between CH2Cl2 and 1 N NaOH. The organic phase was separated, and the aqueous phase was extracted with CH2Cl2. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (MeOH/CH2Cl2 1:125 and then 1:100) afforded a light-yellow gum. The title compound was obtained as a white solid after recrystallization from MeOH. MP: 98.8–99.4° C. MS (ESI, pos. ion) m/z: 428 (M+1). Anal. Calcd for C22H16F3N3O3: C, 61.83; H, 3.77; N, 9.83. Found: C, 62.13; H, 3.87; N, 9.52.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:12]1([C:4]2[CH:3]=[C:2]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:6][C:5]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1oc(Br)cc1-c1ccccc1
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)c1oc(-c2ccccc2)cc1-c1ccccc1
Yield: 103.5 %

Procedure:
Using ethyl 5-bromo-3-phenyl-2-furancarboxylate (1.18 g) and phenylboronic acid (0.98 g), a reaction and treatment was carried out in the same manner as in Reference Example 2, thereby giving 1.21 g of ethyl 3,5-diphenyl-2-furancarboxylate.