Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:7][C:3]=1[C:4]([O-])=[O:5].[C:24]1(C)[C:25](C)=[CH:26]C=[CH:28][CH:29]=1.Cl>[Cl-].[Zn+2].[Cl-].CCC(=O)CC>[CH2:25]([C:24]1[NH:1][C:2]2[C:3]([C:4](=[O:5])[C:29]=1[CH3:28])=[CH:7][C:8]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)=[C:9]([CH3:11])[CH:10]=2)[CH3:26]
Reactant: Cc1cc(N)c(C(=O)[O-])cc1Oc1ccc(OC(F)(F)F)cc1
Reactant: Cc1ccccc1C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(=O)CC
Product: CCc1[nH]c2cc(C)c(Oc3ccc(OC(F)(F)F)cc3)cc2c(=O)c1C
Temperature: 70 °C
Reaction time: 50 h
Yield: 87.3 %

Procedure:
2-amino-4-methyl-5-(4-(trifluoromethoxy)phenoxy)benzoate (3.69 g), 20 ml of xylene, 5.3 ml of 3-pentanone, and 0.256 g of zinc chloride were added into a 50-ml glass flask equipped with a stirring device, a thermometer, a reflux condenser, and a Dean-Stark device under a nitrogen atmosphere, and the temperature was raised to reflux with stirring. A reaction was allowed to proceed for 50 hr while adding 1.1 g of zinc chloride in four divided portions. After the completion of the reaction, the mixture was cooled to 70° C., and 10 ml of 0.1 N hydrochloric acid was added to the cooled solution, followed by cooling to room temperature. The precipitated solid was collected on a suction filter, was washed with an aqueous methanol solution and distilled water, and was dried to give 2-ethyl-3,7-dimethyl-6-(4-(trifluoromethoxy)phenoxy)quinolin-4(1H)-one as a light brown solid (3.29 g, yield: 87.3%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=[C:7]([Cl:15])[CH:6]=1)=O.O1CCCC1.[Li+].[BH4-]>C(OCC)C>[Cl:15][C:7]1[CH:6]=[C:5]([CH2:3][OH:2])[C:13]2[O:12][C:11](=[O:14])[NH:10][C:9]=2[CH:8]=1
Reactant: COC(=O)c1cc(Cl)cc2[nH]c(=O)oc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1[nH]c2cc(Cl)cc(CO)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
5-Chloro-2-oxo-2,3-dihydro-benzooxazole-7-carboxylic acid methyl ester (8 g, 35 mmol) is suspended in diethyl ether (100 mL) and tetrahydrofuran (410 mL) and cooled to zero. The reaction is purged with nitrogen and LiBH4 (6.72 g, 310 mmol) is added portion wise to the reaction. The reaction is warmed to room temperature and stirred for 3 hours. Upon completion the reaction is cooled to 0° C. and quenched by the slow addition of saturated ammonium chloride (250 mL). Water is added to the reaction (500 mL) and the organic layer separated. The water layer is extracted with ethyl acetate (3×100 mL) and the combined organic layers are dried (Na2SO4) filtered and evaporated in vacuo. Product is purified on silica with dichloromethane methanol as the eluent to yield (4.2 g 31 mmol 60%) the title compound (4.2 g 31 mmol 60%). LCMS (ESMS): m/z 200.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[N:5]=[C:4]([CH2:16][CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:30][C:31](OC)=O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:30][C:31]1[NH:20][C:18](=[O:19])[C:3]2[C:4]([CH2:16][CH3:17])=[N:5][N:6]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH3:9])[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccc(OC)c(Cl)c1
Reactant: CCCCCCC(CC)n1nc(CC)c(C(N)=O)c1N
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CC)n1nc(CC)c2c(=O)[nH]c(Cc3ccc(OC)c(Cl)c3)nc21
Yield: 27.7 %

Procedure:
18 mg (0.065 mmol) of 5-amino-3-ethyl-1-(3-nonyl)-1H-pyrazole-4-carboxamide and 69 mg (0.323 mmol) of methyl 3-chloro-4-methoxyphenylacetate are refluxed for 6 hours in 0.5 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 8 mg (28%) of a solid, Rf=0.75 (dichloromethane/methanol=15:1).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:19][CH3:20])=[CH:8][C:9]([C:17]#[N:18])=[C:10]([N:12]=[CH:13][N:14](C)C)[CH:11]=1.N[C:22]1[NH:26][N:25]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=1.O>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]2[C:9]([C:17]([NH:18][C:22]3[NH:26][N:25]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=3)=[N:14][CH:13]=[N:12]2)=[CH:8][C:7]=1[O:19][CH3:20]
Reactant: Nc1cc(CC(=O)O)n[nH]1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCl
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cc(CC(=O)O)n[nH]3)ncnc2cc1OCCCCl
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Alternatively, N′-(5-(3-chloropropoxy)-2-cyano-4-methoxyphenyl)-N,N-dimethylimidoformamide (14.78 g, 50 mmol) in acetic acid (40 ml) was heated at reflux with (5-amino-1H-pyrazol-3-yl) acetic acid (8.1 g, 57.5 mmol) for 1.5 h. The reaction mixture was cooled to ambient temperature, water (250 ml) was added to the mixture and the solid was recovered by suction filtration. The solid was washed with 1) water, ii) ethyl acetate and iii) diethyl ether and dried in vacuo at 50° C. to yield (5-((7-(3-chloropropoxy)-6-methoxy-quinazolin-4-yl)amino)-1H-pyrazol-3-yl)acetic acid as a yellow solid (13.6 g, 69% yield):
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[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>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:21]2[CH:20]=[CH:19][C:18]([C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=3)=[CH:23][CH:22]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccccc2)cc1
Reactant: O=C(Cl)c1ccc(I)cc1
Product: O=C(c1ccc(I)cc1)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
p-Iodobenzoyl chloride was reacted with 4-chlorobiphenyl by the method of Example 6 to give 4'-chloro-4-biphenylyl p-iodophenyl ketone, m.p. 218°C after recrystallisation from benzene.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.Cl[CH2:15][C:16]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][N:17]=1>C(O)C.O>[CH3:23][N:22]([CH3:24])[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:15][S:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH:21]=1
Reactant: CN(C)c1ccnc(CCl)c1
Reactant: Sc1c[nH]c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccnc(CSc2c[nH]c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of S-(3-indolyl)isothioronium iodide (180 mg, 0.75 mmol) of the formula ##STR37## in ethanol (5 ml) was added a 2N aqueous sodium hydroxide solution (0.86 ml) under ice-cooling, and the mixture obtained was stirred at room temperature for 1 hour. The resultant reaction solution containing 3-mercapto-indole so formed was then admixed with 2-chloromethyl-4-dimethylaminopyridine hydrochloride (118 mg, 0.75 mmol), followed by stirring the mixture at room temperature for 1 hour. The resulting reaction was made strongly alkaline with a 2N aqueous sodium hydroxide solution (1.0 ml) and then diluted with water (20 ml) to precipitate crystals, affording the titled compound (130 mg) after filtration.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6](O)[CH3:7])=[CH:4][CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])[CH3:7])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1ccc(Br)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 59.2 %

Procedure:
To a solution of 4-bromo-α-methylbenzylalcohol (3.0 g, 0.015 mol), phthalimide (2.2 g, 0.015 mol) and triphenylphosphine (6.0 g, 0.023 mol) in tetrahydrofuran was added diethyl azodicarboxylate (4.0 g, 0.023 mol) and the reaction mixture was stirred at room temperature for 14 hours. The solution was concentrated and the crude material was purified on silica gel (10˜35% ethyl acetate in hexane) to give 2.93 g of the title compound (60% yield) 1H NMR (300 MHz, CDCl3) δ ppm 1.90 (d, J=7.35 Hz, 3 H) 5.52 (q, J=7.11 Hz, 1 H) 7.34-7.41 (m, 2 H) 7.41-7.50 (m, 2 H) 7.65-7.74 (m, 2 H) 7.76-7.86 (m, 2 H) MS (ESI), m/z 404.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1)(=[O:12])=[O:11].B(Br)(Br)Br.O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)(=[O:11])=[O:12]
Reactant: COc1cccc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cccc(O)c2)c(C)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
N-(2,4-dimethylphenyl)-N-isobutyl-3-methoxybenzenesulfonamide (431.4 mg, 1.242 mmol) was dissolved in dichloromethane (DCM) (10 mL) and cooled to −78° C. BBr3 in DCM (1M) (6.21 mL, 6.21 mmol) was added dropwise and the reaction put under nitrogen. The reaction was allowed to reach room temperature and left to stir overnight. Water (20 mL) was added dropwise into the reaction mixture, until no more fumes were released. The crude product was then extracted to the organic phase of an aqueous work up between DCM (30 mL) and water (20 mL). The aqueous phase was washed with DCM (2×20 mL). The organic phase was then dried and concentrated in vacuo. The crude product was then dissolved in a minimum of DCM, and loaded onto a silica column before being purified by silica (Si) column chromatography (20 minutes, 0-25% EtOAc in cyclohexane). The relevant fractions were then combined and condensed, to give the desired product, 384.4 mg. LCMS [LCMS1] Rt 1.26 min, m/z (ES+) 334 (M+H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[H][H]>C(O)(=O)C.[Pt](=O)=O>[F:18][C:2]([F:1])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: FC(F)(F)Oc1ccc(Oc2ccncc2)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Yield: 162.2 %

Procedure:
After 4-[4-(Trifluoromethoxy)phenoxy]pyridine (2.00 g) was dissolved in acetic acid (20 mL) and platinum(IV) oxide (200 mg) was added. The resulting mixture was stirred under 4 atms of atmosphere of hydrogen at 23-30° C. for 12 hr. The reaction mixture was filtered to remove the catalyst followed by concentration in vacuo to give 3.32 g of yellow oily crude product. The crude product was dissolved in toluene (100 mL) and was washed three times with 10 w/v % NaOHaq (50 mL×3) and then was washed three times with water (50 mL×3). The organic layer was condensed under reduced pressure to give 675 mg (33.0% yield) of a pale yellow crystal target compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CCCCCN1CCC(CN)CC1
Product: CCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 49.6 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-pentyl-piperidine (0.368 g, 2.0 mmol) according to the procedure used for Example 2 to give 0.210 g of the title compound as a white solid (Et2O).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1C(=C)C(=O)NC2C=CC(OC)=CC=2C1=O.[F:20][C:21]1[CH:33]=[CH:32][C:24]2[NH:25][C:26](=[O:31])[CH2:27][CH2:28][C:29](=[O:30])[C:23]=2[CH:22]=1>>[CH3:1][N:2]([CH:19]=[C:28]1[CH2:27][C:26](=[O:31])[NH:25][C:24]2[CH:32]=[CH:33][C:21]([F:20])=[CH:22][C:23]=2[C:29]1=[O:30])[CH3:3]
Reactant: O=C1CCC(=O)c2cc(F)ccc2N1
Reactant: C=C1C(=O)Nc2ccc(OC)cc2C(=O)C1N(C)C
Product: CN(C)C=C1CC(=O)Nc2ccc(F)cc2C1=O

Procedure:
In a manner similar to that described above for 4-dimethylamino-methylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione, 7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-f) was converted to v-f (85%): MS m/z=249 (M+H).
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19].FC1C(F)=C(F)C(F)=C(F)C=1.BrC=CC1C=CC=CC=1>>[F:1][C:2]1[C:7](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19]
Reactant: Fc1c(F)c(F)c(/C=C/c2ccccc2)c(F)c1F
Agent: BrC=Cc1ccccc1
Agent: Fc1cc(F)c(F)c(F)c1F
Product: Fc1c(F)c(F)c(/C=C\c2ccccc2)c(F)c1F

Procedure:
FIG. 33 shows the resultant molecules (E)-1,2,3,4,5-pentafluoro-6-styrylbenzene and when the substrate is pentafluorobenzene and the haloalkene is beta-bromostyrene, and its 1H NMR spectrum. (Z)-1,2,3,4,5-Pentafluoro-6-styrylbenzene is also produced in this synthesis. The synthesis of (E)-1,2,3,4,5-pentafluoro-6-styrylbenzene and (Z)-1,2,3,4,5-pentafluoro-6-styrylbenzene is conducted using copper(I) iodide (19.1 mg, 0.1 mmol), beta-bromostyrene (183 mg, 1.0 mmol), 1,10-phenanthroline (18 mg, 0.1 mmol), pentafluorobenzene (252 mg, 1.5 mmol), K3PO4 (424 mg, 2.0 mmol), and DMF/xylene (0.6 mL). After column chromatography (hexanes) and preparative HPLC (hexanes) 33 mg (12%) of an off-white solid ((Z)-1,2,3,4,5-pentafluoro-6-styrylbenzene) and 207 mg (77%) of a white solid ((E)-1,2,3,4,5-pentafluoro-6-styrylbenzene) are obtained. (E)-1,2,3,4,5-pentafluoro-6-styrylbenzene: 1H NMR (300 MHz, CDCl3) δ 6.98 (d, J=16.6 Hz, 1H), 7.30-7.48 (m, 4H), 7.50-7.56 (m, 2H). Data not shown for (Z)-1,2,3,4,5-pentafluoro-6-styrylbenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][C:4]=1[CH3:12].Br[CH2:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=O>C(Cl)(Cl)Cl>[CH3:12][C:4]1[CH:5]=[C:6]([C:7]2[NH:9][CH:14]=[C:15]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[N:8]=2)[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(=N)N)cc1C
Reactant: O=C(CBr)c1cccs1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(-c3cccs3)c[nH]2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
A slurry of 22 (21.6 g, 0.132 mol) in CHCl3 (300 ml) was treated dropwise over 15 minutes with 2-(bromoacetyl)-thiophene (10.84, 0.0476 mol, 92% pure) in CHCl3 (55 ml). The reaction mixture was stirred at room temperature for 24 hours, and then filtered to remove 10.2 g of the hydrobromide of 22. The mother liquors were concentrated to a semisolid which was swirled with 75 ml of methylene chloride and refrigerated overnight. The resultant gray solid was washed with CH2Cl2 and dried to give 10.2 grams (79%) of 23; m.p. 110°-114°. The analytical sample was dried in vacuo at 85°, m.p. 115°-117°.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[N:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH:30]([F:32])[F:31])[C:24]3=[N:23][CH:22]=2)=[N:5][C:6]([NH:9][CH:10]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15](O)=[O:16])[CH3:11])=[N:7][CH:8]=1)#[N:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Na].C(=O)([O-])O.[Na+]>O1CCCC1>[F:32][CH:30]([F:31])[C:29]1[C:24]2[N:25]([C:21]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][N:7]=[C:6]([NH:9][CH:10]([C:12]4[CH:20]=[CH:19][CH:18]=[C:14]([CH2:15][OH:16])[CH:13]=4)[CH3:11])[N:5]=3)=[CH:22][N:23]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(C(=O)O)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Nc1ncc(C#N)c(-c2cnc3c(C(F)F)cccn23)n1)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
151 mg of the 3-[1-({5-cyano-4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl}amino)ethyl] benzoic acid [100-4] was dissolved in 4 mL of tetrahydrofuran, then 282 mg of N,N-carbonyldiimidazole was added, and stirred overnight at room temperature. The reaction mixture was added with 132 mg of sodium boronhydride in two additions, and stirred at room temperature for 30 minutes. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was added, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by preparative thin-layer chromatography, to obtain 50 mg of 4-[8-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl]-2-({1-[3-(hydroxymethyl)phenyl)ethyl}amino)pyrimidin-5-carbonitrile [101-1] as a pale yellow oily product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].CCN(CC)CC.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:39])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (750 mg, 2.28 mmol) was dissolved in 35 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.35 mL, 2.50 mmol) and benzoyl chloride (260 μL, 2.28 mmol) and the reaction was allowed to warm to room temperature over 2.5 h. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL) and CH2Cl2 (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a tan foam. Mass spectral analysis showed the presence of some bis-amide in addition to the desired product. The tan foam was treated with 1N aqueous HCl solution (50 mL) at 100° C. for 5 h. HPLC analysis showed that all of the bis-amide had been converted to the desired product. The reaction was cooled to room temperature and treated with 10% NaOH until the pH˜11. The mixture was extracted with CHCl3 (3×30 mL). The combined organic extracts were washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. Purification by column chromatography (SiO2, 5–10% MeOH/CHCl3) gave 100 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)benzamide as a white powder. m.p. 184–187° C.;
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:12]1[CH:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[N:13]1>C(Cl)Cl>[CH:1]1([NH:4][C:17]([C:15]2[CH:16]=[N:12][NH:13][CH:14]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cn[nH]c1
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of cyclopropylamine (0.52 mL, 0.43 g, 7.5 mmol) and triethylamine (1.4 mL, 1.01 g, 10.0 mmol) in CH2Cl2 (5 mL) was added to a suspension of 1H-pyrazole-4-carbonyl chloride (0.69 g, 5.3 mmol) in CH2Cl2 (20 mL) at 0° C. The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the crude product was purified by MPLC using EtOAc on silica gel to give 0.79 g (99%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.52-0.62 (m, 2 H), 0.72-0.82 (m, 2 H), 2.69-2.86 (m, 1 H), 7.91 (s, 1 H), 8.09 (s, 1 H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[Cl:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[C:24]([Cl:29])[N:23]=1.O>C(O)C>[Cl:21][C:22]1[N:27]=[C:26]([NH:11][C@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][N:7]=2)[CH3:10])[CH:25]=[C:24]([Cl:29])[N:23]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H](N)c1ccc(F)cn1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](Nc1cc(Cl)nc(Cl)n1)c1ccc(F)cn1
Temperature: 80 °C
Yield: 56.2 %

Procedure:
(S)-1-(5-Fluoropyridin-2-yl)ethanamine hydrochloride (prepared as described in WO2006/123113, 1.05 g, 4.91 mmol) and N,N′-diisopropylethylamine (2.80 mL, 16.36 mmol) were added to a solution of 2,4,6-trichloropyrimidine (0.75 g, 4.09 mmol) in ethanol (15 mL) and the resulting mixture was stirred and heated to 80° C. in a sealed tube for 1 hour. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (×3). The combined organic layers were washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate) to give the title compound (0.66 g, 57%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(O)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[N:18]\[C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2ccc(Br)cc2/C1=N/c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 392.3 %

Procedure:
A mixture of 5-bromo-1H-indole-2,3-dione (1.0 g, 0.442 mmol) and 3-trifluoromethylaniline (0.993 g, 6.2 mmol) in a solution of 1% acetic acid in methanol was stirred at 50° C. for 12 h. The crude product was concentrated in vacuo, giving the desired crude product (640 mg, 40%).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C@H:30]1[CH2:36][N:35]2[C:37]([CH:40]([OH:42])[CH3:41])=[CH:38][N:39]=[C:34]2[C@H:33]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:32][CH2:31]1>C(#N)C>[C:40]([C:37]1[N:35]2[CH2:36][C@H:30]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=3[F:22])[CH2:31][CH2:32][C@@H:33]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:34]2=[N:39][CH:38]=1)(=[O:42])[CH3:41]
Reactant: CC(O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Product: CC(=O)c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Pyridinium dichromate (0.96 g, 2.55 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(1-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (0.52 g, 1.28 mmol) in acetonitrile (10 mL). After 18 h, the reaction was filtered through celite and concentrated. Saturated sodium carbonate was added and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→40% ethyl acetate/dichloromethane) gave the title compound (0.38 g). MS 406.1 (M+1).