Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH:14]=O)[N:9]=[CH:8][CH:7]=[CH:6]2.[O:16]1[C:20]2([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[O:16]1[C:20]2([CH2:25][CH2:24][N:23]([CH2:14][CH2:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][C:3]=3[O:2][CH3:1])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: COc1cc2cccnc2cc1CC=O
Reactant: C1CC2(CCN1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2cccnc2cc1CCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
1.45 g of (6-methoxyquinolin-7-yl)acetaldehyde and 0.63 g of 1,4-dioxa-8-azaspiro[4.5]decane were dissolved in 20 ml of methylene chloride. Thereafter, 0.42 ml of acetic acid and 0.74 g of sodium triacetoxyborohydride were added to the reaction solution, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with methylene chloride. The extract was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol), so as to obtain 445 mg of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(Br)c1CBr

Procedure:
2-bromo-6-chlorotoluene (20.55 g) and N-bromosuccinimide (19.6 g) were stirred together in carbon tetrachloride (100 ml) under reflux for 22 hours exposure to radiation from an infrared lamp. The resulting solution was cooled in ice, filtered and evaporated to yield the title product which was dissolved in petroleum ether (60-80). Part was recrystallised therefrom as pink needles (8.5 g) and part was recovered by evaporation as a dark orange solid (17.7 g) (total yield 26.2 g. 92%).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#[N:5].[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[NH2:10][C:7]1[CH:8]=[CH:9][C:2]([N:17]2[CH2:18][CH2:19][CH:14]([OH:13])[CH2:15][CH2:16]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OC1CCNCC1
Product: N#Cc1cc(N)ccc1N1CCC(O)CC1
Yield: 58.4 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthetic Example 4 using 2-chloro-5-nitrobenzonitrile (36 g) and 4-hydroxypiperidine (50 g), the title compound (25 g) was obtained. melting point: 144-145° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[C:21]([Zn]C#N)#[N:22]>CN(C=O)C.CCOC(C)=O.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>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([C:21]#[N:22])[CH:18]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#C[Zn]C#N
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.355 g, 0.998 mmol) was combined with dicyanozinc (0.100 g, 0.852 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.100 mmol) in DMF (3 mL) and heated at 120° C. for 25 min in a microwave reactor under an inert atmosphere. The reaction mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO3 and twice with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in CH3OH and gravity filtered through a StratoSpheres™ PL-Thiol MP SPE+ cartridge. The filtrate was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give 5-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-1,3-benzenedicarbonitrile (0.200 g, 0.663 mmol, 66.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.91 (s, 2H), 7.46-7.57 (m, 2H), 3.77 (s, 2H), 1.90 (br. s., 2H). LC-MS (ES+) m/z 302.27, 304.19 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[OH:19])[NH2:15].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[NH2:15][C:14]1[CH:16]=[CH:17][C:18]([O:19][C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)=[C:12]([Cl:11])[CH:13]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(Oc2ccc(N)cc2Cl)cc1F

Procedure:
2.00 g (14.4 mmol) of 2,4-difluorobenzonitrile, 2.06 g (14.4 mmol) of 3-chloro-4-hydroxyaniline and 3.97 g (28.8 mmol) of potassium carbonate in 20 ml of acetonitrile are heated at RF for one hour. Ethyl acetate is added, the mixture is filtered and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60), giving the product which is a regioisomer mixture with a ratio of 62:38.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:24])([CH3:23])[CH3:25])[CH:13]=[C:14]([C:16]#[N:17])[N:15]=3)=[O:10])=[C:4]([C:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=3)[CH:3]=2)=[CH:41][CH:42]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(Br)cc1C1=CCCCC1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccc(N)cc2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a mixture of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4-bromo-2-cyclohex-1-enyl-phenyl)-amide (as prepared in the Example 11, step (f), 30 mg, 0.060 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (14.4 mg, 0.066 mmol) and Pd(PPh3)4 (7 mg, 0.006 mmol) in 1 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (0.24 mL, 0.48 mmol). The resulting mixture was stirred at 80° C. for 3 h under Ar, and then cooled to RT. Treated with 50 μL of EtOAc, the mixture was washed with H2O (2×20 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20% EtOAc/hexane) gave 16 mg (85%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 9.76 (s, 1H), 8.37 (d, 1H, J=8.6 Hz), 7.78 (s, 1H), 7.43-7.47 (m, 3H), 7.35 (d, 1H, J=2.1 Hz), 6.84 (d, 2H, J=8.5 Hz), 5.97 (s, 2H), 5.89 (m, 1H), 3.67 (t, 2H, J=8.2 Hz), 2.25-2.34 (m, 4H), 1.77-1.90 (m, 4H), 0.98 (t, 2H, J=8.2 Hz), 0.01 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C29H35N5O2Si, 514.3 (M+H), found 514.1.
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])([OH:4])(=[O:3])=[O:2].[OH:14]O>ClCCl.S(=O)(=O)(O)O>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][OH:14])=[O:9])([OH:4])(=[O:3])=[O:2]
Reactant: OO
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C(OO)c1cccc(S(=O)(=O)O)c1
Temperature: 42 °C
Yield: 64.2 %

Procedure:
To a suspension of 3-sulphobenzoic acid (5 g, 2.5×10-2 moles) in dichloromethane (60 ml) containing a trace of sulphuric acid (5×10-5 moles) was slowly added hydrogen peroxide (3 g; 85%). The suspension was boiled under reflux (42° C.) for 1 hour after which it was cooled to room temperature, the dichloromethane was decanted off and the residue treated with saturated aqueous magnesium nitrate (25 ml). The resultant precipitate was filtered off, dried over phosphorous pentoxide under vacuum to yield the magnesium salt of 3-sulphoperoxybenzoic acid (3.5 g; 5.31% Avox as O; Magnesium content of 4.7%) compared with a theoretical yield of 5.67 g. The IR spectrum was again substantially the same as for the other preparations.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:10])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(Cl)nc1
Yield: 83.1 %

Procedure:
A mixture of 6-chloropyridine-3-carboxamide (14 g), phosphorous oxychloride (35 ml) and chloroform (120 ml) is refluxed for 2 hr, cooled, and concentrated. The residue is stirred with water and the resulting precipitate is collected and recrystallized from ethanol to provide 10.3 g (83 %) of 6-chloropyridine-3-carbonitrile. This nitrile (2.77 g) is added to a solution of sodium octanolate (prepared from 1-octanol (2.78 g) and sodium hydride (0.88g of 60% dispersion) in DMF (20 ml)). After 30 min at room temperature, the mixture is poured into water, and the product extracted with ether. The extracts are concentrated and chromatographed with 2:3 hexane-dichloromethane, to provide 6-(octyloxy)pyridine-3-carbonitrile as a colorless oil (3.7 g, 80%). This nitrile is dissolved in toluene (15 ml), cooled to -20°, and diisobutylaluminum hydride (12.5 ml of 1.5M solution in toluene) is added dropwise. After an hour, the mixture is poured into 1.0N hydrochloric acid and the product extracted with ether. The extracts are dried, filtered, and concentrated to leave 6-(octyloxy)pyridine-3-carboxaldehyde (2.36 g) as a yellow oil.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1>>[CH3:18][C:9]1[CH:14]=[CH:13][C:12]([C:15]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:16])=[CH:11][CH:10]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)N[C@H](C(=O)O)C(C)C)cc1

Procedure:
Racemic valine and p-toluoyl chloride were processed as described in Example 26A to provide the desired product.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:22]4[CH:27]=[C:26]([NH2:28])[C:25]([F:29])=[CH:24][C:23]=4[Cl:30])[C:15](=[O:21])[N:16]3[CH2:19][CH3:20])=[CH:11][N:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C:26]1[C:25]([F:29])=[CH:24][C:23]([Cl:30])=[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[C:17]3[C:12]([CH:13]=2)=[CH:11][N:10]=[C:9]([NH:8][CH3:7])[CH:18]=3)[CH:27]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.5 %

Procedure:
To a solution of Example A4 (3 g, 6.2 mmol) in DCM (100 mL) was added TFA (20 mL) at RT, and the resulting mixture was stirred at RT for 6 h. The mixture was extracted with water (2×) and the combined aqueous layers were neutralized with NH3.H2O. The resulting precipitate was collected by filtration and dried to give 3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (1 g, 44% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.75 (s, 1H), 7.1 (d, J=11.2 Hz, 1H), 7.0 (m, 1H), 6.73 (d, J=9.6 Hz, 1H), 6.43 (s, 1H), 4.95 (br s, 2H), 4.14 (m, 2H), 2.92 (s, 3H), 1.14 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 347.2 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2[S:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:4]=2[O:3]1.[Br:22]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:22][C:17]1[S:16][C:5]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[CH2:8][C@H:2]([CH3:1])[O:3][C:4]=2[C:18]=1[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)c1csc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(C)c1c(Br)sc2c1O[C@@H](C)CN(C(=O)OC(C)(C)C)C2
Yield: 86.3 %

Procedure:
A solution of tert-butyl (2S)-2-methyl-8-(1-methylethyl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (839 mg) obtained in Example 15, step 1, N-bromosuccinimide (503 mg) and acetonitrile (10 mL) was stirred at room temperature for 1.5 hr, 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 3→7% ethyl acetate/hexane) to give the title compound (908 mg, 86%) as a solid.
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C[Si](C)(C)[O:15][CH2:16][CH2:17][O:18][Si](C)(C)C.O=[C:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([O:34][CH3:35])=[O:33])[CH2:27]1>ClCCl>[O:15]1[C:26]2([CH2:31][CH2:30][CH2:29][CH:28]([C:32]([O:34][CH3:35])=[O:33])[CH2:27]2)[O:18][CH2:17][CH2:16]1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: COC(=O)C1CCCC(=O)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of trimethylsilyltrifluoromethanesulfonate (0.034 mL) in dry dichloromethane (5 mL) was added 1,2-bis(trimethylsiloxy)ethane (4.55 mL) followed by methyl 3-oxocyclohexanecarboxylate (2.9 g). The reaction mixture was stirred for 3 hours at −78° C. The reaction mixture was quenched with dry pyridine (0.5 mL), poured into saturated aqueous NaHCO3, and extracted with ether. The ether layer was dried over Na2CO3/Na2SO4. The reaction mixture was concentrated and purified by flash chromatography on silica with 5 to 30% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:25][CH:24]2[NH:26][C:27]2[S:28][CH2:29][C:30](=[O:32])[N:31]=2)=[CH:19][CH:18]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:29]3/[C:30](=[O:32])[N:31]=[C:27]([NH:26][CH:24]4[CH2:25][CH:23]4[C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[S:28]/3)[CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CSC(NC2CC2c2ccc(F)cc2)=N1
Reactant: CCOc1ccnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOc1ccnc2ccc(/C=C3\SC(NC4CC4c4ccc(F)cc4)=NC3=O)cc12

Procedure:
The similar procedure as described in example 35 was used, starting with 4-ethoxy-quinoline-6-carbaldehyde (example 3b), 2-[2-(4-fluoro-phenyl)-cyclopropylamino]-thiazol-4-one, sodium acetate and acetic acid to give 5-[1-(4-ethoxy-quinolin-6-yl)-meth-(Z)-ylidene]-2-[2-(4-fluoro-phenyl)-cyclopropylamino]-thiazol-4-one. LC-MS m/e 434.5 (MH+).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C[O-].[Na+].[CH3:21][O:22][CH2:23]CCOS(C1C=CC(C)=CC=1)(=O)=O>CO.O>[CH3:21][O:22][CH2:23][CH2:16][CH2:15][S:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([OH:5])=[O:7])[CH2:13][CH2:12]1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCCCSC1CCN(C(=O)O)CC1
Reaction time: 0.25 h

Procedure:
Amine preparation: A mixture of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.82 g) and potassium thioacetate (2.31 g) was heated to 60° C. in DMF (10 mL). After 4 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo and then purified by flash chromatography to give 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.80 g). To a solution of 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (607 mg) in dry MeOH (5 mL) was added a solution of sodium methoxide in MeOH (25% wt, 0.59 mL). After stirring for 15 min, toluene-4-sulfonic acid 3-methoxy-propyl ester (described elsewhere, 571 mg) was added in MeOH. After 24 h, the reaction mixture was diluted with water, extracted with ethyl acetate, dried (MgSO4), filtered and concentrated in vacuo to yield 4-(3-methoxy-propylsulfanyl)-piperidine-1-carboxylic acid tent-butyl ester. Treatment with mCPBA (as described above) yielded 4-(3-methoxy-propane-1-sulfonyl)-piperidine-1-carboxylic acid tert-butyl ester. Treatment of this compound with HCl in DCM/MeOH yielded the desired amine, isolated as the hydrochloride salt.
Reaction SMILES: C(OC(=O)C[C@H]([NH:20][C:21](N)=[O:22])CC1C=CC(C2C=CC=CC=2)=CC=1)C.Br[CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CCO>[CH2:31]([O:30][C:28]([C:27]1[N:20]=[CH:21][O:22][CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(N)=O
Solvent: CCO
Product: CCOC(=O)c1cocn1
Temperature: 25 °C

Procedure:
To a suspension of (R)-4-biphenyl-4-yl-3-ureido-butyric acid ethyl ester (169 mg, 0.518 mmol) in EtOH (5 ml) at ice bath is added ethyl bromopyruvate (0.098 ml, 0.777 mmol). The reaction is warmed up slowly to room temperature and stirred at reflux overnight. The reaction is concentrated and the residue is taken up in EtOAc and H2O. The combined organic layer is washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-(R)-1-biphenyl-4-ylmethyl-2-ethoxycarbonyl-ethylamino)-oxazole-4-carboxylic acid ethyl ester. HPLC retention time=1.42 minutes (condition B); MS (m+1)=423.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]2[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[N:14]=2)[CH:8]=1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([N+:28]([O-:30])=[O:29])=[C:7]([NH:9][C:10]3[S:11][C:12]([C:25]([NH2:27])=[O:26])=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=4)[N:14]=3)[CH:8]=2)[CH2:34][CH2:33]1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(C(F)(F)F)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(C(F)(F)F)c4)c(C(N)=O)s3)c2)CC1
Reaction time: 16 h
Yield: 82.7 %

Procedure:
A mixture of 0.1289 g (0.295 mmole) of 2-(5-formyl-2-nitro-phenylamino)-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.48b), 6.5 mL of dichloromethane, 0.1 mL (0.892 mmole) of 1-methyl piperazine and 0.3321 g (1.489 mmole) of sodium triacetoxyborohydride was stirred for 16 hours. The mixture was quenched by the addition of 1 mL of saturated ammonium chloride, 1 mL of water and 5 mL of dichloromethane, followed by the addition of 10 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane. The mixture was stirred for 45 minutes and then diluted with 75 mL of dichloromethane and 5 mL of water. The aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 1:99-20:80) to give 0.127 g of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(3-trifluoromethylphenyl)-thiazole-5-carboxylic acid amide (VI.48c) as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][NH:30][CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].CCN(CC)CC.[C:41](Cl)(=[O:43])[CH3:42]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:32][CH3:33])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:28][CH2:27][CH:26]5[CH2:29][N:30]([C:41](=[O:43])[CH3:42])[CH2:31][CH:25]45)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)Cl
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CNCC21
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CN(C(C)=O)CC21
Reaction time: 2 h
Yield: 36.7 %

Procedure:
To a mixture of N-(3-chloro-4-fluorophenyl)-6-(3-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)propoxy)-7-methoxyquinazolin-4-amine (0.10 g) and Et3N (0.072 g) at 0° C. was added acetyl chloride (0.019 g) dropwise and the reaction was continued to stir for 2 h at same temperature. Then the mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and filtered. The solvent of the filtrate was removed by reduce vacuum pressure, and the residue was recrystallized from DCM/PE to give the title compound (0.04 g, 40.00%), HPLC: 96.24%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 514.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.50-1.53 (m, 2H), 1.83-1.87 (m, 2H), 2.25-2.29 (m, 3H), 2.30 (s, 3H), 2.44 (t, J=4.2 Hz, 2H), 2.90-2.93 (m, 1H), 3.50-3.61 (m, 4H), 4.03 (s, 3H), 4.08 (t, J=4.8 Hz, 2H), 7.16 (s, 1H), 7.26 (s, 1H), 7.45 (s, 1H), 7.57-7.60 (m, 1H), 7.91-7.95 (m, 1H), 8.64 (s, 1H) ppm.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30]O)[CH:25]=1)#[N:23]>C(Cl)Cl>[C:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][Br:1])[CH:25]=1)#[N:23]
Reactant: N#Cc1ccnc(CO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccnc(CBr)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
Bromine (1.07 mL, 20.8 mmol) was added slowly at 0° C. to a solution of triphenylphosphine (5.53 g, 21.1 mmol) in methylene chloride (97 mL). The solution was warmed to room temperature and a white precipitate was observed. 4-Cyano-2-hydroxymethylpyridine 36 (2.61 g, 19.5 mmol) in methylene chloride (20 mL) was added dropwise and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed with saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give a white solid. Purification by flash column chromatography (silica, 99:1 methylene chloride/methanol) gave 4-cyano-2-bromomethylpyridine (3.95 g), which was used immediately in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ 8.76 (d, J=5.0 Hz, 1H), 7.7 (s, 1H), 7.46 (dd, J=5.0, 1.3 Hz, 1H), 4.58 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([O:27][CH2:2][C:3]2[C:4]([S:9][CH2:10][CH:11]3[CH2:13][CH2:12]3)=[N:5][CH:6]=[CH:7][CH:8]=2)=[C:22]([F:28])[CH:21]=1)[CH3:15]
Reactant: ClCc1cccnc1SCC1CC1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Product: CCOC(=O)CCc1cc(F)c(OCc2cccnc2SCC2CC2)c(F)c1
Yield: 80 %

Procedure:
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.07 g, 0.32 mmol) obtained in Step C of Preparation Example 18 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.1 g, 80%).