Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8]Cl)(=[O:3])[CH3:2].[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][P:13]([O:14][CH2:15][CH3:16])([O:12][CH2:10][CH3:11])=[O:17])(=[O:3])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CC(=O)OCCOCCl
Product: CCOP(=O)(COCCOC(C)=O)OCC
Temperature: 25 °C
Yield: 68.1 %

Procedure:
A mixture of 1-acetoxy-2-(chloromethoxy)ethane (67.8 g, 444 mmol) and triethylphosphite (81.3 g, 490 mmol) was heated at 105°-110° C. for 12 hours. Vigorous gas evolution was noted initially. The reaction mixture was next cooled to room temperature and the crude material purified by distillation (0.9 mmHg, 130°-134° C.) to afford 76.9 g (68%) of 1-acetoxy-2-(diethylphosphonomethoxy)ethane as a colorless liquid.
Reaction SMILES: C(NC1C=[C:12]([CH:51]=C(C)C=1)[C:13]([NH:15][C@@H:16]([CH2:42][C:43]1[CH:48]=[C:47]([F:49])[CH:46]=[C:45]([F:50])[CH:44]=1)[C@@H:17]([C@H:26]1[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][N:27]1C(OC(C)(C)C)=O)[O:18][Si](C(C)(C)C)(C)C)=[O:14])(=O)C1C=CC=CC=1.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H](NC(=O)C1C=[C:80]([C:82]2[O:83][CH:84]=[CH:85][N:86]=2)[CH:79]=[C:78]([C:87]([N:89]2[CH2:93][CH2:92][CH2:91][C@@H:90]2[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=1)CC1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.COC[C@H]1CCCN1C(C1C=C(C=C(C2OC=CN=2)C=1)C(O)=O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:49][C:47]1[CH:48]=[C:43]([CH2:42][C@H:16]([NH:15][C:13](=[O:14])[C:12]2[CH:51]=[C:80]([C:82]3[O:83][CH:84]=[CH:85][N:86]=3)[CH:79]=[C:78]([C:87]([N:89]3[CH2:93][CH2:92][CH2:91][C@@H:90]3[CH2:94][O:95][CH3:96])=[O:88])[CH:77]=2)[C@H:17]([OH:18])[C@H:26]2[CH2:30][C@@H:29]([O:31][CH2:32][CH2:33][CH3:34])[CH2:28][NH:27]2)[CH:44]=[C:45]([F:50])[CH:46]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(NC(=O)c3ccccc3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC[C@H]1CCCN1C(=O)c1cc(C(=O)O)cc(-c2ncco2)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C(=O)N3CCC[C@@H]3COC)cc(-c3ncco3)c2)C1
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Step 11 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)-5-(oxazol-2-yl)benzoic acid (Preparation H, 40 mg, 0.12 mmol) in dichloromethane (3 mL) was added Hunig's base (46 mg, 0.36 mmol) to make a clear solution and HATU (60 mg, 0.156 mmol) was then added. After stirring for 20 min, the reaction mixture was added (2R,4R)-tert-butyl 2-((1S,2S)-2-amino-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate (Step 1 (A), 64 mg, 0.12 mmol) and the reaction mixture was stirred at rt for 16 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 30% to 50% to 70% EtOAc/Hexane step gradient) to give 70 mg of the title compound (70% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.07 (3H, s), 0.84 (9H, s), 0.87 (3H, m), 1.46-1.50 (1H, m), 1.74 (1H, m), 1.92-2.06 (3H, m), 2.17-2.23 (2H, m), 2.66 (1H, m), 2.77-2.81 (2H, m), 2.92 (1H, m), 3.05 (1H, m), 3.29-3.38 (4H, m), 3.48 (1H, m), 3.58 (1H, m), 3.66 (1H, m), 3.76 (1H, m), 3.98 (1H, m), 4.07-4.09 (1H, m), 4.12-4.14 (1H, m), 4.43 (1H, brd s), 4.61 (1H, m), 6.58 (1H, m), 6.77 (2H, d, J=10 Hz), 7.22 (1H, s), 7.69 (1H, s), 8.10 (1H, s), 8.28 (1H, s), 8.53 (1H, brd s), 8.64 (1H, s). MS (ESI) (M+H)+ 841.61.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=1>C(OCC)C>[Br:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Brc1cccc(Br)n1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: Clc1ccc(CNc2cccc(Br)n2)cc1
Temperature: 150 °C
Yield: 100.8 %

Procedure:
A microwave vial was charged with 4-chloro benzylamine (700 mg; 5 mmol; 5 equivalents) and 2,6-dibromo pyridine (238 mg, 1 mmol). The reaction mixture was stirred in the microwave at 150° C. for three times ten minutes (200 W maximum). The reaction mixture was diluted with diethyl ether (50 ml), washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic was dried over magnesium sulfate and, after filtration, concentrated in vacuo to afford an oil as the title compound (300 mg, 100% yield). LC/MS: 299 [M+H]
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[CH:6][CH:7]=1
Reactant: c1c[nH]cn1
Reactant: Clc1ccc(Cl)nn1
Solvent: Clc1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(-n2ccnc2)nn1
Yield: 37.5 %

Procedure:
A solution of 3,6-dichloropyridazine (Aldrich, 300 mg, 2.0 mmol), imidazole (Aldrich, 163 mg, 2.4 mmol), and diisopropylethylamine (620 mg, 4.8 mmol) in 1.5 mL 1,2-dichlorobenzene was heated in a sealed tube to 120° C. at 330 watts for 45 min in an Emry™ Creator microwave. The crude reaction mixture was purified by column chromatography (SiO2, 1% methanol-CH2Cl2) to give 135 mg of the title compound (0.75 mmol, 38% yield) as the major product. MS (DCl/NH3) m/z 181 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:36])[CH2:16]P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:13]>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9]/[CH:10]=[CH:16]/[C:15]([O:14][CH2:12][CH3:13])=[O:36])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CCOC(=O)C[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
2-(Tert-butyldimethylsilyloxy)acetaldehyde (10.0 g, 57.3 mmol) was added to a solution of (2-ethoxy-2-oxoethyl)triphenylphosphorane (20.0 g, 57.4 mmol) in 150 mL toluene, the mixture was stirred at RT overnight and then heated to 50° C. for 5 hrs. Solvents were removed and the residue was suspended in 400 mL of hexane. The solution was filtered, the filtrate was concentrated to give the product 3A as a colorless liquid 13.7 g (98%). 1H NMR (400 MHz, CDCl3) δ ppm 0.08 (s, 6H), 0.92 (s, 9H), 1.30 (t, 3H, 6 Hz), 4.21 (q, 2H, 6 Hz), 4.34 (dt, 2H), 6.09 (dt, 1H), 7.00 (dt, 1H); ESI-MS:m/z 245.3 (M+H)+, HPLC retention time: T=2.737 min (analytical-3).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12](=O)[CH:11]2[O:15][CH:10]12)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][SH:22].C(N(CC)CC)C.[CH3:30][OH:31]>>[Si:1]([O:8][CH:9]1[CH2:10][C:11](=[O:15])[C:12]([S:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:30][OH:31])=[CH:13]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)C2OC12
Reactant: CO
Reactant: OCCCCCS
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1C=C(SCCCCCCO)C(=O)C1
Reaction time: 0.17 h
Yield: 31 %

Procedure:
1.26 g (5.94 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2,3-epoxy cyclopentanone and 804 mg (6.0 mmoles) of 5-hydroxy-1-pentanethiol were dissolved in 10 ml of methanol, and 606 mg (6 mmoles) of triethylamine was added. After the reaction was carried out for 10 minutes, the solvent was evaporated to give 2.1 g of a crude product. The crude product was subjected to dry column chromatography and developed with hexane/ethyl acetate (7/3) to give 710 mg (2.16 mmoles; yield 31%) of 4-t-butyldimethylsilyloxy-2-(6-hydroxyhexylthio)-2-cyclopentenone.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=1.[Se](=O)=[O:19]>O1CCOCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([CH:15]=[O:19])[CH:12]=[CH:11][CH:10]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc(-c2ccccc2C(F)(F)F)n1
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccccc2C(F)(F)F)n1
Reaction time: 48 h

Procedure:
0.6 g of 6-(2-trifluoromethylphenyl)-2-methylpyridine was dissolved in 50 ml of 1,4-dioxane, 0.43 g of selenium dioxide (Aldrich, Gold Label) was added and the mixture was refluxed for 48 hours. A further 0.7 g, selenium dioxide and 50 ml dioxane were added and refluxing was continued for a further 48 hours. The solids were removed by filtration and the dioxane evaporated to afford crude 6-(2-trifluoromethylphenyl)-2-pyridinecarboxaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH:13]=C)[C@H:9]2[CH2:10][C@H:5]([C@@H:6]([CH3:12])[C:7](=[O:11])[CH2:8]2)[O:4][O:3]1.[O:15]=[O+][O-].O=O.CSC>CO>[CH3:1][C@:2]1([CH:13]=[O:15])[C@H:9]2[CH2:10][C@H:5]([C@@H:6]([CH3:12])[C:7](=[O:11])[CH2:8]2)[O:4][O:3]1.[CH3:1][C@@:2]1([CH:13]=[O:15])[C@H:9]2[CH2:10][C@H:5]([C@@H:6]([CH3:12])[C:7](=[O:11])[CH2:8]2)[O:4][O:3]1
Reactant: O=[O+][O-]
Reactant: C=CC1(C)OO[C@@H]2C[C@H]1CC(=O)[C@@H]2C
Agent: O=O
Solvent: CSC
Solvent: CO
Product: C[C@H]1C(=O)C[C@@H]2C[C@H]1OO[C@@]2(C)C=O
Product: C[C@H]1C(=O)C[C@@H]2C[C@H]1OO[C@]2(C)C=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
33 g of (1R,4RS,5S,8R)-4,8-dimethyl-4-vinyl-2,3-dioxabicyclo[3.3.1]nonan-7-one [obtained in accordance with Example 2(a)] are dissolved in 100 ml of methanol and cooled to -70° under argon. A stream of ozone from 40 1 of oxygen/h is introduced and maintained up to saturation (pale blue colour). After 3-4 hours the source of current is switched off and the excess ozone is displaced by oxygen. 40 ml of dimethyl sulphide are added thereto and the suspension is then allowed to warm to room temperature. The methanol is distilled off and the residue is purified and separated by column chromatography on silica gel while eluting with hexane/ethyl acetate (2:1 to 1:2). After crystallization from hexane/ethyl acetate at 0° there are obtained (1R,4R,5S,8R)-4,8-dimethyl-7-oxo-2,3dioxabicyclo[3.3.1]nonane-4-carboxaldehyde [m.p. 92°] and (1R,4S,5S,8R)- 4,8-dimethyl-7-oxo-2,3-dioxabicyclo[3.3.1]-nonane-4-carboxaldehyde [m.p. 97°].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:4]=1.[C:16](Cl)(Cl)=[S:17]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([N:7]=[C:16]=[S:17])=[C:5]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(N)c(N2CCOCC2)c1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N=C=S)c(N2CCOCC2)c1

Procedure:
Reaction of 4-methoxy-2-morpholinoaniline (4.7 g) and thiophosgene (2.9 ml) in dioxan (25 ml) and water (75 ml) for 30 minutes at 0° C. and 3 hours at room temperature yielded a residue which was extracted with dichloromethane to give 4-methoxy-2-morpholinophenyl isothiocyanate as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[NH2:25].[CH3:26][N:27](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.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>[NH2:25][C:3]1[CH:4]=[C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[C:26]#[N:27]
Reactant: CN(C)C=O
Reactant: Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Temperature: 100 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a solution of 2-bromo-5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenylamine (Example I3) (0.840 g, 1.84 mmol) in N,N-dimethylformamide (3 ml) under a nitrogen atmosphere was added zinc(II) cyanide (0.346 g, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.255 g, 0.22 mmol). The reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was diluted with toluene and the phases were separated. The aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine and aqueous ammonium hydroxide (saturated), dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/cyclohexane 1:5) to give 2-amino-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzonitrile (0.480 g, 36% yield). 1H-NMR (CDCl3, 400 MHz): 7.45 (m, 4H), 7.08 (s, 1H), 6.95 (q, 1H), 4.52 (s, 2H), 4.02 (d, 1H), 3.62 (d, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.[CH2:19]([C:23]1[NH:24][C:25](=[O:32])[CH:26]=[C:27]([CH:31]=1)[C:28](O)=[O:29])[CH2:20][CH2:21][CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C>CN(C=O)C>[CH2:19]([C:23]1[NH:24][C:25](=[O:32])[CH:26]=[C:27]([C:28]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:29])[CH:31]=1)[CH2:20][CH2:21][CH3:22]
Reactant: OCc1ccccc1
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1cc(C(=O)OCc2ccccc2)cc(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
13.3 g (123 mmol) of benzyl alcohol and 4.7 g (31 mmol) of hydroxybenzotriazole are added to a solution of 6.0 g (31 mmol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 100 ml of DMF. The resulting clear solution is cooled to 0° C. followed by the addition of 7.0 g (34 mmol) of dicyclohexylcarbodiimide and 4.2 ml (31 mmol) of triethylamine. The mixture is allowed to thaw at 20° C., stirred for a further 2 hours and subjected to aqueous work-up. 6.8 g (77%) of theory of the title compound are obtained.
Reaction SMILES: BrC1C(N2CCN(CC3C=NC=CC=3)CC2)=C2N=C(C3C=CC(CN)=CC=3)NC2=NC=1.[Br:32][C:33]1[C:34]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)[CH2:53][CH2:52]2)=[C:35]2[N:41]=[C:40]([CH2:42][NH:43]C(=O)OC(C)(C)C)[NH:39][C:36]2=[N:37][CH:38]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:33]1[C:34]([N:51]2[CH2:52][CH2:53][N:54]([CH2:57][C:58]3[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=3)[CH2:55][CH2:56]2)=[C:35]2[N:41]=[C:40]([CH2:42][NH2:43])[NH:39][C:36]2=[N:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)NCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Agent: NCc1ccc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Yield: 87 %

Procedure:
This was prepared using the same procedure as for (4-(6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)phenyl)methanamine, but here using tert-butyl (6-bromo-7-(4-(pyridin-3-ylmethyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)methylcarbamate (10 mg, 0.020 mmol), TFA (0.2 mL) and CH2Cl2 (1 mL). The same purification procedure gave the desired product (7 mg, 88%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.60 (s, br, 4H, piperazine N(CH2)2), 3.57 (s, br, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2Ar), 4.04 (s, br, 2H, CH2NH2), 7.38 (dd, J=7.7, 4.7 Hz, 1H, pyridine H-5), 7.77 (dt, J=7.8, 1.7 Hz, 1H, pyridine H-4), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.7, 1.5 Hz, 1H, pyridine H-6), 8.56 (d, J=1.6 Hz, 1H, pyridine H-2);
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[N:6][CH:7]=1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]#[N:11])=[N:6][C:7]=1[Br:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CCCc1cnc(N)cn1
Solvent: ClCCl
Product: N#CCCc1cnc(N)c(Br)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(5-aminopyrazin-2-yl)propanenitrile (45 mg, 0.304 mmol) in DCM (1519 μL) was added NBS (48.7 mg, 0.273 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min. After quenched with NaHCO3, the reaction mixture was extracted with EtOAc 3 times. The combined organic layer was washed with water and brine, dried over anhydrous sodium sulfate. Filtered and concentrated in vacuo. The crude product was used in next step reaction without purification. LCMS (m/z): 227/229.1 (MH+), 0.45 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][C:28](=[O:35])[NH:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:16])([F:15])[F:17])[CH:12]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:35])[NH:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Reactant: Nc1cc(F)cc2[nH]c(=O)ccc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2[nH]c(=O)ccc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC

Procedure:
In the same way as in Example 148, 173 mg (0.51 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 90 mg (0.51 mmol) of 5-amino-7-fluoroquinolin-2(1H)-one and 0.32 ml of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}-7-fluoroquinolin-2(1H)-one. 270 mg of crude imine are cyclized in the same way as in Example 148 at −30° C. with 7.6 ml (7.6 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-70%) yields 26 mg of desired product.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C@@:13]3([C:26]4([CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[N:25]4[C@@H:20]([C:21](=[O:46])[O:22][C@@H:23]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C@H:24]4C4C=CC=CC=4)[C@@H:19]3[C:47]3[CH:52]=[CH:51][N:50]=[C:49]([Cl:53])[C:48]=3[F:54])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[Cl-].[NH4+].[CH3:57][OH:58]>>[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]3([C@@H:19]([C:47]4[CH:52]=[CH:51][N:50]=[C:49]([Cl:53])[C:48]=4[F:54])[C@H:20]([C:21]([NH:3][C@@H:6]4[CH2:7][CH2:12][C@@H:13]([CH2:14][OH:18])[O:58][CH2:57]4)=[O:46])[N:25]([C@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:23]([OH:22])[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:26]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: CO
Reactant: CCN(CC)CC
Reactant: CC1(C)CCC2(CC1)N1[C@H](c3ccccc3)[C@H](c3ccccc3)OC(=O)[C@H]1[C@H](c1ccnc(Cl)c1F)[C@@]21C(=O)Nc2cc(Cl)ccc21
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(C)CCC2(CC1)N([C@H](c1ccccc1)[C@@H](O)c1ccccc1)[C@@H](C(=O)N[C@@H]1CC[C@@H](CO)OC1)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Temperature: 50 °C
Reaction time: 120 h
Yield: 89 %

Procedure:
The compound (131 mg, 1.00 mmol) obtained in Step 3 of Reference Example 2 and triethylamine (0.14 ml, 1.00 mmol) were added to a methanol (4 ml) solution of the compound (268 mg, 0.40 mmol) obtained in Step 1 of Example 16 and the resulting mixture was stirred at 50° C. for 5 days. After cooling, saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [chloroform:methanol=100:0→30:1 (v/v)] to give 288 mg (89%) of the title compound as a colorless amorphous solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[N:15]=[C:16]([O:19][CH3:20])[S:17][CH:18]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][N:32]([CH3:38])[C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:22]#[N:23])[C:10]([CH3:21])=[C:11]([C:14]4[N:15]=[C:16]([O:19][CH3:20])[S:17][CH:18]=4)[C:12]=3[N:35]3[CH2:36][CH2:37][C@H:33]([N:32]([CH3:38])[CH3:31])[CH2:34]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2F)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1nc(-c2c(C)c(C#N)c3nc(C4CC4)oc3c2N2CC[C@H](N(C)C)C2)cs1
Temperature: 90 °C
Reaction time: 18 h
Yield: 11.1 %

Procedure:
2-Cyclopropyl-7-fluoro-6-(2-methoxy-1,3-thiazol-4-yl)-5-methyl-1,3-benzoxazole-4-carbonitrile (I-179) (120 mg, 0.36 mmol) was dissolved in dimethyl sulfoxide (2.4 ml), then at room temperature, triethylamine (76 μl, 0.55 mmol) and (3S)-3-(dimethylamino)pyrrolidine (56 μl, 0.44 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 18 hours, then cooled to room temperature. This was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC, in which, as the mobile layer, chloroform:methanol=9:1 was first used and then chloroform:7 N ammonia-containing methanol solution=97:3 was used, thereby obtaining a roughly-purified product (17 mg). This was washed with diisopropyl ether to obtain the entitled compound (6.5 mg, 4.2%) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11]([CH3:16])=[C:12]([CH2:14]Cl)[N:13]=2)=[CH:5][CH:4]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C.O>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:14][C:12]3[N:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH3:2])=[CH:4][CH:5]=4)[NH:10][C:11]=3[CH3:16])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1ccc(-c2nc(CCl)c(C)[nH]2)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)c(C)[nH]2)cc1

Procedure:
50 Grams (0.2 mol) of 2-(4-methylphenyl)-4-chloromethyl-5-methyl-1H-imidazole hydrochloride dissolved in 200 ml of a mixture of ethanol:water 6:4 were added dropwise to a refluxing solution of 55 grams (0.2 mol) of N-(diphenylmethyl)piperazine and 24 grams (0.6 mol) sodium hydroxide in 200 ml of a mixture of ethanol:water 6:4. After 2 to 3 hours 1-diphenylmethyl-4-[(2-(4-methylphenyl)-5-methyl-1H-imidazol-4-yl)methyl]piperazine precipitated from the reaction mixture. After having left the crystals standing at room temperature, they were removed by filtration and recrystallized from methanol to give the free base which melted at 220°-222° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16]Br)[CH2:5]1)(=[O:3])[CH3:2].[C-:18]#[N:19].[Na+]>CC#N.C1OCCOCCOCCOCCOCCOC1>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH2:15][CH2:16][C:18]#[N:19])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCBr)c2c(C)cc(C)cc21
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CC(CCC#N)c2c(C)cc(C)cc21
Yield: 101.9 %

Procedure:
1-Acetyl-3-(2-bromoethyl)-4,6-dimethylindoline (5.4 g), NaCN (3.7 g) and 18-crown-6 (480 mg) were suspended in CH3CN (50 ml), and the suspension was refluxed for 15 hr. CH3CN was evaporated under reduced pressure. CHCl3 (100 ml) was added, and the mixture was washed with water and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: CHCl3 /MeOH=50/1-10/1) to give 4.5 g of 1-acetyl-3-(2-cyanoethyl)-4,6-dimethylindoline.