Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)(C)(C)C.[CH3:26][C:27]([Mg]Br)=[CH:28][CH3:29].[Cl-:32].[NH4+]>O1CCCC1>[ClH:32].[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:7][C:8]2[C:13]3[NH:14][C:28]([CH3:29])=[C:27]([CH3:26])[C:12]=3[CH:11]=[N:10][CH:9]=2)=[CH:23][CH:22]=1
Reactant: CC=C(C)[Mg]Br
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1cnccc1[N+](=O)[O-]
Reactant: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(NCc3ccc(F)cc3)cncc2c1C
Product: Cl
Temperature: -20 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
(4-Fluorobenzyl)-(4-nitropyridin-3-yl)-carbamic acid tert-butyl ester (5.1 g) prepared in Step 2 was dissolved in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere. 1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution, 55.0 ml, 65.2 mmol) was added at −78° C. to the solution, which was then stirred for 5 hours at −20° C. 20 ml of 20% ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate (200 ml) twice. The separated organic layer was dried on anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1 (v/v)), dissolved in 1 ml of ethyl acetate and then saturated with hydrochloric acid gas. The resulting precipitate was filtered to give the titled compound as a pale yellow solid (2.1 g, 35.0%).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23].C(OCC)(=O)C>ClCCl>[Br:20][CH2:21][C:22]([NH:9][C:8]1[CH:10]=[CH:11][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[CH3:12])=[O:23]
Reactant: Cc1cc(C(C)(C)C)ccc1N
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C(C)(C)C)ccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 g (33.69 mmol) of 4-tert-butyl-2-methylaniline and 3.75 g (37.06 mmol) of triethylamine are initially charged in 150 ml of dichloromethane. At 0°-5° C., 7.48 g (37.06 mmol) of bromoacetyl bromide, dissolved in 90 ml of dichloromethane, are added dropwise, and a light-brown precipitate is formed. The mixture is stirred at room temperature overnight. 150 ml of ethyl acetate are then added to the reaction mixture, which is extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate soluton and water. The organic phase is dried over magnesium sulphate and freed from the solvent under reduced pressure. The residue is purified chromatographically. The product is recrystallized from ethyl acetate and n-pentane, filtered off with suction and dried under reduced pressure at 40° C. This gives 6.53 g (68% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([N:18]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19]2)[CH2:14][CH2:13]1)=[O:10].[O-:25][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([N:18]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19]2)[CH2:16][CH2:17]1)=[O:10]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C=O)c3)CC2)c(Cl)c1Cl
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(n3ccc(C(=O)O)c3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Solutions of 3,4-dichloro-N-[1-(3-formyl-1H-pyrrol-1-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 259, 90 mg, 0.24 mmol) in 10 ml acetone and KMNO4 (39 mg, 0.24 mmol) in 3 ml water were combined and stirred at ambient temperature overnight. Due to incomplete conversion, solutions of KMnO4 (15 and 20 mg) in 3 ml water were added at 5 hour intervals. The mixture was quenched with aqueous NaHSO3 and partitioned between EtOAc and water. The EtOAc was separated and washed with brine. Drying (MgSO4) and removal of solvent gave product as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[Na+].[CH3:12]I.Cl[C:15]([O:17][CH3:18])=[O:16]>CO>[CH3:18][O:17][C:15]([NH:1][C@@H:2]([C:3]([CH3:5])([S:6][CH3:12])[CH3:4])[C:7]([OH:9])=[O:8])=[O:16]
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)SC
Temperature: 0 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
A solution of L-penicillamine (0.5 g, 3.35 mmol) in methanol (3.3 mL) at 0° C. was treated with aqueous NaOH solution (3.7 mL, 1 N) and methyl iodide (0.23 mL, 3.69 mmol), stirred at 0° C. for 16 hours, treated with additional aqueous NaOH solution (3.5 mL, 3 N) at 0° C., followed by methyl chloroformate (0.5 mL, 6.47 mmol), warmed to 25° C. and stirred for 3 hours, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.428 g, 58% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH3:8][NH:9][C:10](=[S:13])[NH:11][NH2:12]>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH:5]1[N:9]([CH3:8])[C:10](=[S:13])[N:11]=[N:12]1)[CH3:2]
Reactant: CNC(=S)NN
Reactant: CCOCC(=O)Cl
Solvent: c1ccncc1
Product: CCOCC1N=NC(=S)N1C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Ethoxyacetyl chloride (57 g) was added slowly to a stirred solution of 4-methylthiosemicarbazide (53.5 g) in dry pyridine (500 ml) at 0°-5°. The mixture was allowed to attain room temperature and stirring was continued for 18 hours. Following concentration under reduced pressure the residue was treated with a solution of sodium (21.4 g) in ethanol (500 ml) and the mixture was heated under reflux for 24 hours. Following concentration and acidification with hydrochloric acid a solid was obtained. After partial concentration the solid was collected and recrystallised from ethyl acetate to give 3-ethoxymethyl-4-methyl-1,2,4-triazoline-5-thione (53 g) m.p. 137°-138°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.C(Cl)(=O)C(Cl)=O.[C:29]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])#[N:30].CN(C=O)C>CN(C=O)C.C(Cl)Cl>[C:29]([C:31]1[CH:32]=[C:33]([NH:34][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:22])[CH:35]=[CH:36][CH:37]=1)#[N:30]
Reactant: N#Cc1cccc(N)c1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4cccc(C#N)c4)cc3)c2)o1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 8.2 %

Procedure:
2′-Methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (100 mg, 0.34 mmol), oxalyl chloride (0.03 ml, 0.41 mmol), and DMF (1 drop) were mixed in DCM (5 ml) and stirred at room temperature for 35 min. 3-Cyanoaniline (44 mg, 0.374 mmol) was added to the solution and the mixture stirred for 2 h; DMF (1 ml) was added and stirring continued for 18 h. The solvents were evaporated from the reaction under vacuum and the residue chromatographed on an SPE (silica, 5 g), eluting with DCM and then DCM/ethanol/ammonia (300:8:1). The product fractions were concentrated in vacuo to give N-(3-cyanophenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide as a white solid (11 mg, 8%). NMR; δH [2H6]—DMSO 10.65,(1H, b), 8.28,(1H, m), 8.07,(3H, m), 7.91,(1H, dd), 7.79,(1H, d), 7.62-7.56,(5H, m), 2.57,(3H, s), 2.33,(3H, s). LCMS; retention time 3.49 min, MH+ 395
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6][N:5]=1.C([Li])CCC.CCCCCC.[CH2:31]=[O:32]>C1COCC1.CCOCC>[C:13]1([C:7]2[O:6][N:5]=[C:4]([C:3]#[C:2][CH2:31][OH:32])[C:8]=2[C:9]([F:12])([F:11])[F:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=O
Reactant: FC(F)(F)c1c(C=C(Br)Br)noc1-c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC#Cc1noc(-c2ccccc2)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 62.6 %

Procedure:
To a solution of 3-(2,2-dibromovinyl)-5-phenyl-4-(trifluoromethyl)isoxazole (Preparation 62A, 0.496 g, 1.19 mmol) in THF (6.0 mL) at −78° C. was slowly added a 2.5 M solution of butyl lithium in hexane (1.05 mL, 2.61 mmol). The reaction mixture was stirred at −78° C. for 25 min. and then warmed to room temperature gently with a heat gun. Once at room temperature, paraformaldehyde (0.713 g, 23.74 mmol) was added, and the reaction mixture was stirred for 5 min. The mixture was diluted with ether, washed with water (2×), and washed with brine. The combined aqueous layers were extracted with ether, and the combined organics layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (1%-5%-20%) to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)prop-2-yn-1-ol (0.199 g, 0.745 mmol, 63% yield) as a yellowish-orange solid. The product had an HPLC ret. time=2.39 min.−Column: Chromolith SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=268.17.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[OH-:9].[K+].[CH2:11]=O.Cl>O>[F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][C:7]=1[CH2:11][OH:9]
Reactant: Oc1cccc(F)c1
Reactant: [OH-]
Reactant: C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: OCc1ccc(O)cc1F
Temperature: 40 °C
Reaction time: 18 h
Yield: 8 %

Procedure:
to a stirred solution of 3-fluorophenol (10.4 g) and potassium hydroxide (85%, 6.1 g) in water (20 ml) at 60° C. was added dropwise over 1 h a solution of 37% aqueous formaldehyde solution (14.3 ml) in added water (20 ml). The mixture was cooled to 40° C., stirred for 18 h then cooled to room temperature and acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed (water, brine), dried (sodium sulfate), concentrated in vacuo and purified by column chromatography (SiO2; ethyl acetate-isohexane, 1:1) to give the product as a white, crystalline solid (1.0 g, 8%): δH (400 MHz, DMSO-d6) 9.70 (1H, m, OH), 7.21 (1H, t, J 8.5 Hz), 6.58 (1H, dd, J 8, 2, Hz), 6.51 (1H, dd, J 12, 2 Hz), 4.98 (1H, m, OH) and 4.41 (2H, s); HPLC (XTERRA, 50/80, 235 nm) 93% (0.54 min).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH:17]=2)=[CH:9][C:8]=1[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(N(CC)CC)C.ClCCl>C1COCC1>[CH3:1][S:2]([O:21][CH2:20][CH2:19][CH2:18][N:16]1[CH:17]=[C:13]([C:10]2[CH:11]=[N:12][C:7]([NH2:6])=[C:8]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[CH:9]=2)[CH:14]=[N:15]1)(=[O:4])=[O:3]
Reactant: Nc1ncc(-c2cnn(CCCO)c2)cc1-c1nc2ccccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CS(=O)(=O)OCCCn1cc(-c2cnc(N)c(-c3nc4ccccc4o3)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonyl chloride (0.577 ml) was added to 3-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]propan-1-ol (1.25 g, Example 29-1), triethylamine (1.559 ml) dissolved dichloromethane (20 ml) and THF (20 ml) at 0° C. The resulting suspension was stirred at 25° C. for 2 hours. The suspension was filtered and washed with water (3 time) and dried over night on reduce pressure to afford 3-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]pyrazol-1-yl]propyl methanesulphonate (0.988 g). NMR Spectrum: (DMSOd6) 2.21-2.32 (m, 2H), 3.23 (s, 3H), 4.21-4.33 (m, 4H), 7.42-7.51 (m, 2H), 7.68 (bs, 2H), 7.81 (d, 1H), 7.86 (d, 1H), 7.98 (s, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 8.54 (s, 1H)
Reaction SMILES: C(OC(=O)COC1C=CC(SCC2C=C(C3C=CC(C(F)(F)F)=CC=3)OC=2)=CC=1C)C.[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][C:39]=1[CH3:45])[CH3:33].[F:47][C:48]1[CH:53]=[C:52]([C:54]([F:57])([F:56])[F:55])[C:51]([F:58])=[CH:50][C:49]=1[C:59]1[S:63][C:62]([CH2:64]O)=[C:61]([CH3:66])[CH:60]=1>>[CH2:32]([O:34][C:35](=[O:46])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:64][C:62]2[S:63][C:59]([C:49]3[CH:50]=[C:51]([F:58])[C:52]([C:54]([F:55])([F:57])[F:56])=[CH:53][C:48]=3[F:47])=[CH:60][C:61]=2[CH3:66])=[CH:40][C:39]=1[CH3:45])[CH3:33]
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: Cc1cc(-c2cc(F)c(C(F)(F)F)cc2F)sc1CO
Agent: CCOC(=O)COc1ccc(SCc2coc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(OCc2sc(-c3cc(F)c(C(F)(F)F)cc3F)cc2C)cc1C

Procedure:
The title compound was prepared by a method analogous to that used for the preparation of ethyl{2-methyl-4-[({5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetate (example 1) using ethyl(4-hydroxy-2-methylphenoxy)acetate (intermediate 7) and {5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methanol (intermediate 120).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:21]=[CH:20][C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[C:6]([O:22][CH3:23])[CH:5]=1.[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:25]1([N:17]2[CH2:16][CH2:15][C:14]3[CH:20]=[CH:21][C:11]([O:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:24])=[CH:5][C:6]=4[O:22][CH3:23])=[CH:12][C:13]=3[CH2:19][CH2:18]2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCC1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(OC)c1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
N-Methyl-3-(methyloxy)-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E264, Step 6) (78 mg, 0.24 mmol) was dissolved in dry dichloromethane (5 ml), treated with cyclobutanone (0.04 ml, 0.48 mmol) and acetic acid (1 drop) and the resulting mixture stirred for 15 minutes. Sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added and the mixture stirred for 30 minutes. The mixture was diluted with methanol and applied to a SCX column eluting with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.5:4.5:95 0.880) to afford the title compound (20 mg); MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[O:22]1[C:31]2[C:26](=[N:27][CH:28]=[C:29]([CH:32]=O)[CH:30]=2)[O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[O:22]1[C:31]2[C:26](=[N:27][CH:28]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:21])[CH2:6][CH2:7]3)[CH:30]=2)[O:25][CH2:24][CH2:23]1
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Reactant: O=Cc1cnc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cnc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.9 %

Procedure:
To a solution 211 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one and 120 mg of 2,3-dihydro(1,4)dioxino(2,3-b)pyridine-7-carbaldehyde in 22 mL of chloroform, 88 mg of acetic acid was added, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture, 232 mg of sodium triacetoxyborohydride was added, and the mixture was stirred for 2 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC., and an eluent of chloroform:methanol=10:1 to obtain 185 mg of 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-b)pyridin-7-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light yellow solid.
Reaction SMILES: FC1C(O[C:9]([C:11]2([F:30])[C:20]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=3[CH3:29])=[CH:19][C:14]3=[N:15][CH2:16][N:17]([CH3:18])[C:13]3=[CH:12]2)=[O:10])=C(F)C(F)=C(F)C=1F.Cl.[NH2:36][NH2:37].C(N(CC)CC)C.O>ClCCl>[F:30][C:11]1([C:9]([NH:36][NH2:37])=[O:10])[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[CH3:29])=[CH:19][C:14]2=[N:15][CH2:16][N:17]([CH3:18])[C:13]2=[CH:12]1
Reactant: NN
Reactant: Cc1cc(I)ccc1NC1=CC2=NCN(C)C2=CC1(F)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(I)ccc1NC1=CC2=NCN(C)C2=CC1(F)C(=O)NN
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a stirring suspension of 5-fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid pentafluorophenyl ester (0.223 g, 0.355 mmol) and hydrazine hydrochloride (0.026 g, 0.355 mmol) in dichloromethane (10 mL) was added triethylamine (0.11 mL, 0.554 mmol). After stirring for 16 hours at ambient temperature, water was added to the reaction mixture. The afforded solids were filtered off and washed several times with water. The solids were dried under house vacuum at 60° C., which afforded 5-fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrazide as a white solid (0.050 g, 42.4%). mp=232–234° C.; APCI+440.1; 1H NMR (400 MHz, DMSO-D6) δppm 2.3 (s, 3 H) 3.9 (s, 3 H) 6.2 (m, 1 H) 5.3 (m, 1 H) 5.3 (s, 2 H) 5.4 (s, 1 H) 5.5 (s, 1 H) 5.9 (s, 1 H) 8.3 (s,1 H). Step B: To a stirring solution of 5-fluoro-6-(4-iodo-2-methyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid hydrazide (0.055 g, 0.125 mmol) in dioxane (5 mL) was added cyanogen bromide (0.015 g, 0.138 mmol) and NaHCO3 (0.12 g, 0.138 mmol) in water (1 mL) and the mixture was allowed to stir overnight at ambient temperature. To the reaction mixture was added saturated NaHCO3 and the afforded solids were filtered and washed with water. The solids were collected and dried in vacuo at 50° C. to afford [6-(5-amino-[1,3,4]oxadiazol-2-yl)-4-fluoro-1-methyl-1H-benzoimidazol-5-yl]-(4-iodo-2-methyl-phenyl)-amine (0.051 g, 88%). mp=258–260° C.; APCI+=465.0; 1H NMR (400 MHz, DMSO-D6) δ ppm 2.2 (s, 3 H) 3.8(s,3 H) 4.5 (s,2 H) 6.1 (m,1 H) 5.2 (d, J=9.0 Hz, 1 H) 5.4 (d, J=1.5 Hz, 1 H) 5.5(s, 1 H) 8.1 (s, 1 H) 8.3 (s, 1 H) 9.8 (s,1 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].O>C1COCC1>[C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Sodium hydride (1.99 g, 50% in oil, 41.4 mmol, extracted with hexanes) was stirred in THF (50 ml) in a flame-dried flask at 0° C. under nitrogen. Indole-3-carboxaldehyde (5.00 g, 34.5 mmol) was added as a powder in small portions, and then the mixture was warmed to 40° C. for 30 min. The mixture was again cooled to 0° C., and benzyl chloroformate (4.92 ml, 34.5 mmol) was added. After warming to room temperature and stirring overnight, the mixture was poured into water (50 ml) and extracted with CH2Cl2 (50 ml). The organic layer was washed with water (50 ml), dried with MgSO4, filtered and evaporated to 9.2 g (95%) of a gold-brown oil. Crystallization from hot hexane gave 8.47 g (88%) of white crystalline product: mp 70°-71° Anal. Calcd for C17H13NO3 : C, 73.19; H, 4.70; N, 5.02. Found: C, 72.79; H, 5.16; N, 5.24.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[S:7])C=1.[CH2:13]([CH:15]1[CH2:20][CH2:19][CH:18]([CH:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH2:34])=[C:29]([F:35])[CH:28]=3)[CH2:23][CH2:22]2)[CH2:17][CH2:16]1)[CH3:14]>ClCCl>[F:35][C:29]1[CH:28]=[C:27]([CH:24]2[CH2:25][CH2:26][CH:21]([CH:18]3[CH2:17][CH2:16][CH:15]([CH2:13][CH3:14])[CH2:20][CH2:19]3)[CH2:22][CH2:23]2)[CH:32]=[C:31]([F:33])[C:30]=1[N:34]=[C:6]=[S:7]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCC1CCC(C2CCC(c3cc(F)c(N)c(F)c3)CC2)CC1
Solvent: ClCCl
Product: CCC1CCC(C2CCC(c3cc(F)c(N=C=S)c(F)c3)CC2)CC1
Temperature: 25 °C
Yield: 59 %

Procedure:
9.5 g of 1,1-thiocarbonyldiimidazole are added to 85 g of 4-(4′-ethylbicyclohexyl-4-yl)-2,6-difluorophenylamine in 100 ml of dichloromethane, and the mixture is stirred at RT. Conventional work-up gives 4′-(3,5-difluoro-4-isothiocyanatophenyl)-4-ethylbicyclohexyl, yield 59%, having the following properties: C 33 N 198.2 I; Δε 15.3; Δn 0.1930.
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[C:10]([F:19])[CH:9]=1.[CH3:20][C:21]([CH3:23])=O>[Cl-].[Cl-].[Zn+2]>[C:5]([C:21]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]#[N:18])=[C:10]([F:19])[CH:9]=1)([CH3:23])[CH3:20])#[N:6]
Reactant: N#CCCCc1ccc(N)cc1F
Reactant: CC(C)=O
Reactant: C[Si](C)(C)C#N
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(C#N)Nc1ccc(CCCC#N)c(F)c1
Yield: 96.4 %

Procedure:
TMSCN (0.37 mL, 2.78 mmol) was added to a mixture of compound 68 (165 mg, 0.93 mmol), acetone (0.41 mL, 5.58 mmol) and ZnCl2 (12 mg, 0.09 mmol) with stirring. The reaction mixture was stirred at room temperature for 1 h, and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness to give compound 69 (220 mg, 96%) as a light yellow oil. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ7.02-7.10 (m, 1H), 6.58-6.65 (m, 2H), 2.72 (t, 2H, J=7.3 Hz), 2.34 (t, 2H, J=7.1 Hz), 1.90-2.00 (m, 2H), 1.71 (s, 6H).