Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)=[C:10]2[CH:9]=[CH:8]1.O=[C:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:67].O1CCOCC1>C1COCC1>[ClH:67].[ClH:67].[ClH:67].[NH:34]1[CH2:35][CH2:36][CH:31]([N:23]2[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]3[CH:20]=[C:16]([C:15]4[CH:14]=[CH:13][N:12]=[C:11]5[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[CH:8]=[CH:9][C:10]=45)[CH:17]=[N:18]3)[CH2:24]2)[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile.2[HCl] (347 mg, 0.70 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (134 mg, 0.70 mmol) and N,N-diisopropylethylamine (0.467 mL, 2.68 mmol) in THF (10.0 mL) was added sodium triacetoxyborohydride (284 mg, 1.34 mmol). The mixture was stirred at room temperature for 2 hours and quenched with brine. The resulting solution was extracted with EtOAc (2 times). The combined extracts were washed with water, brine and dried over Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography on silica gel eluting with 50-100% EtOAc/hexanes. The purified intermediate (MS: [M+H]+=592.3) was dissolved in THF (6 mL). To the solution was added a 4.0 M solution of HCl in 1,4-dioxane (6 mL, 24 mmol). The mixture was stirred at room temperature for 2 hours and concentrated to give 260 mg of {1-piperidin-4-yl-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a yellowish solid. LC/MS found: 492.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6), δ 9.45 (s, 1H), 8.96 (s, 1H), 8.73 (s, 1H), 8.35 (d, 1H), 8.46 (s, 1H), 8.33 (d, 1H), 7.81 (d, 1H), 7.50 (d, 1H), 7.10 (m, 1H), 5.69 (s, 2H), 4.93 (d, 2H), 4.54 (d, 2H), 3.75-3.60 (m, 1H), 3.55 (s, 2H), 3.55 (s, 2H), 3.52 (t, 2H), 3.49-3.37 (m, 2H), 2.81 (m, 2H), 2.12 (d, 2H), 1.80 (m, 2H), 0.82 (t, 2H), −0.11 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C:18]1[CH:19]=[C:20]([NH:28][C:29]2[N:38]=[CH:37][C:36]3[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=3[N:30]=2)[CH:21]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:23]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][C:14](=[O:16])[NH:17][C:18]2[CH:23]=[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=[C:20]([NH:28][C:29]3[N:38]=[CH:37][C:36]4[N:35]([CH3:39])[C:34](=[O:40])[CH2:33][N:32]([CH:41]([CH3:43])[CH3:42])[C:31]=4[N:30]=3)[CH:19]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CC(=O)O)C1
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(S(C)(=O)=O)c3)nc21
Product: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(NC(=O)C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc(S(C)(=O)=O)c3)nc21
Yield: 82 %

Procedure:
The (S)-enantiomer was prepared with the same procedure used for the (R)-enantiomer and described in Scheme 12 starting from (S)-3-carboxymethyl-pyrrolidine-1-carboxylic acid tert butyl ester (132 mg; 0.576 mmol) and 2-(3-Amino-5-(methylsulfonyl)-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (150 mg; 0.384 mmol), 190 mg (0.316 mmol; 82% yield) of product were obtained.
Reaction SMILES: CN([C:4]([CH:6]=[CH2:7])=[O:5])C.P(Cl)(Cl)(Cl)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>C(#N)C.O.C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:22](=[O:26])[N:23]([CH3:25])[C:24]=2/[CH:7]=[CH:6]/[CH:4]=[O:5])=[CH:18][CH:19]=1
Reactant: C=CC(=O)N(C)C
Reactant: Cn1cc(-c2ccc(F)cc2)n(-c2ccccc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Cn1c(/C=C/C=O)c(-c2ccc(F)cc2)n(-c2ccccc2)c1=O
Reaction time: 0.17 h

Procedure:
1.54 ml (14 mmol) of N,N-dimethylaminoacrolein in 5.3 ml of acetonitrile are added dropwise at 0°-5° C. in the course of 10 minutes under a nitrogen atmosphere to 1.37 ml (15 mmol) of phosphorus oxychloride in 8.5 ml of acetonitrile. After 10 minutes, a solution of 1.3 g (5 mmol) of the compound from Example 4 in 10 ml of acetonitrile is added and the mixture is heated overnight to boiling. 3.7 g of sodium hydroxide in 50 ml of water/50 ml of toluene are added at 10° C., the aqueous phase is washed again with toluene, the organic phases are dried and 0.85 g is obtained after crystallization from ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[F:10]F>C(#N)C>[Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][C:5]([F:10])=[CH:6][N:7]=1
Reactant: FF
Reactant: N#Cc1nccnc1Cl
Solvent: CC#N
Product: N#Cc1nc(F)cnc1Cl
Temperature: 25 °C

Procedure:
In 15 mL of acetonitrile was dissolved 0.3 g of 3-chloro-2-pyrazinecarbonitrile. At an ice-cooled temperature, 10% fluorine gas (a fluorine gas diluted with nitrogen gas) was introduced into the solution at a rate of 45 mL per minute for a period of 20 minutes. Then, while elevating the temperature from the ice-cooled temperature to room temperature, nitrogen gas was introduced over a period of one hour. The reaction mixture was concentrated under reduced pressure and the oily product thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.12 g of 3-chloro-6-fluoro-2-pyrazinecarbonitrile as a colorless oily product.
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=O.[NH2:22][NH2:23]>C1COCC1>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:6]2[C:5]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:2]([SH:1])[NH:22][N:23]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: COc1cccc(C(=O)C(=C2SCS2)c2ccncc2)c1
Solvent: C1CCOC1
Product: COc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
2-[1,3]Dithietan-2-ylidene-1-(3-methoxy-phenyl)-2-pyridin-4-yl-ethanone (1.18 g, 3.17 mmol) was suspended into a 1 M solution of hydrazine in THF and heated to 70° C. for two hours. The suspension was then concentrated under reduced pressure, taken up with a small volume of ethanol and diluted with THF (10 mL) and stirred for 5 minutes. The solid was filtered, washed with THF and dried at 50° C. for 2 hours. 1.26 g of 5-(3-methoxy-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol were obtained as an orange solid and used in the following step without further purification.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][NH:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CCOC(C)=O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][N:27]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1C#N
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)OC(C)(C)C)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 3) (70 mg, 0.170 mmol) and caesium carbonate (167 mg, 0.511 mmol) in dry DMF (5 ml) were treated with tert-butyl bromoacetate (0.038 ml, 0.256 mmol) and stirred at RT for 3 hours to give a single product. EtOAc (40 ml) was added and the mixture washed with water (2×50 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (85 mg) as a clear, colourless oil. MS (ES) C28H32N4O4 requires 488; found 489 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42]Cl)[CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]1[CH2:41][CH2:40][O:39][CH:38]([CH2:42][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)[CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC4CN(Cc5ccccc5)CCO4)c4cc(Cl)ccc34)CC2)c2ccc(F)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with commercially available 4-benzyl-2-(chloromethyl)morpholine gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>O>[OH:12][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([C:8]([CH3:9])([CH3:11])[CH3:10])=[CH:6][C:5]=1[CH:25]=[O:26]
Reactant: CC(C)(C)c1ccc(O)cc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: CC(C)(C)c1cc(C=O)c(O)cc1Cl
Temperature: 25 °C
Yield: 17 %

Procedure:
A mixture of 9.65 g (52.2 mmol) of 3-chloro-4-(1,1-dimethylethyl)phenol and 7.37 g (52.2 mmol) of hexamethylenetetramine was refluxed in 150 ml of trifluoroacetic acid for 3 hours. The solution was cooled to ambient temperature and diluted with 500 ml of water. The aqueous residue was extracted with ether. The organic phase was washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was chromatographed on 250 g of silica gel using a gradient from hexane to 20:80 (v/v) ether: hexane as eluent. There was obtained 1.87 g (8.79 mmol, 17%) of 2-hydroxy-4-chloro-5-(1,1-dimethylethyl)benzaldehyde; mp 38°-39° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=O)C.O.[NH2:18][NH2:19]>>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[NH:19][N:18]=[C:4]([OH:3])[CH:5]=2)=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Solvent: O
Product: COc1ccc(-c2cc(O)n[nH]2)cc1
Yield: 103.8 %

Procedure:
5-(4-Methoxy-phenyl)-1H-pyrazol-3-ol (30.8 g, 99%) was prepared as a white solid from 3-(4-methoxy-phenyl)-3-oxo-propionic acid ethyl ester (29.9 mL, 156 mmol) and hydrazine hydrate (14.6 mL, 468 mmol) by a procedure analogous to Example 22. C10H10N2O2: 1H NMR (D6-DMSO): δ 7.55 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.75 (s, 1H), 3.73 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[C:40]3[C:35](=[CH:36][C:37]([F:42])=[C:38]([F:41])[CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C@@H:9]([C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[C:40]3[C:35](=[CH:36][C:37]([F:42])=[C:38]([F:41])[CH:39]=3)[N:34]=[CH:33][CH:32]=2)[C@@H:9]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:18])=[CH:29][CH:30]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1)C(c1ccc(Cl)cc1)c1ccnc2cc(F)c(F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1ccnc2cc(F)c(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the slower-eluting isomer of tert-butyl N-(4-{(1S)-1-[(4-chlorophenyl)(6,7-difluoroquinolin-4-yl)methyl]butyl}benzoyl)-β-alaninate from Step G (34 mg, 0.058 mmol) in CH2Cl2 (2.0 mL) was treated with TFA (1.0 mL). After stirring at room temperature overnight, the solution was concentrated. The residue was purified by preparative reverse phase HPLC, eluting with acetonitrile/water+0.1% formic acid. Following lyophilization, this afforded the title compound as a fluffy, white solid: 1H NMR (500 MHz, CDCl3): δ 8.95 (s, 1H); 8.10-8.01 (m, 2H); 7.85 (d, J=5.0 Hz, 1H); 7.53 (d, J=7.8 Hz, 2H); 7.38 (d, J=8.4 Hz, 2H); 7.34 (d, J=8.4 Hz, 2H); 7.21 (d, J=7.8 Hz, 2H); 6.97 (s, 1H); 4.93 (d, J=11.4 Hz, 1H); 3.65-3.54 (m, 3H); 2.56 (t, J=5.5 Hz, 2H); 1.65-1.53 (m, 2H); 1.13-0.97 (m, 2H); 0.75 (t, J=7.2 Hz, 3H); LC4: 2.26 min. (M+H) 537.
Reaction SMILES: CO.[C:3]([NH:8][C@H:9]([C:20]([O:22]C)=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:7])/[CH:4]=[CH:5]/[CH3:6].[OH-].[Na+]>O>[C:3]([NH:8][C@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:7])/[CH:4]=[CH:5]/[CH3:6]
Reactant: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C/C=C/C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reaction time: 20 h
Yield: 71.7 %

Procedure:
To methanol (230 mL) solution of the compound obtained in Example 161 (4.4 g) was added 1 mol/L of an aqueous sodium hydroxide solution (23 mL), and the mixture was allowed to stir for 20 hours. Water was added to the residue obtained by distilling off the solvent under a reduced pressure, and the mixture was made acidic with a 10% aqueous citric acid solution. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, to give the captioned compound (3.0 g, 71%) as an amorphous solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:29])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:11]=2[CH:12]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Cl)cc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2cc3cc(C(F)(F)F)ccc3o2)c(Cl)c1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a mixture of 0.38 g of 3-chloro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine and 4 ml of chloroform was added 0.41 g of 70% m-chloroperbenzoic acid under ice-cooling. This mixture was stirred under ice-cooling for 30 minutes and subsequently at room temperature for 2 hours. The reaction mixture was diluted with chloroform, and sequentially washed with a 5% aqueous solution of sodium hydroxide and saturated brine. The organic layer was dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.32 g of 3-chloro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine 1-oxide (hereinafter, referred to as “Present Active Compound 7”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Br[CH2:13][CH:14]([CH3:16])[CH3:15]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)CBr
Product: CC(C)Cn1nc(I)c2cc(F)ccc21
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield from 5-fluoro-3-iodo-indazole and 1-bromo-2-methylpropane according to the general procedure for Preparation 10A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.92 (6H, d, J=6.8 Hz), 2.30-2.37 (1H, m), 4.16 (2H, d, J=7.2 Hz), 7.11 (1H, dd, J=2.4, 8.8 Hz), 7.19 (1H, td, J=2.4, 8.8 Hz), 7.32 (1H, dd, J=4.0, 8.8 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:19][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: COC(CN)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(CNC1CCN(C(=O)OC(C)(C)C)CC1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (10.56 g, 53.0 mmol) was dissolved in 1,2-dichloroethane (100 ml). 4 Å Molecular sieves were added to the mixture followed by aminoacetaldehyde dimethyl acetal (8.0 ml, 73.4 mmol). Mixture was heated to reflux and held with stirring for 2 hours. Mixture was cooled to room temperature. Sodium triacetoxyborohydride (12.05 g, 56.9 mmol) was added to the mixture. Reaction stirred at room temperature for 3 hours. Another 3.22 g of sodium triacetoxyborohydride was added to the mixture. Reaction stirred at room temperature for 17 hours. Mixture was filtered over celite. Solids were washed with 50 mL dichloromethane. Material was extracted from the filtrate 3 times with 1N hydrochloric acid and the organic phase was discarded. Aqueous phase was made basic with sodium carbonate. Material was extracted three times with dichloromethane and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as amber oil in 74% yield. MS (M+H)+=289.1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].O>C1COCC1>[CH3:15][S:16]([O:5][CH2:4][CH2:3][C:2]([CH3:7])([CH3:6])[CH3:1])(=[O:18])=[O:17]
Reactant: CC(C)(C)CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)CCOS(C)(=O)=O
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To a solution of 3,3-dimethylbutan-1-ol (20.2 g) and triethylamine (41.3 mL) in THF (200 mL) was added methanesulfonyl chloride (24.9 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (36.5 g) as a red-orange oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][CH:13]([OH:17])[NH:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:27]1C[CH2:30][CH2:29][CH2:28]1.C([O-])(=O)C=C.[Cl-]>C1(C)C=CC=CC=1.O>[C:28]([O:17][CH:13]([NH:14][CH2:15][CH3:16])[CH2:12][C:11]1[CH:18]=[CH:19][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:27])[CH:29]=[CH2:30]
Reactant: C1CCOC1
Reactant: CCNC(O)Cc1ccc(Cc2ccccc2)cc1
Agent: C=CC(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CC(=O)OC(Cc1ccc(Cc2ccccc2)cc1)NCC
Temperature: 0 °C

Procedure:
In a three-aperture flask, 6.64 g (26 mmol) of p-benzyl-ethylaminophenethyl alcohol, 5.79 g (57.2 mmol) of triethylamine, and 50 mL of dehydrated tetrahydrofuran were poured, and the mixture was stirred under an argon atmosphere and an ice-cooling condition. Then, 4.70 g (52 mmol) of chloride acrylate was delivered by drops into the reaction solution for 30 minutes. Upon completion of the dripping, the reaction solution was further stirred for 3 hours. The reaction solution was poured to 100 mL of water and then an extract was obtained therefrom by using toluene, followed by washing with water three times. The toluene solution was dried with anhydrous magnesium sulfate, and then the solvent was distilled away to purify the toluene solution by silica gel chromatography using a mixture solvent of hexane/ethyl acetate (5/1) as an eluent to thereby synthesize 3.21 g (yield: 40% by mass) of p-benzyl-ethylaminophenethyl acrylate of the exemplified compound No. 22 represented by the following structural formula.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17](O)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12].F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:54][C@H:55]([CH2:58][CH2:59][CH2:60][CH3:61])[CH2:56][OH:57]>CN(C=O)C>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([NH:54][C@H:55]([CH2:58][CH2:59][CH2:60][CH3:61])[CH2:56][OH:57])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)c(F)ccn2c1C(=O)O
Reactant: CCCC[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCC[C@H](CO)NC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)c(F)ccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14 mg (0.04 mmol) of 8-[(2,6-difluorobenzyl)oxy]-7-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 112A, 20 mg (0.06 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 17 mg (0.17 mmol) of 4-methylmorpholine were initially charged in 0.28 ml of DMF. 7.5 mg (0.06 mmol) of (2R)-2-aminohexan-1-ol were then added, and the mixture was stirred at RT overnight. Another 2.6 mg of TBTU, 4 mg of 4-methylmorpholine and 1 mg of (2R)-2-aminohexan-1-ol were added, and the mixture was stirred at RT for 2 h. The reaction mixture was concentrated and purified by thick-layer chromatography (mobile phase: dichloromethane/methanol=10/1). This gave 12 mg (66% of theory; purity 99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:14][O:15][CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCC1CCCCC1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reaction time: 8 h
Yield: 39 %

Procedure:
To a solution of 0.58 g (1.48 mmol) 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) in 6 mL N,N-dimethylformamide, 71 mg (1.5 mmol, 55% dispersion in mineral oil) sodium hydride and after 5 min. 0.32 g (1.78 mmol) bromomethylcyclohexane were added. The reaction mixture was warmed to 50° C. and after 4 h another 71 mg sodium hydride and 0.32 g (1.78 mmol) bromomethylcyclohexane were added. A third batch sodium hydride and bromomethylcyclohexane were added after 3 h. After stirring overnight the reaction mixture was poured on water and ethyl acetate, extracted, the aqueous phase extracted twice with ethyl acetate and the aqueous phase extracted twice with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over magnesium sulfate and evaporated. The crude product was purified by silica gel column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethylacetate (1:0 to 4:1) to yield the title compound as a white solid (39%). MS (Turbo Spray): m/z=487.3 [M+H].