Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([O-:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11].[OH-].[K+].C(O)C>O>[Cl:1][C:2]1[C:3]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[Cl:11]
Reactant: O=C([O-])COc1cc2ccsc2c(Cl)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cc2ccsc2c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7.5 g of ethyl[(6,7-dichlorobenzo[b]thien-5-yl oxy]acetate, 15 g of potassium hydroxide pellets, 125 ml of ethanol and 125 ml of water is refluxed for 1 hour. Ethanol is removed under reduced pressure at 60° and the aqueous suspension is acidified with conc hydrochloric acid. The slurry is stirred at room temperature for 30 min. and extracted with ether (3×250 ml-portions). The combined ether extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give an off-white crystalline mass. Recrystallization of the crude product from acetone-cyclohexane gives 6.5 g of [(6,7-dichlorobenzo[b]thien-5-yl)oxy]acetic acid as an off-white powder, mp 166°-167°.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:33])=[N:13][C:14]2[N:15]([N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)[C:16]=1[CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([CH3:33])=[N:13][C:14]2[N:15]([N:23]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH:25]=2)[C:16]=1[CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc(-c3cccc(Cl)c3)nn2c(C2CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Yield: 90.2 %

Procedure:
A solution of (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.048 g, 0.102 mmol) and 1M NaOH (1.021 ml, 1.021 mmol) in MeOH (5 mL) was heated at reflux for h. Then, cooled, neutralized with 1M HCl (0.8 mL), concentrated and the residue was taken up in Et2O (25 mL), washed with water (5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give (S)-2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-cyclohexyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid (0.0426 g, 0.092 mmol, 90% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.95 (s, 1H), 7.86 (d, J=7.3 Hz, 1H), 7.42-7.32 (m, 2H), 6.77 (s, 1H), 5.46 (br. s., 1H), 3.43 (br. s., 1H), 2.97-2.84 (m, 2H), 2.72 (br. s., 3H), 1.98-1.70 (m, 4H), 1.58-1.32 (m, 4H), 1.28 (br. s., 9H). LCMS (M+H) calcd for C25H31ClN3O3: 456.21. found: 456.3. Examples 150-157 were prepared using the synthetic route similar to Scheme 10.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4].[Br:25]N1C(=O)CCC1=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([Br:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4]
Reactant: COC(=O)c1ncc2c(Oc3ccccc3OC)cccc2c1O
Reactant: O=C1CCC(=O)N1Br
Product: COC(=O)c1nc(Br)c2c(Oc3ccccc3OC)cccc2c1O

Procedure:
The title compound was synthesized from 4-hydroxy-8-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and N-bromosuccinimide in analogy to example 19e; MS-(+)-ion: M+1, 79Br/81Br=404.3 and 406.3.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:9])([CH2:7][NH2:8])[CH2:5][NH2:6].Cl.[NH2:11][C:12](N)=N.C[O-].[Na+]>>[F:3][C:4]1([F:9])[CH2:7][NH:8][C:12]([NH2:11])=[N:6][CH2:5]1
Reactant: NCC(F)(F)CN
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: NC1=NCC(F)(F)CN1
Temperature: 150 °C

Procedure:
A mixture of 2.95 g (16.12 mmol) of 2,2-difluoro-1,3-propandiamine dihydrochloride (Tetrahedron (1994) 50(29), 8617-8632), 1.54 g (16.12 mmol) of guanidine hydrochloride and 2.19 g (32.23 mmol) of sodium methylate was heated at 150° C. during 18 h. The cooled mixture was used as such in the subsequent step.
Reaction SMILES: [F:1][CH:2]1[CH2:15][C:14]2[CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:6][CH:7]=2.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[C:5]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:4]=2
Reactant: CCCCCCOc1ccc2c(c1)CC(F)c1cc(OCCCCCC)ccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccc2c(c1)cc(F)c1cc(OCCCCCC)ccc12

Procedure:
From 9-fluoro-2,7-dihexyloxy-9,10-dihydrophenanthrene by dehydrogenation with DDQ in toluene.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([NH2:19])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:3][CH2:4][CH3:5].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(C)C>[CH:20](=[N:19][N:7]1[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=[C:6]1[CH2:2][CH2:3][CH2:4][CH3:5])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: CCCCc1nc2cnc3ccccc3c2n1N
Agent: Cl
Solvent: CC(C)O
Product: CCCCc1nc2cnc3ccccc3c2n1N=Cc1ccccc1
Yield: 96.2 %

Procedure:
A solution of 2-butyl-1H-imidazo[4,5-c]quinolin-1-amine hydrochloride (503 mg, 1.82 mmol) in 10 mL of isopropanol was treated with benzaldehyde (220 μL, 2.17 mmol) and 200 mg of DOWEX W50-X1 acid resin. The reaction mixture was heated to reflux overnight. The reaction mixture was filtered, and the filtrate was treated with 0.5 mL of triethylamine and concentrated under reduced pressure. The resulting oil was dissolved in 75 mL of CH2Cl2 and washed with saturated NaHCO3 solution, H2O and brine. The organic was dried over Na2SO4, filtered and concentrated to give N-benzylidene(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (575 mg) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([C:21]([O:23]CC)=[O:22])([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>P([O-])([O-])([O-])=O.C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([C:21]([OH:23])=[O:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(NC(=O)OC(C)(C)C)(C(=O)OCC)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C[C@@](NC(=O)OC(C)(C)C)(C(=O)O)C(=O)OCC
Temperature: 30 °C
Reaction time: 4 h
Yield: 108.4 %

Procedure:
1.0 g of pig liver esterase produced by Sigma [PLE (27 kU/g), lyophilized product, product number: E3019] was dissolved in a 0.1 mol/L phosphate buffer adjusted to pH 7.5 (90 mL), and the solution was added with a solution of diethyl 2-t-butyloxycarbonylamino-2-ethoxycarbonylsuccinate (1.0 g) dissolved in acetonitrile (10 mL). The mixture was stirred at 30° C. for 4 hours to allow the reaction. After completion of the reaction, the reaction mixture was filtered by using a filtration aid (KC Floc 100) to remove the insoluble matter. The filtrate was cooled, and adjusted to pH 2 by adding 6 mol/L hydrochloric acid, then the objective substance was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][OH:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]>C(Cl)(Cl)Cl>[Cl:24][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=[O:20])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: O=C(NCCCO)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Solvent: ClC(Cl)Cl
Product: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-N-(3-hydroxypropyl)-4-nitrothiophene-2-carboxamide (800 mg, 1.2 mmol) in chloroform (15 mL) was added Dessmartin reagent (611 mg, 1.4 mmol) at 0° C. The resulting reaction mixture was warmed up to ambient temperature and stirred at this temperature for 6 hours. After this time, the reaction mixture was diluted with chloroform and washed with brine and water. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 97:3 mixture of dichloromethane and methanol as eluent to afford the title product as a solid (430 mg, 89% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.64 (1H, s), 8.98 (2H, s), 8.91 (1H, m), 8.39 (1H, s), 3.46 (2H, m), 2.66 (2H, m). MS m/z: 404.04, 406.03 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)=[O:24])[CH:22]=1)[O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1.O>[OH:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:23]([NH:25][C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)=[O:24])[CH:22]=1)[O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3cc[nH]n3)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2)cc(C(=O)Nc2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.8 %

Procedure:
A solution of ethyl 4-{3-[(1S)-2-hydroxy-1-methylethoxy]-5-[(1H-pyrazol-3-ylamino)carbonyl]phenoxy}benzoate (175 mg, 0.4 mmol) in THF (5 mL) and water (1 mL) was treated with 1N sodium hydroxide solution (3 mL) and the reaction stirred at RT for 16 hours. On completion, the solvent was removed in vacuo and 1N citric acid added until pH 3-4. The white precipitate was collected by filtration and dried in vacuo to give the desired product as a white solid (138 mg, 85%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([F:37])=[C:14]([CH2:19][NH:20][C:21]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[N:25][C:24]=2[Cl:36])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].N(OC(C)(C)C)=O>C(#N)C.CCOC(C)=O>[Cl:36][C:24]1[N:25]=[CH:26][N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=1[C:21]([NH:20][CH2:19][C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([O:11][C:3]2[CH:2]=[CH:7][C:6]([F:8])=[C:5]([C:9]#[N:10])[CH:4]=2)[C:13]=1[F:37])=[O:22]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2N)c1F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2ccc(F)c(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (110 mg, 0.194 mmol) in Acetonitrile (8 ml) was added tert butyl nitrite (0.046 ml, 0.387 mmol) and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-4-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (49 mg, 0.089 mmol, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (t, 1H), 7.98 (s, 1H), 7.42-7.59 (m, 3H), 7.29-7.42 (m, 2H), 5.49 (s, 2H), 4.48 (d, 2H), 3.38 (t, 2H), 0.75 (t, 2 H), −0.09 (s, 9H).
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:38]=[CH:37][CH:36]=[CH:35][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([NH:27]C(=O)OC(C)(C)C)[CH3:26])=[CH:21][CH:20]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:27][CH:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:13]2[N:12]=[C:11]([CH2:10][CH2:9][C:8]3[CH:35]=[CH:36][CH:37]=[CH:38][C:7]=3[C:4]3([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]3)[C:16]([Cl:17])=[CH:15][N:14]=2)=[CH:24][CH:23]=1)[CH3:26]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a solution of tert-butyl (1-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)phenyl)ethyl)carbamate 24 (0.012 g, 0.022 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.5 mL). The mixture was stirred at ambient temperature for 2 hours before the volatiles were removed in vacuo. The crude residue was loaded onto an SCX cartridge conditioned with methanol. The cartridge was washed with methanol and then 2 N ammonia in ethanol. The basic fractions were combined and the solvent removed in vacuo to give the title compound 24A as a colourless oil (0.009 g, 92%). LCMS-C: rt 4.41 min; m/z 436 [M+H]+.
Reaction SMILES: [C:1]([CH:3]([OH:33])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)[C:7]=3[C:6]1=2)#[N:2].N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>CN(C=O)C>[Si:43]([O:33][CH:3]([C:1]#[N:2])[CH2:4][C@H:5]1[CH2:16][CH2:15][C:14]2[S:13][C:12]3[N:11]=[CH:10][N:9]=[C:8]([O:17][CH:18]4[CH2:19][CH2:20][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]4)[C:7]=3[C:6]1=2)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(O)C#N)CC4)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(C#N)O[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
Reference: For the preparation of the starting material compound 48.1, please refer to the experimental procedure for the synthesis of compound I-57. Into a 50-mL round-bottom flask, a solution of tert-butyl N-(4-[[(3R)-3-(2-cyano-2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (1.9 g, 4.02 mmol, 1.00 equiv) in 10 mL of distilled DMF was added imidazole (544 mg, 8.00 mmol, 2.0 equiv) and tert-butyl(chloro)dimethylsilane (905 mg, 6.00 mmol, 1.49 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at 20° C. After completion, the reaction was then quenched by the addition of 20 mL of water and extracted with 3×80 mL of ethyl acetate. The combined organic layers were washed with brine (three times), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with EtOAc/petroleum ether (1:20 to 1:5) to give 2.2 g (93%) of the desired tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]-2-cyanoethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate as a yellow oil. MS: m/z 587 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=12.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.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>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:2]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)=[C:6]3[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][N:5]3[N:4]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1ccc2c(Br)c(-c3ccc(F)cc3)nn2c1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C#N)ccc23)cc1
Yield: 6.4 %

Procedure:
To a solution of 3-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carbonitrile (0.24 g 0.76 mmol) in DMF (20 ml) was added 4-methanesulfonylphenylboronic acid (0.202 g 1.1 mmol), ground potassium phosphate (0.45 g 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.03 g) and the mixture heated to 90° for 6 h under nitrogen. The cooled mixture was poured into water (200 ml) and extracted with ethyl acetate (3×40 ml). The combined organic phases were washed with water (50 ml), brine (50 ml) and dried. Removal of solvent gave a solid which was purified by biotage chromatography. Elution with cyclohexane:ethyl acetate (4:1) gave the title compound as a white solid (0.019 g 6%). MH+: 392; NMR: (CDCl3) δ 3.14 (3H, s) 7.09 (2H, t) 7.30 (1H, dd) 7.50-7.56 (4H, m) 7.62 (1H, dd) 8.00 (2H, d) 8.9 (1H, s).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[O:16]1[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][NH:10][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:14][CH2:15]1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1NCCN1CCOCC1

Procedure:
According to a similar manner to that in Reference Example 3, the title compound was synthesized from 2-fluorobenzonitrile and 4-(2-aminoethyl)morpholine.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[N:39][N:40]([C@@H:42]2[CH2:46][CH2:45][O:44][CH2:43]2)[CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[CH:38]=[N:39][N:40]([C@@H:42]4[CH2:46][CH2:45][O:44][CH2:43]4)[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnn([C@@H]2CCOC2)c1
Product: C[C@@H](c1ccc(-c2cnn([C@@H]3CCOC3)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 31 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 4-bromo-1-[(R)-tetrahydro-furan-3-yl]-1H-pyrazole following a procedure analogous to that described in Example 1. Yield: 31% of theory; LC (method 3): tR=3.16 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH2:16][NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1.[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=2[S:37][C:38]=1[C:39]([N:17]([CH2:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH:18]1[CH2:19][CH2:20][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:22][CH2:23]1)=[O:40]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: COc1ccc(-c2ccc(Cl)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(Cl)cc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 34 (348 mg, 0.76 mmol) is treated with 3-chloro-benzo[b]thiophene-2-carbonyl chloride (210 mg, 0.91 mmol) using Method D to give the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9].S(Cl)(Cl)=O.[CH3:15]O>>[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10][CH3:15])=[O:9]
Reactant: CO
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)C1COCCN1
Temperature: -20 °C
Reaction time: 16 h

Procedure:
Morpholine-3-carboxylic acid hydrochloride (1.04 g) was dissolved in methanol (20 ml) and the solution cooled to -20° C. Thionyl chloride (1 ml) was added dropwise to the stirred reaction mixture such that the temperature did not rise above -10°. After the addition was complete the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the resultant pale grey residue was partitioned between 2N Na2CO3 and dichloromethane. The organic phase was separated, dried, and the solvent was removed in vacuo to give the title compound as an oil (220 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[NH:20][C:12]3=[N:13][CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=[C:11]3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[H][H]>[Pd].CO>[NH2:17][C:15]1[CH:16]=[C:11]2[CH:10]=[C:9]([C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])[NH:20][C:12]2=[N:13][CH:14]=1
Reactant: O=C(c1cc2cc([N+](=O)[O-])cnc2[nH]1)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2[nH]c(C(=O)N3CCOCC3)cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
An autoclave is charged with 313 mg (1.13 mmol) of the morpholino(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)methanone formed during the preceding stage, 100 mL of methanol and 31 mg of palladium on charcoal at 10%. The autoclave is placed under 20 bar of hydrogen and the solution is stirred at room temperature for 18 hours, The solution is then filtered on Celite, the Celite is rinsed with 50 mL of methanol and the filtrate is evaporated under reduced pressure. 280 mg of a white solid is recovered, and is used in the next stage without further purification (quantitative raw yield).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C([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)C>>[F:26][C:24]1[CH:25]=[C:20]([CH2:19][CH2:18][C:17]([OH:29])=[O:16])[CH:21]=[C:22]([F:28])[C:23]=1[O:27][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CC(C)CSc1ncccc1CCl
Product: CC(C)CSc1ncccc1COc1c(F)cc(CCC(=O)O)cc1F
Yield: 60 %

Procedure:
3-Chloromethyl-2-isobutylsulfanyl-pyridine (0.048 g, 0.22 mmol) obtained in Step C of Preparation Example 12 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.051 g, 0.22 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (60% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(O)CC(C)C)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)CC(C)C)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 4-(1-hydroxy-3-methyl-butyl)-benzoic acid methyl ester (19.72 g, 88.78 mmol) in dichloromethane (300 mL) is added pyridinium chlorochromate (22.03 g, 97.65 mmol). The mixture is allowed to stir at room temperature, and the solution turns black over time. The reaction is monitored by HPLC. Upon complete conversion, the reaction is diluted with dichloromethane and silica gel (2% by weight) is added to the mixture. The mixture is purified by flash column chromatography using dichloromethane as mobile phase, producing 15.79 g (72%) of product. MS (ES): 221.3 (M+1)+.