Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[C:14](=[O:16])[N:13]([CH3:17])[CH2:12]2.CO>ClCCl>[OH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[C:14](=[O:16])[N:13]([CH3:17])[CH2:12]2
Reactant: COc1cccc2c1C(=O)N(C)C2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CN1Cc2cccc(O)c2C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
100 ml of a 1 M solution of boron tribromide in dichloromethane at −78° C. were added dropwise to a solution of 3.7 g of 7-methoxy-2-methyl-2,3-dihydroisoindol-1-one in 50 ml of dichloromethane. The reaction medium was stirred at −78° C. for 1 hour and then left to return to 0° C. for 1 hour. The reaction medium was cooled to −78° C. and then slowly hydrolyzed by adding, dropwise, 20 ml of methanol (temperature below −60° C.). The reaction medium was washed with 30 ml of a 1 M sodium dihydrogen phosphate solution and the aqueous phase was extracted with ethyl acetate (2×50 ml). The organic phases were combined, dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether. 2.6 g of 7-hydroxy-2-methyl-2,3-dihydroisoindol-1-one were obtained.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:40]2[CH2:44][CH2:43][C:42](=[O:45])[CH:41]=2)O1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:40]4[CH2:44][CH2:43][C:42](=[O:45])[CH:41]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: CC1(C)OB(C2=CC(=O)CC2)OC1(C)C
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C1C=C(c2ccc3c(C(=O)NCC4(O)CCC(F)(F)CC4)c(Cl)ccc3n2)CC1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclo hexyl methyl)-amide, cesium carbonate, 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopent-2-enone and tetrakis(triphenyl phosphine)palladium(0). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.83-8.86 (bs, 1H), 8.27-8.29 (m, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.12-8.14 (m, 1H), 7.87 (d, J=9.1 Hz, 1H), 7.12 (s, 1H), 4.72 (s, 1H), 3.42-3.44 (m, 2H), 3.20-3.22 (m, 2H), 2.55-2.57 (m, 2H), 2.07-2.10 (m, 2H), 1.89-2.01 (m, 2H), 1.70-1.77 (m, 4H).
Reaction SMILES: N#N.[ClH:3].C([O:8][C:9](=[O:29])[C@H:10]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[N:21]C(OC(C)(C)C)=O)[O:17][CH:18]([CH3:20])[CH3:19])[NH2:11])(C)(C)C.Cl>O1CCOCC1>[ClH:3].[ClH:3].[NH:21]=[C:16]([O:17][CH:18]([CH3:20])[CH3:19])[NH:15][CH2:14][CH2:13][CH2:12][C@@H:10]([C:9]([OH:29])=[O:8])[NH2:11]
Reactant: CC(C)OC(=NC(=O)OC(C)(C)C)NCCC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Solvent: C1COCCO1
Product: CC(C)OC(=N)NCCC[C@H](N)C(=O)O
Reaction time: 14 h
Yield: 271.5 %

Procedure:
To a 0° C. stirred solution of 0.54 g (1.32 mmol) N2 -(tert-butoxycarbonyl) N5 -(iminoisopropoxymethyl)-L-ornithine tert-butyl ester hydrochloride in 2 ml dioxane was added 10 mL of 4N hydrochloric acid in dioxane solution. The solution was stirred 14 h leaving a pale yellow precipitate. The dioxane was removed under reduced pressure and the residue suspended in ether. After stirring for 3 h, the ether was decanted and the solids dried under vacuum to give 0.52 g N5 -(iminoisopropoxymethyl)-L-ornithine dihydrochloride. TLC (silica gel, ammonium hydroxide:methanol/1:25) Rf=0.27.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:38]1[CH:39]=[N:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C@H:10]([NH:25]C(OCC1C=CC(OC)=CC=1)=O)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C>ClCCl>[NH2:25][C@@H:10]([C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:38]1[CH:39]=[N:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C#CCC[C@@H](NC(=O)OCc2ccc(OC)cc2)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C#CCC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(Cl)nc2)cc1
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a stirred solution of the title compound from Step A (83.0 g, 0.13 mol) in dichloromethane (400 mL) was added triethylamine (20 mL) and the resulting mixture was stirred for 3 h. The reaction mixture turned to dark red color. All volatiles were evaporated and the residue was diluted with water and based by NaHCO3. It was then extracted with dichloromethane (3×250 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography with dichloromethane/methanol=20:1 to afford 47.0 g (77%) of the title compound as yellow gum. 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.6 Hz, 1H), 4.55 (d, J=4.7 Hz, 1H), 3.93 (s, 3H), 2.96-2.93 (m, 1H), 2.64-2.53 (m, 2H), 1.71-1.68 (m, 1H), 1.52-1.41 (m, 3H), 0.90 (s, 9H), 0.20 (s, 3H), 0.00 (s, 3H). MS: m/z (ESI) 473 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:25])=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]([F:18])=[C:7]([OH:17])[C:8]=1[NH:9][C:10](=O)[C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])#[N:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:18][C:6]1[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([CH3:25])[C:3]([C:1]#[N:2])=[C:8]2[C:7]=1[O:17][C:10]([C:11]([CH3:14])([CH3:15])[CH2:12][OH:13])=[N:9]2
Reactant: Cc1c(C#N)c(NC(=O)C(C)(C)CO)c(O)c(F)c1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)CO)nc2c1C#N
Temperature: 25 °C
Yield: 67.7 %

Procedure:
N-(3-Cyano-6-fluoro-5-hydroxy-2-methyl[1,1′-biphenyl]-4-yl)-3-hydroxy-2,2-dimethylpropanamide (I-98) (184 mg, 0.54 mmol) was dissolved in toluene (3.7 ml), pyridinium p-toluenesulfonate (34 mg, 0.13 mmol) was added, followed by stirring under heat for 15 hours. After cooling to room temperature, this was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with diisopropyl ether/ethyl acetate to obtain the entitled compound (118.6 mg, 68%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].Br[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1ccc(O)cc1
Reactant: CC(C)CCBr
Solvent: CC(C)=O
Product: CCOC(=O)CSc1ccc(OCCC(C)C)cc1
Temperature: 25 °C

Procedure:
To stirred solution of (4-Hydroxy-phenylsulfanyl)-acetic acid ethyl ester (2.12 g, 10 mmol), k2CO3 (anhydrous, 10 g) and 1-bromo-3-methyl butane (3 g, excess) was added in boiling acetone. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. The reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform; washed well with water and concentrated. The crude product obtained was taken to next step with out purification. Yield 2.7 g (94%); (M+H)+ 283.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:32]#[N:33])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][C:26]([N:28]([CH3:30])[CH3:29])=[N:25][C:24]=3[CH:31]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].C[O-].[Na+].CO>>[C:32]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([N:28]([CH3:29])[CH3:30])=[N:25][C:24]=4[CH:31]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:7])[N:9]=1)#[N:33]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4oc(N(C)C)nc4c3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)c1nc2cc(Oc3ccc4c(C#N)nc(C(=O)NCC(=O)O)c(O)c4c3)ccc2o1
Temperature: 25 °C
Yield: 82 %

Procedure:
A mixture of 1-cyano-6-(2-dimethylamino-benzooxazol-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (55 mg, 0.12 mmol), glycine (186 mg, 2.47 mmol) and 0.5 M sodium methoxide/methanol (4.7 mL) was refluxed for twenty-five hours before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (35 mL) and washed with dichloromethane (2×25 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.5 mL). The white precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (44 mg): MS: (+) m/z 448.27 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32].C(N(CC)CC)C>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][S:33]([CH2:30][CH2:31][CH3:32])(=[O:35])=[O:34])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(C3C(C#N)=C(C)NC(C)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 200 mg (0.512 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 219 mg (1.54 mmol) propane-1-sulfonyl chloride and 0.21 ml (1.54 mmol) triethylamine. The mixture was stirred at room temperature for 12 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 28 mg (11% of th.) of the title compound.
Reaction SMILES: [C:1]1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[C:18]([O:21][C@@H:22]1[C@H:28]2[C@H:29]3[C@H:38]([CH2:39][CH2:40][C@:25]2([CH2:26][CH3:27])[C:24](=[O:42])[CH2:23]1)[C@@H:37]1[C:32](=[CH:33][C:34](=[O:41])[CH2:35][CH2:36]1)[CH2:31][CH2:30]3)(=[O:20])[CH3:19]>COC(OC)(C)C>[C:18]([O:21][C@@H:22]1[C@H:28]2[C@H:29]3[C@H:38]([CH2:39][CH2:40][C@:25]2([CH2:26][CH3:27])[C:24](=[O:42])[CH2:23]1)[C@@H:37]1[C:32]([CH:33]=[C:34]([O:41][CH3:1])[CH2:35][CH2:36]1)=[CH:31][CH2:30]3)(=[O:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Agent: c1cc[nH+]cc1
Solvent: COC(C)(C)OC
Product: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(OC)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Temperature: 25 °C
Yield: 498.3 %

Procedure:
Pyridinium p-Toluenesulfonate (260 mg, 1.03 mmol) was added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (2 g, 5.8 mmol) in 2,2-dimethoxypropane (20 ml). The mixture was stirred under reflux for 7 h and at room temperature overnight. It was then cooled to −10° C. for 1 h. The precipitate was filtered, washed with cooled MeOH and dried under vacuum to afford 15α-acetoxy-3-methoxy-18-methyl-estra-3,5-dien-17-one (1.84 g, yield: 88%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=1>O1CCCC1>[CH:19]1([CH2:18][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[N:37][CH:36]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 38 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide (81.7 mg, 0.26 mmol) in tetrahydrofuran (10 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) and nicotinoyl chloride hydrochloride (47 mg, 0.26 mmol). The resulting reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 90/10 ethyl acetate/heptane) afforded N-{4-[2-cyclopentyl-1-(pyridin-2-ylcarbamoyl)-ethyl]-phenyl}-nicotinamide (40.9 mg, 21.7%) as a yellow solid: mp 160-163° C.; EI-HRMS m/e calcd for C25H26N4O2 (M+) 414.2055, found 414.2056.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]([O:11][CH3:12])=[C:6]([CH:8](Cl)[CH3:9])[CH:7]=1.[CH3:27][C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[NH:30][N:29]=1>>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([CH:8]([C:6]3[C:5]([O:11][CH3:12])=[C:4]([CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)[C:3]([CH3:26])=[C:2]([Cl:1])[CH:7]=3)[CH3:9])[N:29]=[C:28]([CH3:27])[C:36]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1n[nH]c2ncnc(N)c12
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared according to the procedure of Example 139 step 5, using of tert-butyl 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]piperidine-1-carboxylate and 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine as the starting materials. LCMS calculated for C26H36ClN6O3 (M+H)+: m/z=515.3; Found: 515.2.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([CH3:19])([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-])=O)[CH3:5].C(OCC)(=O)C.[H][H]>[Pd].CO>[CH3:20][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[NH2:16])([CH3:19])[CH3:5]
Reactant: [H][H]
Reactant: CN(C)CC(C)(C)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)CC(C)(C)c1ccc(C(F)(F)F)cc1N
Reaction time: 12 h

Procedure:
A 50 mL round-bottom flask containing dimethyl-[2-methyl-2-(2-nitro-4-trifluoromethyl-phenyl)-propyl]-amine (0.61 g, 2.1 mmol) was charged with 10% palladium on carbon (0.23 g, 0.21 mmol) under nitrogen. Ethyl acetate (5 mL) and methanol (5 mL) were added sequentially via syringe. The atmosphere was replaced with hydrogen, and the reaction was stirred rapidly under 1 atm hydrogen overnight. After approximately 12 h, the reaction was flushed with nitrogen and filtered through a pad of celite, rinsing with methanol. Removal of the solvent in vacuo gave the title compound as a clear and colorless oil. MS m/z 261=[M+H]+. Calc'd for C13H19F3N2: 260.30.
Reaction SMILES: [Na:1].C[C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C1(C)OCC2(OCCO2)CO1.ClC1C=CC=C(C(OO)=O)C=1.[CH3:45][C:46]1([CH2:57]CO)[O:56][CH2:55][C:49]2([O:54][CH2:53][CH2:52][CH2:51][O:50]2)[CH2:48][O:47]1>>[Na:1].[CH3:45][C:46]1([CH2:57][CH2:10][O:9][C:8]2[CH:7]=[CH:6][N:5]=[C:4]([CH2:22][S:23]([C:25]3[NH:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[N:26]=3)=[O:24])[CH:3]=2)[O:47][CH2:48][C:49]2([O:50][CH2:51][CH2:52][CH2:53][O:54]2)[CH2:55][O:56]1
Reactant: CC1(CCO)OCC2(CO1)OCCCO2
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na]
Product: CC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2)OCC2(CO1)OCCCO2
Yield: 11.4 %

Procedure:
The same procedure as in the steps (5d) to (5h) of Example 5 (a reprecipitation operation was not performed in oxidation step with 3-chloroperbenzoic acid) was repeated using 2-(9-methyl-1,5,8,10-tetraoxaspiro[5.5]undec-9-yl)ethanol obtained in the step (76d) above to obtain the title compound (228 mg, total 11.4% yield) as a white solid.
Reaction SMILES: [S:1]1C2=CN=CC=C2C(C2OC3=CN=CC=C3C=2)=C1.[I:19][C:20]1[CH:25]=[N:24][C:23]([NH2:26])=[C:22]2[O:27][C:28]([C:30]3[CH:39]=CC=[C:36]4[C:31]=3[CH:32]=[CH:33][N:34]=[CH:35]4)=[CH:29][C:21]=12>>[I:19][C:20]1[CH:25]=[N:24][C:23]([NH2:26])=[C:22]2[O:27][C:28]([C:30]3[C:31]4[C:36](=[CH:35][N:34]=[CH:33][CH:32]=4)[S:1][CH:39]=3)=[CH:29][C:21]=12
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Reactant: c1cc2cc(-c3csc4cnccc34)oc2cn1
Product: Nc1ncc(I)c2cc(-c3csc4cnccc34)oc12
Yield: 77 %

Procedure:
The title compound was prepared in 77% yield from 2-thieno[2,3-c]pyridin-3-yl-furo[2,3-c]pyridin]-7-ylamine by a procedure analogous to Intermediate 10, Step B. 1H NMR (300 MHz, CDCl3+CD3OD): δ 6.83 (s, 1H), 7.82 (s, 1H), 8.11 (d, J=5.6 Hz, 1H), 8.26 (s, 1H), 8.44 (d, J=5.8 Hz, 1H), 9.02 (s, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>C(OCC)(=O)C.C1CCCCC1.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:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(Br)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3cccc(C(F)(F)F)c3)nc2)CC1
Yield: 65.3 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 1.28 g (3.43 mmol) of 2-(ethyloxy)-2-oxoethyl 4-(6-bromo-3-pyridyl)-1-piperazinecarboxylate, obtained in step 7.4., 1.96 g (10.29 mmol) of 3-(trifluoromethyl)phenylboronic acid, 2.91 g (13.72 mmol) of hydrated potassium phosphate and 0.40 g (0.34 mmol) of tetrakis(triphenylphosphine)palladium, and after chromatography on silica gel, eluting with a mixture 35/65 of ethyl acetate and cyclohexane, 0.98 g of pure product is obtained in the form of an oil that crystallizes at room temperature.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[N:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[O:15][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:26])[F:27])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)CCc1cnc(O)c(Br)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cnc(OCc2ccc(C(F)(F)F)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 101.1 %

Procedure:
A solution of Intermediate 36 (71.5 mg) in chloroform (7 ml) was added with 4-trifluoromethylbenzyl bromide (109.2 mg, TCI) and silver carbonate (120 mg, WAKO), and stirred at room temperature for 11 hours under light shielding. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. E-13, 114 mg).
Reaction SMILES: [C:1]([O:5][C:6]1[C:7]([CH:12]=O)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:16])[NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]1[C:7]([CH2:12][N:24]2[CH2:23][CH2:22][CH:21]([CH2:20][O:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[C:14]([NH2:15])=[O:16])[CH2:26][CH2:25]2)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1ccccc1OCC1CCNCC1
Reactant: CC(C)(C)Oc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1nccnc1CN1CCC(COc2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
After dissolving 106 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 105 mg of 4-(2-carbamoylphenoxymethyl)piperidine in 5 ml of dichloromethane, 153 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (171 mg, 95% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[CH:15][C:13]=1[NH2:14]>>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([Cl:19])=[CH:18][C:12]=2[O:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Product: COc1cc(Nc2nc(Cl)ncc2F)c(OC)cc1Cl

Procedure:
In like manner to the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 2,5-dimethoxy-4-chloroaniline gave 2-chloro-N4-(2,5-dimethoxy-4-chlorophenyl)-5-fluoro-4-pyrimidineamine. LCMS: purity: 97%; MS (m/e): 316 (M-2H) and 320 (M+2H).
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:5]1=[O:16])([CH3:3])[CH3:2].C([Li])CCC.C[O:24][C:25](=O)[C:26]([N:28]([CH3:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27].O>O1CCCC1>[CH:1]([C:4]1([CH3:17])[C:5](=[O:16])[NH:6][C:7]([C:9]2[C:14]([C:25](=[O:24])[C:26]([N:28]([CH3:35])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:27])=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:8]1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Reactant: COC(=O)C(=O)N(C)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)C(=O)N(C)c2ccccc2)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
To a stirred solution of 2.5 g(0.011 mole) of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2 -yl)-5-methyl pyridine in 100ml of anhydrous tetrahydrofuran cooled to -70° C. under the presence of nitrogen was added dropwise a 9.68 ml of 2.5 molar n-butyllithium, thus maintaining temperature below -65° C. The solution was stirred at -70° C. for 3 hr and a solution 1.96 g of N-methyl-N-phenyl oxamic acid methyl ester(3.4 g, 0.016 mole) in 10 ml of anhydrous tetrahydrofuran was added dropwise while maintaining temperature below -65° C. After stirring another hour at -70° C., the solution was poured into water and extracted with methylene chloride. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography to produce 1.76 g of pale yellow solid(m.p.=153°~156° C.).