Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:19][CH3:20])[C:11](F)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:21]2[CH2:23][CH2:22]2)[CH:7]=1)=[O:5])C.F[B-](F)(F)F.[H+].[N:30]1([CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)[CH:34]=[CH:33][N:32]=[N:31]1>>[CH:21]1([N:8]2[C:9]3[C:14](=[CH:13][C:12]([F:17])=[C:11]([N:37]4[CH2:38][CH2:39][CH:35]([N:30]5[CH:34]=[CH:33][N:32]=[N:31]5)[CH2:36]4)[C:10]=3[O:19][CH3:20])[C:15](=[O:16])[C:6]([C:4]([OH:3])=[O:5])=[CH:7]2)[CH2:22][CH2:23]1
Reactant: c1cn(C2CCNC2)nn1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Agent: F[B-](F)(F)F
Agent: [H+]
Product: COc1c(N2CCC(n3ccnn3)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
Ethyl-6,7-difluoro-1-cyclopropyl-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate was complexed with fluoroboric acid according to the procedure described in Example 34, and then reacted with 3-(1,2,3-triazol-1-yl)pyrrolidine under the same reaction conditions, followed by hydrolysis to yield the desired product, m.p. 200°-201° C. 1H NMR (TFA) δ: 9.34 (s, 1H), 8.69 (d, 1H), 8.58 (d, 1H), 8.09 (d, 13.3HZ, 1H), 5.93-5.8 (m, 1H), 4.83-4.34 (m, 4H), 4.2-4.0 (m, 2H), 3.79 (s, 3H), 3.05-2.75 (m, 2H), 1.7-1.1 (m, 4H). Anal. calcd. for C20H20FN5O4 . 1/2 H2O: C, 56.87; H, 5.01; N, 16.58. Found: C, 56.86; H, 4.68; N, 16.24.
Reaction SMILES: CO[CH2:3][O:4][CH2:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Br-].[Mg+2].[Br-]>ClCCl>[S:8]1[C:7]2[CH2:6][CH2:5][O:4][CH2:3][C:11]=2[CH:10]=[CH:9]1
Reactant: COCOCCc1cccs1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.7 %

Procedure:
61.2 g of 2-(2-methoxymethoxyethyl)thiophene obtained in Example 19 and 130.8 g of magnesium bromide were added to 850 mL of dichloromethane, and the resulting mixture was refluxed for 2 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. To the residue, 500 mL of water and 800 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. Aqueous layer was discarded, and the organic layer was washed twice with 300 mL portions of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 40.7 g (yield of 82%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(OCC)=O)C.[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>C1COCC1>[Si:22]([O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1/[CH:32]=[CH:11]/[C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1C=O
Reactant: CCOP(=O)(CC(=O)CCCCC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(=O)/C=C/c1ccccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 0.26 g (10.87 mmol) of sodium hydride was added to a solution of 3.20 g (10.87 mmol) of methyl 7-(diethoxyphosphoryl)-6-oxoheptanoate from Ex. XIIb in 53 ml of THF. The mixture was stirred at room temperature for 30 min, a solution of 9.06 mmol of 2-{[tert-butyl(dimethyl)silyl]oxy}benzaldehyde from Ex. XIIa in 20 ml of THF was added and the mixture was stirred at room temperature for 18 h. Water was added, the mixture was extracted with ethyl acetate, the combined organic phases were dried over Na2SO4 and the solvent was removed. The product was purified chromatographically (silica gel, cyclohexane/EA 10:1). This gave 2.51 g (67.8%) of a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:9][N:10](C)C=O>[C-]#N.[C-]#N.[Zn+2].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([CH:7]=1)[C:9]#[N:10]
Reactant: CN(C)C=O
Reactant: Fc1cncc(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1cncc(F)c1
Temperature: 130 °C

Procedure:
Zn(CN)2 (2.45 g, 0.020 mol) and 1,1′-bis(diphenylphosphino)ferrocene (0.045 g, 0.0008 mol) were added to a solution of 3-bromo-5-fluoro pyridine (3.5 g, 0.0198 mol) in dimethylformamide. The reaction vessel was purged with argon for 10 min. Next, Pd2(dba)3 (0.04 g, 0.000043 mol) was added and the reaction vessel was purged with argon for another 5 min. The reaction mixture heated to 130° C. for 40 min under microwave irradiation. The reaction mixture was cooled to RT, diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×100 mL) and dried over sodium sulphate. The combined organic layers were then concentrated under vacuum to get crude product, which was purified by silica gel column chromatography to afford 5-fluoronicotinonitrile. 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.71-8.70 (d, J=4 Hz, 1H), 7.70-7.76 (d, J=4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+]([C:15]1[CH:20]=CC(O)=C[CH:16]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[N:8]=[CH:20][CH:15]=[CH:16]2
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: O=[N+]([O-])c1cc(F)cc2cccnc12
Temperature: 130 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
4-Fluoro-2-nitro-phenylamine (15 g, 96 mmol) was added to a mixture of 4-nitrophenol (9.5 g, 144 mmol) and glycerol (27 ml), then concentrated sulphuric acid (8.3 ml, 154 mmol) was added dropwise. The mixture was stirred at 130° C. for 4 hours. For the workup, the reaction mixture was cooled to room temperature, then poured into ice-water. The precipitate was filtered and the aqueous phase was made basic with sodium hydroxide (15% solution). There were obtained 2.0 g (11%) of 6-fluoro-8-nitro-quinoline as a brown solid; (calculated) C9H5FN2O2 [192.2]; (found) [M+H]+=193.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.CCN(CC)CC.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O.[NH4+].[Cl-]>O1CCOCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:17])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc(Br)ccc1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 79.4 %

Procedure:
To a solution of 4-bromo-2-methylaniline (1 g, 5.37 mmol,) in 1,4-dioxane (11 mL) and H2O (4 mL), at r.t., were added Et3N (2.7 mL, 1.2 eq) and BOC2O (4.2 g, 1.2 eq). The reaction mixture was stirred at r.t. for 96 hr. Sat.aq. NH4Cl and EtOAc (20 mL) were added and the phases were separated. The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anh. Na2SO4, the solids were filtered and the solvent evaporated. The residue was purified on an SCX cartridge (CH2Cl2, MeOH and NH3(0.5 M in MeOH)) to give the title compound as a white solid (1.22 g, 79%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:44]2[CH:43]=[N:42][C:41]([Sn](CCCC)(CCCC)CCCC)=[N:40][C:39]=2[C:38]([CH3:58])=[N:37]1>O1CCOCC1.[Cu]I.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>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:41]4[N:42]=[CH:43][C:44]5[N:36]([CH3:35])[N:37]=[C:38]([CH3:58])[C:39]=5[N:40]=4)[CH:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc2c(n1)c(C)nn2C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ncc5c(n4)c(C)nn5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
A mixture of (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (0.055 g, 0.107 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-pyrazolo[4,3-d]pyrimidine (0.058 mg, 0.133 mmol), copper(I) iodide (6 mg, 0.032 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.012 mmol) in dioxane was heated at 90° C. for 16 hr. Reaction mixture was cooled to rt, filtered through a syringe filter and purified by CombiFlash (12 g, Gold, 10-100% EtOAc/Hex, then 15% MeOH/CH2Cl2 to elute product) to give impure product that was used in next step without further purification. LCMS-ESI+: calc'd for C33H32ClN6O3S: 627.2 (M+H+); Found: 627.2 (M+H+).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][N:8]1[CH2:12][CH2:11]OC1=O)([CH3:4])([CH3:3])[CH3:2].[BrH:14].ClCCl>C(O)(=O)C>[BrH:14].[BrH:14].[C:1]([N:5]1[CH2:6][CH2:7][NH:8][CH2:12][CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NCCN1CCOC1=O
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)N1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To crude 3-[2-(tert-butylamino)ethyl]oxazolidin-2-one (1.18 g, 6.33 mmol) was added acetic acid (8.8 mL) and then 45% hydrobromic acid in acetic acid (19.5 mL). The reaction solution was stirred at room temperature for 3 d, poured into dichloromethane (250 mL), and filtered to give 1.87 g of a brown solid. The solid was heated at reflux in n-butanol for 2 d and the reaction mixture concentrated in vacuo. The residual solid was slurried in 3:1 diethyl ether:dichloromethane and filtered. The filtered solid was heated in ethanol, cooled to room temperature, and filtered to give 0.57 g (30%) of a white solid.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:17])=O>C(Cl)(Cl)Cl>[C:1]([O:9][CH2:10][C:11]([Cl:17])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)COC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(Cl)COC(=O)c1ccccc1
Reaction time: 5 h

Procedure:
4.1 g (0.023 m) Benzoyloxy acetic acid (as synthesized in Example XIII) was combined with 2.96 ml (4.3 g, 0.032 m) oxalyl chloride in 50 ml petroleum ether. This was stirred under a CaSO4 drying tube for 5 hrs., at which time 2.0 ml more oxalyl chloride and 50 ml chloroform were added. The reaction was stirred overnight.
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.ClC(Cl)C.[C:26]1([C:32]#[C:33][P:34](=[O:50])([O:38][C:39]([CH2:41][CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH2:40])[O:35][CH2:36][CH3:37])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>[Au]>[CH2:36]([O:35][P:34]1(=[O:50])[CH:33]=[C:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:40]=[C:39]([CH2:41][CH2:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:38]1)[CH3:37]
Reactant: C=C(CCCc1ccccc1)OP(=O)(C#Cc1ccccc1)OCC
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(CCCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Method 1—A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tent-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl 5-phenylpent-1-en-2-yl phenylethynylphosphonate (Example 5, 106.3 mg, 0.3 mmol) was put thereinto, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-3-phenylpropyl-1,2-oxaphosphorin 2-oxide (89.3 mg, 84%) which is a title compound.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16](O)=[O:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:19][C@H:20]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH3:21])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:44](CC)CC)C.Cl.CN(C)CCCN=C=NCC.N.O1CCOCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([NH2:44])=[O:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:19][C@H:20]([C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH3:21])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: C[C@H](O[C@@H]1CC[C@H]2[C@H](C(=O)O)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](O[C@@H]1CC[C@H]2[C@H](C(N)=O)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid (Example 130; 4.82 g, 6.99 mmol), triethylamine (2.93 ml, 20.97 mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (2.68 g, 13.98 mmol), 4-dimethylaminopyridine (10 mg), and ammonia in dioxane (41.94 ml, 20.97 mmol, 0.5M solution) were combined in dichloromethane (40 ml) and stirred in a sealed flask for 2 hours at room temperature. The reaction mixture was then diluted with water and the organics removed and the aqueous further extracted with dichloromethane (×2). All organics were combined, dried (MgSO4) and concentrated in vacuo to give a brown oil which was purified by flash column chromatography [3% methanol in dichloromethane] to give the title compound as a cream-coloured solid (1.76 g, 60%).
Reaction SMILES: C([O:8][C@H:9]([CH:11]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:10])C1C=CC=CC=1>C1CCCCC=1.C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C@H:9]([CH:11]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[N:22]=[CH:21]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:10]
Reactant: C[C@H](OCc1ccccc1)C(CCc1ccccc1)n1cnc(C(N)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: C[C@H](O)C(CCc1ccccc1)n1cnc(C(N)=O)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
Twenty percent palladium hydroxide on carbon (30 mg) was added to a stirred solution of 1-[(2S)-2-benzyloxy-5-phenyl-3-pentyl]imidazole-4-carboxamide (obtained in Example 3(1))(107 mg) in cyclohexene (5 ml) and ethanol (12.5 ml). The resulting mixture was stirred at reflux temperature for 12 hours. After cooling to room temperature, the mixture was filtered through Celite, and the insoluble material on the filter was washed with ethanol. The filtrate and washing were combined and then concentrated in vacuo. The resulting residue was purified by silica gel (3 g) chromatography eluted with chloroform/methanol (50:1) to give 1-[(2S)-2-hydroxy-5-phenyl-3-pentyl]imidazole-4-carboxamide (69.1 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[C:20]1([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=3[CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccccc3)cc2C1
Yield: 81.3 %

Procedure:
A mixture of tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of phenylboronic acid (111 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (160 mg, 77.3%) as an oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([NH2:19])[CH:18]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([NH:19][C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]3)[CH:18]=1
Reactant: Clc1nccc2ncccc12
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Product: Clc1ccc(Oc2ccccc2)c(Nc2nccc3ncccc23)c1

Procedure:
The product from Example 36e (0.040 g, 0.24 mmol) was reacted with 5-chloro-2-phenoxy-phenylamine as (0.048 g, 0.24 mmol) for 48 h at 100° C. following the procedure from Example 7g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.046 g, 40%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.96 (d, J=7.35 Hz, 2 H) 7.00-7.10 (m, 2 H) 7.22-7.39 (m, 4 H) 7.66 (dd, J=8.46, 4.41 Hz, 1 H) 7.91 (d, J=1.84 Hz, 1 H) 8.07 (d, J=6.25 Hz, 1 H) 8.76 (d, J=8.46 Hz, 1 H) 9.07 (d, J=3.31 Hz, 1 H); MS (ESI+) m/z 348.0 (M+H)+; (ESI−) m/z 346.1 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:11](/[CH:28]=[CH:29]\[CH3:30])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH2:35](Br)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O>CN(C=O)C>[CH2:35]([O:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:19][CH2:20]2)=[C:11](/[CH:28]=[CH:29]\[CH3:30])[CH:10]=1)([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:31])[F:32])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C/C=C\c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
tert-Butyl (Z)-4-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(prop-1-en-1-yl)phenyl]piperazine-1-carboxylate (85 mg, 0.181 mmol) was dissolved in N,N′-dimethylformamide (1.8 mL), added sodium hydride (9.5 mg, 217 mmol) and benzyl bromide (23 μL, 0.190 mmol) under ice-cold conditions, and the mixture was stirred at room temperature overnight. The reaction solution was added water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (67 mg) was obtained as a yellow oil.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[N:18]1([C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: c1ccc(CN2CCc3c(ncnc3N3CCOCC3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: c1nc2c(c(N3CCOCC3)n1)CCNC2
Yield: 69.3 %

Procedure:
7-Benzyl-4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 5a (0.55 g, 1.77 mmol) was dissolved in methanol (35 mL) under nitrogen. 10% Pd/C (0.55 g) was added under nitrogen followed by ammonium formate (1.12 g, 17.72 mmol) and the mixture was heated to reflux for 12 h. The catalyst was removed by filtration, washed with MeOH and the filtrate was concentrated. Flash column chromatography eluting with 5% MeOH/CH2Cl2 containing 0.5% of NH4OH gave 0.27 g of 4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 6a as a pale yellow dense liquid.
Reaction SMILES: Cl.[CH:2]12[NH:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH2:5][CH:4]([NH:11][C:12]([CH:14]1[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:21][C:20]3[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:3]2.[CH:28]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO>[CH:28]1([CH2:36][N:10]2[CH:6]3[CH2:7][CH2:8][CH2:9][CH:2]2[CH2:3][CH:4]([NH:11][C:12]([CH:14]2[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21][C:20]4[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=4)=[O:13])[CH2:5]3)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(NC1CC2CCCC(C1)N2)C1c2ccccc2Oc2ccccc21
Reactant: O=CC1CCCCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: O=C(NC1CC2CCCC(C1)N2CC1CCCCCCC1)C1c2ccccc2Oc2ccccc21
Reaction time: 12 h
Yield: 19 %

Procedure:
38.5 mg of N-(9-azabicyclo[3.3.1]nonan-3-yl)xanthene-9-carboxamide hydrochloride and 44.1 mg of cyclooctanecarbaldehyde were suspended in 3 ml of methanol at room temperature, and 1.60 g of sodium triacetoxyborohydride was added thereto, followed by stirring for 12 hours at the same temperature. Saturated aqueous sodium bicarbonate was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by preparative thin layer chromatography (Kieselgel™60F254, Art5744 produced by Merck Co.: chloroform/methanol=19/1), and 9.0 mg of the title compound as a white solid was obtained.