Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CC[C@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.6 %

Procedure:
To a solution of (S)-(+)-N-Boc-2-phenethylpyrrolidine (0.53 g, 1.93 mmol) in 5 mL of CH2Cl2 at 0° C. was added 5 mL of TFA. The solution was warmed to room temperature and stirred for 3 hours. The organic layer was concentrated under reduced pressure and redissolved in CH2Cl2. The organic layer was washed with 1 M NaOH, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a light yellow oil (0.31 g, 91%). ES (+) MS m/e=176 (M+H).
Reaction SMILES: [C:1]1([Li])C=CC=C[CH:2]=1.C1CCCCC1.CCOCC.[C:19]1([CH2:25][O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=2[N+:35]([O-:37])=[O:36])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCCCCC>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1>[C:19]1([CH2:25][O:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[CH:1][CH3:2])=[CH:29][C:28]=2[N+:35]([O-:37])=[O:36])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [Li]c1ccccc1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of (ethyl)triphenylphosphonium bromide (63.3 g, 170.5 mmol) in 270 mL of dry THF under Ar at 20° C., was added 91 mL of 1.8M phenyllithium in 70% cyclohexane/Et2O solution (163 mmol). After 30 minutes the reaction was cooled to -78° C., and a solution of 4-phenylmethoxy-3-nitrobenzaldehyde (38.96 g, 151.6 mmol) in 138 mL of THF was added by cannula over 25 minutes. The reaction was maintained at -78° C. for 60 minutes and stirred at 20° C. overnight prior to addition of 400 mL hexane. The supernatant was decanted and the solids stirred twice with additional THF/hexane which was also decanted. After concentration of the combined supernatants, the title compound (11.33 g, 1:1 trans to cis ratio) was eluted from silica gel by 0% to 25% EtOAc/hexane.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][C:32]=1[C:33]#[N:34])[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26](O)=[O:27])[CH2:21][C:20]1=[O:29])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC(C)C)=O.C1(C)C=CC=CC=1.[Cl:56][C:57]1[CH:62]=[CH:61][C:60]([NH2:63])=[C:59]([NH2:64])[CH:58]=1>C1COCC1.C(Cl)Cl>[NH2:63][C:60]1[CH:61]=[CH:62][C:57]([Cl:56])=[CH:58][C:59]=1[NH:64][C:26](=[O:27])[CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:17]2[CH:30]=[CH:31][C:32]([C:33]#[N:34])=[C:15]([N:14]=[C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=2)[C:20](=[O:29])[CH2:21]1
Reactant: Nc1ccc(Cl)cc1N
Reactant: N#Cc1ccc(CN2CCC(CC(=O)O)CC2=O)cc1N=C(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(CC(=O)Nc3cc(Cl)ccc3N)CC2=O)cc1N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a slurry of the {1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-2-oxo-piperidin-4-yl}-acetic acid (190 mg, 0.422 mmol) in THF (5 mL) and methylene chloride (3 mL) is added triethylamine (0.09 ml, 0.633 mmol). The solution is cooled to 0° C., and 1M isopropyl chloroformate in toluene (0.422 mL, 0.422 mmol) is added. The homogenous mixture is allowed to warm to room temperature, and 4-chloro-1,2-phenylene-diamine (150 mg, 1.06 mmol) is added. The reaction is stirred at room temperature overnight. The volatile solvents are removed, and the resulting residue is chromatographed (SiO2, 5% MeOH/EtOAc) to give N-(2-amino-5-chloro-phenyl)-2-{1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-2-oxo-piperidin-4-yl}-acetamide (200 mg, 82% yield). C34H30ClN5O2 MS m/z: 576, 578.
Reaction SMILES: C(O[C:6]([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C>O1CCCC1.CNC>[CH3:36][C:35]1[C:30]([N:27]2[CH2:26][CH2:25][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]([CH3:39])[CH3:6])=[O:38])=[O:23])[CH2:29][CH2:28]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C)C)CC2)c(C)c1
Yield: 44.6 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl) piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl) benzamide (186 mg) described in Example 769 and 2 mol/L dimethylamine tetrahydrofuran solution (180 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (60 mg) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ccc(C(F)(F)F)cn2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-5-trifluoromethyl-pyridine.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[OH-].[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17].Cl>O>[C:16]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of (−) tyrosine xxvii (2.50 g, 13.8 mmol) in NaOH (aq) (2 N, 7.59 mL, 15.2 mmol) was added H2O (6 mL). This vigorously stirred solution was cooled to 0° C., and acetic anhydride (3.25 mL, 3.52 g, 34.5 mmol) was added via syringe pump over 30 min. During this addition, excess NaOH (aq) (2 N, 34.5 mL, 69.0 mmol) was added in 10 portions. After the addition was complete, the reaction was warmed to room temperature and stirred for 45 min. The colorless solution was then carefully acidified to pH 2 with 6 N HCl (aq). After concentrating under reduced pressure, the resulting solid was extracted with 15% H2O in acetone (4×). The filtrate was concentrated under reduced pressure to afford a slightly yellow oil. The addition of H2O (1.5 mL) afforded N-acetyl tyrosine as a white precipitate (670 mg, 3.00 mmol, 22%) that was washed with H2O (3×). The washings were saved for later precipitations. To a solution of N-acetyl tyrosine (72 mg, 0.32 mmol) in 1:1 THF:H2O (1 mL) was added NaOH (aq) (1 N, 0.32 mL, 0.32 mmol). Benzyl chloroformate (49 μL, 58 mg, 0.34 mmol) was added followed by the dropwise addition of K2CO3 (aq) (2 N, 0.16 mL, 0.32 mmol). After stirring for 7 h at rt, the reaction was poured over H2O (10 mL) and carefully acidified to pH 2 with 6 N HCl (aq). The product was extracted from the water layer with EtOAc (3×), and the combined organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product xxix as a white solid (81 mg, 0.24 mmol, 75%).
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C@@:12](O)([CH:13]=[CH:14][C@@H:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)C(O)=O>O1CCCC1>[C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@@]12C
Agent: O=C(O)C(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=CC=C3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 35.4 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 350 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregna-6-en-5α-ol, followed by addition of 50 mg of dichloroacetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 124 to give 120 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregna-5,7 -diene showing the following physical properties.
Reaction SMILES: [CH2:1](Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:10][C:11]1[CH:22]=[CH:21][C:14](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=1[O:23][CH2:24][CH2:25][CH3:26]>CC(=O)CC>[CH2:1]([O:10][C:11]1[CH:22]=[CH:21][C:14](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:13][C:12]=1[O:23][CH2:24][CH2:25][CH3:26])[CH3:2]
Reactant: CCBr
Reactant: CCCOc1cc(/C=C/C(=O)OC)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cc(/C=C/C(=O)OC)ccc1OCC
Temperature: 25 °C

Procedure:
0.49 ml (6.60 mmol) of ethyl bromide and 1.37 g (9.9 mmol) of potassium carbonate are added to a mixture of 780 mg (3.30 mmol) of methyl (E)-4-hydroxy-3-propoxycinnamate and 10 ml of 2-butanone and then refluxed for 2 hours. Thereafter, the reaction mixture is cooled to room temperature and is partitioned between ethyl acetate and water, and the organic phase is washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over silica gel using 9:1 cyclohexane/ethyl acetate gives methyl 3(E)-[4-ethoxy-3-propoxyphenyl]acrylate.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[CH3:12][Si:13]([CH2:16][Mg]Cl)([CH3:15])[CH3:14].CN(C)C=O.CCCCCC>C(OCC)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:2][O:4]2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)CC1(c2ccc(F)cc2)CO1
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
1.068 g (6.2 mmole) of 2-chloro-4'-fluoroacetophenone were dissolved in 20 ml of diethyl ether, and the ethereal solution was stirred under a stream of nitrogen, whilst 7.5 ml of an ethereal solution containing 7.4 mmole of trimethylsilylmethylmagnesium chloride was added dropwise at such a rate that the temperature of the reaction mixture did not exceed -10° C. to -5° C. The reaction mixture was then stirred for a further 15 minutes whilst being kept within this temperature range. At the end of this time, 3.5 ml of dimethylformamide were added dropwise to the reaction solution at such a rate that the temperature of the reaction mixture did not exceed -10° C. to -5° C. The reaction mixture was then stirred for a further 10 minutes and, whilst it was being kept within this temperature range, 6 ml of hexane and then 6 ml of water were added. The reaction mixture was then stirred for 5 minutes, after which it was poured into 10 ml of water and extracted with 100 ml of hexane. The organic extract was washed with 50 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.39 g (yield 100%) of the title compound, as an oily substance.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH2:5]1)(=[O:23])=[O:22]
Reactant: O=C(Nc1ccccc1)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1
Temperature: 0 °C
Yield: 89.7 %

Procedure:
To a solution of 3-hydroxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (1.18 g, 4.29 mmol) (obtained as described in Reference Example 32(2)) in methylene chloride (60 ml) were added methanesulfonyl chloride (0.50 ml, 6.44 mmol) and triethylamine (0.90 ml, 6.44 mmol) in an ice bath, and then the mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:ethyl acetate (9:1) as the eluant to afford 3-methanesulfonyloxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (1.36 g, yield 89%) as a pale yellow solid.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]([O:16][CH3:17])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:28]([O:30][CH:31]1[CH:38]2[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:40][CH:32]1[CH2:33]3)[CH2:37]2)=[O:29]>C(Cl)Cl.CCOCC>[C:2]1([C:8]2([C:14]([O:16][CH3:17])=[O:15])[CH2:9][CH2:10][N:11]([C:28]([O:30][CH:31]3[CH:32]4[CH2:40][CH:36]5[CH2:35][CH:34]([CH2:39][CH:38]3[CH2:37]5)[CH2:33]4)=[O:29])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Reactant: COC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C1(c2ccccc2)CCN(C(=O)OC2C3CC4CC(C3)CC2C4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.3 %

Procedure:
To a stirred, ice-cold solution of methyl 4-phenylpiperidine-4-carboxylate hydrochloride (983 mg, 3.8 mmol) and i-Pr2NEt (1.88 mL, 10.5 mmol) in CH2Cl2 (25 mL) was added 2-adamantyl chloroformate (750 mg, 3.5 mmol). The ice bath was allowed to melt and the mixture was stirred overnight at rt. The mixture was diluted with ether (150 mL), washed with 5% aq HCl (2×30 mL) and satd aq NaHCO3 (30 mL) and dried over MgSO4. Removal of the solvent left the crude product (1.37 g, 99%) as a white solid. A 40-mg portion was purified by prep HPLC to afford the title compound (32 mg). LC-MS Method 1 tR=2.4 min, m/z=398, 1H NMR (CDCl3) 1.58 (m, 2H), 1.70-2.10 (14H), 2.56 (d, 2H), 3.10 (br d, 2H), 3.68 (s, 3H), 4.08 (d, 2H), 4.83 (s, 1H), 7.27 (m, 1H), 7.36 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)[CH:17]=2)=[O:13])[NH:3]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]3[N:31]=[CH:30][NH:29][N:28]=3)[CH:17]=2)=[O:13])[NH:3]1
Reactant: O=C(NCc1cccc(OCCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1)c1nc2ccccc2c(=O)[nH]1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(OCCCOc2nc[nH]n2)c1)c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a suspension of 4-oxo-N-({3-[(3-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}propyl)oxy]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 86 (0.285 g, 0.430 mmol) in acetonitrile (6 mL) were added trifluoroacetic acid (1.27 mL) and triethylsilane (0.082 mL, 0.516 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diethyl ether-EtOH to give the title compound as a white powder (0.173 g, 96%).
Reaction SMILES: CS(O[C@@H:6]([CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[NH:18][C:17]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:16][C:15]=2[N:14]([CH3:31])[C:12]1=[O:13])(=O)=O.[C-:33]#[N:34].[K+]>CS(C)=O>[C:33]([C@H:6]([CH3:32])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[NH:18][C:17]([CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:16][C:15]=2[N:14]([CH3:31])[C:12]1=[O:13])#[N:34]
Reactant: [C-]#N
Reactant: C[C@@H](CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O)OS(C)(=O)=O
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](C#N)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A suspension of (S)-1-(5-methanesulfonyloxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.47 g, 1.0 mmol) and potassium cyanide (0.39 g, 6.0 mmol) in dimethylsulfoxide (8.0 ml) was stirred at 60° C. overnight. The reaction was quenched by addition of water (30 ml) and extracted with ethyl acetate (3×15 ml). The combined extracts were washed with water (2×15 ml), saturated aqueous sodium chloride solution (15 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with 15% methanol-ethyl acetate to give (R)-1-(5-cyanohexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.25 g, 62% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:22])=[CH:13]/[C:14]3[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][CH:15]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:19][CH2:18][C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[C:12](/[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[O:5][CH2:4][CH2:3][C:2]3([CH3:23])[CH3:1])\[CH3:22])=[CH:21][CH:20]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: C/C(=C\c1ccc(CO)cc1)c1ccc2c(c1)C(C)(C)CCO2
Solvent: c1ccncc1
Product: CC(=O)OCc1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCO3)cc1

Procedure:
By treating p-[(E)-2-(4,4-dimethyl-6-chromanyl)propenyl]benzyl alcohol with acetyl chloride and pyridine there is obtained p-[(E)-2-(4,4-dimethyl-6-chromanyl)propenyl]benzyl acetate.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[C:18]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+]>CO>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([C:7]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[C:18]([CH2:24][C:25]([OH:27])=[O:26])=[CH:17][N:16]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)n2ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cnc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)n2ccnc12
Reaction time: 1 h
Yield: 78.1 %

Procedure:
To a solution of methyl [5-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)imidazo[1,2-c]-pyrimidin-8-yl]acetate (20 mg, 0.04 mmol) in methanol (1 mL) was added 1M NaOH aqueous solution (0.2 mL) at room temperature, and the mixture was stirred for 1 hour. After the removal of methanol under reduced pressure, water was added to the residue. The solution was washed with diethyl ether and neutralized by aqueous hydrochloric acid. The resulting precipitates were collected by filtration and dried under reduced pressure to give [5-(4-{[4-(trifluoromethyl)-benzoyl]amino}benzyl)imidazo[1,2-c]pyrimidin-8-yl]acetic acid (14.2 mg, 73%) as slightly brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:17]=[CH:18][C:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(S(=O)(=O)c3ccc(F)cc3)cc2)CC1
Temperature: 120 °C
Yield: 77.3 %

Procedure:
A solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (427 mg; 2.13 mmol), bis(4-fluorophenyl) sulfone (493 mg; 1.94 mmol) and potassium carbonate (1.01 g; 7.76 mmol) in dimethylsulfoxide (5 mL) is heated over night at 100° C. The temperature is then increased to 120° C. and the mixture is reacted at this temperature for 24 hours. The reaction is then diluted with dichloromethane (100 mL), filtered and the filtrate is washed with aq. 1N hydrochloric acid (2×20 mL), and water (2×20 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is finally purified by column chromatography on silica gel (dichloromethane:methanol 100:0 (200 mL) and then 98:2 (150 mL)) to afford the desired product (653 mg; 1.50 mmol).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][N:19]1[CH2:24][CH2:23][CH2:22][O:21][C:20]1=[O:25]>>[O:25]=[C:20]1[N:19]([NH:18][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH2:24][CH2:23][CH2:22][O:21]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NN1CCCOC1=O
Product: O=C(NN1CCCOC1=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-aminotetrahydro-2H-1,3-oxazin-2-one (CAN 54924-47-9) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 332.1612 (M+H)+.