Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4](O[C@H](C2C=CC(Cl)=CC=2N2C=CC(C)=N2)C(F)(F)F)[N:3]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C@@H:47]([OH:52])[C:48]([F:51])([F:50])[F:49])=[C:43]([N:53]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[N:54]2)[CH:42]=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:52][C@H:47]([C:44]2[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][C:43]=2[N:53]2[CH:57]=[CH:56][C:55]([C:58]([F:59])([F:60])[F:61])=[N:54]2)[C:48]([F:50])([F:51])[F:49])[N:3]=1
Reactant: O[C@H](c1ccc(Cl)cc1-n1ccc(C(F)(F)F)n1)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2-n2ccc(C(F)(F)F)n2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(4-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol (Intermediate 39).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]CC)=O.[NH2:12][C:13]([NH2:15])=[O:14]>>[NH:12]1[C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7](=[O:9])[NH:15][C:13]1=[O:14]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NC(N)=O
Product: O=c1[nH]c2c(c(=O)[nH]1)CCC2

Procedure:
Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of cyclopentanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclopentanecarboxylate. Reaction of ethyl 2-oxocyclopentanecarboxy late with urea at 175-185° C. produced 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Reaction of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. Reaction of 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine with methyl 3-(bromomethyl)benzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione.
Reaction SMILES: [CH:1]1([NH:11][CH:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br.[O:15]=O.[Cl-].[Na+]>C(O)(=O)C.O.C(C(C)=O)C(C)C>[O:15]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][CH:12]=[O:13])[CH2:2][CH2:3]1
Reactant: O=CNC1CCCc2ccccc21
Reactant: O=O
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)O
Solvent: O
Product: O=CNC1CCC(=O)c2ccccc21
Temperature: 76 °C

Procedure:
A mixture of N-(1,2,3,4-tetrahydro-1-naphthyl)-formamide (2.0 g), cobaltous acetate tetrahydrate (0.95 g), a 30% solution of hydrobromic acid in acetic acid (0.925 g) and a 1:1 mixture of acetic acid: methyl isobutyl ketone (40 ml) is stirred and oxygen introduced via a capillary gas delivery tube. The blue reaction mixture is gradually heated to 76° C. in 42 minutes during which time the color changes to purple. The reaction mixture is then allowed to cool to room temperature. Water (40 ml) is added and the mixture saturated with sodium chloride. The mixture is extracted with chloroform (3×20 ml), the combined extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to dryness in vacuo. The residual red oil is triturated with ether and after cooling the title compound (0.4 g) collected. Further work-up of the mother liquor affords an additional 0.6 g of title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[N:14]1([C@H:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]2[NH2:7])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CCCC[C@@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
cis-(2-Pyrrolidin-1-yl-cyclohexyl)-carbamic acid tert-butyl ester (1.8 g, 6.7 mmol) was dissolved in dioxane. 4H HCl in dioxane (17 mL, 67 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was crystallized with ethanol and yielded cis-2-pyrrolidin-1-yl-cyclohexylamine dihydrochloride as a white solid (1.37 g, 85%), MS: m/e=169.2 [(M+H)+].
Reaction SMILES: FC(F)(F)C(O)=O.CC([N:12]([C:16]([CH3:36])([CH3:35])[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33][CH3:34])=[CH:24][CH:25]=1)=[O:18])C(=O)[O-])(C)C>ClCCl>[CH2:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[O:26][C:23]1[N:22]=[CH:21][C:20]([NH:19][C:17](=[O:18])[C:16]([CH3:36])([CH3:35])[NH2:12])=[CH:25][CH:24]=1)[CH3:34]
Reactant: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N(C(=O)[O-])C(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccc(NC(=O)C(C)(C)N)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL round-bottomed flask 1,1-dimethylethyl[2-({6-[(2-ethylphenyl)oxy]-3-pyridinyl}amino)-1,1-dimethyl-2-oxoethyl]carbamate (Intermediate 77, 88.6 mg) was dissolved in dichloromethane (2 mL) to give a yellow solution. Trifluoroacetic acid (2 mL, 26.0 mmol) was added. The reaction mixture was stirred at room temperature. After 20 minutes, the solvent was evaporated under vacuum affording a yellow oil that was charged on a 5 g SCX cartridge and was then flushed with mL of MeOH followed by 25 mL of 2M solution of ammonia in MeOH. The ammonia eluate was evaporated under vacuum to afford the title compound as a yellow oil which solidified (67.1 mg).
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[NH2:21][CH2:22][CH2:23][P:24](=[O:27])([O-:26])[O-:25].[OH-].[Na+]>C(O)C.O>[P:24]([CH2:23][CH2:22][NH:21][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6])([OH:27])([OH:26])=[O:25]
Reactant: NCCP(=O)([O-])[O-]
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncnc2c1nc(NCCP(=O)(O)O)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 110 °C

Procedure:
A mixture of 8-bromoadenosine (1 mmol), arninoethylphosphonate (2 mmol), and sodium hydroxide (2 mmol) in ethanol-water in a sealed tube was warmed at 110° C. under nitrogen. After 24 h the cooled reaction mixture was purified through preparative HPLC to give 8-(2-phosphonoethylamino)-adenosine (4.1). mp 175° C.; Anal. calcd. for C12H19N6O7P+0.5 H2O: C, 36.10; H, 5.05; N, 21.05; P, 7.76. Found: C, 36.08; H, 4.83; N, 20.36; P, 7.86.
Reaction SMILES: [F:1][CH2:2][C@@:3]12[C:32]3[CH:33]=[C:34]([N+:37]([O-])=O)[CH:35]=[CH:36][C:31]=3[O:30][CH2:29][CH2:28][C@@H:4]1[S:5](=[O:27])(=[O:26])[C:6]([CH3:25])([CH3:24])[C:7]([N:9]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8]2>CCOC(C)=O.CCO.[Pd]>[F:1][CH2:2][C@@:3]12[C:32]3[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:31]=3[O:30][CH2:29][CH2:28][C@@H:4]1[S:5](=[O:26])(=[O:27])[C:6]([CH3:24])([CH3:25])[C:7]([N:9]([C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[C:17](=[O:18])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:8]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc([N+](=O)[O-])ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc(N)ccc3OCC[C@@H]2S(=O)(=O)C1(C)C
Yield: 100.2 %

Procedure:
A solution of tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-nitro-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (647 mg, 1.13 mmol) in EtOAc (15 mL) and EtOH (5 mL) was hydrogenated at 1 atm. in the presence of palladium (10% wt. on activated carbon) (120 mg, 1.13 mmol) for 5 h at RT. The mixture was filtered through the pad of celite and washed 3 times with EtOAc. The filtrate was concentrated in vacuo to give tert-butyl N-[(4aS,11bS)-11b-(fluoromethyl)-3,3-dimethyl-10-amino-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (613 mg, 100%) as a white solid. LC/MS (ESI+) m/z=564 (M+Na).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].FC1C=CC([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])=C([N+]([O-])=O)C=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:19][C@H:20]([CH2:24][CH3:25])[C:21]([OH:23])=[O:22])[CH:7]=1
Reactant: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: CC[C@@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Yield: 83 %

Procedure:
2,4-Difluoronitrobenzene was treated according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield (R)-2-(5-fluoro-2-nitrophenylamino)-butyric acid (83%). MS (ESI) m/z 243 ([M#H]+); MS (ESI) m/z 241 ([M−H]−); HRMS: calcd for C10H11FN2O4, 242.07031; found (ESI+), 243.07712.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[CH2:28]([O:30][C:31]([C:33]1[CH:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3C=N[CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)[C:37]([C:55](=[O:57])[NH2:56])=[C:36]([CH2:58][CH3:59])[NH:35][C:34]=1[CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)=[O:32])[CH3:29].FC(F)(F)C(O)=[O:72]>C(Cl)Cl>[CH2:28]([O:30][C:31](=[O:32])[C:33]1[C:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:54])[NH:46][CH2:47][C:48]3[O:72][CH:51]=[CH:52][CH:53]=3)=[CH:41][CH:40]=2)=[C:37]([C:55](=[O:57])[NH2:56])[C:36]([CH2:58][CH3:59])=[N:35][C:34]=1[CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][CH:63]=1)[CH3:29]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C1=C(CCc2ccc(F)cc2)NC(CC)=C(C(N)=O)C1c1ccc(C(=O)NCc2cccnc2)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc(CC)c(C(N)=O)c1-c1ccc(C(=O)NCc2ccco2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
An aqueous solution of CAN (1 M, 1 mL) was added to 2 mL of DCM solution of compound 16 (˜0.25 mmol) and trifluoroacetic acid (0.1 mL). The resulting mixture was vigorously stirred for 20 min at r.t. The organic layer was separated, washed with water, dried over MgSO4, and concentrated in vacuo to yield the crude product. Purification by preparative LCMS (PE SCIEX, C18, acetonitrile—water with 0.035% trifluoroacetic acid) yielded the title compound in 18.5 mg yield. LC/MS (gradient 40-99%, 5 min.) RT=3.215. Calculated mass=243.2. Mass observed=243.7. 1H NMR (500 MHz, CDCl3): δ 0.88 (t, 3H), 1.36 (t, 3H), 2.98 (bq, 2H), 3.07 (bq, 2H), 3.15 (bq, 2H), 3.94 (q, 2H), 4.65 (d, 2H), 5.61 (bs, 1H), 6.32 (m, 1H), 6.36 (m, 1H), 6.61 (bt, 1H), 6.96 (t, 2H), 7.18 (t, 2H), 7.39 (s, 1H), 7.40 (d, 2H), 7.81 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[N+:10]([O-])([OH:12])=[O:11]>>[Cl:1][C:2]1[C:3]([Cl:9])=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: Clc1cccc(Cl)c1Cl
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl

Procedure:
the reaction of 1,2,3-trichlorobenzene with a nitration reagent, in particular nitric acid, to give 2,3,4-trichloronitrobenzene (A),
Reaction SMILES: C(OC(=O)C)(=O)C.O[N:9]=[C:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=1[N+:24]([O-:26])=[O:25])C(O)=O>C(O)(=O)C>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:10]#[N:9])=[C:16]([N+:24]([O-:26])=[O:25])[CH:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(CC(=NO)C(=O)O)c([N+](=O)[O-])c1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(C)c1ccc(CC#N)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
To a stirred solution of 1.18 mL of acetic anhydride in 5 mL of acetic acid was added a solution of 2.214 g of 2-hydroxyimino-3-(4-isopropyl-2-nitrophenyl)propionic acid in 5 mL of acetic acid at room temperature, and the mixture was stirred at 50° C. for 2 hours. After the reaction mixture was concentrated under reduced pressure, to the residue were added ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. After being washed with water, and brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 1.835 g of (4-isopropyl-2-nitrophenyl)acetonitrile.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18]N)=[CH:13][CH:12]=1.O1C2C=CC=CC=2[N:22]=[C:21]1[C:29]1C=CC(CCCC#N)=CC=1.O1C2C=CC=CC=2N=C1C1C=CC(CCCCN)=CC=1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH2:29][CH2:21][NH2:22])=[CH:15][CH:16]=1
Reactant: N#CCCCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: NCCc1ccc(-c2nc3ccccc3o2)cc1
Agent: Cl
Agent: NCCCCc1ccc(-c2nc3ccccc3o2)cc1
Product: CC(CCN)c1ccc(-c2nc3ccccc3o2)cc1

Procedure:
When 4-(benzoxazol-2-yl)benzyl cyanide of Example 42, Step D is replaced by 4-[4-(benzoxazol-2-yl)phenyl]butyronitrile, then the product prepared is 4-[4-(benzoxazol-2-yl)phenyl]butylamine (m.p. 220° C. dec.).
Reaction SMILES: [CH3:1][C:2](=[O:23])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([C:18](=[O:22])[CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH2:24](O)[CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:24]1[CH2:25][O:26][C:2]([C@@H:3]2[C@:20]3([CH3:21])[C@H:6]([C@H:7]4[C@H:17]([C:18](=[O:22])[CH2:19]3)[C@:15]3([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]3)[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)([CH3:1])[O:23]1
Reactant: OCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1([C@H]2CC[C@H]3[C@@H]4CC[C@H]5CC=CC[C@]5(C)[C@H]4C(=O)C[C@]23C)OCCO1
Reaction time: 8 h

Procedure:
5α-Pregn-2-ene-11,20-dione (10 g) in benzene (300 ml) was treated with ethylene glycol (30 ml) and toluene-4-sulphonic acid (100 mg), and the vigorously stirred mixture was refluxed through a Dean and Stark separator for 8 hours. The reaction mixture was partitioned between ether/ethyl acetate and dilute sodium bicarbonate solution. The organic layer was washed with water (3 times), dried over sodium sulphate and evaporated to a solidifying oil which was triturated with petrol to give title compound (9.42 g) as an off-white solid, m.p. 130°-135°, [α]D +111°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][N:10]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9]2)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH2:32])=[S:31])=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:32][C:14]([C@@H:13]2[CH2:12][CH2:11][N:10]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][C@H:8]2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:16])=[S:31])=[CH:28][CH:27]=1
Reactant: O=C(O)[C@@H]1CCN(CCc2ccccc2)C[C@H]1c1ccc(F)cc1
Reactant: NC(=S)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(NC(=S)c1ccc(Cl)cc1)[C@@H]1CCN(CCc2ccccc2)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (3R*,4R*)-3-(4-fluorophenyl)-1-phenethyl-piperidine-4-carboxylic acid (50 mg, 0.137 mmol, prepared according to the procedure disclosed in WO 2002/068387) and 4-chlorothiobenzamide (28.3 mg, 0.165 mmol) in CH2Cl2 (1.0 ml) was treated with HBTU (62.5 mg, 0.165 mmol) and DMAP (10 mg, 0.082 mmol) at rt. The mixture was stirred at rt for 6 h and then concentrated. The resulting residue was purified by RP-HPLC(C18, water, acetonitrile, 0.05% TFA) to afford the title compound, which was contaminated with 4-chlorothiobenzamide and was used in the next step without further purification. HPLC/MS: 481.3, 483.1 (M+1); Rt=1.14 (LC-2 HPLC conditions).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20](=[O:34])[N:21]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=[N:23]3)=[CH:18][C:17]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][O:35][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:23]=[CH:22][N:21]([CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[C:20]2=[O:34]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.32 g, 4.6 mmol) in methylene chloride (23 ml) containing TFA (5 ml) was stirred at ambient temperature for 1 hour. The volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and sodium hydrogen carbonate. The organic solvent was removed under vacuum and the residue was filtered. The precipitate was washed with water, and dried under vacuum. The solid was azeotroped with toluene and dried under vacuum to give 6-methoxy-7-(piperidin-4-ylmethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.7 g, 92%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1OS(C(F)(F)F)(=O)=O)[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2].[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][CH2:26][C:27]#[CH:28].[Cl-]>C(NCC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[C:28]#[C:27][CH2:26][CH2:25][CH2:24][C:23]([O:30][CH3:31])=[O:29])[C:8]([O:10][CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: C#CCCCC(=O)OC
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(NC(C)=O)c1
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)CCCC#Cc1ccc(C(=O)OC)cc1NC(C)=O
Temperature: 20 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A mixture of methyl 3-acetamido-4-trifluoromethane-sulfonyloxybenzoate (1.43 g), methyl 5-hexynoate (582 mg), palladium(II) chloride (14 .9 mg), triphenylphosphine (43.8 mg) and cooper(I) chloride (32 mg) in diethylamine (18 ml) was stirred at 20° C. for 14 hours. The solvent was evaporated in vacuo an the residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (1:2) to give methyl 3-acetamido-4-(5-methoxycarbonyl-1-pentynyl)-benzoate (1.15 g) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[N:11]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B:31](OC(C)C)([O:36]C(C)C)[O:32]C(C)C.CC(O)=O>C1COCC1>[C:12]([N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[B:31]([OH:36])[OH:32])=[N:8][N:9]=[N:10]1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -25 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
A solution of 5-phenyl-1-trityl-1H-tetrazole (70.0 g, 180.2 mmol, 1.0 equiv) in THF (dried) (560 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. The mixture was cooled to −25° C. Butyllithium was added to quench the trace of water in the reaction mixture until the color of the mixture remained red for at least 5 minutes. Butyllithium (80.0 mL, 2.5 mol/L) was then added dropwise to the mixture over a period of about 40 minutes at a temperature below −25° C. The temperature of the mixture was raised to −5° C., and the mixture was stirred at −5° C. for 3 hours. The mixture was then cooled to −25° C. and triisopropyl borate (50.8 g, 270.1 mmol, 1.5 equiv) was added dropwise. The mixture was warmed to temperature in the range of 25-35° C. and stirred for 2 hours. The mixture was cooled again in the range of 0-5° C., and 3% aqueous AcOH (470 mL) was slowly added over 30-40 minutes. The mixture was stirred for 30-40 minutes and then filtered. The crude product was washed with water (2×300 mL) and dried over reduced pressure. The crude product was then purified by re-crystallization from EtOAc (1 g/15 ml) to yield 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid (54 g) as a white solid. ES m/z: [M+H]+ calcd for C26H21BN4O2, 433.1. found 433.1.
Reaction SMILES: [C:1]([CH2:4][N:5](C1C=C(OCCCCCCCCCC)C=C(OCCCCCCCCCC)C=1)CC(O)=O)([OH:3])=[O:2].C(N(CC)C(C)C)(C)C.[OH:47][CH2:48][CH2:49][N:50]([CH2:55][CH2:56][OH:57])[C:51](=[O:54])[CH2:52]Cl.N(CCO)CCO.ClCC(Cl)=O.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C>[OH:47][CH2:48][CH2:49][N:50]([CH2:55][CH2:56][OH:57])[C:51]([CH2:52][O:3][C:1](=[O:2])[CH2:4][NH2:5])=[O:54]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Reactant: O=C(CCl)N(CCO)CCO
Agent: O=C(Cl)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: OCCNCCO
Product: NCC(=O)OCC(=O)N(CCO)CCO
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1.0 g (1.92 mmol) of N-(carboxymethyl)-N-[3,5-bis(decyloxy)phenyl]glycine, 2.6 ml of N,N-diisopropylethylamine and a solution of N,N-bis(2-hydroxyethyl)-2-chloroacetamide [prepared from the reaction of 2.1 g (20 mmol) of diethanolamine, 1.6 ml (20 mmol) of chloroacetyl chloride and 3.1 ml (22 mmol) of triethylamine in 25 ml of DMF] was stirred at room temperature for 17 hours. Sodium iodide (3.0 g, 20 mmol) was added and the reaction mixture was stired and heated at 60° under argon for 25 hours. The mixture was concentrated at reduced pressureand NaHCO3 solution was added to the residue. The product was extracted with ethyl acetate and the extract was washed with water, dried and concentrated to an oil which was crystallized from methylene chloride-ether to give 0.455 g (29% yield, mp 104°-107°) of N-[3,5-bis(decyloxy)phenyl]-N-[[bis(2-hydroxyethyl)amino]carbonyl]methoxy]-2-oxoethyl]glycine [[bis(2-hydroxyethyl)amino]carbonyl]methyl ester.