Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16]>C(O)CCC>[Br:14][C:12]1[CH:11]=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[C:8]([NH:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Reactant: NC1CCCC1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCCC1
Temperature: 100 °C

Procedure:
Add cyclopentanamine (32 mL) to a solution of 2,4-dibromo-1-nitro-benzene (20 g) in 1-butanol (160 mL). Heat the mixture at 100° C. overnight. Remove the solvent under vacuum, add water and extract with EA. Wash the organic layer sequentially with an aqueous saturated solution of sodium bicarbonate and then water. Dry over magnesium sulfate and remove the solvent under vacuum to afford 22 g of the title compound. MS (ES+): m/z=286 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:32][CH2:28][CH2:29][CH2:30][CH3:31])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: CCCCN
Solvent: CN(C)C=O
Product: CCCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Yield: 56 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (4.5 g) in anhydrous dimethylformamide (100 cc), N,N'-carbonyldiimidazole (2 g) and butylamine (0.73 g). After recrystallization in acetonitrile, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-butylacetamide (2.35 g), m.p. 170° C., is obtained.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:11]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(OCC)OCC)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[O:8][CH:11]=[N:10][N:9]=2)=[CH:3][CH:4]=1
Reactant: NNC(=O)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Product: c1cc(-c2nnco2)ccn1
Temperature: 130 °C
Yield: 57738.3 %

Procedure:
A mixture of the isonicotinic hydrazide (13.7 g, 100 mmol), triethylorthoformate (60 ml) and p-toluenesulfonic acid (30 mg) was heated at 130° C. for 12 hours. Excess triethylorthoformate was removed under vacuum. The residue was crystallized from ethyl acetate to give 2-(4-pyridyl)-[1,3,4]oxadiazole (14.8 g); H1 NMR [(CD3)2SO]: δ 9.46 (1H, s), 8.8 (2H, dd), 7.9 (2H, dd).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[N:40]=3)[C:19](=[O:37])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28]CC4C=CC=CC=4)=[CH:24][C:23]=3[F:36])[N:15]2[C:14](=[O:46])[CH2:13][N:12]1[CH2:47][CH:48]=[CH2:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH2:1]([NH:8][C:9]([N:11]1[C@H:16]2[CH2:17][N:18]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[N:40]=3)[C:19](=[O:37])[C@H:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=3[F:36])[N:15]2[C:14](=[O:46])[CH2:13][N:12]1[CH2:47][CH:48]=[CH2:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN1CC(=O)N2[C@@H](Cc3ccc(OCc4ccccc4)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: C=CCN1CC(=O)N2[C@@H](Cc3ccc(O)cc3F)C(=O)N(Cc3cccc(F)n3)C[C@@H]2N1C(=O)NCc1ccccc1
Yield: 99.6 %

Procedure:
To a mixed solution of (6S,9aS)-N-benzyl-6-((4-(benzyloxy)-2-fluorophenyl)methyl)-8-((6-fluoropyridin-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide (5.04 g, 7.56 mmol) described in Production Example 1-1-5 and TFA (20 mL) was added thioanisole (3.55 mL, 30.2 mmol) at room temperature. The resultant mixture was stirred at room temperature for 13 hours and 50 minutes. The reaction mixture was concentrated under a reduced pressure, sodium hydrogen carbonate and water were added to the residue, and the resultant solution was extracted with ethyl acetate. An organic layer was dried over anhydrous magnesium sulfate and then filtrated. The solvent was evaporated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate:methanol=20:1) to give the title compound (4.34 g, yield: quantitative).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[N:7]=[C:8]2[N:13]([CH:14]=1)[CH2:12][C@H:11]([OH:15])[CH2:10][O:9]2)([O-:5])=[O:4].[Br:16][C:17]1[S:18][C:19]([CH2:22]Br)=[CH:20][CH:21]=1>CN(C=O)C>[Br:16][C:17]1[S:18][C:19]([CH2:22][O:15][C@@H:11]2[CH2:10][O:9][C:8]3=[N:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][N:13]3[CH2:12]2)=[CH:20][CH:21]=1
Reactant: BrCc1ccc(Br)s1
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](O)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Br)s1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
NaH (60% w/w, 0.60 g, 15 mmol) was added to a solution of (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol (2.00 g, 10.8 mmol) and 2-bromo-5-(bromomethyl)thiophene (prepared by the method of Mamane et al., Synthesis, 3; 2003; 455-467) (3.20 g, 12.5 mmol) in DMF (40 mL) at 0° C. The mixture was stirred at 0° C. for 2 h, then poured onto ice and extracted with EtOAc (2×200 mL). The organic layer was dried and evaporated. Column chromatography (hexanes/EtOAc, gradient elution) gave the titled compound (2.985 g, 77%) as a white solid. APCI MS m/z 360, 362 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.11 (d, J=3.7 Hz, 1H), 6.95 (d, J=3.7 Hz, 1H), 4.79 (d, J=13.2 Hz, 1H), 4.76 (d, J=13.2 Hz, 1H), 4.60 (dt, J=12.0, 1.6 Hz, 1H), 4.44 (d, J=12.0 Hz, 1H), 4.19-4.25 (m, 3H).
Reaction SMILES: [CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=O)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.C(Cl)(=O)C(C)(C)C.[CH2:26]([C@H:33]1[CH2:37][O:36][C:35](=[O:38])[NH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([Li])CCC>C1COCC1>[CH2:26]([CH:33]1[CH2:37][O:36][C:35](=[O:38])[N:34]1[C:6](=[O:8])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH2:9])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=C(CCCC)C(=O)O
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(CCCC)C(=O)N1C(=O)OCC1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-n-butyl acrylic acid (9.90 g, 77.2 mmol, and 1 equiv.) is dissolved in dry THF (260 mL) and cooled to −78° C. under nitrogen. Hunig's base (17.5 mL, 100.4 mmol, 1.3 equiv.) and pivaloyl chloride (9.5 mL, 77.2 mmol, 1 equiv.) are added at such a rate that the temperature remains below −60° C. The mixture is stirred at −78° C. for 30 minutes, warmed to rt for 2 hours, and finally cooled back to −78° C. In a separate flask, (S)-(−)-4-benzyl-2-oxazolidinone (13.49 g, 77.24 mmol) is dissolved in dry THF (150 mL) and cooled to −78° C. under nitrogen. n-butyllithium (2.5 M solution in hexanes, 30.9 mL, 77.2 mmol, 1 equiv.) is added slowly at −78° C., and the mixture is stirred for 30 minutes at rt. The resulting anion is slowly transferred via a cannula into the original reaction vessel. The mixture is allowed to warm to rt and is stirred overnight at rt. The reaction is quenched with 1 M KHCO3, and the solvents are removed under reduced pressure. The residue is partitioned between EtOAc and water. The organic layer is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil which is purified by FC (hexane:EtOAc=4:1) to yield the title compound A-3 as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CC(C1C=CC([N+]([O-])=O)=CC=1)=O.[N+](C1C=CC([C@H](O)C)=CC=1)([O-])=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([OH:12])[CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: C[C@@H](O)c1ccc([N+](=O)[O-])cc1
Product: C[C@H](O)c1ccc([N+](=O)[O-])cc1
Reaction time: 96 h
Yield: 45 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized soy bean protein for the substrate (+)-1-(4-nitrophenyl)ethanol (200 mg) requires 4 days by going through bioconversion to 4-nitroacetophenone accompanying sterically selective oxidation of (R)-1-(4-nitrophenyl)ethanol to obtain 90 mg of (S)-1-(4-nitrophenyl)ethanol at a yield of 45%. Optical purity was obtained at 99% e.e.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][C:14]4[S:15][CH:16]=[CH:17][C:18]=4[C:11]=3[N:10]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:9]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][Si:23]([CH3:26])([CH3:25])[CH2:22][CH2:21][O:20][CH2:19][N:10]1[C:11]2[C:18]3[CH:17]=[CH:16][S:15][C:14]=3[CH2:13][C:12]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:3][CH:4]=2)=[N:9]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(O)cc3)cc2)c2c1-c1ccsc1C2
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of the corresponding inteimmediate 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.9 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (0.33 g, 1.5 mmol), Na2CO3 (2 M, 2.7 mL), and Pd(PPh3)2Cl2 (8 mg, 0.075 mmol) in toluene/ethanol (1:1, 6 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give 4′-[4-(2-Trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pe ntalen-6-yl]-biphenyl-4-ol as brown solid in 52% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]1([CH:41]=O)[CH2:40][O:39][CH2:38]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:36][C:37]3([CH3:41])[CH2:40][O:39][CH2:38]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CC1(C=O)COC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(C=C(C#N)C(=O)N2CCC[C@H]2Cn2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)COC1
Reaction time: 3 h

Procedure:
To a slurry of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (74 mg, 0.16 mmol) in ethanol (3 mL) was added 3-methyloxetane-3-carbaldehyde (78.54 mg, 0.78 mmol) and then piperidine (0.02 mL, 0.16 mmol) and the mixture heated to 80° C. with stirring. After 3 h, the mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and the filtered. Solvents were removed to afford an oil which was purified by column chromatography (gradient from neat methylene chloride to 95-5 methylene chloride:MeOH). The pure fractions were concentrated, then taken up in acetonitrile/water, frozen and lyophilized to afford 2-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidine-1-carbonyl]-3-(3-methyloxetan-3-yl)prop-2-enenitrile as a colorless solid weighing 14 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[C:41]=5[F:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-difluoro-phenylboronic acid.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:3]1=[O:12].[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:39])([F:38])[F:37])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2([C:36]([F:38])([F:37])[F:39])[O:25][N:24]=[C:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30]([NH:1][N:2]4[CH2:6][CH2:5][N:4]([CH2:7][C:8]([F:9])([F:11])[F:10])[C:3]4=[O:12])=[O:31])=[C:28]([CH3:35])[CH:27]=3)[CH2:22]2)[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: NN1CCN(CC(F)(F)F)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NN1CCN(CC(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Into a 25-mL round-bottom flask, was placed 1-amino-3-(2,2,2-trifluoroethyl)imidazolidin-2-one (90 mg, 0.49 mmol, 1.00 equiv), 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (200 mg, 0.48 mmol, 0.97 equiv), EDCI (192 mg, 1.00 mmol, 2.04 equiv), HOBT (135 mg, 1.00 mmol, 2.03 equiv), triethylamine (303 mg, 2.99 mmol, 6.09 equiv), dichloromethane (10 mL). The resulting solution was stirred for 30 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 39 mg (13%) of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methyl-N-[2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl]benzamide as a white solid. (ES, m/z): 583 [M−H]−; 1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.43-7.62 (m, 6H), 4.06-4.12 (m, 1H), 3.54-3.89 (m, 7H), 2.47 (s, 3H).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C[O:33][CH2:32]C1>C(OCC)=O>[CH:32]([CH:12]1[C:11]2[CH:10]=[C:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][C:15]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:16][CH:17]=2)=[O:33]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cc(NC(=O)OC(C)(C)C)ccc1-2
Solvent: CCOC=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(C=O)c1cc(NC(=O)OC(C)(C)C)ccc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Purified 2,7-di(Boc-amino)fluorene (5 g, 12.5 mmol) (prepared from step A, above), was dissolved in ethyl formate (50 mL) and anhydrous THF (60 mL) with gentle heating. (Note: ethyl formate was stored over K2CO3 to remove formic acid.) The solution was cooled in an ice bath and sodium hydride 60% in mineral oil was added portion-wise (5.5 eq, 69 mmol, 2.75 g). The reaction was slowly warmed to room temperature and then heated to 50° C. after fitting with a reflux condenser. After two hours, the reaction was cooled in an ice bath and quenched by the slow addition of deionized water (50 mL). The aqueous layer was adjusted to pH 5 with glacial acetic acid and extracted with ethyl acetate (2×400 mL). The combined organic layers were dried with Na2SO4, filtered and evaporated under reduced pressure. The crude product (dark brown solid) was purified by flash chromatography: silica gel 60 Å step-wise gradient elution 1-5% methanol in chloroform. Yield (4.8 g, ˜90%) of a yellow to brown solid, depending on purity. 1H-NMR (d6-DMSO): δ (ppm) 11.0 (s, 0.9H, enol); 9.3 (2 s, 1.9H, NH urethane); 7.2-8.3 (m, Ar, C10H enol); 6.5 (2 s, 0.1H, NH urethane); 4.1 (m, 0.3H, CH); 1.5 (s, 18H, Boc).
Reaction SMILES: [N+](=[CH:3][CH3:4])=[N-].[OH:5][CH:6]([CH2:25][O:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:8][N:9]1[C:13](=[O:14])[CH2:12][S:11](=[O:15])[CH:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CCOCC>[OH:5][CH:6]([CH2:25][O:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:8][N:9]1[C:13](=[O:14])[CH2:12][S:11](=[O:15])[CH:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:3][CH3:4])=[O:23]
Reactant: CC=[N+]=[N-]
Reactant: CCCOCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)O
Solvent: CCOCC
Product: CCCOCC(O)CCN1C(=O)CS(=O)C1CCCCCCC(=O)OCC
Reaction time: 4 h

Procedure:
A solution of diazoethane (approximately 3.4 g., 0.06 mole) in ether (100 ml.) is slowly added to a solution of 7-[3-(3-hydroxy-4-propoxybutyl)-1,4-dioxo-2-thiazolidinyl]heptanoic acid (11.3 g., 0.03 mole) in ether (50 ml.) with stirring and cooling (0° to 5° C.). The resulting solution is allowed to warm to and stand at room temperature for 4 hours. After destroying excess diazoethane with acetic acid, the reaction solution is washed with 5% sodium bicarbonate solution and water, dried over sodium sulfate, and filtered. In vacuo evaporation of the filtrate leaves the title compound as an essentially colorless, viscous oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[BH3-]C#N.[Na+].[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CS(O)(=O)=O>CO>[F:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(OCc2cccc(F)c2)cc1
Reactant: N[C@H]1CCNC1=O
Agent: CS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C1NCC[C@@H]1NCc1ccc(OCc2cccc(F)c2)cc1
Reaction time: 0.17 h

Procedure:
To a 2M solution of (S)-3-aminopyrrolidin-2-one (1.47 g, 14.6 mmol), prepared as described in Example 5, in anhydrous methanol 2.0 g of 3 Å molecular sieves and 0.77 g NaBH3CN (12 mmol) were added; after 10 minutes, 3.4 g (14.8 mmol) of 4-(3-fluorobenzyloxy)benzaldeyde in 40 ml of anhydrous methanol were added. The reaction was carried out for 3 hours, then the mixture filtered, the solution was evaporated yielding a residue which was directly flash-chromatographed on silica gel (eluant: CHCl3:CH3OH:NH3 (30%) 97:3:0.3, v:v:v) to give a white solid (3.4 g; 74%). The free base thus obtained was treated with a stoichiometric amount of methanesulfonic acid to give the title compound m.p. 140.5-143.5° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:29]=[CH:28][C:22]([C:23](OCC)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:30].Cl.[CH3:32][NH2:33]>>[CH3:32][NH:33][C:23](=[O:24])[C:22]1[CH:28]=[CH:29][C:19]([N:16]2[CH2:15][CH2:14][CH:13]([CH2:12][C:10]3[CH:9]=[CH:8][C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:30])[NH:4][C:5]=4[CH:11]=3)[CH2:18][CH2:17]2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Reactant: CN
Agent: Cl
Product: CNC(=O)c1ccc(N2CCC(Cc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1

Procedure:
Saponification of 390D was performed using the general procedure for hydrolysis of carboxylic esters. The resulting carboxylic acid and methylamine hydrochloride were used in the general procedure for coupling an amine to a carboxylic acid to give the title compound as a pinkish, tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.28 (m, 2H) 1.40 (d, J=6.57 Hz, 3H) 1.55-1.71 (m, 3H) 2.44 (d, J=6.57 Hz, 2H) 2.62-2.78 (m, 5H) 3.82 (d, J=12.63 Hz, 2H) 4.61 (q, J=6.65 Hz, 1H) 6.65-6.77 (m, 2H) 6.82-6.95 (m, 3H) 7.67 (d, J=9.09 Hz, 2H) 8.05-8.15 (m, 1H) 10.59 (s, 1H). ESI-MS: m/z 394.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([C:10]2[CH2:11][CH2:12][N:13](CC3C=CC=CC=3)[CH2:14][CH:15]=2)[S:8][CH:9]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].C(OC(Cl)=O)=C>ClCCCl>[CH3:4][C:2]([C:5]1[N:6]=[C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)[S:8][CH:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1csc(C2=CCN(Cc3ccccc3)CC2)n1
Agent: C=COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CC(C)(C)c1csc(C2=CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.5 g 4-(4-(1,1-dimethylethyl)-2-thiazolyl)-1-phenylmethyl-1,2,3,6-tetrahydropyridine, 2.5 g K2CO3 and 50 ml 1,2-dichloroethane are treated dropwise at -10° to -7° under stirring with 3.75 ml chloroformic acid vinyl ester. The mixture is stirred at -10° to -7° for 3 hours. The solvent is evaporated, the residue partitioned between water and hexane. and the water phase extracted with hexane. The combined organic layers are washed with saturated brine solution, filtered and dried (Na2SO4). The solvent is evaporated and the oily residue is added under ice-cooling to 20% aqueous hydrochloric acid. The mixture is heated on a steam bath for 4 hours, then cooled to room temperature and extracted once with dichloromethane.The aqueous acidic solution is filtered, made alkaline with aqueous NaOH and extracted with ethyl ether. After evaporation of ether, the heading compound is obtained as an oily residue. M.p. of the hydrogenmaleinate is 170°-171°.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C@@H:51]1[CH2:55][CH2:54][C@@H:53]([CH3:56])[NH:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:52]2[C@H:53]([CH3:56])[CH2:54][CH2:55][C@H:51]2[CH3:50])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: C[C@@H]1CC[C@@H](C)N1c1nc(C(C)(C)C)nc2c1nnn2Cc1ccccc1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (2R,5R)-2,5-dimethylpyrrolidine and isolated as colorless gum (11.2 mg, 60%). MS(m/e): 399.4 (MH+).