Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[NH:12][C:13](=O)[CH3:14].CO>O1CCCC1>[CH2:13]([NH:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH3:14]
Reactant: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1F
Solvent: C1CCOC1
Solvent: CO
Product: CCNc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 48 h
Yield: 95.5 %

Procedure:
To a cold (0°C.), stirred solution of 6.3 g (0.029 mole) of N-(2,5-difluoro-4-nitrophenyl)acetamide in 100 ml of dry tetrahydrofuran was added dropwise 8.8 ml of a 10M boranedimethyl sulfide complex in tetrahydrofuran. The reaction mixture was heated until a gentle reflux was maintained with no external heating. When this reflux subsided, the mixture was reheated at reflux for three hours. The reaction mixture was cooled to 0° C., and methanol was added dropwise until no gas evolution was seen upon subsequent addition. This mixture was allowed to stand at room temperature for two days. The solvent was removed from the mixture by distillation under reduced pressure, leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride to yield 5.6 g of N-ethyl-2,5-difluoro-4-nitroaniline as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][C:12]([F:15])([F:14])[F:13])[C:9]=1[OH:10])[C:5]#[N:6].[F:16][C:17]([F:44])([F:43])[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][C:32]([C:34]3[CH:42]=[CH:41][C:37]([C:38](O)=O)=[CH:36][CH:35]=3)=[O:33])[CH2:26][CH2:25]2)[N:19]=1>>[C:5]([C:4]1[CH:7]=[C:8]([O:11][C:12]([F:13])([F:14])[F:15])[C:9]2[O:10][C:38]([C:37]3[CH:36]=[CH:35][C:34]([C:32]([NH:31][CH2:30][CH:27]4[CH2:28][CH2:29][N:24]([C:20]5[N:19]=[C:18]([C:17]([F:43])([F:44])[F:16])[CH:23]=[CH:22][N:21]=5)[CH2:25][CH2:26]4)=[O:33])=[CH:42][CH:41]=3)=[N:1][C:2]=2[CH:3]=1)#[N:6]
Reactant: O=C(O)c1ccc(C(=O)NCC2CCN(c3nccc(C(F)(F)F)n3)CC2)cc1
Reactant: N#Cc1cc(N)c(O)c(OC(F)(F)F)c1
Product: N#Cc1cc(OC(F)(F)F)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1

Procedure:
The title compound was prepared from 3-amino-4-hydroxy-5-(trifluoromethoxy)benzonitrile and 4-{[({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)amino]carbonyl}benzoic acid (INTERMEDIATE 25) by a procedure analogous to that described in EXAMPLE 109. Mass spectrum (ESI) 591.1 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.47 (d, J=4.8 Hz, 1H), 8.36 (d, J=8.2 Hz, 2H), 8.06 (s, 1H), 7.97 (d, J=8.2 Hz, 2H), 7.59 (s, 1H), 6.72 (d, J=4.6 Hz, 1H), 6.33 (t, J=5.9 Hz, 1H), 4.87 (d, J=13.5 Hz, 2H), 3.45 (t, J=6.4 Hz, 2H), 2.93 (m, 2H), 2.00 (m, 1H), 1.90 (br d, J=11.6 Hz, 2H), 1.31 (m, 2H).
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1>C1COCC1.CN(C=O)C>[Si:21]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of estrone (1, 29 g, 107.3 mmol) and tert-butyldimethylsilyl chloride (18 g, 118 mmol) in THF (350 mL) at room temperature under argon was added imidazole (18 g, 264 mmol) in DMF (350 mL). After stirring the reaction mixture overnight, the THF was evaporated and the reaction mixture was poured onto ice water. The resulting white precipitate was collected by filtration, dissolved in CH2Cl2, and the solution was dried (MgSO4). The desiccant was filtered and the solvent was evaporated under reduced pressure to afford 38.8 g of 2 as a white, crystalline solid (94% yield), m.p. 171-172° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH2:20][C:19]2=[O:28])[CH2:12][CH2:11]1.O.[OH-].[Li+].Cl>C1COCC1>[O:28]=[C:19]1[N:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:29])=[O:2])[CH2:11][CH2:12]2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: COC(=O)c1ccccc1C1CCN(CCN2C(=O)COc3ccccc32)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1C1CCN(CCN2C(=O)COc3ccccc32)CC1
Temperature: 40 °C
Yield: 98 %

Procedure:
2-{1-[2-(3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-ethyl]-piperidin-4-yl}-benzoic acid methyl ester Compound 93 (1.2 g, 3.0 mmol) was dissolved in THF (10 mL) and treated with lithium hydroxide monohydrate (864 mg, 21 mmol). The reaction mixture was heated to 40° C. for 24 hrs, cooled to rt, adjusted to pH 3 with 1N HCl, and concentrated in vacuo. Purification by Gilson HPLC (elution with 10 to 90 gradient of H2O 0.2% TFA buffer/acetonitrile with 0.1% TFA buffer) afforded Compound 3-1 as a white solid (1.45 g, 2.93 mmol, 98%). 1H NMR (300 MHz, CDCl3) δ 8.71 (d, J=5 Hz, 1H), 7.92 (m, 1H), 7.59-7.43 (m, 2H), 7.32-7.22 (m, 1H), 7.14-6.89 (m, 3H), 4.62 (s, 2H), 3.97-3.68 (m, 2H), 3.45-2.94 (m, 4H), 2.71-2.33 (m, 3H), 2.13-1.96 (m, 2H), 1.80-1.65 (m, 2H); MS (ES+) m/z 381.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:18][C@H:10]1SC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:53])CC)C.BrN1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:19]([CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:18][C@@H:10]1[F:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@H]2O[C@@H](Sc3ccccc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClCCl
Product: F[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -15 °C
Reaction time: 0.03 h
Yield: 73.4 %

Procedure:
To a solution of 10 (10.0 g, 15.82 mmol, 1 eq) in dry CH2Cl2 (191 mL) under argon at −15° C. were added diethylaminosulfur trifluoride (3.14 mL, 23.73 mmol, 1.5 eq) and, after 2 min, N-bromosuccinimide (3.66 g, 20.57 mmol, 1.3 eq). After being stirred at −15° C. for 30 min the reaction was diluted with CH2Cl2 (420 mL) and poured into a cold saturated aqueous NaHCO3 solution (195 mL). The organic layer was dried over MgSO4 and concentrated. Purification by flash chromatography on silica gel (petroleum ether/EtOAc 94:6) afforded 11 as viscous syrup (6.3 g, 73%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:22][O-:23].[Na+]>CC(N(C)C)=O>[CH3:22][O:23][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[C:14]([CH3:21])[CH:13]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1cc(-c2cc3ncccc3c(Cl)n2)ccc1N(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1nc(-c2ccc(N(C)C)c(C)c2)cc2ncccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
100 mg (0.31 mmol) of 6.1 was placed in 0.5 ml dimethylacetamide and then 60 mg (1.1 mmol) sodium methoxide were added. The reaction mixture was stirred for 1 h at 50° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([OH:24])[C:19]([O:21]CC)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:18]([OH:24])[C:19]([OH:21])=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 50 °C

Procedure:
Ethyl 3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoate (4550 mg raw material from previous step 22.1; max. 10.72 mmol) dissolved in 13 ml of ethanol was treated with 6.43 ml 2N aq. NaOH overnight at room temperature. To complete the reaction, the mixture was then heated to 50° C. for 2 h. Water was added followed by extraction with MTBE (3×). The aqueous layer was acidified to pH 3 using 2M HCl and extracted three times with dichloromethane. The combined dichloromethane layers were then successively washed with water and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. The title compound was obtained as a pale brown powder (2450 mg, yield: 58%).
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[O:7]1[CH2:12][CH2:11][CH:10]([NH:13][NH2:14])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[CH3:6][C:2]1[CH:3]=[C:4]([NH2:5])[N:13]([CH:10]2[CH2:11][CH2:12][O:7][CH2:8][CH2:9]2)[N:14]=1
Reactant: NNC1CCOCC1
Reactant: C/C(N)=C/C#N
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)n(C2CCOCC2)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
(2Z)-3-Amino-2-butenenitrile (0.538 g, 6.55 mmol), tetrahydro-2H-pyran-4-ylhydrazine (1 g, 6.55 mmol) and triethylamine (0.913 mL, 6.55 mmol) were added to ethanol (300 mL), and the reaction mixture was stirred at 75° C. for 16 hours. The solvent was removed in vacuo, and the crude material suspended in EtOAc. The organic phase was washed with water and then brine. The organic layer was then dried over MgSO4, filtered, and concentrated in vacuo. Half of the crude material was purified by reverse HPLC (mobile phase: 0-30% ACN/H2O, 0.1% TFA) to afford 380 mg of the desired product. The other half of the crude material was purified via silica gel chromatography (eluent: 0% to 100% EtOAc:Hex then 0% to 20% MeOH:DCM). An additional 300 mg of the desired product was obtained (overall yield: 57%). LCMS E-S (M+H)=182.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.78 (dd, 2H), 1.94 (qd, J=12.13, 4.55 Hz, 2H), 2.19 (s, 3H), 3.30-3.46 (m, 2H), 3.99 (dd, J=11.49, 4.17 Hz, 2H), 4.49 (m, J=11.65, 11.65, 4.11, 3.92 Hz, 1H), 5.53 (s, 1H).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:17]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:18]>C(Cl)(Cl)Cl>[CH3:8][CH:5]1[CH2:6][CH2:7][N:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:3][CH2:4]1
Reactant: CC1CCN(N)CC1
Reactant: CCCCCCCCCCCCCCCCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCOC(=O)NN1CCC(C)CC1
Temperature: 25 °C

Procedure:
6.3 Grams of N-amino-4-methylpiperadine, 6.0 g of triethylamine and 120 ml of chloroform were charged in a flask equipped with a stirrer, a condenser and a calcium chloride drying tube and stirred with ice cooling. To the solution was slowly added dropwise 15.2 g of hexadecyl chloroformate. After completion of the addition, the temperature of the solution was returned to room temperature, followed by refluxing with heating for 0.5 hour. The reaction mixture was cooled to room temperature, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 16.8 g of the desired product. m.p. 92° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:25][NH2:26])[CH3:24].C(#N)C>O>[CH2:23]([N:25]1[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[C:16]2[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:26]1)[CH3:24]
Reactant: CCNN
Reactant: O=C1CCCCC1C(=O)C1CCN(Cc2ccccc2)CC1
Solvent: CC#N
Solvent: O
Product: CCn1nc2c(c1C1CCN(Cc3ccccc3)CC1)CCCC2

Procedure:
The title compound was prepared from the semi-crude (1-benzylpiperidin-4-yl)-(cyclohexanon-2-yl)ketone from step A and 34% aqueous ethylhydrazine in 4:1 acetonitrile and water at room temperature. This provided 8:1 ratio of isomeric ethyl pyrazoles in favor of the title compound. (Note: Use of ethyl hydrazine oxalate in the presence of DIEA gave about 2:1 ratio of the same isomers.) The 1-benzylpiperidine-4-carboxylic acid ethyl ester present in the starting β-diketone was removed after saponification of the crude product with sodium hydroxide in water ethanol mixture followed by extractive work-up. The desired ethyl isomer is the higher Rf isomer. It was isolated on silica gel chromatography (60˜100% ethyl acetate in hexanes and 5˜20% methanol in ethyl acetate, both with 1% triethylamine).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[CH:10]=[S:11]([CH3:14])([CH3:13])=[O:12])=[CH:4][CH:3]=1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[C:10](=[S:11]([CH3:13])([CH3:14])=[O:12])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: CS(C)(=O)=CC(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Temperature: 50 °C
Yield: 40 %

Procedure:
To a stirred solution of 7.72 grams (0.03 mole) of N-(4-chlorophenyl)-2-(dimethyloxosulfuranylidene)acetamide, prepared in Part A of this Example, in 80 milliliters of anhydrous acetonitrile, was added 1.70 grams (0.02 mole) of ethyl chloroformate dropwise at room temperature and the resulting mixture then heated and stirred at 50° C. for an approximate 16-hour period. The hydrochloride by-product was filtered off and the filtrate vacuum evaporated to give a yellow solid. The latter was digested with cold 2N HCl to remove unreacted starting material and the undissolved solid was collected and recrystallized from methanol. Vacuum drying of the resulting solid gave 2.73 grams (0.008 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate having a melting point of 162° C.-163° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([C:15]([F:18])([F:17])[F:16])[N:3]=1.P(Cl)(Cl)([Cl:21])=O>CN(C)C1C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:5]1[C:6]([Cl:21])=[N:7][C:2]([CH3:1])=[N:3][C:4]=1[C:15]([F:18])([F:17])[F:16])[CH3:14]
Reactant: CCOC(=O)Cc1c(C(F)(F)F)nc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Cc1c(Cl)nc(C)nc1C(F)(F)F
Yield: 98 %

Procedure:
A solution of ethyl (2-methyl-6-trifluoromethyl-3H-pyrimidin-4-on-5-yl)acetate (2.50 g, 9.46 mmol), N,N-dimethylaniline (3 drops), and phosphorus oxychloride (35 mL) was heated under reflux for 4.5 h. The mixture was concentrated, cooled, and ice water was added. Solid KOH was added to neutralize the mixture and it was extracted with ether. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 2.61 g (98%) of product as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[N:10][C:11]([N:12]3[CH2:18][CH:17]4[O:19][CH:14]([CH2:15][CH2:16]4)[CH2:13]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:29][C:5]1[C:6]2[C:7](=[N:8][C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[N:10][C:11]=2[N:12]2[CH2:13][CH:14]3[O:19][CH:17]([CH2:16][CH2:15]3)[CH2:18]2)[N:3]([CH2:1][CH3:2])[N:4]=1
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(Br)c2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Yield: 29.3 %

Procedure:
To a solution of 1-ethyl-6-(4-nitrophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (7.9 g)(20.8 mmol) in DMF (140 mL) was added N-bromosuccinimide (18.5 g) and heated to 85 C for 24 hr. The reaction was cooled and poured into water (1.0 L) to precipitate tan solids. The solids were filtered off and washed with water. The crude solid was purified by silica gel chromatography (EtOAc/Hexanes) to give 2.8 g of a yellow solid. MS m/z=459.2 (M+H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17]Br)=[O:5])[CH3:2].[CH2:19]([O:21][C:22](=[O:36])[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[O:34][CH3:35])[CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:36])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1CBr
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccccc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
A mixture of 4-bromomethyl-2-phenyl-thiazole-5-carboxylic acid ethyl ester (5.29 g, 16.3 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (4.12 g, 16.3 mmol) and potassium carbonate (3.37 g, 24.4 mmol) in anhydrous dimethylformamide (50 mL) was stirred at room temperature for 16 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.72 g): MS: (+) m/z 499.0 (M+H+), 521.2 (M+Na+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18](O)=[O:19])[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:43][C:44]([F:56])([F:55])[C:45]1[CH:50]=[CH:49][C:48]([C@H:51]([NH2:54])[CH2:52][CH3:53])=[CH:47][CH:46]=1>CN(C)C=O>[F:43][C:44]([F:55])([F:56])[C:45]1[CH:46]=[CH:47][C:48]([C@H:51]([NH:54][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:19])[CH2:52][CH3:53])=[CH:49][CH:50]=1
Reactant: CC[C@@H](N)c1ccc(C(F)(F)F)cc1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (150 mg, 0.593 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (80 mg, 0.593 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (114 mg, 0.593 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-(4-trifluoromethyl-phenyl)-propylamine (120 mg, 0.593 mmol) was added and the mixture was stirred at 25° C. overnight. The mixture was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 163 mg (65%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(4-trifluoromethyl-phenyl)-propyl]-amide as white solid. LC/MS (method 4): Rt=1.29 min; m/z=464.22 (M+H+). 1H-NMR: δ (ppm)=8.18 (1H, d), 7.69 (2H, d), 7.55 (2H, d), 7.26 (1H, s), 4.96 (1H, d), 4.83-4.92 (2H, m), 4.20-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.69, (2H, bs), 2.06 (1H, m), 1.96 (1H, m), 1.76-1.85 (3H, m), 1.54-1.59 (1H, m), 1.19 (3H, d), 0.90 (3H, t).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].OS(O)(=O)=O>>[Cl:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)ccc(C(=O)O)c1Cl
Agent: O=S(=O)(O)O
Product: Cc1c(F)c([N+](=O)[O-])cc(C(=O)O)c1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Aq HNO3 (65%, 0.39 mL) is added at 0° C. to a mixture of 2-chloro-3-methyl-4-fluoro-benzoic acid (880 mg, 4.7 mmol) and 8 mL conc H2SO4 and it is stirred for 2 h without further cooling. The mixture is poured into ice water and the precipitate is collected by filtration and dried.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([C:13]([OH:15])=O)[CH2:11][S:10][CH:9]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH2:29][S:30][CH3:31])[NH2:27].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH2:29][S:30][CH3:31])[NH:27][C:13]([CH:12]1[CH2:11][S:10][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCSC)NC(=O)C1CSC(c2cccnc2)N1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 600 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid in 10 ml of tetrahydrofuran, there were added, at 4° C. or below, 390 mg of L-methionine methyl ester hydrochloride, 390 mg of 1-hydroxybenzotriazole, 190 mg of N-methylmorpholine and 440 mg of dicyclohexylcarbodiimide, in that order. The mixture was stirred at 4° C. or below for 1 hour and then at room temperature for 1 hour. The resultant precipitate was filtered off, the filtrate was concentrated under reduced pressure, 50 ml of ethyl acetate was added, the insoluble matter was filtered off, and the filtrate was washed in sequence with 0.5M aqueous citric acid, water, 5% aqueous sodium hydrogen carbonate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 440 mg of [N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carbonyl]-L-methionine methyl ester as an oil.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH2:28][CH2:29]O[SiH](C)C)[CH2:23]C(C)(C)C)=[CH:17][CH:16]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:52]1CCCC1>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH:22]([CH2:28][CH3:29])[CH2:23][OH:52])=[CH:19][CH:20]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: C[SiH](C)OCCC(CC(C)(C)C)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCC(CO)Oc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To the product of Example 3D (0.3 g, 0.6 mmol) in a 10 mL round bottom flask was added tetrahydrofuran (2 mL). Upon solution, tetrabutylammonium fluoride (1.8 mmol, 1.8 mL, 1M solution in THF) was added and the reaction mixture was stirred for 90 minutes. The contents were then concentrated under reduced pressure and the crude mixture purified by flash chromatography using silica gel (hexanes:ethyl acetate) to obtain 185 mg (80%) of pure desired product. 1H(CDCl3) δ (ppm): 7.74 (s, 1H), 7.3 (d, 2H), 6.9 (d, 2H), 5.2 (s, 2H), 4.3 (m, 1H), 3.81-3.77 (two br s, 2H), 1.84 (br t, 1H), 1.77-1.69 (m, 2H), 1.64 (s, 9H), 0.98 (t, 3H); 13C (CDCl3) δ (ppm): 159.2, 158.9, 153.9, 129.2, 127.5, 125.4, 116.6, 80.4, 71.9, 66.5, 64.2, 28, 23.5, 9.7.