Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].CO[C:5]([C:7]1[N:8]=[C:9]([CH:12]([OH:37])[CH2:13][CH:14]([N:18]([CH3:36])[C:19](=[O:35])[CH:20]([NH:25][C:26]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][N:29]2[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])[CH:15]([CH3:17])[CH3:16])[S:10][CH:11]=1)=[O:6]>C1COCC1.CO>[OH:37][CH:12]([C:9]1[S:10][CH:11]=[C:7]([C:5](=[O:6])[NH:2][CH3:1])[N:8]=1)[CH2:13][CH:14]([N:18]([CH3:36])[C:19]([CH:20]([NH:25][C:26]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH3:34])=[O:27])[CH:21]([CH3:24])[CH2:22][CH3:23])=[O:35])[CH:15]([CH3:16])[CH3:17]
Reactant: CN
Reactant: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)OC)cs1)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)C(NC(=O)C1CCCCN1C)C(=O)N(C)C(CC(O)c1nc(C(=O)NC)cs1)C(C)C
Temperature: 100 °C
Yield: 51.9 %

Procedure:
In a sealed tube, 10.0 mL of a 2.0 M solution of methylamine (5.00 mmol) in THF was added to a 0.02 M solution of 23 (27.0 mg, 0.0529 mmol) in MeOH (2.50 mL). The reaction solution was heated to 100° C. for 21 h. After the solution cooled to rt, the solvent was removed under reduced pressure. Reverse-phase HPFC (20:80 to 100:0 MeCN/H2O) followed by lyophilization provided compound 25 (14.0 mg, 52%) as an amorphous solid. The 1H NMR corresponds to a 6:1 mixture of rotamers, with the major isomer reported. [α]D23=−2.9 (c=1.0, MeOH). 1R: 1070, 1499, 1551, 1646, 2876, 2961 cm−1. 1H NMR (500 MHz, MeOD): δ 0.83 (d, 3H, J=6.5 Hz), 0.90 (t, 3H, J=7.5 Hz), 0.966 (d, 3H, J=6.5 Hz), 0.974 (d, 3H, J=6.5 Hz), 1.15-1.25 (m, 1H), 1.25-1.32 (m, 1H), 1.48-1.66 (m, 4H), 1.72 (d, 2H, J=10.5 Hz), 1.81-1.99 (m, 3H), 2.00-2.10 (m, 1H), 2.16 (s, 3H), 2.19-2.37 (m, 1H), 2.53-2.58 (m, 1H), 2.87-2.94 (m, 1H), 2.92 (s, 3H), 3.17 (s, 3H), 4.16-4.58 (br s, 1H), 4.64 (dd, 1H, J=2.3, 10.3 Hz), 4.72 (d, 1H, J=9.0 Hz), 8.06 (s, 1H). 13C NMR (125 MHz, MeOD) δ 11.1, 16.1, 20.5, 20.6, 24.4, 25.9, 26.3, 26.4, 31.3, 31.7, 37.8, 38.8, 44.8, 55.4, 56.7, 70.0, 70.6, 124.2, 151.0, 164.4, 175.3, 175.7, 179.4. HRMS (FAB) calcd for C25H44N5O4S (M+H): 510.3114. Found: 510.3098.
Reaction SMILES: O1CCCCC1O[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH2:16]2)[CH:10]=1.S(Cl)([Cl:33])=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:33][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH2:16]2)[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCN(c2cc(COC3CCCCO3)ccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2cc(CCl)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of benzyl 4-(4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)piperazine-1-carboxylate (7.3 g, 17.7 mmol) in DCM (30 mL), thionyl chloride (7.7 mL, 106.6 mmol) was added slowly at RT, followed by the addition of H2O (0.05 mL). The mixture was stirred at RT overnight, poured into a solution of aqueous NaHCO3 (sat., 50 mL), and extracted with DCM (2×30 mL). The combined organic layers were washed with H2O (50 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=3:1) to give benzyl 4-(4-(chloromethyl)pyridin-2-yl)piperazine-1-carboxylate as a yellow solid (5.0 g, 82%). MS (ES+) C18H20ClN3O2 requires: 345, found: 346 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](=[S:33])[NH:24][C@H:25]([CH:30]([CH3:32])[CH3:31])[C:26]([O:28][CH3:29])=[O:27])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23](=[S:33])[NH:24][C@H:25]([CH:30]([CH3:31])[CH3:32])[C:26]([O:28][CH3:29])=[O:27])[O:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(N)cc2)no1)C(C)C
Reactant: O=C=Nc1ccccc1F
Product: COC(=O)[C@H](NC(=S)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1)C(C)C
Yield: 65 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and (R)-methyl 2-(3-(4-aminophenyl)isoxazole-5-carbothioamido)-3-methylbutanoate was used in place of methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate to yield 65% of the title compound. MS (ESI): m/z 471(M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 10.935 (s, 1H), 9.355 (s, 1H), 8.640 (s, 1H), 8.161 (s, 1H), 7.891 (s, 2H), 7.634 (d, 3H), 7.256 (s, 1H), 7.162 (s, 1H), 7.038 (s, 1H), 4.835 (s, 1H), 3.689 (s, 3H), 2.507 (s, 1H), 1.049 (d, 6H).
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(Cl)(Cl)Cl.CO>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH:3]2[O:17][C:6]3=[C:7]4[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]3[CH2:4]2)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]4)[CH2:28][CH2:27]1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: COc1ccccc1N1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1N1CCN(CC2Cc3cc(C)c4[nH]c(=O)ccc4c3O2)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.824 g) and 1-(2-methoxyphenyl)piperazine (5.000 g) was stirred in a hot bath at 150° C. in the stream of argon gas for 1 hour. The reaction product was dissolved in a solvent mixture of chloroform and methanol (5:1), and washed with sodium bicarbonate water, and water in this order. After dried and condensed, n-hexane was added to the residue, and the mixture was allowed to stand. As a result, 4.349 g of a free base of the title compound was obtained as pale yellow flakes (mp.: 245°-247° C. (dec.)).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2.NC1C(C)=CC([O:30][C:31]([F:34])([F:33])[F:32])=CC=1C(OC)=O>>[F:32][C:31]([F:34])([F:33])[O:30][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:11]=1)[NH:8][N:7]=[CH:6]2
Reactant: COC(=O)c1cc(OC(F)(F)F)cc(C)c1N
Reactant: COC(=O)c1cc(C(F)(F)F)cc2cn[nH]c12
Product: COC(=O)c1cc(OC(F)(F)F)cc2cn[nH]c12

Procedure:
The title compound was prepared as in the method of compound 4 from methyl 2-amino-3-methyl-5-(trifluoromethoxy)benzoate to give an off-white solid (0.355 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH2:5][CH2:6][CH3:7].[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:18])[CH:4]([N:8]1[C:9](=[O:17])[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][C:19]1=[O:20])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(NC(=O)c1ccccc1N)C(=O)OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(C(=O)OC)n1c(=O)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.7 %

Procedure:
To a solution of 2-(2-amino-benzoylamino)-pentanoic acid methyl ester (575 mg, 2.30 mmol) and 1,1′-carbonyldiimidazole (930 mg, 5.74 mmol) in THF (25 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-enc (0.9 mL, 6.02 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with EtOAc (100 mL) and is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, concentrated and the resulting residue is purified by flash chromatography with 50% EtOAc in Hexane as the eluent to afford the desired 2-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-pentanoic acid methyl ester (284 mg, 45%).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=2[C:7]=1[CH3:8].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:6]=3[C:7]=2[CH3:8])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(Cl)C2CCCCC2)oc2ccc(F)cc12
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Yield: 49.9 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-fluoro-3-methyl-1-benzofuran (400 mg) synthesized in Example A37(3) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (336 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4), the title object compound (321 mg, 50%) was obtained as a pale-brown solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)([O-:8])=[O:7]>O1CCCC1>[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)=[CH:4][CH2:3][CH2:2][CH2:1][CH2:11][CH2:10][CH2:9][CH2:16][CH3:15]
Reactant: [Li]CCCC
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CCCCCCCCC=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
Phosphonium salt (141 g) obtained from n-nonyl bromide (115 ml) and triphenylphosphine (78.5 g) was dissolved in dry tetrahydrofuran (500 ml) and thereto was dropwise added n-butyl lithium (372 ml, 1.6M hexane solution) over not less than 1 hour at 0° C. After the dropwise addition, the reaction mixture was stirred at said temperature for 30 minutes and at room temperature for 1 hour. A solution of 4-nitrobenzaldehyde (45.3 g) in tetrahydrofuran (150 ml) was dropwise added thereto at 0° C. over 1 hour. The reaction mixture was stirred at room temperature for 10 hours and filtered. The residue was washed with ether. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate=100:1) to give 70.9 g of 4-(1-decenyl)-nitrobenzene (cis/trans=7:3).
Reaction SMILES: [C:1]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1>[CH2:3]([C@@H:2]([C:1]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7])[CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)CBr
Reactant: CCCCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[C@H](CC(=O)OC)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-hexanoyl-4-(S)-benzyloxazolidin-2-one (7.3 mmol) in THF at −78° C. was added 1.0 M sodium hexamethyldisilazide (NaHMDS, 8.8 mmol) and the reaction stirred at −78° C. for 1 hr. A solution of methyl bromoacetate (8.8 mmol) in THF was then added dropwise, and the resulting mixture was stirred at −78° C. for 1 hr and then at room temperature overnight. The reaction was quenched with NH4Cl, concentrated, then suspended in ethyl acetate and washed with 0.5 N HCl and brine, dried, and purified by silica gel chromatography (ethyl acetate/hexanes) to afford the methyl 3-(R)-(n-butyl)-3-[4-(S)-benzyloxazolidin-2-one-3-ylcarbonyl)propionate.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH:13]1[CH2:17][CH2:16][S:15][CH2:14]1>>[S:15]1[CH2:16][CH2:17][CH:13]([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14]1
Reactant: BrC1CCSC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\OC1CCSC1)C(C)=O
Yield: 68 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (1.68 g) was treated with 3-bromotetrahydrothiophene as described in Example 4a, method 2, to give the title compound (1.7 g, 68%) as a colourless liquid; [Found M+ 245.0719, C10H15NO4S requires M 245.0722]. νmax (film) 2890, 2940, 1745, 1695, and 1600 cm-1. δH (CDCl3) 1.33 (3H, t), 2.02 (1H, m), 2.41 (3H, s), 2.47 (1H, m), 2.89 (2H, m), 3.13 (2H, m), 4.35 (2H, q), and 5.14 (1H, m). δc (CDCl3) 14.1, 25.2, 28.6, 35.7, 62.0, 88.3, 150.8, 60.7, and 192.6.
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[NH:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CCOC(C)=O.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([Cl:1])[CH:3]([NH:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH2:4]1
Reactant: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1Cl)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOP(=O)(NC1CN(c2ccncc2N)CCC1Cl)OCC
Reaction time: 18 h
Yield: 83 %

Procedure:
To a solution of diethyl 4-chloro-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate (1.0 equiv.) in degassed EtOAc (0.1M) was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen atmosphere for 18 h. Filtered and concentrated the filtrate to yield diethyl 1-(3-aminopyridin-4-yl)-4-chloropiperidin-3-ylphosphoramidate in 83% yield. LCMS (m/z): 363.1 (MH+), Rt=1.89 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:11].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:28](Cl)[C:29]([OH:31])=[O:30]>CC(O)C.O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[C:10](=[O:11])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH:28]([C:29]([OH:31])=[O:30])[O:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(C(=O)c2ccccc2O)c(O)c1
Reactant: O=C(O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2c(c1)OC(C(=O)O)Oc1ccccc1C2=O
Reaction time: 48 h

Procedure:
(2-Hydroxy-4-methoxyphenyl)(2-hydroxyphenyl)methanone (16.1 g, 65.9 mmol), 36.5 g (258 mmol) of potassium carbonate, and 3.00 g (18 mmol) of potassium iodide were suspended in 250 ml of 2-propanol and heated with stirring. Dichloroacetic acid (6.00 ml, 72.6 mmol) was added slowly with a syringe and the mixture heated at reflux with stirring. After 48 hours another 5.00 ml of dichloroacetic acid was added and the reaction continued for another 48 hours. The mixture was then allowed to cool and was concentrated by evaporation under reduced pressure to obtain a solid residue. The residue was dissolved in 500 ml of water and the solution extracted with 200 ml of ether. The aqueous layer was then acidified with concentrated aqueous hydrochloric acid and then extracted twice with 500 ml portions of ether and once with 300 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 3-methoxy- 12H-dibenzo[d,g][1,3]dioxocin-12-one-6-carboxylic acid as a semi-solid residue. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:56]([Si](C)(C)C)=[N+:57]=[N-:58]>O1CCCC1>[C:1]1([N:7]2[C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:58][N:57]=[N:56]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2)CC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnnn2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
Part B: To a solution of tert-butyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (4.24 g, 13.9 mmol) and diisopropylazodicarboxylate (5.40 mL, 27.9 mmol) in tetrahydrofuran (100 mL) at 25° C. was added triphenylphosphine (7.31 g, 27.9 mmol). The resulting reaction mixture showed a slight exotherm, and the solution then was stirred at ambient temperature for ˜0.25 h until the reaction mixture had returned to 25° C. To the resulting mixture was added azidotrimethylsilane (3.65 mL, 27.9 mmol). A precipitate formed within minutes, and the mixture then was stirred at 25° C. for 7 days. The reaction mixture was concentrated under vacuum to afford the crude product. Column chromatography on silica gel (elution: 10-50% ethyl acetate/hexane) afforded tert-butyl 4-(1-phenyl-1H-tetrazol-5-yl)piperidine-1-carboxylate (2.58 g) as a white solid, following crystallization from a mixture of 1-chlorobutane/hexane; 1H NMR (300 MHz, CDCl3) δ 7.58 (m, 3H), 7.38 (m, 2H), 4.12 (m, 2H), 2.98 (m, 1H), 2.76 (m, 2H), 1.96-1.74 (m, 4H), 1.42 (s, 9H).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:13][O:14][C:15](=[O:36])[CH2:16][O:17][CH2:18][C:19]#[C:20][CH2:21][N:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:29][O:30]C(OCC)C>CO>[CH3:13][O:14][C:15](=[O:36])[CH2:16][O:17][CH2:18][C:19]#[C:20][CH2:21][N:22]1[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C@@H:23]1[CH2:29][OH:30]
Reactant: CCOC(C)OC[C@H]1CCCC(=O)N1CC#CCOCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1CO
Reaction time: 20 h
Yield: 25.6 %

Procedure:
p-Toluenesulfonic acid hydrate (289 mg, 1.52 mmol) was added to a solution of {4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester (494 mg, 1.45 mmol) in MeOH (5.0 mL) at rt. After 20 h at rt, the mixture was concentrated in vacuo, treated with saturated aqueous NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 100 mg (26%) of [4-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21](=[O:22])[CH:20]([N:6]1[C:5]2[CH:11]=[CH:12][C:2]([CH3:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])[CH3:26])[CH3:25]
Reactant: Cc1ccc2c(c1)OCC(=O)N2
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(C)ccc21
Temperature: 70 °C
Yield: 98 %

Procedure:
To a mixture of 7-methyl-4H-benzo[1,4]oxazin-3-one (14.1 g, 86 mmol) and Cs2CO3 (70.4 g, 216 mmol) in DMF (500 mL) was added ethyl 2-bromopropanoate (31.3 g, 173 mmol) at ambient temperature and the reaction mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to ambient temperature and the DMF was removed in vacuo. Water (500 mL) was added to the residue and the aqueous solution was extracted with EtOAc (3×150 mL). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10% EtOAc in petroleum ether) to give 2-(7-methyl-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as brown solid (22.2 g, 98%). TLC (eluting with 20% EtOAc/heptane) Rf=0.3.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:20]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.O>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([Cl:20])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(Cl)c21
Temperature: 20 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A solution of (S)—N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.62 g, 2.1 mmol) in dichloromethane (10 mL) was treated with N-chlorosuccinimide (0.284 g, 2.1 mmol) and trifluoromethanesulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16 h at 20° C., diluted with water (20 mL) and extracted with dichloromethane (25 mL). The organics were dried with MgSO4, filtered and concentrated. HPLC purification was done to provide 0.078 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.32-7.25 (m, 1H), 6.97-6.93 (m, 1H), 4.27-4.24 (m, 0.6H), 4.19-4.13 (m, 1H), 4.08-4.01 (m, 1H), 3.91-3.86 (0.8H, m), 3.74-3.69 (m, 0.8H), 3.45-3.37 (m, 1H), 3.31-3.21 (m, 1H), 2.96-2.80 (m, 1H), 1.28-1.22 (m, 3H). MS calculated for C13H12Cl2F3NO+H: 326, observed: 326.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=NC1CCCCC1
Reactant: O=C(OCCCc1cccnc1)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1C(=S)NC1CCCCC1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A mixture of cyclohexylisothiocyanate (120 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 160 mg (47%) of the compound of Example 3 (Compound 3, Table I). 1H NMR (CDCl3, 300 MHz): δ 1.16-1.40 (m, 6H); 1.50-1.71 (m, 4H); 1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.40-3.60 (m, 2H); 4.17-4.26 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m, 1H). Analysis calculated for C20H29N3O2S: C, 63.97; H, 7.78; N, 11.19. Found: C, 63.25; H, 7.80; N, 11.07.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[F:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:56][S:57][C:58]1[N:63]=[C:62]([C:64]2[CH:69]=[CH:68][NH:67][C:66](=[O:70])[CH:65]=2)[CH:61]=[CH:60][N:59]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:67]2[CH:68]=[CH:69][C:64]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]([S:57][CH3:56])[N:63]=3)=[CH:65][C:66]2=[O:70])[C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@H](O)c1ccc(Cl)c(F)c1
Reactant: CSc1nccc(-c2cc[nH]c(=O)c2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccn([C@@H](c3ccc(Cl)c(F)c3)[C@H]3CCCN3C(=O)OC(C)(C)C)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (R)-tert-butyl 2-((R)-(4-chloro-3-fluorophenyl)(hydroxy)methyl)pyrrolidine-1-carboxylate (0.662 g, 2.01 mmol) and triphenylphosphine (0.658 g, 2.51 mmol) in THF (40 mL) was placed in an ice bath, and diisopropyl azodicarboxylate (0.518 mL, 2.51 mmol) was added. The cold bath was removed after 10 minutes, and the reaction mixture was stirred at room temperature for 10 minutes. 4-(2-(Methylthio)pyrimidin-4-yl)pyridin-2(1H)-one (0.22 g, 1.00 mmol) was added, and the reaction was left at room temperature for 1 hour. The reaction mixture was concentrated, and the crude product was purified via column chromatography, eluting with hexanes/ethyl acetate (1:1) to give (R)-tert-butyl 2-((S)-(4-chloro-3-fluorophenyl)(4-(2-(methylthio)pyrimidin-4-yl)-2-oxopyridin-1(2H)-yl)methyl)pyrrolidine-1-carboxylate (contaminated with large amounts of PPh3O). m/z (APCI-pos) (M+1)-Boc=431.2, 433.2.