Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([N+:28]([O-])=O)[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C(OC(=O)C)C>O.C1COCC1.[Zn]>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([NH2:28])[C:14]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[F:27])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c2n(c1=O)CCN2C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.3 %

Procedure:
Zinc (284 mg, 0.004 mol) was added to a stirred solution of 7-(4-bromo-2-fluoro-phenylamino)-6-methyl-8-nitro-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (350 mg, 0.0007 mol) and NH4Cl (310 mg, 0.006 mol) in water and THF (10 mL). The resulting mixture was stirred at room temperature for 40 minutes. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer was washed with saturated NaHCO3 solution and concentrated to afford 150 mg of the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH:10]2[CH2:14][CH:13]([C:15](O)=[O:16])[CH:12]([C:18](=[O:30])[NH:19][C:20]3([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH:21]3[CH:23]=[CH2:24])[CH2:11]2)[CH:6]=[C:5]([O:31][CH3:32])[N:4]=1.[CH3:33][NH:34][CH:35]=[CH:36][CH2:37][CH2:38][CH2:39][CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([O:27][C:25]([C:20]1([NH:19][C:18]([CH:12]2[CH2:11][CH:10]([O:9][C:7]3[CH:6]=[C:5]([O:31][CH3:32])[N:4]=[C:3]([O:2][CH3:1])[N:8]=3)[CH2:14][CH:13]2[C:15](=[O:16])[N:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:33])=[O:30])[CH2:22][CH:21]1[CH:23]=[CH2:24])=[O:26])[CH3:29]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Reactant: CCCCC=CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(OC)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Yield: 67.9 %

Procedure:
The acid 18d (1.2 g, 2 mmol) was reacted with N-methylhexeneamine (0.34 g, 3.0 mmol), DIEA (1.29 g, 10.0 mmol) and HATU (1.1 g, 3 mmol) in dry DMF (30 ml) according to the procedure described in Example 13 step c. Purification by column chromatography on silica gel gave the title compound (0.74 g, 74%), (M+H)+545.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[N:13]=[CH:12]3)=[CH:7][C:6]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH3:33]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[N:13]=[CH:12]3)=[CH:7][C:6]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:5]([CH3:33])[CH:4]=1
Reactant: CB(O)O
Reactant: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC)cc1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of Intermediate 4 (23 mg) in DMF (1.0 ml) was added with methyl boronic acid (18 mg, Ald), sodium carbonate (30 mg), and PdCl2dppf·CH2Cl2 (8.0 mg, Ald), and stirred at 120° C. for 8 hours. The reaction mixture was added with water (30 ml), and ethyl acetate (30 ml×2) for extraction, and then successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (yield: 15 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:34]=[C:35](/[C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)\[CH3:36])[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: CC(=CBr)c1ccc(Cl)c(Cl)c1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CCN(C)CC2)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-Chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (74 mg, 0.31 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (6 mg, 0.032 mmol), L-proline (7 mg, 0.063 mmol) and K3PO4 (134 mg, 0.63 mmol) were added and the reaction mixture was stirred for 10 min. at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-dichlorobenzene (100 mg, 0.378 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 74 mg. 1HNMR (CD3OD, TFA salt) δ (ppm): 7.82 (d, 1H), 7.62 (d, 2H), 7.57 (s, 1H), 7.18 (d, 2H), 7.10 (d, 1H), 3.78 (m, 2H), 3.40 (m, 4H), 3.20 (m, 2H), 3.06 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[C:36](O)=[O:37])[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:35]=4[N:26]=[CH:27][CH:28]=[CH:29]5)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(O)c1cccc2cccnc12
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cccnc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-8-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[F:44][C:39]1[CH:38]=[C:37](/[C:35](/[CH3:36])=[CH:34]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:42]=[CH:41][C:40]=1[F:43]
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CCN(C)CC2)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (77 mg, 0.36 mmol) was dissolved in DMF (6 mL). Copper (I) iodide (8 mg, 0.036 mmol), L-proline (9 mg, 0.086 mmol) and K3PO4 (183 mg, 0.86 mmol) were added and the reaction mixture was stirred for 10 min at RT. 4-(1-Bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.43 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). Yield: 52 mg. 1HNMR (CD3OD, Oxalate salt) δ (ppm): 7.60 (m, 1H), 7.50 (m, 1H), 7.30 (m, 2H), 7.0 (s, 3H), 3.60 (m, 4H), 3.25 (m, 4H), 3.05 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[CH2:28](O)[CH3:29].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21](=[O:25])[C:22]([O:24][CH2:28][CH3:29])=[O:23])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/C(=O)C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C(=O)/C=C/c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Yield: 86 %

Procedure:
To a mixture of (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvic acid (1.3 g) and ethanol (50 ml) was added conc. sulfuric acid (0.1 ml). The mixture was heated for 8 hours under reflux, then the reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), followed by distilling off the solvent. The residue was subjected to a silica gel column chromatography. From the fractions eluted with ethyl acetate-hexane (1:3, v/v), ethyl (E)-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylidenepyruvate (1,2 g, 86%) was obtained. Recrystallization from ethyl acetate-hexane gave pale yellow prisms. Melting point: 110-111° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[S:16][C@@H:17]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C@@H:18]([OH:23])[C:19]([O:21]C)=[O:20].C(=O)(O)[O-].[Na+].O>CO.O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:3]=1[S:16][C@@H:17]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C@@H:18]([OH:23])[C:19]([OH:21])=[O:20]
Reactant: COC(=O)[C@H](O)[C@@H](Sc1c(N)cccc1OCc1ccccc1)c1ccc(OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc([C@H](Sc2c(N)cccc2OCc2ccccc2)[C@@H](O)C(=O)O)cc1
Temperature: 22 °C

Procedure:
To a solution of 2.95 g (6.71 mmol) of (+/−)-(2S,3S)-methyl 3-(2-amino-6-(benzyloxy)phenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoate in 34 mL of 9:1 methanol/water was added 5.64 g (67.1 mmol) of sodium bicarbonate. The mixture was refluxed for 16 hours, cooled to 22° C., and 500 mL of water was added. The aqueous layer was washed with ethyl acetate (2×) and then acidified to ph 4-5 with conc. HCl. The mixture was extracted 3 times with a 7:3 ethyl acetate/methanol solution. The organic layers were combined, dried (Na2SO4), and evaporated to give (+/−)-(2S,3S)-3-(2-amino-6-(benzyloxy)phenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:18])[C:16]#[CH:17])=[O:8].I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCCCCC.CCOC(C)=O>CCN(CC)CC.CCOCC.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.[Cu]I>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:18])[C:16]#[C:17][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: C#CC(C)c1ccccc1C(=O)c1ocnc1C
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ncoc1C(=O)c1ccccc1C(C)C#Cc1ccccc1
Yield: 83.5 %

Procedure:
A solution of 40.0 mg (0.167 mmol, 1.0 eq) of alkyne 11b in 750 μL of dry Et3N was stirred in a 5 mL round bottom flask at room temperature under argon. To this solution was then added 23 μL (0.20 mmol, 1.2 eq) of iodobenzene. The resulting solution was sparged with argon for 5 minutes, at which time 6.0 mg (0.008 mmol, 0.05 eq) of PdCl2(PPh3)2 and 1.5 mg (0.008 mmol, 0.05 eq) of CuI were added and the reaction was stirred at room temperature until complete by TLC (1:1 hexane:EtOAc, Rf=0.42). Upon completion (˜5 hours) the solution was diluted with Et2O and washed sequentially with 1.0 M HCl and H2O. The organic fraction was then dried over MgSO4, concentrated and purified via silica gel chromatography (hexane/EtOAc) to give 44 mg (83%) of 11d as a pale brown oil, Rf 0.42 (1:1 hexane:EtOAc). 1H-NMR (500 MHz, CDCl3): 7.89 (1H, s), 7.82 (1H, d, J=7.3 Hz), 7.57 (1H, dt, J=7.8 Hz, 1.9 Hz), 7.42 (1H, m), 7.38 (1H, m), 7.34 (2H, m), 7.28 (3H, m), 4.34 (1H, q, J=7.1 Hz), 2.37 (3H, s), 1.62 (3H, d, 7.1 Hz). 13C-NMR (500 MHz, CDCl3): 185.67, 152.11, 146.95, 145.47, 142.66, 136.49, 131.69, 131.68, 128.64, 128.37, 128.19, 128.07, 126.62, 123.55, 92.70, 82.47, 29.37, 24.61, 14.18. IR (cm−1): 1653 (vs), 1579 (s), 1487 (m), 1442 (w), 1384 (m), 1355 (m), 900 (m), 757 (s). HRMS (EI) calcd. for C21H17NO2: 315.1259. found: 315.1244.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1.[OH-].[Na+].[N:39]1([NH:44][C:45](=[O:53])[O:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1.C1(OC(Cl)=O)C=CC=CC=1.NN1CCCC1.Cl>CO.CN(C=O)C>[N:39]1([NH:44][C:45](=[O:53])[O:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:40][CH2:41][CH2:42][CH2:43]1.[Cl:1][C:2]1[CH:3]=[C:4]([S:33]([NH:36][C:45](=[O:46])[NH:44][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)(=[O:35])=[O:34])[CH:5]=[CH:6][C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(F)cc1
Agent: Cl
Agent: NN1CCCC1
Agent: O=C(Cl)Oc1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(SCc2ccc(S(=O)(=O)NC(=O)NN3CCCC3)cc2Cl)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.7 %

Procedure:
To a stirred solution of 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)benzenesulfonamide (76 mg, 0.13 mmol, 1.0 eq) in MeOH (0.5 mL) was added sodium hydroxide (5 mg, 0.13 mmol, 1.0 eq, dissolved in 0.5 mL MeOH). The mixture was stirred at room temperature for 16 h then concentrated in vacuo. The residue was diluted with anhydrous DMF (0.5 mL) and then charged with a solution of phenyl pyrrolidin-1-ylcarbamate (30 mg, 0.14 mmol, 1.1 eq) in 0.5 mL of DMF. Phenyl pyrrolidin-1-ylcarbamate was prepared by treatment of phenychloroformate with 1-aminopyrrolidine. The reaction mixture was then heated at 50° C. overnight. The mixture was cooled, acidified with 1M HCl and extracted with ethyl acetate (3×). The organic layers were washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography (30% methanol/ethyl acetate) provided the title compound (15 mg) as a white foam. 1H NMR (CD2Cl2, 400 MHz): δ 8.98 (br s, 1H), 8.00 (s, 1H), 7.82 (dd, J=8.3, 2.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.18 (s, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.85-6.78 (m, 4H), 6.32-6.27 (m, 2H), 4.33 (s, 2H), 3.22-3.13 (2H), 2.48-2.38 (m, 2H), 1.86-1.78 (m, 4H), 1.47 (s, 6H); MS (EI) m/z 695 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:12])=[N:8][C:9]=2Cl)[N:4]=[CH:3]1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:12][C:7]1[N:6]=[C:5]2[C:10]([N:2]([CH3:1])[CH:3]=[N:4]2)=[C:9]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: Cn1cnc2nc(Cl)nc(Cl)c21
Reactant: NC1CCCCC1
Product: Cn1cnc2nc(Cl)nc(NC3CCCCC3)c21

Procedure:
Was prepared according to Example 4 from 7-methyl-2,6-dichloro-7H-purine and cyclohexylamine.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@H:12]([O:21][Si](C(C)(C)C)(C)C)[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=O)=O)=CC=1.[H-].[Na+].[F:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:36]=[CH:37][C:38]=1O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[F:32][C:33]1[CH:34]=[C:35]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:36]=[CH:37][C:38]=1[O:10][CH2:11][C@H:12]([OH:21])[CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1ccc(-c2ccccc2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](CCc2cccnc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
Prepared according to the method described in Example 26e) from (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-pyridyl)-1-butyl para-toluenesulfonate (1.0 g), sodium hydride (60% dispersion in mineral oil, 0.115 g) and 3-fluorobiphenyl-4-ol (0.52 g) in dimethylformamide (15 ml). The adduct was dissolved in tetrahydrofuran (10 ml) and tetrabutylammonium fluoride (1.08 g) was added. The reaction was stirred at ambient temperature for 3 hours and was then poured into brine and extracted with ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) to give the title compound as a white solid (0.25 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].CC(=[O:13])C>>[CH3:7][CH:6]([CH:5]([CH3:8])[C:4](=[O:3])[CH3:9])[C:2](=[O:13])[CH3:1]
Reactant: Cc1oc(C)c(C)c1C
Reactant: CC(C)=O
Product: CC(=O)C(C)C(C)C(C)=O
Temperature: 25 °C
Yield: 42.5 %

Procedure:
Compound 219A was made in accordance with the procedures described in Hancock et al. J. Org. Chem. 42, 1850-1856 (1977) & Amarnath et al. J. Org. Chem., 60, 301-307 (1995). 2-Propanone (100 mL, 1.1 mol) was refluxed over PbO2 (26.7 g, 0.112 mol) for 28 h. After cooling to rt, the reaction mixture was filtered and the residue was washed with acetone. The filtrate was concentrated under reduced pressure to remove the acetone and then distilled at 20 Torr. The fraction that came over between 100-120° C. was collected to give 6.75 g (42.5%) of 3,4-dimethylhexane-2,5-dione as a light yellow oil.
Reaction SMILES: C([SiH](CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20](=O)[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:14][NH:15]2)([O-:10])=[O:9]>C(O)(C(F)(F)F)=O>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][NH:15]2)([O-:10])=[O:9]
Reactant: CCOC(=O)CCC(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CCCC1CNc2cccc([N+](=O)[O-])c21
Reaction time: 3 h

Procedure:
Triethylsilane (11 mL, 68 mmol) was added to a solution of ethyl 4-(4-nitro-1H-indol-3-yl)-4-oxobutanoate from Step A (960 mg, 3.31 mmol) in TFA (15 mL). After 3 h, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with a gradient of CHCl3:MeOH—100:0 to 94:6, to give the title compound. MS: m/z=279 (M+1).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>ClCCl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:9][CH2:8][CH:5]2[CH2:6][CH2:7][C:2]([F:10])([F:1])[CH2:3][CH2:4]2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: OCC1CCC(F)(F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 370A (8.5 g, 57 mmol) in dichloromethane (100 mL) were added triethylamine (Aldrich, 25 mL, 180 mmol) and tosyl chloride (Aldrich, 11.4 g, 60 mmol). The reaction mixture was stirred at room temperature for 16 hours and washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.17-1.42 (m, 2H), 1.57-1.69 (m, 1H), 1.70-1.91 (m, 4H), 1.93-2.18 (m, 2H), 2.46 (s, 3H), 3.86 (d, J=6.4 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[Cl:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 187 %

Procedure:
A mixture of 1.85 g of 2-amino-5-chloro-3-methylbenzoic acid, 0.90 g of triphosgene and 10 ml of tetrahydrofuran was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and a precipitated crystal was washed with water to obtain 1.20 g of 6-chloro-8-methyl-1H-benzo[d]-1,3-oxazine-2,4-dione of the formula:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:27]([NH2:32])([CH2:30][CH3:31])([CH3:29])[CH3:28].C(N(CC)CC)C>C(#N)C>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:26])[F:25])[CH:4]=1)=[N:32][C:27]([CH3:29])([CH3:28])[CH2:30][CH3:31])#[N:24]
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Reactant: CCC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC(C)(C)N=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 49 %

Procedure:
A solution of N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.78 mmol, 290 mg), tert-amylamine (0.85 mmol, 0.100 ml) and triethylamine (0.85 mmol, 0.119 ml) in acetonitrile (2 ml) was stirred for 25 h at 75° C. followed by work-up as described in EXAMPLE 5, b) to give the title compound (140 mg, 46%) as white crystals. Mp 149-150° C.; EI SP/MS: 366 (M+); 1H-NMR (CDCl3): δ 0.85 (t, 3H),1.35 (s, 6H), 1.75 (q, 2H), 4.65 (br s,1H), 7.70 (br s, 3H), 8.95 ppm (br s, 1H); MA calc for C15H16F6N4. 0.15 H2O: C, 49.37%; H, 4.57%; N, 14.76%. Found: C, 49.72%; H, 4.56%; N, 14.76%.