Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C@@H:12]([CH:21]([C:23]1[O:24][C:25]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][C:26]=2[N:27]=1)[OH:22])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(OCC1C=CC=CC=1)=O>[Pd].CO>[C:32]([C:29]1[CH:30]=[CH:31][C:25]2[O:24][C:23]([CH:21]([OH:22])[C@H:12]([NH2:11])[CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:27][C:26]=2[CH:28]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1ccc2oc(C(O)[C@@H](CCc3ccccc3)NC(=O)OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc2oc(C(O)[C@H](N)CCc3ccccc3)nc2c1
Reaction time: 10 h
Yield: 81.5 %

Procedure:
A mixture of N-CBz-(1R)-1-[(RS)-(5-tert-butyl-2-benzoxazolyl)hydroxymethyl]-3-phenylpropylamine (360 mg), anhydrous methanol (8 ml), and 10% palladium-on-charcoal (40 mg) was degassed, under reduced pressure, and then stirred vigorously under hydrogen atmosphere for 10 h. The mixture is filtered on a nylon pad (0.45 μm porosity) and concentrated in vacuo to afford the title product (210 mg) as a clear oil: 1H NMR (400 MHz, CDCl3, 3:2 mixture of diastereomers) δ 1.80-2.02 (m, 2H), 2.65-2.89 (m, 2H), 3.23 (m, 0.4H), 3.39 (m, 0.6H), 4.76 (d, J=1.8 Hz, 0.6H), 4.84 (d, J=2.4 Hz, 0.4H), 7.09 (m, 3H), 7.29 (m, 2H), 7.43 (m, 2H), and 7.76 (s, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[C:38]([F:44])=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40]>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[C:38]=2[F:44])=[O:21])[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)on4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 42.3 %

Procedure:
A mixture of phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (prepared as described in Example 162A steps 1 and 2) (211 mg, 0.714 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared as described in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 36 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (104 mg, 42%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) 89.96 (brs, 1H), 8.87 (brs, 1H), 8.58 (s, 1H), 8.08 (m, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.27 (m, 1H), 7.15 (m, 1H), 6.81 (s, 1H), 4.66 (d, J=47 Hz, 4H), 4.01 (s, 6H), 1.34 (s, 3H); LC-MS (ESI) m/z 518 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH2:12][C@H:13]2[C@H:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14]2)=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:19]2[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14][C@H:13]2[CH2:12][NH:11][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:37][N:36]=[N:35][N:2]=3)[CH:4]=2)=[O:10])[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cccc(C#N)c2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cccc(-c3nnn[nH]3)c2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-({[(3-cyanophenyl)carbonyl]amino}methyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (100 mg) in DMF (4 mL) were added sodium azide (38.7 mg) and ammonium chloride (37.1 mg) at room temperature, and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (32 mg).
Reaction SMILES: [CH:1]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[O:26][C:25]([C:27]([O:29]C)=[O:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].Cl>O>[CH:1]([O:14][CH:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]2[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=2)[CH2:19][CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)o1
Yield: 70.4 %

Procedure:
A mixture of 465 mg of methyl 5-(4-benzhydryloxypiperidin-1-ylmethyl)furan-2-carboxylate synthesized in Production Example 2, 1.7 mL of ethanol, and 3.4 mL of a 1-N sodium hydroxide aqueous solution was heated under reflux for 40 minutes. To the mixture were added 10 mL of water and 3.4 mL of 1-N hydrochloric acid, and the resulting mixture was stirred. The precipitated crystal was separated by filtration and washed with water. The resulting product was dried to give the title compound (316 mg).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[CH:6]=1.B1([C:14]2[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=2)OCCCO1.C([O-])([O-])=O.[Na+].[Na+]>CCO.C1(C)C=CC=CC=1>[Br:7][C:5]1[CH:6]=[C:2]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)c1
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Brc1csc(-c2cccnc2)c1
Yield: 72.2 %

Procedure:
A mixture of 2,4-dibromothiophene (3 g, 12.4 mmol) and pyridine-3-boronic acid-1,3-propanediol cyclic ester (2.22 g, 13.6 mmol) in EtOH (30 ml) and toluene (30 ml) together with 2N Na2CO3 solution (12.4 ml) was degassed with a stream of N2 for 10 min. Tetrakis-(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction heated at reflux for 4 h. The mixture was concentrated under reduced pressure to remove the organic solvents and H2O (100 ml) was added. The organics were extracted with EtOAc (200 ml) and then washed with brine (75 ml), dried (MgSO4), and concentrated under vacuum. The resulting crude residue was purified by column chromatography on silica using 70% diethyl ether in hexane as the eluent to yield 3-(4-bromothien-2-yl)pyridine (2.15 g, 75%): δH (360 MHz, CDCl3) 7.26 (1H, s), 7.32 (1H, dd, J 8.6 and 4.9), 7.81 (1H, dt, J 8.6 and 1.7), 8.56 (1H, s), 8.86 (1H, s); m/z (ES+) 240, 242 (1:1) (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[C:16]3[S:21][CH2:20][CH2:19][CH2:18][S:17]3)[CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH2:24]>O1CCCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14](=[C:16]3[S:17][CH2:18][CH2:19][CH2:20][S:21]3=[O:24])[CH3:15])=[CH:12][CH:13]=2)=[CH:22][CH:23]=1
Reactant: O
Reactant: COc1ccc(Oc2ccc(C(C)=C3SCCCS3)cc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc(C(C)=C3SCCCS3=O)cc2)cc1
Yield: 16.2 %

Procedure:
2-[1-{4-(4-Methoxyphenoxy)phenyl}ethan-1-ylidene]-1,3-dithiane, 5 g, was dissolved in a solvent mixture of 100 ml of tetrahydrofuran and 50 ml of methanol and, 15 g of an aqueous solution containing 2.45 g of oxon was dropwise added to the solution under ice cooling. After stirring for an hour at the same temperature, water was added to the reaction mixture followed by extraction with chloroform. The organic phase was washed with a sodium thiosulfate aqueous solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride) to give 0.85 g of white crystals.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.ClCCl>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: Nc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Nc1ncc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)cn1
Temperature: 140 °C
Yield: 14 %

Procedure:
A degassed mixture of 6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (74.4 mg, 0.197 mmol), 2-aminopyrimidine-5-boronic acid, pinacol ester (45.8 mg, 0.207 mmol), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (8.1 mg, 9.87 umol, 5.0 mol %) in acetonitrile (0.74 mL) and 1M aqueous potassium carbonate solution (0.74 mL) was heated under microwave irradiation (140° C.) for 30 minutes. Further portions of the boronate ester (1.0 eq) and catalyst (5 mol %), acetonitrile (0.74 mL), and 1M aqueous potassium carbonate solution (0.74 mL) were added and the mixture heated under microwave irradiation (140° C.) for an additional 30 minutes. The mixture was concentrated in vacuo and the residue dissolved in water and DMF, and acidified with 10% (v/v) sulfuric acid. The resultant solid was removed by filtration and the filtrate concentrated in vacuo. The resultant residue was dissolved in DMSO and purified by preparative HPLC [0-30% MeCN/water modified with 0.1% formic acid] to afford an orange fluffy solid (5.1 mg, 14%). LCMS (Method E): RT=5.45 min, M+H+=436.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.C1C(=O)N(Br)C(=O)C1.[CH3:43][CH:44]([CH3:48])[C:45](=[S:47])[NH2:46]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:47][C:45]([CH:44]([CH3:48])[CH3:43])=[N:46][C:9]=2[C:11]2[C:12]([F:29])=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C(N)=S
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 45.3 %

Procedure:
In a 250 mL flask was placed N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (4 g, 9.05 mmol) and DMF (60 mL) was added. NBS (1.62 g, 9.10 mmol) was added and, after stirring at rt for 40 min, 2-methylpropanethioamide (1.4 g, 13.6 mmol), prepared by a procedure analogous to Intermediate 1, was added. After 4 h at rt, the reaction mixture was poured into 800 mL of EtOAc and washed 4 times with 250 mL of H2O, washed once with 200 mL of brine, and dried over NaSO4. Silica gel was added and the volatiles were removed under reduced pressure. Column chromatography with 10% to 60% EtOAc:Hexane gave 2.15 g (45%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.06 (d, J=5.3 Hz, 1H), 8.12-8.30 (m, 1H), 7.93-8.06 (m, 2H), 7.84 (t, J=7.9 Hz, 1H), 7.75 (t, J=9.2 Hz, 2H), 7.37 (d, J=5.3 Hz, 1H), 3.77-3.93 (m, 1H), and 1.89 (d, J=6.8 Hz, 6H). MS (ESI): 524 [M]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[S:16][C:15]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:14][C:13]=3[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=2)=[N:7][CH:8]=1)#[N:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[S:16][C:15]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:14][C:13]=3[CH:12]=[C:11]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[CH:10]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccc(C#N)cn3)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccc(C#N)cn3)c2s1
Temperature: 80 °C

Procedure:
A stirred mixture of the crude trifluoro-methanesulfonic acid 7-(5-cyano-pyridin-2-yl)-2-(3-ethyl-ureido)-benzothiazol-5-yl ester (108 mg, 0.23 mmol), 3-pyridineboronic acid (56 mg, 0.46 mmol), aqueous caesium carbonate (0.155 ml, 0.57 mmol, 3.7M), dimethylformamide (2.4 ml) and water (0.4 ml) was purged with nitrogen for 15 min. treated with tetrakistriphenylphosphine palladium (0) (27 mg, 0.023 mmol), sealed and heated at 80° C. for 8 h. After cooling to ambient temperature, the mixture was filtered through celite and washed through with methanol. The filtrate was evaporated in vacuo to give the crude 1-[7-(5-Cyano-pyridin-2-yl)-5-pyridin-3-yl-benzothiazol-2-yl]-3-ethyl-urea as a brown solid.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:26].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[CH:9][C:10]([O:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:26]
Reactant: CC1Oc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1Oc2ccc(OC3CCNCC3)cc2NC1=O
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a 40 mL vial containing tert-butyl 4-(2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yloxy)piperidine-1-carboxylate 394D (0.223 g, 0.615 mmol) was added 50% solution of TFA in DCM (2.0 mL, 12.98 mmol) to give a clear brown solution. The reaction was monitored by HPLC. At 0.5 hr, the reaction was pulled and concentrated in vacuo, affording the product as a clear, brown oil (0.161 g, 100% yield). ESI-MS: m/z 263.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([I:11])[N:8](S(C3C=CC=CC=3)(=O)=O)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([I:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)ncnc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]c(I)cc12

Procedure:
To a stirred solution of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (538 mg, 1.283 mmol) in THF (6.0 mL) was added 5 M sodium hydroxide methanolic solution (1.8 mL, 0.009 mmol). After 10 min the solvent was removed under reduced pressure, sat. ammonium chloride solution (5.0 mL) was added and the mixture evaporated to dryness. The resulting solid was triturated with water to afford 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (d6-DMSO, 400 MHz) 6.90(1H, s) and 8.55 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.[CH:29]1([CH2:32][NH2:33])[CH2:31][CH2:30]1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:28])[CH:4]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH2:5][C:6]1[C:7]([NH:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Cl)c1ccc(OC)cc1
Reactant: NCC1CC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1NCC1CC1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(4-chloro-2-phenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (45 mg, 0.11 mmol) (from Example 12a supra) and cyclopropylmethylamine (1.0 mL) (Lancaster) was stirred at room temperature for 24 hours. The reaction mixture was then diluted with ethyl acetate (50 mL) and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3-(2-phenylamino-4-cyclopropylmethylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester which was used in the next step without further purification. (Yield 51.3 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25](=O)[CH3:26])[O:22][N:21]=2)=[CH:16][CH:15]=1>C1COCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]=[C:23]([CH:25]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH3:26])[O:22][N:21]=2)=[CH:18][CH:19]=1
Reactant: Ic1ccncc1
Reactant: CC(=O)c1cc(-c2ccc(F)cc2)no1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccncc1)c1cc(-c2ccc(F)cc2)no1
Reaction time: 0.17 h
Yield: 30.8 %

Procedure:
To a stirred solution of 4-iodopyridine (0.3 g, 1.463 mmol) in THF (10 mL) was added n-BuLi (0.6 mL, 0.96 mmol) at −78° C. and stirred for 10 min. A solution of 1-(3-(4-fluorophenyl)isoxazol-5-yl)ethanone (0.1 g, 0.484 mmol) in THF (5 mL) was added to the reaction and the mixture stirred at −78° C. for 2 h. The reaction was quenched with saturated ammonium chloride solution (10 mL) and diluted with ethyl acetate (50 mL). The organic layer was separated, washed with saturated ammonium chloride (3×150 mL) followed by brine solution (2×20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200μ silica gel; 50% ethyl acetate in hexane) to obtain 3-(4-fluorophenyl)-5-(1-(pyridin-4-yl)ethyl)isoxazole as off-white solid (0.04 g, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.55 (d, 2H), 7.91 (dd, 2H), 7.46 (d, 2H), 7.32 (t, 2H), 6.81 (s, 1H), 7.04 (s, 1H), 1.86 (s, 3H); LC-MS m/z calculated for [M+H]+ 285.10. found 285.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH2:23][C:24]2[N:29]=[C:28]([N+:30]([O-])=O)[C:27]([O:33][CH2:34][CH2:35][OH:36])=[CH:26][CH:25]=2)[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1>C(O)C.C(O)(=O)C.C([O-])(O)=O.[Na+].[Fe]>[NH2:30][C:28]1[C:27]([O:33][CH2:34][CH2:35][OH:36])=[CH:26][CH:25]=[C:24]([CH2:23][N:9]2[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=3)=[CH:11][CH:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:29]=1
Reactant: CCCOc1ccc(-c2ccc(-c3ccccc3Cl)n2Cc2ccc(OCCO)c([N+](=O)[O-])n2)cc1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOc1ccc(-c2ccc(-c3ccccc3Cl)n2Cc2ccc(OCCO)c(N)n2)cc1
Temperature: 96 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
To a solution of 0.1 gm (0.2 mmol) of 2-{6-[2-(2-Chlorophenyl)-5-(4-propoxyphenyl)-pyrrol-1ylmethyl]-2-nitro-pyridin-3-yloxy}-ethanol in 4 mL of 1:1 ethanol-acetic acid was added 0.55 gm of Fe powder. The reaction mixture was allowed to stir at 96° C. for 2 h. The mixture was cooled and poured in 100 mL of saturated NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4) and the solvents removed under reduced pressure. The residue was purified by column chromatography using 1%-2% methanol-chloroform-0.5% Et3N as an eluent to yield 0.037 gm (39% yield) of a solid mp 89-92° C. 1H NMR (500 MHz, CDCl3) δ: 1.00 (t, 3H, J=7.4 Hz), 1.23 (br s, 3H), 1.77 (m, 2H), 3.88 (m, 4H), 3.98 (t, 2H, J=4.3 Hz), 4.99 (s, 2H), 5.65 (d, 1H, J=8.05 Hz), 6.29 (s, 2H), 6.72 (d, 1H, J=8.05 Hz), 6.84 (d, 1H, J=8.78 Hz), 7.21 (m, 2H), 7.25 (m, 3H), 7.36 (m, 1H); MS (ES) m/z 478.2 ([M+H]+).
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:10][C:5]=2[CH2:4][CH2:3]S1.C[N+]1([O-])CCOCC1.[OH:30][S:31]([O-:33])=O.[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[O:30]=[S:31]1(=[O:33])[CH2:3][CH2:4][C:5]2[CH:10]=[C:9]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:8]=[CH:7][C:6]=2[CH2:1]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCSC3)C(=O)O1
Reactant: O=S([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCS(=O)(=O)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
A solution of (−)-N-[[(5S)-3-(3,4-dihydro-1H-2-benzothiopyran-6-yl)-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 10, 545 mg, 1.78 mmol) in acetone/H2O (3/1, 36 mL) under N2 is treated with N-methylmorpholine N-oxide (521 mg, 4.45 mmol) and OsO4 (2.5 wt % in tBuOH, 1.11 mL, 5 mol %), and the resulting mixture is stirred at ambient temperature for 18 hrs and is then cooled in an ice bath and treated with half-saturated aqueous NaHSO3 (50 mL). The mixture is extracted with CH2Cl2 (3×75 mL), and the combined organic phase is washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product which is then chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-4/96). Those fractions with an Rf=0.39 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated and the product triturated with CH2Cl2/Et2O to give 517 mg (86%) of the title compound as a white solid, mp 177-178° C. MS (ESI+) for C15H18N2O5S m/z 339 (M+H)+; [α]25D=−23° (c 0.97, DMSO).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3[NH2:26].[C:28](Cl)(=[O:36])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[N:7][C:8]2[NH:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:27]=3)[CH2:15][CH2:16][C:17]3[CH:25]=[C:21]([NH:22][C:23]=1[N:24]=2)[CH:20]=[CH:19][C:18]=3[NH:26][C:28](=[O:36])[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a solution of 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine trihydrochloride (100.0 mg, 0.223 mmol) in pyridine (1 mL) was added carbonochloridic acid, phenyl ester (42.0 μL, 0.335 mmol). The reaction solution was stirred at room temperature overnight. The reaction solution was concentrated and diluted with water. The resulting precipitate was filtered and dried under vacuum to give the desired product (100 mg, 88%). LCMS for C24H20ClN6O2 (M+H)+: m/z=459.2.