Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:24][O:25][CH2:26][CH2:27]Br>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[C:12]1[N:13]([CH3:17])[N:14]=[CH:15][CH:16]=1
Reactant: COCCBr
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(NC(C)=O)cc1-c1ccnn1C
Temperature: 110 °C
Yield: 85 %

Procedure:
A mixture of N-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (1.16 g, 5.00 mmol), cesium carbonate (3.26 g, 10.00 mmol), and 2-bromoethyl methyl ether (0.666 mL, 7.00 mmol) in 10 mL of DMF was heated to 110° C. for 15 minutes under microwave irradiation in a heavy-walled sealed tube. The solvent was evaporated under reduced pressure, and the residue was taken up in water and extracted three times with dichloromethane. The combined extracts were dried with sodium sulfate, filtered, and evaporated to dryness to afford the title compound (1.23 g, 85.0% yield) as a tan solid which was used without further purification. LCMS m/z (%) 290.1 (M+H, 100%). 1H NMR (400 MHz, DMSO-d6) δ 2.01 (s, 3H) 3.22 (s, 3H) 3.55-3.60 (m, 2H) 3.65 (s, 3H) 4.06-4.12 (m, 2H) 6.22 (d, J=1.77 Hz, 1H) 7.10 (d, J=9.09 Hz, 1H) 7.43 (d, J=2.02 Hz, 1H) 7.49 (d, J=2.78 Hz, 1H) 7.59 (dd, J=8.97, 2.65 Hz, 1H) 9.90 (s, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1.[C:41]([O:45][C:46](=[O:54])[NH:47][CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][NH2:51])([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][NH:47][C:46](=[O:54])[O:45][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of 6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-yl)amino)nicotinic acid (340 mg), tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (316 mg) and TBTU (501 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude product, tert-butyl 3-(6-(6-(4-hydroxybenzylamino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate, which was purified by silica gel chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.S(Cl)([Cl:19])(=O)=O>C(OCC)C>[NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([Cl:19])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1c(O)cccc1C(=O)O
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1c(O)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
A 25-mL round bottomed flask equipped with a magnetic stirrer was charged with 2-amino-3-hydroxybenzoic acid (0.852 g, 5.59 mmol), acetic acid (0.4 mL) and diethyl ether (0.4 mL). After cooling to 0° C. sulfuryl chloride (0.754 g, 5.59 mmol) was added and the reaction stirred at ambient temperature for 4 h. Dilution with ether (15 mL), filtration and purification by preparative HPLC afforded 0.500 g (48% yield) of 2-amino-5-chloro-3-hydroxybenzoic acid as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.29 (d, J=9.5 Hz, 1H), 6.76 (d, 1H, J=9.5 Hz, 1H) MS (ESI) m/z 186 (M−H).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2=[C:9]3[C:13](=[CH:14][CH:15]=[C:7]2[O:6][CH2:5][CH2:4][N:3]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:12][CH:11]=[CH:10]3.[H-].[Na+].[CH3:25][C:26]1[O:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[CH3:25][C:26]1[O:27][C:28]([CH3:35])=[CH:29][C:30]=1[S:31]([N:12]1[C:13]2[C:9](=[C:8]3[CH:2]([CH3:1])[N:3]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:4][CH2:5][O:6][C:7]3=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)(=[O:33])=[O:32]
Reactant: CC1c2c(ccc3[nH]ccc23)OCCN1C(=O)OC(C)(C)C
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)n2ccc3c4c(ccc32)OCCN(C(=O)OC(C)(C)C)C4C)c(C)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
tert-Butyl 1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 42, 25 mg, 0.083 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 4.0 mg, 0.17 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes before 2,5-dimethyl-3-furansulfonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at room temperature overnight. The reaction was quenched by addition of water and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give tert-butyl 8-[(2,5-dimethyl-3-furyl)sulfonyl]-1-methyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (19 mg) which was dissolved in DCM (1 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour and the solvent was removed under reduced pressure. The crude material was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (2 mg). MS m/z 361 [M+H]+.
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[C:18]([O:19][C:20]2([CH:26]([N:30]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:27]([OH:29])=O)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:17]([F:45])[C:16]([F:46])=[CH:15][CH:14]=1>CN(C=O)C.O>[CH2:38]([N:30]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:26]1[C:20]2([CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[O:19][C:18]2[C:17]([F:45])=[C:16]([F:46])[CH:15]=[CH:14][C:13]=2[NH:12][C:27]1=[O:29])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: Nc1ccc(F)c(F)c1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Nc2ccc(F)c(F)c2OC2(CCOCC2)C1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
H2O (70.5 mg, 460 μmol, Eq: 1.2) and EDCI (88.2 mg, 460 μmol, Eq: 1.2) were added to a solution of [4-(6-amino-2,3-difluoro-phenoxy)-tetrahydro-pyran-4-yl]-dibenzylamino-acetic acid (185 mg, 383 μmol, Eq: 1.00) in DMF (5 mL). The mixture was stirred at RT overnight, diluted with H2O and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography to afford 3-(dibenzylamino)-8,9-difluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-4(5H)-one (102 mg, 57% yield). MS m/z 465.0 (MH+)
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][C:10]([C:19]1[S:20][CH:21]=[C:22]([CH3:24])[CH:23]=1)([CH3:18])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12].O>C(COC)OC>[CH3:18][C:10]([C:19]1[S:20][C:21]([N+:7]([O-:8])=[O:6])=[C:22]([CH3:24])[CH:23]=1)([CH3:9])[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12]
Reactant: O=[N+]=O
Reactant: Cc1csc(C(C)(C)C(=O)N2CCCC2)c1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: COCCOC
Product: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1[N+](=O)[O-]

Procedure:
Nitronium tetrafluoroborate (0.168 g, 1.26 mmol) was added to a solution of 1-[2-methyl-2-(4-methyl-2-thienyl)propanoyl]pyrrolidine (0.145 g, 0.61 mmol) in dimethoxy ethane (5 ml) cooled to −50 C. The mixture was allowed to warm to −30 C over 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and washed sequentially with a saturated solution of sodium bicarbonate and then with a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated to afford 1-[2-methyl-2-(4-methyl-5-nitro-2-thienyl)propanoyl]pyrrolidine as a yellow solid which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:9][N:8]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:67][NH:68][CH2:69][CH2:70][OH:71]>CN(C=O)C>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([N:17]3[CH2:18][CH2:19][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([N:68]([CH2:69][CH2:70][OH:71])[CH3:67])=[O:28])=[CH:25][N:24]=4)[CH2:21][CH2:22]3)=[N:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CNCCO
Reactant: O=C(O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)c1ccc(N2CCN(c3nnc(Cc4ccc(F)cc4)c4ccccc34)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
6-{4-[4-(4-Fluoro-benzyl)-phthalazin-1-yl]-piperazin-1-yl}-nicotinic acid (100 mg, 0.225 mmol), DMF (0.5 mL), Diisopropylethylamine (195 μL, 1.125 mmol), HBTU (102 mg, 0.270 mmol), and 2-(methylamino)ethanol (18 μL, 0.225 mmol) are combined in a 10 mL flask and stirred for 4 h at room temperature. Concentrate to remove DMF in vacuo. The residue is purified by flash chromatography on silica gel (0-25% MeOH/CH2Cl2 with 5% TEA) to afford the title compound (68.2 mg, 61%).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:28][C@H:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:30]([CH3:32])[OH:31].Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([NH:28][C@H:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
1.14 g (3 mmol) of Boc-Lys(Z)-OH, 0.51 g (3 mmol) of H-Thr-OMe.HCl, 0.68 g of (3.6 mmol) of EDCI, 0.58 g (3.6 mmol) of HOBT and 0.66 ml (6 mmol) of NMM are dissolved at -10° C. in 10 ml THF and stirred at room temperature for 15 hours. The THF is distilled off under vacuum, the residue dissolved in 50 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5 N HCl, 10% NaHCO3 solution and water respectively. The organic phase is dried with MgSO4 and the solvent distilled off under vacuum. 1.36 g (92%) of thin-layer chromatographically identical Boc-Lys(Z)-Thr-OMe are obtained as a colourless foam.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH:28]C1N=CC(C(O)=O)=CC=1.S(Cl)(Cl)=O.NC1N=C(N(C)C2C=CC=CC=2)N=C(C(=N)NO)N=1.NC1N=C(N(C)C2C=CC=C(C)C=2)N=C(C(NO)=N)N=1>>[NH2:27][C:15]1[N:16]=[C:17]([N:19]([CH3:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:18]=[C:13]([C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:28])=[N:7][CH:6]=3)[O:12][N:11]=2)[N:14]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(Cl)nc3)n2)n1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CN(c1ccccc1)c1nc(N)nc(C(=N)NO)n1
Agent: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Solvent: O=S(Cl)Cl
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(O)nc3)n2)n1

Procedure:
Prepared according to the method described for Intermediate 135 above from 6-Hydroxypyridine-3-carboxylic acid (0.556 g, 4 mmol, thionyl chloride (1.2 mL, 16 mmol) and 4-amino-N-hydroxy-6-[methyl(phenyl)amino]-1,3,5-triazine-2-carboximidamide (prepared in an analogous manner to Intermediate 1, 0.52 g, 2 mmol). Method B HPLC-MS: MH+ requires m/z=363 Found: m/z=363, Rt=1.52 min (87%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:43][C@H:44]1[CH2:47][C@@H:46]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])[C:45]1([CH3:57])[CH3:56].CCN(CC)CC>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:43][C@H:44]4[CH2:47][C@@H:46]([C:48]([N:50]5[CH2:55][CH2:54][O:53][CH2:52][CH2:51]5)=[O:49])[C:45]4([CH3:57])[CH3:56])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1(C)[C@@H](N)C[C@H]1C(=O)N1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@H]3C[C@@H](C(=O)N4CCOCC4)C3(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.4 g, 0.803 mmol) in DCM (1 ml) 2M solution of (COCl)2 in DCM (4 ml, 8.03 mmol) was added at about 0° C. and the reaction mixture was stirred at room temperature for about 3 hours. After completion of the reaction (monitored by TLC) the solvent was evaporated under nitrogen atmosphere and dissolved in DCM (4 ml), which was added to a solution of ((1R,3S)-3-amino-2,2-dimethylcyclobutyl)(morpholino)methanone (Intermediate 11, 0.306 g, 1.45 mmol) in DCM (5 ml) and Et3N (0.22 ml, 1.61 mmol) at about 0° C. and allowed to stir at room temperature for about 16 hours. After completion of the reaction (monitored by TLC) the reaction mixture was diluted with DCM and washed with water, 1N HCl, water brine and dried with Na2SO4, the solvent was evaporated and purified by silica gel column (100-200 mesh, elution 10% EtOAc in hexane) to afford the title compound as an off white solid. Wt: 0.380 g: Yield: 68.4%; 1H NMR (300 MHz, CDCl3): δ 5.88 (d, 1H), 4.73 (s, 1H), 4.58 (s, 1H), 4.51-4.42 (m, 1H), 4.17-4.06 (m, 1H), 3.80-3.41 (m, 7H), 3.17-3.08 (m, 1H), 2.93-2.84 (m, 1H), 2.50-2.29 (m, 2H), 2.05 (s, 3H), 1.99-1.86 (m, 3H), 1.80-1.02 (m, 22H), 0.95, 0.92 (s, 9H), 0.83 (s, 15H); Mass: [M+Na]+ 693 (100%); M.R: 144.8° C.-156.2° C.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH2:20].C(O)(C)C.CCOCC>CCOCC>[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH:20][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([N:2]([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:14][CH:13]=1)=[S:17]
Reactant: CCOC(=O)CN(C)c1ccc(N=C=S)cc1
Reactant: CC(=O)N(C)N
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)CN(C)c1ccc(NC(=S)NN(C)C(C)=O)cc1

Procedure:
A solution of 1.25 g (5.0 mmol) of ethyl N-methyl-N-(4-isothiocyanatophenyl)glycinate and 0.44 g (5.0 mmol) of 1-methyl-1-acetylhydrazine in 40 ml of 1/1 isoproply alcohol/ether was left uncovered so the ether could evaporate over a 24 hr period. The product was collected and washed with isopropyl alcohol to give 1.32 g (3.9 mmol, 78%), mp 162° dec. Anal. C15H22N4O3S (338): Calcd.: C,53.24; H,6.55; N,16.56; S,9.48. Found: C,53.12; H, 6.45; N,17.05; S,8.90. MS(FD) m/z 338. 1H NMR(DMSO-d6)δ: 9.76,s,2H,NH; 7.11,d,2H,ArH; 6.58,d,2H,ArH; 4.15,s,2H,CH2—N; 4.05,q,2H,CH2—O; 2.93,s,3H,CH3—N; 1.92,s,3H,CH3CO; 1.14,t,3H,CH3—C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[N:38]1.C(=O)([O-])O.[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH2:21][C:22]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=2)[C:14]2[N:19]=[CH:18][C:17]([C:40]3[CH:39]=[N:38][N:37]([CH3:36])[CH:41]=3)=[CH:16][N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(Br)cn2)C1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cn1cc(-c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H]3CCN(C(=O)OC(C)(C)C)C3)nc2)cn1
Temperature: 95 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a mixture of (S)-3-[(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.2 mmol, 1.28 g), 1-methylpyrazol-3-yl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (2.7 mmol, 0.72 g), tetrakis(triphenylphosphine)palladium(0) (0.22 mmol, 260 mg) and 2M aqueous sodium hydrogen carbonate (3.2 mL) in 1,2-dimethoxy-ethane (15 mL) is allowed to warm to 95° C. and stirred for 3 hours. The mixture is cooled to room temperature and then added water. The mixture is extracted with CH2Cl2. The combined organic layer is dried over Na2SO4, filtrated, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc) to give (S)-3-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]amino}-pyrrolidine-1-carboxylic acid tert-butyl ester 766 mg, 61%). ESI-MS m/z: 571 [M+1]+, Retention time 2.25 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19].[CH3:22]I.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:22])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CI
Reactant: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)Oc1ccc2c(c1Cl)Sc1ccccc1N2C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro-3-isobutyryloxy-10H-phenothiazine (see Example 8) (202 mg) in DMF (5 ml) was added methyl iodide (0.2 ml) and sodium hydride (18 mg) at 0° C. The reaction mixture was stirred at ambient temperature for 12 hours. To the reaction mixture was added water and the resulting aqueous layer extracted with EtOAc. The organic layers were collected, dried and evaporated to give a residue which was purified by chromatography on silica gel (plates) to give 100 mg of 4-chloro-3-isobutyryloxy-10-methyl-10H-phenothiazine (m.p. 147° C.).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:45](OC1C(C(O)=O)=NC(CC2(N3C4=NC=CC=C4C=C3)CCCC2)=NC=1O)[C:46]1C=CC=C[CH:47]=1.[Si](OCCNC1CCC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:44]1[CH2:47][CH2:46][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1CCC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1CCC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amide (425) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (8f) (140 mg, 0.32 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amine (108 mg, 0.47 mmol) to get a white sticky solid (200 mg, 97%, impure).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]1[CH:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][CH2:2][C:3]([N:5]([CH2:20][C:18]1[O:17][N:16]=[C:15]([CH3:14])[CH:19]=1)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: Cc1cc(CCl)on1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(CN(C(=O)CCl)c2c(C)cccc2C)on1
Yield: 30 %

Procedure:
A mixture of 4.54 g N-chloroacetyl-2,6-dimethylaniline and 3 g 3-methyl-5-chloromethylisoxazole (prepared as in Example 8 above) in 100 ml dry dimethylformamide was treated with 1.33 g sodium hydride as in Example 3 above. After workup, the solid product was purified by column and high-pressure liquid chromatography to yield 2.0 g pure product, m.p. 78°-82° C. This product is shown as Compound 1 in Table I. C15H17ClN2O2 : calc., %C 61.54, %H 5.81, %N 9.57; found, %C,63.37, %H 6.16, %N 9.65.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[O:11].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[O:11])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1cc(F)c(F)cc1C(=O)c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(F)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 117 mg of (2-Amino-4,5-difluoro-phenyl)-pyridin-4-yl-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.28 (s, 9H), 7.17 (t, 1H, J=8.4 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.54 (d, 2H, J=4.4 Hz), 7.64 (dd, 1H, J=11.6 Hz, 6.8 Hz), 7.72 (d, 2H, J=8.4 Hz), 8.85 (d, 2H, J=5.2 Hz), 10.42 (s, 1H). MS: m/z 431.1 (M++1).