Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(Cl)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (311 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white solid (210 mg, 39%).
Reaction SMILES: OO.[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:6])([CH3:5])[CH3:4].C([O-])([O-])=[O:38].[K+].[K+].CS(C)=O>O>[C:3]([O:7][C:8](=[O:36])[N:9]([CH2:16][CH:17]1[C:26]2[C:21](=[C:22]([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:38])[NH2:35])=[CH:30][N:29]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:5])([CH3:6])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C#N)cn3)cccc21)C(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)CCCN(CC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 197.2 %

Procedure:
Add 30% aq. H2O2 (239 uL) to a suspension of [5-(5-cyano-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4-methyl-pentyl)-carbamic acid tert-butyl ester (111 mg, 0.239 mmol), K2CO3 (16 mg, 0.120 mmol) and DMSO (3 ml) stirring in an ice/water bath. After 1.5 hours, pour the reaction mixture into water and extract with EtOAc. Wash the extract with water and brine before drying (MgSO4) and concentrating to give [5-(5-Carbamoyl-pyridin-2-yloxy)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-(4 methyl-pentyl)-carbamic acid tert-butyl ester (114 mg) as a white foam. Use this material without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7](Cl)[N:6]=[CH:5]2.[O:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([NH:25][C:24]1[CH:23]=[CH:22][C:21]([N:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)=[CH:27][CH:26]=1)[N:6]=[CH:5]2
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1cc2nc(Cl)ncc2cc1Br
Solvent: CC(C)O
Product: COc1cc2nc(Nc3ccc(N4CCOCC4)cc3)ncc2cc1Br
Temperature: 120 °C

Procedure:
To a 0.12M suspension of 6-bromo-2-chloro-7-methoxyquinazoline (1.0 eq) in isopropanol was added 4-morpholinoaniline (1.0 eq). The reaction mixture was heated to 120° C. in an oil bath for 5 h. LCMS showed that reaction was complete under the condition. The reaction mixture was allowed to cool to room temperature and was filtered. The filter cake was rinsed with ethyl acetate and allowed air dry. Desired product was a brown solid as HCl salt. ES/MS m/z 415/417 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:21][CH2:20]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:33].[H-].[Na+].Br[CH2:37][C:38]([O:40][CH3:41])=[O:39].O>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])[CH2:23][CH2:24]3)=[N:14][CH:15]=2)[N:10]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:9]1=[O:33]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CN1C(=O)N(c2ccccc2Cl)Cc2cnc(N[C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)CC3)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(Chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (972 mg, 2 mmol) (prepared as described in Example 81) was suspended in 1-methyl-2-pyrrolidinone (15 mL), and sodium hydride (88 mg, 2.2 mmol (60% oil dispersion)) was added. The reaction mixture was stirred at room temperature for 30 minutes, methyl bromoacetate (0.190 mL, 2 mmol) was added. The mixture was stirred for 6 hours. The reaction mixture was added to water and extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated under reduced pressure. :The residue was purified by column chromatography on silica gel using 70:30 hexane/acetone as eluant. The fractions containing the product were combined and evaporated under reduced pressure to give 425 mg of 3-(2-chlorophenyl)-7-(trans-4-tert-butyldimethylsilyloxycyclohexylamino)-1-methoxycarbonylmethyl-3,4-dihydropyrimido-[4,5-d]pyrimidin-2(1H)-one as a white solid ((M+H)+560, m.p.165.7-167.4° C.
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][O:11]C(C)(C)C)[C:6]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([CH2:10][OH:11])[C:6]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1c(COC(C)(C)C)noc1C1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(CO)noc1C1CCC1
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a solution of ethyl 5-cyclobutyl-3-{[(1,1-dimethylethyl)oxy]methyl}-4-isoxazole carboxylate (1.40 g, 5.48 mmol) in dichloromethane (250 mL) was added trifluoroacetic acid (250 mL, 3.25 mol). The solution was stirred for approximately 30 minutes and then concentrated. The residue was taken up with ethyl acetate and poured into water. The mixture was stirred as solid sodium carbonate was added until the pH was basic. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography (silica gel, 20% ethyl acetate in hexanes) to afford ethyl 5-cyclobutyl-3-(hydroxymethyl)-4-isoxazolecarboxylate (848 mg, 69%). 1H-NMR (400 MHz, DMSO-d6) δ 5.27 (t, J=6 Hz, 1H), 4.63 (d, J=6 Hz, 2H), 4.21 (q, J=7 Hz, 2H), 4.18-4.08 (m, 1H), 2.33-2.27 (m, 4H), 2.10-2.00 (m, 1H), 1.90-1.83 (m, 1H), 1.26 (t, J=7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])[C:13]([CH3:27])=[N:12][C:11]=2[CH:28]([CH3:30])[CH3:29])[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:37]([O:43][CH2:44]I)(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39]>CN(C)C=O>[C:20]([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[C:11]([CH:28]([CH3:30])[CH3:29])[N:12]=[C:13]1[CH3:27])(=[O:26])[CH2:21][CH2:22][C:23]([O:25][CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:24]
Reactant: CC(C)(C)C(=O)OCI
Reactant: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC(=O)CCC(=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Sc2c(C(C)C)nc(C)n2COCCOC(=O)CCC(=O)OCOC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a suspension of the compound 68 (100 mg, 0.230 mmol) and potassium carbonate (48.0 mg, 0.345 mmol) in N,N-dimethylformamide (1 mL) was added pivaloyloxymethyl iodide (61 mg, 0.252 mmol), and stirred at room temperature for 2 hours. The reaction mixture was partitioned between ice-water and ethyl acetate - hexane (1:1)). The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluate: hexane - ethyl acetate (1:1)) to give the compound 74 (111 mg, 88%) as pale yellow oil. Rf 0.15 (1:1 EtOAc-hexane).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](O)[CH:9]=2)[N:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:9]=2)[N:4]=1)#[N:2]
Reactant: ClCOCc1ccccc1
Reactant: N#Cc1ccc2cc(O)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc2cc(COCc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of 2-cyano-6-hydroxyquinoline (100 mg) in 10 mL of acetone was added potassium carbonate (122 mg). After stirring at RT for three minutes, the solution was put on ice. Benzyl chloromethyl ether (122 μL) was added through a needle and the resultant solution was stirred on ice for 2 hours. The solvent was then removed under vacuum and the residue was purified by flash chromatography with dichloromethane. 157 mg was obtained.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:39])([F:38])[C:9]([NH:11][C:12]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:13]=1[O:14][CH2:15][CH2:16][N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[O:10].CI>>[CH3:1][C:13]1([CH:31]=[CH:32][CH:33]=[C:34]([N+:35]([O-:37])=[O:36])[CH:12]1[NH:11][C:9](=[O:10])[C:8]([F:38])([F:39])[F:7])[O:14][CH2:15][CH2:16][N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18](=[O:23])[C:19]([F:21])([F:20])[F:22]
Reactant: O=C(Nc1c(OCCN(Cc2ccccc2)C(=O)C(F)(F)F)cccc1[N+](=O)[O-])C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CC1(OCCN(Cc2ccccc2)C(=O)C(F)(F)F)C=CC=C([N+](=O)[O-])C1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.7 %

Procedure:
A suspension of potassium carbonate (1.44 g, 10.4 mmol), N-[2-(2-{2,2,2-trifluoroacetamidyl}-3-nitro-phenoxy)-ethyl]-N-benzyl-2,2,2-trifluoro-acetamide (1.0 g, 2.09 mmol) and methyl iodide (2.96 g, 20.9 mmol, previously filtered through basic alumina) in anhydrous dimethylsulfoxide (11 mL) was allowed to stir at room temperature for 24 h. The reaction mixture was poured into methylene chloride (200 mL) and extracted with water (2×80 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum to afford a yellow thick oil. Purification by chromatography (30% ethyl acetate-hexanes) afforded 960 mg (93.3%) of a light yellow solid, mp 90-92.5° C.; MS m/e EI 493 (M+).
Reaction SMILES: C(OC(=O)[NH:10][C:11]([CH3:24])([CH2:13][CH2:14][N:15]([CH2:20][CH2:21][O:22][CH3:23])[CH2:16][CH2:17][O:18][CH3:19])[CH3:12])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:23][O:22][CH2:21][CH2:20][N:15]([CH2:16][CH2:17][O:18][CH3:19])[CH2:14][CH2:13][C:11]([CH3:24])([NH2:10])[CH3:12]
Reactant: COCCN(CCOC)CCC(C)(C)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCN(CCOC)CCC(C)(C)N
Temperature: 85 °C
Yield: 100 %

Procedure:
A glass microwave reaction vessel was charged with benzyl(4-(bis(2-methoxyethyl)amino)-2-methylbutan-2-yl)carbamate (500 mg, 1.42 mmol) in TFA/DCM (1:1, 4 mL). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc.) at 85° C. for 7 h. The solvent was removed and the residue was filtered through a plug of Si-carbonate (0.59 mmol/g) and washed with DCM (300 mL, 5% MeOH in DCM (200 mL) and the filtrate was concentrated to give N1,N1-bis(2-methoxyethyl)-3-methylbutane-1,3-diamine (310 mg, 1.42 mmol, 100% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 3.47 (4H, t, J=6.1 Hz), 3.34 (6H, s), 2.71 (4H, t, J=6.1 Hz), 2.60-2.67 (2H, m), 1.50-1.59 (2H, m), 1.10 (6H, s).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39](O)=[O:40])(=[O:13])=[O:12].[C:42]([O:46][C:47](=[O:58])[CH2:48][NH:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([CH3:45])([CH3:44])[CH3:43].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:42]([O:46][C:47](=[O:58])[CH2:48][N:49]([C:39]([C@@H:15]1[CH2:16][C@@H:17]([S:19][C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][N:14]1[S:11]([C:2]1[CH:1]=[CH:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=1)(=[O:12])=[O:13])=[O:40])[CH2:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: O=C(O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)CNCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of 800 mg (1.38 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid and 390 mg (1.66 mmol) crude phenethylamino-acetic acid tert-butyl ester in 14 ml THF was cooled to 0° C. and treated with 318 mg (1.66 mmol) EDCI and 19 mg (0.14 mmol) HOBT. The reaction was warmed up to RT over night and partitioned between aqueous 10% KHSO4/ethyl acetate (3×). The organic phases were washed with aqueous saturated NaHCO3 solution and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 4:1 to 1:1) gave 290 mg (26%) (2S,4R)-{[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid tert-butyl ester, MS: 797 (MH+)
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][C@H:13]2[CH2:22][OH:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>ClCCl>[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([O:23][CH2:22][C@@H:13]2[CH2:14][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:11])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (28.8 g: 77 mmole) in dichloromethane (150 ml) under ice cooling, p-toluenesulfonyl chloride (19.11 g: 1.3 eq.), triethylamine (10.4 ml: 1.3 eq.) and dimethylaminopyridine (0.94 g: 0.1 eq.) are added. The mixture is stirred at 25° C. for 7 hours. The reaction mixture is diluted with ice water. The resultant organic layer is taken, successively washed with aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from n-hexane to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (37.7 g). Yield: 93%. NMR δ(CDCl3) ppm: 2.20 to 2.50(m, 1H), 2.44(s, 3H), 3.05(s, 3H), 3.45 to 4.60(m, 5H), 5.18(s, 2H), 5.26(br s, 1H), 7.34(d, J=8 Hz, 2H), 7.50(d, J=8 Hz, 2H), 7.75(d, J=8 Hz, 2H), 8.23(d, J=8 Hz, 2H). IR ν (CHCl3) cm-1 : 1700, 1599.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:11](OCC)(=[O:13])[CH3:12]>CN(C)C=O.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:12][CH:11]=[O:13]
Reactant: CCOC(C)=O
Reactant: Oc1cccc(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=CCOc1cccc(F)c1
Temperature: 60 °C
Yield: 78.1 %

Procedure:
2.00 g (17.8 mmol) of m-fluorophenol was dissolved in 50 ml of dimethylformamide, 785 mg (19.6 mmol, 60% by weight, mineral) of sodium hydride and 3.21 ml (21.3 mmol) of bromoacetaldehydediethylacetal were successively added thereto, and the mixture was heated to 60° C. After completion of the reaction, brine was added thereto and the mixture was extractedwith ethyl acetate. Theorganiclayerwaswashedwith brine, dried over magnesium sulfate and then evaporated, to give a crude product. The crude product was subjected to 105 g of Cromatorex NH silica gel (ethyl acetate:hexane=1:40), to give 3.17 g (13.9 mmol, 78.1%) of the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1.I[CH2:25][CH3:26]>>[CH2:25]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]3[CH2:20][CH2:21][CH2:22][O:23][C:12]=23)=[O:10])[CH2:3][CH2:2]1)[CH3:26]
Reactant: CCI
Reactant: O=C(NCC1CCNCC1)c1c2n(c3ccccc13)CCCO2
Product: CCN1CCC(CNC(=O)c2c3n(c4ccccc24)CCCO3)CC1

Procedure:
N-(4-Piperidylmethyl) 3,4-dihydro-2 H-[1,3]oxazino[3,2-a]indole- 10-carboxamide (E21) was alkylated with iodoethane using the method of Example 22. The title compound was obtained as a white solid (27%), which was converted to its hydrochloride salt and crystallised from acetone/ethanol/ether as a white solid mp 243°-245° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[S:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=3)[N:13]=2)=[C:9]([CH3:11])[N:10]=1.[N+]([O-])(OC(=O)C)=O.C([O-])(O)=O.[Na+]>CC(OC(C)=O)=O>[CH3:5][C:6]1[S:7][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[C:21]([N+:1]([O-:4])=[O:2])[CH:20]=3)[N:13]=2)=[C:9]([CH3:11])[N:10]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc(C)c(-c2ccnc(Nc3ccc(N(C)C)cc3)n2)s1
Agent: CC(=O)O[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(N(C)C)c([N+](=O)[O-])c3)n2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
HNO3 (69% aq, 24 μL, 0.36 mmol) was added dropwise to Ac2O (1 mL) at room temperature, keeping the internal temperature below 25° C. The mixture was stirred at room temperature for 15 min before cooling to −5° C. in an ice-MeOH bath. Compound N-[4-(2,4-dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-N′,N′-dimethyl-benzene-1,4-diamine (50 mg, 0.15 mmol) was slurried in Ac2O (1 mL) and added dropwise to the cooled solution of acetyl nitrate. The mixture was stirred with cooling for 1 h then a further 2 h at room temperature. The mixture was poured into ice-water (20 mL) and the pH was adjusted to 7-8 by addition of saturated aq NaHCO3 solution. The mixture was extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, and filtered. The solvent was evaporated in vacuo to give a dark solid, which was purified by flash chromatography, eluted with heptane/EtOAc to afford 32 mg of the title compound as a pale reddish solid. RP-HPLC: tR=12.7 min (10-70% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>95%). 1H-NMR (DMSO-d6): δ 2.62 (s, 3H, CH3), 2.64 (s, 3H, CH3), 2.74 (s, 6H, CH3), 7.09 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 7.23 (d, 1H, J=8.8 Hz, Ph-H), 7.77 (dd, 1H, J=8.7, 2.7 Hz, Ph-H), 8.39 (d, 1H, J=2.7 Hz), 8.51 (d, 1H, J=5.1 Hz, pyrimidinyl-H), 9.81 (br. s, 1H, NH).
Reaction SMILES: C[Al](C)C.[I:5][C:6]1[N:15]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:9]2=[N:10][CH:11]=[C:12]([NH2:14])[CH:13]=[C:8]2[CH:7]=1.[F:25][C:26]1[C:35]([N:36]([S:43]([CH2:46][CH2:47][CH3:48])(=[O:45])=[O:44])[S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])=[CH:34][CH:33]=[C:32]([F:49])[C:27]=1[C:28](OC)=[O:29]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:25][C:26]1[C:35]([N:36]([S:37]([CH2:40][CH2:41][CH3:42])(=[O:39])=[O:38])[S:43]([CH2:46][CH2:47][CH3:48])(=[O:44])=[O:45])=[CH:34][CH:33]=[C:32]([F:49])[C:27]=1[C:28]([NH:14][C:12]1[CH:13]=[C:8]2[CH:7]=[C:6]([I:5])[N:15]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[C:9]2=[N:10][CH:11]=1)=[O:29]
Reactant: Nc1cnc2c(c1)cc(I)n2S(=O)(=O)c1ccccc1
Reactant: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)OC)c1F)S(=O)(=O)CCC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)cc(I)n3S(=O)(=O)c2ccccc2)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.8 %

Procedure:
Trimethylaluminum (0.51 mL, 1.01 mmol, 2.0M solution in toluene) was added dropwise via a syringe to a cold (0° C.) suspension of 2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-amine (0.135 g, 0.338 mmol) in toluene (10 mL). The cold bath was removed and the mixture was stirred at room temperature for 20 minutes. Methyl 2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzoate (0.149 g, 0.372 mmol) was added, and the reaction mixture was heated to 90° C. under N2 for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) 30% Aqueous potassium sodium tartrate solution (50 mL) was carefully added, and the resulting emulsion was stirred at room temperature for 30 minutes. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (4:1), hexanes/ethyl acetate (2:1) to give 2,6-difluoro-N-(2-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.225 g, 87%) as a foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20](Br)=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14].[CH3:27][O-:28].[Na+]>C(#N)C.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[C:3]=1[NH:12][S:13]([C:16]1[N:26]=[C:19]2[C:20]([O:28][CH3:27])=[N:21][CH:22]=[C:23]([Br:24])[N:18]2[N:17]=1)(=[O:15])=[O:14]
Reactant: C[O-]
Reactant: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(Br)ncc(Br)n2n1
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: COC(=O)c1cccc(F)c1NS(=O)(=O)c1nc2c(OC)ncc(Br)n2n1

Procedure:
A solution of 686 mg (1.35 mmol) of N-(2-fluoro-6-methoxycarbonylphenyl)-5,8-dibromo[1,2,4]triazolo-[1,5-a]pyrazine-2-sulfonamide in 10 mL dry acetonitrile was treated with 3.0 mL (3.0 mmol) of a 1M solution of 15 sodium methoxide in dry methanol at 0° C. with stirring. The reaction was quenched after 5min with 0.5mL of glacial acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue was triturated with water and the resulting light brown solid was collected by filtration and dried in a vacuum oven. This crude material was purified by flash column chromatography on silica gel using a 0.5 to 2percent ethanol/dichloromethane gradient as eluent to obtain 538 mg (87 percent of theory) of the title compound as a white glassy foam solid melting at 201°-202° C.