Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.Cl.Cl.[NH2:29][CH2:30][C@H:31]1[CH2:35][NH:34][CH2:33][C@H:32]1[OH:36]>C(Cl)Cl.CCCCCC>[NH2:29][CH2:30][C@H:31]1[C@@H:32]([OH:36])[CH2:33][N:34]([C:2]2[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)=[CH:20][C:5]([C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:13][CH:14]=3)=[O:7])=[CH:4][N:3]=2)[CH2:35]1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: NC[C@H]1CNC[C@H]1O
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: NC[C@@H]1CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cc2-c2ccn[nH]2)C[C@@H]1O

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 48 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1) and cis-4-(aminomethyl)pyrrolidin-3-ol dihydrochloride (Stage 80.1). The crude product was purified by preparative HPLC (Condition 10). Fractions containing product were combined, treated with sat. aq. Na2CO3 and the MeCN was evaporated off under reduced pressure to give an aq. residue which was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was suspended in DCM/n-hexane, filtered and dried to afford the title product as a beige solid. HPLC (Condition 7) tR=5.38 min, UPLC-MS (Condition 3) tR=0.78 min, m/z=479 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85-2.05 (m, 1H) 2.38-2.86 (m, 2H) 2.88-3.06 (m, 1H) 3.08-3.23 (m, 1H) 3.24-3.37 (m, 2H) 3.91-4.18 (m, 1H) 6.33-6.42 (m, 1H) 7.32 (d, J=8.60 Hz, 2H) 7.68-7.91 (m, J=9.00 Hz, 3H) 7.97-8.06 (m, 1H) 8.68-8.78 (m, 1H) 10.20 (s, 1H) 12.94 (br. s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>N1C=CC=CC=1>[S:23]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:22])=[CH:7][N:8]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:12]=[C:9]32)=[CH:4][CH:3]=1)([CH3:26])(=[O:25])=[O:24]
Reactant: CCOC(=O)c1cnc2c3cc(N)ccc3c(C)cn2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc2c3cc(NS(C)(=O)=O)ccc3c(C)cn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution oe ethyl 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (800 mg) in pyridine (60 ml) was added mesyl chloride (0.28 ml) at ice bath temperature. The reaction mixture was allowed to stir overnight at room temperature and then concentrated in vacuo. The residue was collected, washed successively with 0.1N hydrochloric acid and water and recrystallized from N,N-dimethylformamide to give ethyl 10-mesylamino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (0.76 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[C:9]([CH2:11][C:12]([OH:14])=[O:13])#[N:10].N1CCCCC1>C(O)C>[C:9]([C:11](=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:12]([OH:14])=[O:13])#[N:10]
Reactant: O=Cc1cccnc1
Reactant: N#CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1cccnc1)C(=O)O
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
A mixture of 3.8 g of 3-pyridinecarbaldehyde, 3.0 g of cyanoacetic acid, 3.0 g of piperidine, and 30 ml of ethanol is stirred at 100° C. for 4 hours. The reaction mixture is concentrated, and 20 ml of water is added. The mixture is adjusted to pH 4.5 with 10% hydrochloric acid. The resulting precipitate is collected and recrystallized from ethanol to give 3.8 g of the title compound, m.p. 223°-227° C.
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][C:14]([F:18])=[C:15]([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:18][CH:14]([CH:15]([F:17])[F:16])[CH:13]=[CH:12][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2o1
Reactant: FC(F)=C(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)C(F)C=CSc1nc2ccccc2o1
Reaction time: 2 h
Yield: 103.2 %

Procedure:
2-Mercaptobenzoxazole (2 g), 4-bromo-1,1,2-trifluorobut-1-ene (2.75 g) and potassium carbonate (1 g) were stirred together in 40 ml of acetone and heated to reflux. After 2 hours the reaction mixture was allowed to cool, filtered to remove insoluble potassium salts and the filterate was evaporated under reduced pressure to yield 3.54 g of a brown oil which was used in step b without purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(CC)CC)C.[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][CH:28]=[C:27]2[S:35](Cl)(=[O:37])=[O:36]>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[NH:29][CH:28]=[C:27]2[S:35]([N:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:3]([CH2:2][OH:1])[CH2:8]1)(=[O:37])=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c2cc(Br)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c[nH]c(=O)c3ccc(Br)cc23)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.8 %

Procedure:
To a solution of tert-butyl (2R)-2-(hydroxymethyl)piperazine-1-carboxylate (0.479 g) and triethylamine (0.618 mL) in THF (6 mL) was added dropwise a solution of 6-bromo-1-oxo-1,2-dihydroisoquinoline-4-sulfonyl chloride (Example 46a, 0.715 g) in THF (10 mL). The reaction was stirred at room temperature for 20 min. The resulting solution was concentrated under reduced pressure before adding water and extracting into ethyl acetate. The combined organics were dried (MgSO4), filtered and evaporated under reduced pressure. Trituration with ethyl acetate gave the subtitle compound (0.855 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O>>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][C:5]([CH:16]2[CH2:17][CH2:18][O:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: OB(O)c1ccco1
Reactant: CCOC(=O)c1nc(Br)ccc1N
Product: CCOC(=O)c1nc(C2CCOC2)ccc1N

Procedure:
According to step 1 and 2 of example 96, the title compound was prepared starting from ethyl 3-amino-6-bromopicolinate and furan-2-ylboronic acid. Light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH:13]=C)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].CO.CC[O:19]C(C)=O>CC(O)C.O.C(Cl)Cl.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][CH2:12][CH:13]=[O:19])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1)=[O:4]
Reactant: CCOC(C)=O
Reactant: C=CCCC1(C(=O)OC)CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: COC(=O)C1(CCC=O)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4-But-3-enyl-tetrahydro-pyran-4-carboxylic acid methyl ester (6 g, 30 mmol) was dissolved in iPrOH (150 mL). To this was added a aqueous solution of NaIO4 (14 g, 65.2 mmol, 2.18 equiv.) in water (150 mL), followed by addition of OsO4 (25 mg, crystals, in one portion) at rt. The solution was stirred with a mechanical stirrer at rt (water bath). After 30 min, milky cloudy product was formed. Stirring was continued for 4 h. TLC (1% MeOH in DCM, and 5% MeOH in DCM) did not detect the starting material. An aliquot was taken and dissolved in CDCl3 to run 1H NMR, there was no alkene peak in the sample. The reaction was judged to be complete. The reaction mixture was poured into ice water (200 mL) and EtOAc (200 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (5×50 mL). More water was added to dissolve the solid resulting in a clear solution. The combined extracts were washed with brine, and concentrated to dryness to get a liquid. The liquid was subject a reduced distillation to remove isopropanol. The remaining liquid was purified on a 50-g silica gel column, eluted with 50% EtOAc in Heptane. Note: the product is not UV active. Anisaldehyde visualization was used. The product fractions were collected and concentrated to yield 5.62 g (94% yield) of the title compound as a liquid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].Cl.O1CCOCC1>>[C:13]1([C:11]2[CH:12]=[C:6]3[C:5]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=[N:8][N:7]3[CH:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c(C(N)=O)cnn3cc(-c4ccccc4)cc23)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1cnn2cc(-c3ccccc3)cc2c1N[C@H]1CCCNC1
Yield: 122.6 %

Procedure:
A flask containing (S)-tert-butyl 3-(3-carbamoyl-6-phenylpyrrolo[1,2-b]pyridazin-4-ylamino)piperidine-1-carboxylate (62 mg, 0.142 mmol) was added HCl in dioxane (2 mL, 8 mmol). TLC indicated complete consumption of starting material at 3 h at which time the volatiles were removed via nitrogen sweep and the crude salt was dried under high vacuum to afford the hydrochloride salt of the title compound (58.4 mg, 87% yield) as a yellow solid. A portion of the solids were purified via preparative HPLC (Phenomenex Luna 21.2×100 mm, 1/9 MeOH/H2O to 9/1 MeOH/H2O, 0.1% TFA; 20 mL/min, 10 minute gradient). LCMS: 336.1 (M+H)+; HPLC (conditions E): retention time=5.82 min; 1H NMR (MeOD, 400 MHz) δ 8.21 (s, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.78 (dd, J=1.4, 8.4 Hz, 2H), 7.75 (t, J=7.9 Hz, 2H), 7.26 (m, 2H), 4.68 (m, 1H), 3.73 (dd, J=3.5, 9.0 Hz, 1H), 3.35 (m, 1H), 3.17 (m, 2H), 2.34 (m, 1H), 2.17 (m, 1H), 1.99 (m, 1H), 1.85 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:16]1[C:25]2[C:24]3[CH:26]=[CH:27][O:28][C:23]=3[CH2:22][CH2:21][C:20]=2[N:19]=[C:18]([NH2:29])[N:17]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:29][C:18]4[N:17]=[CH:16][C:25]5[CH2:24][CH2:26][C:27]6[O:28][CH:23]=[CH:22][C:21]=6[C:20]=5[N:19]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Nc1ncc2c(n1)CCc1occc1-2
Solvent: c1ccncc1
Product: O=C(Nc1ncc2c(n1)-c1ccoc1CC2)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 5,6-dihydrofuro[3,2-f]quinazolin-3-amine (37 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 375.4, found 375.1 (M+1)+. Retention time 2.61 minutes.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Na]>ClCCl.C(O)(=O)C.FC(F)(F)C(O)=O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(NC2CCNCC2)cc1

Procedure:
Was synthesised in the same way as (A) from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol), 4-chloro-phenylamine (1.15 g, 9.0 mmol) and sodium triacetoxyborhydride (5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.5 g, 79%
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]1=[O:19])[CH2:2][CH3:3].[O:20]=[S:21]1(=[O:37])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35]Br.C(N(CC)CC)C.O>CN(C)C=O>[O:37]=[S:21]1(=[O:20])[C:25]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=2[C:23](=[O:31])[N:22]1[CH2:32][CH2:33][CH2:34][CH2:35][N:16]1[CH2:17][CH2:18][CH:13]([N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([CH2:1][CH2:2][CH3:3])[C:5]2=[O:19])[CH2:14][CH2:15]1
Reactant: CCCn1c(=O)n(C2CCNCC2)c2ccccc21
Reactant: O=C1c2cc(Cl)ccc2S(=O)(=O)N1CCCCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)n(C2CCN(CCCCN3C(=O)c4cc(Cl)ccc4S3(=O)=O)CC2)c2ccccc21
Temperature: 50 °C

Procedure:
To a solution of 4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidine (440 mg, 1.7 mmol) in dry dimethylformamide (6 mL), under an argon atmosphere was added 1,1-dioxido-2-(4-bromobutyl)-5-chloro-1,2-benzisothiazol-3(2H)-one (615 mg, 1.74 mmol, prepared as shown in Example 22) followed by triethylamine (0.25 mL, 1.8 mmol). This solution was heated at 50° C. for four hours and then cooled to room temperature as water was added. The product was extracted, dried (Na2SO4) and evaporated. The residue was chromatographed on a column of silica gel eluting with a gradient of 0.5-2% methanol/chloroform containing 0.2% NH4OH to give 1,1-dioxido-2-(4-(4-(3-propyl-2-oxo-1-benzimidazolinyl)piperidin-1-yl)butyl)-5-chloro-1,2-benzisothiazol-3(2H)-one as a viscous oil. 1H NMR (400 MHz, CDCl3): d 8.02 (s, 1H), 7.84 (quartet, J=8 Hz, 2H), 7.30 (broad d, 1H), 7.05 (broad quintet, 2H), 6.98 (broad d, J=8 Hz, 1H), 4.40 (multiplet, 1H), 3.84 (t, J=7.1 Hz, 4H), 3.07 (broad d, J=11.1 Hz, 2H),2.43-2.47 (m, 4H),2.14 (broad t, J=11 Hz, 2H), 1.88-1.93 (quintet, 2H), 1.75-1.81 (multiplet, 4H), 1.62-1.66 (multiplet, 2H), 0.97 (t, J=7.3 Hz, 3H). This oil was converted to its hydrochloride salt and crystallized from methanol upon addition of diethyl ether to give a crystalline white solid, melting point 225-227° C.: Analysis calculated for C26H31ClN4O4S.HCl: C, 55.02; H, 5.68; N, 9.87; found: C, 54.76; H, 5.66; N, 9.80.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:24]([OH:26])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O-])=O.CO.[Cl-].[NH4+]>[Zn]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][CH2:11][C@H:12]([C:24]([OH:26])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: O=C(N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O)OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Nc1ccccc1SC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a yellow solution of 17.0 g (45.2 mmol) of S-(o-nitrophenyl)-N-carbobenzyloxy-D-cysteine in 800 mL of methanol containing 4.84 g (90.4 mmol) of ammonium chloride (NH4Cl) was added 41.1 g (633 mmol) of zinc dust. The resulting gray slurry was refluxed for 4 hours. The hot solution was then filtered, and the solid residue washed with an additional 200 mL of methanol. The filtrate was evaporated and the solid residue triturated with 320 mL of 1N HCl. Upon stirring for 1/2 hour, the initial gummy mass crystallized to a white solid. Filtration of the solid yielded 13.1 g (84%) of S-(o-aminophenyl)-N-carbobenzyloxy-D-cysteine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:13])=[CH:5]2.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:42][C:43]([F:58])([F:57])[C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][CH:53](O)[CH2:52][CH2:51]2)=[CH:46][CH:45]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:58][C:43]([F:42])([F:57])[C:44]1[CH:45]=[CH:46][C:47]([N:50]2[CH2:55][CH2:54][CH:53]([O:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]=[CH:7][C:6]([C:12]([NH:14][CH:15]3[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]3)=[O:13])=[CH:5]4)[CH2:52][CH2:51]2)=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3ccc(O)cc3c2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3c2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
To a stirred suspension of the product of step 2 above (0.7 g, 1.88 mmol) in toluene (15 mL) at room temperature was added diisopropyl azodicarboxylate (557 μl, 2.83 mmol), 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (0.693 g, 2.83 mmol), and triphenyl phosphine (0.742 g, 2.83 mmol). The mixture was stirred at 50° C. overnight and then concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 3% methanol in methylene chloride) to afford tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)quinoline-3-carboxamido)piperidine-1-carboxylate as a white solid (0.306 g, 27%). LCMS (m/z): 599 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][S:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)(=[O:28])=[O:27])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with thiophene-2-sulfonyl chloride (0.192 g, 1.0 mmol) and pyridine (3 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (7 mL) was added and the mixture allowed to stand 1.75 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL) and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a purple-tinted solid. The solid was triturated with hexanes/ethyl acetate, 1/1, v/v to give the product (0.322 g), mp 211-213° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([O:20][CH3:21])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C(=O)C)[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].O.C(=O)(O)[O-].[Na+]>CO>[CH2:6]([O:5][P:4]([CH:9]([O:20][CH3:21])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(OCC)C(OC)c1cccc(OC(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOP(=O)(OCC)C(OC)c1cccc(O)c1
Reaction time: 48 h

Procedure:
Diethyl-1-methoxy-1-(3-acetoxyphenyl)methanephosphonate from Example 8 (10.29 g., 32.56 mmol) was dissolved in methanol (35 ml). Water (5 ml), and sodium bicarbonate (5 g, 60 mmol) were then added with stirring. After 48 hours at room temperature, the reaction mixture was concentrated in vacuo to remove methanol. The residue was treated with 150 ml dichloromethane and washed with water (2×50 ml). The organic layer was rotory evaporated and pumped at high vacuum to yield 8.21 g. (93%) of the product as a light yellow, viscous oil. Spectral data (Tables 5 and 9) are in accordance with the structure: ##STR34##
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31].CO>O1CCCC1.C(Cl)Cl.O>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(Cc1ccccc1)C1OC[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=NN(CCCl)C(=O)N(Cc1ccccc1)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 76 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-benzyl-3-(L-arabinopyranosyl)urea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is further stirred at the same temperature for 10 minutes. After the reaction, 10 ml of methanol and 3 ml of water are added to the mixture, and the aqueous mixture is stirred vigorously for 10 minutes. Said aqueous mixture is dried and filtered. The filtrate is evaporated to remove solvent. Then, the residue obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol (5:2:1)). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-benzyl-3-(L-arabinopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]2=[N:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[OH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:5]3=[N:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Nc1ccc(CO)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(CO)cc3)nc12
Temperature: 110 °C
Yield: 215.4 %

Procedure:
To a 35 ml sealed tube, 1-(2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-yl)-2,2-dimethylpropane-1-one (2.0 g, 0.0048 mole) and (4-aminophenyl)methanol (0.78 g, 0.0063 mole) was taken in toluene (20.0 ml). The reaction mixture was purged with argon for 15 min at RT followed by Cs2CO3 (4.7 g, 0.0144 mole) was added and further purged for 30 min with argon. BINAP (0.06 g, 0.0001 mole) and Pd(OAc)2 (0.021 g, 0.0001 mole) were added to reaction mixture and heated to 110° C. for 4 hr. After completion of the reaction, the reaction mixture was filtered through celite bed and washed with ethyl acetate. Filtrate was collected and concentrated to afford crude product which was subjected for the column purification. The reaction with repeated twice and the crude product from each reaction was mixed and then purified using column purification by eluting the compound with 25-30% ethyl acetate in hexanes to yield 4.7 g of 1-(2-(4-(hydroxymethyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethylpropan-1-one.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:33])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C>Cl.O1CCOCC1.CO>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:33])([CH:14]([F:15])[F:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(c2cc(NC(=O)c3ccc(Br)cn3)ccc2F)(C(F)F)COC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1=NC(c2cc(NC(=O)c3ccc(Br)cn3)ccc2F)(C(F)F)COC1
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.184 mmol) (5-{5-[(5-bromo-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester in 1.4 ml 4N HCl in dioxane was stirred at 50° C. After 15 min 0.3 ml 3N HCl in MeOH were added and the now homogeneous solution was stirred for 3 h. The mixture was concentrated and crystallized from EtOH/TBME to yield the title compound.