Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CN1C(SC[CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=3)[CH2:13][CH2:12][NH:11]2)=NN=N1.C(=O)(O)[O-].[Na+].O1CCCC1.Cl[C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34]>O>[Cl:38][C:37]([Cl:40])([Cl:39])[CH2:36][O:35][C:33]([CH:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:21])=[C:17]([OH:20])[CH:18]=2)[CH2:13][CH2:12][NH:11]1)=[O:34]
Reactant: Cn1nnnc1SCC1NCCc2cc(O)c(O)cc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)C1NCCc2cc(O)c(O)cc21
Yield: 78.2 %

Procedure:
A suspension of 1-(1-methyl-1H-tetrazol-5-yl)thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (50 g) in water (300 ml) was dissolved at 61° to 65° C. To the solution was added sodium bicarbonate (13.3 g) over 15 minutes at the same temperature. Tetrahydrofuran (250 ml) was added to the suspension at 50° C. The suspension was cooled and weakly alkalified by adding sodium bicarbonate (30 g) at 0° to 3° C. To the mixture was added 2,2,2-trichloroethyl chloroformate (40.2 g) over 30 minutes below 3° C. Water (300 ml) was added to the reaction mixture and the mixture was twice extracted with ethyl acetate (900 ml and 600 ml). The extract was washed with a sodium chloride aqueous solution (300 ml) and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized with ether to give 1-(1-methyl- 1H-tetrazol-5-yl)thiomethyl-2-(2,2,2-trichloroethoxycarbonyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (40.4 g), mp 201° to 207° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[OH:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:25][CH:26](O)[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:26]([CH3:27])[CH3:25])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:5])[CH3:2]
Reactant: CC(C)O
Reactant: CCOC(=O)C1(NCc2cccc(C)c2O)Cc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1(NCc2cccc(C)c2OC(C)C)Cc2ccccc2C1
Reaction time: 24 h
Yield: 180.8 %

Procedure:
A 100 mL round bottom flask containing the 2-(2-hydroxy-3-methyl-benzylamino)-indan-2-carboxylic acid ethyl ester (364, 1.01 g, 3.10 mmol) is charged with dry tetrahydrofuran (THF, 10 mL). A stirring bar is added and stirring is initiated. After dissolution, iPrOH ([67-63-0], 0.47 mL, 6.21 mmol) and triphenylphosphine ([603-35-0], 1.63 g, 6.21 mmol) are added in turn. After dissolution of the triphenylphosphine, diisopropylazodicarboxylate (1.20 mL, 6.21 mmol) is added. The reaction flask is capped and allowed to stir at ambient temperature overnight. After 24 h, tlc analysis (silica, 1:2 EtOAc/Heptanes) indicates that the starting material is completely consumed and converted to a higher moving spot as visualized by UV. The stirring bar is removed from the reaction flask and the solvent removed under reduced pressure. Pumping to constant weight gives 2.06 g of viscous yellow oil. This is dissolved in DCM (10 mL) and applied to an ISCO Companion which had been fitted with a 40 g column (silica). The column is eluted with EtOAc/heptanes (5%) for 4 column volumes followed by a linear gradient to 60% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 17 mL fractions of UV Active eluent are collected. Fractions 5-14 are combined and evaporated by pumping to constant weight to give viscous residue (0.42 g, 37%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]2[C:8](=[C:9]([CH3:15])[C:10]=1[CH2:11][C:12]([CH3:14])=[CH2:13])[N:7]([CH:16]=[O:17])[C:6]([CH3:19])([CH3:18])[CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:26](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCl.CO>[I:26][CH2:13][C:12]1([CH3:14])[O:1][C:2]2=[C:3]([CH3:20])[C:4]3[CH2:5][C:6]([CH3:19])([CH3:18])[N:7]([CH:16]=[O:17])[C:8]=3[C:9]([CH3:15])=[C:10]2[CH2:11]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(C)c2c(c(C)c1O)CC(C)(C)N2C=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)C(C)(C)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
To a solution of 2,3-dihydro-5-hydroxy-2,2,4,7-tetramethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (1.90 g, 6.95 mmol) in dichloromethane (20 ml) and methanol (10 ml) were added calcium carbonate (0.90 g, 9.0 mmol) and benzyltrimethylammonium dichloroiodate (2.66 g, 7.64 mmol), and stirred for 15 minutes at room temperature. The reaction mixture was filtered and concentrated under reduced pressure. To the residue was added a 5% aqueous solution of sodium hydrogen sulfite (15 ml), and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine and water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 2.40 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH:7](NS(CC)(=O)=O)[C:6]=2[CH:18]=1.[H-].[Na+].C(I)CCC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]2[O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: CCS(=O)(=O)NC1CCCOc2c(C)cc(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCI
Product: Cc1cc(Cl)cc2c1OCCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.8 g (2.6 mmol) of 7-chloro-9-methyl-5-(N-ethylsulfonylamino)-2,3,4,5-tetrahydro-1-benzoxepine (Example 10c) in 10 ml of DMF was added dropwise under nitrogen to a suspension of 0.1 g (2.7 mmol) of 80 percent sodium hydride in 8 ml of DMF. After stirring at RT for 30 min, 0.68 g (3.7 mmol) of butyl iodide was added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. After washing the organic phase with dil. hydrochloric acid in water, and drying over magnesium sulfate, it was concentrated in vacuo. 0.9 g of 5-N-butyl-N-ethylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 83-87° C.
Reaction SMILES: C(O[C:4](=[O:24])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:24])=[C:14]2[CH:15]=[N:16][N:17]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1O

Procedure:
250 g of [[[1-(2-furyl)methyl-5-pyrazolyl]amino]methylene]-malonic acid diethyl ester (0.75 mol) is dissolved in 1 liter of diphenyl ether and heated to 240° for 2 hours. The ethanol formed is continuously distilled off. The solvent is removed in vacuo. The 4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester remains and is recrystallized from methanol, yield 248 g (86%), m.p. 103°-106°.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:2]=1.Cl[C:18]1[NH:27][C:26](=[O:28])[C:25]2[C:20](=[CH:21][C:22]([O:31][CH3:32])=[C:23]([O:29][CH3:30])[CH:24]=2)[N:19]=1.C(N(CC)CC)C.C(O)C>COC(O)C>[CH3:30][O:29][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][C:22]=1[O:31][CH3:32])[N:19]=[C:18]([N:12]1[CH2:13][CH2:14][C:15]3[N:7]([C:3]4[CH:2]=[C:1]([CH3:16])[CH:6]=[CH:5][CH:4]=4)[CH:8]=[N:9][C:10]=3[CH2:11]1)[NH:27][C:26]2=[O:28]
Reactant: Cc1cccc(-n2cnc3c2CCNC3)c1
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Agent: COC(C)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCc4c(ncn4-c4cccc(C)c4)C3)[nH]c(=O)c2cc1OC
Temperature: 100 °C
Yield: 56.9 %

Procedure:
A mixture of 1-m-tolyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine 18a (100 mg, 0.5 mmol), 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (100 mg, 0.4 mmol), and triethylamine (140 μL, 1.0 mmol) in 10 mL methoxyethanol was heated at 100° C. under nitrogen for 12 hr. The mixture was pumped to constant weight. The resulting residue was slurried with hot ethanol and allowed to reach ambient temperature. Vacuum filtration provided 95 mg of 6,7-dimethoxy-2-(1-m-tolyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-3H-quinazolin-4-one, 601, [M+H]+=418, as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[CH2:24]([C:26]1[N:31]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:30](=[O:39])[C:29]([C:40](O)=[O:41])=[CH:28][CH:27]=1)[CH3:25].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:29]5[C:30](=[O:39])[N:31]([C:32]6[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=6)[C:26]([CH2:24][CH3:25])=[CH:27][CH:28]=5)=[O:41])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: CCc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)c(=O)n1-c1ccc(F)cc1
Yield: 74.4 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.324 mmol), 6-ethyl-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (101.5 mg, 0.389 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (111 μL, 0.648 mmol) and HATU (148 mg, 0.389 mmol) and in the same manner as in Example 57, the title compound (133 mg, 74%) was obtained as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2/[CH:11]=[CH:12]\[CH2:13][OH:14])=[N:3]1.[CH3:15]CCCCC.C([Zn]CC)C.ICI>C(Cl)Cl.[Cl-].[NH4+].O>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[C:8]2[C@H:11]2[CH2:15][C@H:12]2[CH2:13][OH:14])=[N:3]1
Reactant: Cn1cc2c(/C=C\CO)cccc2n1
Reactant: CCCCCC
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ICI
Solvent: ClCCl
Product: Cn1cc2c([C@H]3C[C@H]3CO)cccc2n1
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
Under argon gas atmosphere, to a suspension of (2Z)-3-(2-methyl-2H-indazol-4-yl)prop-2-en-1-ol (60.0 mg, 0.319 mmol) in methylene chloride (3 mL) was added 1 M diethylzinc hexane solution (1.60 mL, 1.60 mmol) under ice-cooling and the mixture was stirred for 10 min. Diiodomethane (128 μL, 1.59 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction solution was diluted with saturated aqueous ammonium chloride solution and water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (40.5 mg, yield 63%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8](O)[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1)[CH3:2].[Cl-].[Cl:15]C=[N+](C)C>C(Cl)(Cl)Cl>[CH2:1]([S:3][C:4]1[N:9]=[C:8]([Cl:15])[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1)[CH3:2]
Reactant: CCCc1cc(O)nc(SCC)n1
Reactant: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCCc1cc(Cl)nc(SCC)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 85.6 %

Procedure:
To the solution of 2-ethylthio-4-hydroxy-6-propylpyrimidine (406 mg) in CHCl3 (6 mL) was added (chloromethylene)-dimethylammonium chloride (Villsmier reagent) (786 mg). The reaction was stirred at room temperature under nitrogen for 40 min. Filtration through silica gel followed by removal of solvent provided 380 mg of the title compound as yellowish oil. 1H NMR (500 MHz, CDCl3): δ 6.81 (s, 1H); 3.17 (q, J=7.3 Hz, 2H); 2.65 (t, J=7.5 Hz, 2H); 1.76 (m, J=7.6 Hz, 2H); 1.41 (t, J=7.3 Hz, 3H); 0.99 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH:18](C)C)[NH:5][S:6]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH:11](C)C)(=[O:8])=[O:7].N[C@H](C(OC)=O)C.Cl.S(N)(N)(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH3:18])[NH:5][S:6]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH3:11])(=[O:7])=[O:8]
Reactant: COC(=O)[C@@H](NS(=O)(=O)N[C@H](C(=O)OC)C(C)C)C(C)C
Agent: COC(=O)[C@H](C)N
Agent: Cl
Agent: NS(N)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](C)NS(=O)(=O)N[C@@H](C)C(=O)OC
Yield: 31 %

Procedure:
In a procedure similar to the preparation of sulfamide (8b), H-Ala-OMe.HCl (2.18 g, 15.56 mmol) was subjected to sulfamide formation conditions (SO2Cl2, Et3N, CH2Cl2 0° C., room temperature, 2 hours). Flash chromatography (SiO2, Hexanes/EtOAc) yielded 617 mg (31%) of sulfamide (8a) as a white solid. mp=91-92° C.; TLC Rf=0.40 in (2:1 Hexanes/EtOAc); [α]25D=−75.8 (c=1.003, CHCl3); 1H NMR (CDCl3, 400 MHZ) δ5.24 (d, J=8.0 Hz, 2H), 4.09 (dq, J=7.3.7.3 Hz, 2H), 3.75 (s, 6H), 1.43 (d, J=7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHZ) δ173.7,52.7,51.8,19.2; FTIR (neat) 3273, 1734, 1457, 1378, 1353, 1137 cm−1; HRMS (M+H)+ calculated for C8H17N2O6S 269.0807, found 269.0791.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][CH:17]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:18]([NH2:20])=[O:19])=[C:5]([F:26])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:33]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[CH:17]([NH:16][C:6]1[C:5]([F:26])=[CH:4][C:3]([C:1]([NH2:2])=[O:33])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][C:22]([F:23])([F:25])[F:24]
Reactant: CC(=O)O
Reactant: Cc1cc(Nc2cc(NC(CC(F)(F)F)C(N)=O)c(F)cc2C#N)sn1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(NC(CC(F)(F)F)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4,4,4-trifluorobutanamide (98 mg, 0.250 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (1 mL) was added. The mixture was purified by HPLC to give the titled compound (28 mg). MS 406.1 (M+H); UV 204.7, 287.8 nm.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:23][C:24](=O)[O:25]C1C=CC([N+]([O-])=O)=CC=1>O.C1COCC1.Cl>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH2:22][O:23][C:24]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9])=[O:25]
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: O=C(OCc1cccs1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@H]1CCCC[C@H]1C(=O)O)OCc1cccs1
Temperature: 25 °C

Procedure:
To a solution of Trans-2-amino-1-cyclohexane carboxylic acid (100 mg, 0.7 mmol) in 1 mL of water is added 2M aqueous Na2CO3 until pH=9-10 (2 mL). A solution of the carbonic acid 4-nitro-phenyl ester thiophen-2-ylmethyl ester (195 mg, 0.7 mmol) in THF (1 mL) is added at 0° C. and, after 10 minutes, 1 ml of the 2M Na2CO3 is added to the reaction. The mixture is allowed to warm to RT and vigorously stirred overnight. The reaction mixture is diluted with 0.5N HCl until pH=4-3 and the water layer is extracted three times with CH2Cl2 (10 ml). The organic phases are combined, dried (MgSO4), and concentrated under reduced pressure. The resulting product is used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10]O)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:45]I>C1COCC1>[C:1]([O:5][C:6](=[O:20])[C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10][I:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCO)C(=O)OC(C)(C)C
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of the title E compound, (2R)-(t-butyloxycarbonylamino)-5-hydroxypentanoic acid t-butyl ester (9.12 g, 31.5 mmol), imidazole (3.22 g, 47.3 mmol) and triphenylphosphine (12.40 g, 47.3 mmol) in 300 mL of THF is treated portionwise over 5 min with iodine (9.60 g, 37.8 mmol) at RT. After 2 h, the mixture is filtered and concentrated. The residue is first filtrated though silica gel (eluant; ethyl acetate) then purified by chomatography on silica gel (eluant; 10% ethyl acetate in hexane) affording 9.05 g (72%) of (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester as a colorless oil: NMR(CDCl3)) 1.42 (s, 9H), 1.46 (s, 9H), 1.65-1.95 (m, 4H), 3.14-3.28 (m, 2H), 4.19-4.26 (m, 1H), 5.06 (br d, 1H, J=7.4); IR 1712, 1500, 1155; ESI-MS 400 (M++1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1>>[F:14][C:15]1[CH:16]=[C:17]([C:5]2[CH:4]=[N:3][C:2]([NH:30][C:27]3[CH:28]=[CH:29][N:25]([CH3:24])[N:26]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)[CH:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Reactant: Cn1ccc(N)n1
Product: Cc1ccc2c(-c3cccc(F)c3)cnc(Nc3ccn(C)n3)c2n1

Procedure:
The title compound, MS: m/e=334.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3-fluorophenylboronic acid and 1-methyl-1H-pyrazol-3-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4N)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl[C:27]1C=C2C(C3N=C(N[C@H]4CCCC[C@@H]4N)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.C=O.[BH3-][C:64]#[N:65].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]4[N:65]([CH3:64])[CH3:27])[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCC[C@@H]4N)n3)c3cc(Cl)cnc32)cc1
Reactant: N[C@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)[C@H]1CCCC[C@@H]1Nc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reaction time: 4 h

Procedure:
To a mixture of (1S,2S)—N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,2-diamine, 23b, (0.08 g, 0.22 mmol) in acetonitrile (1.6 mL) at room temperature was added formaldehyde (0.09 mL of 37% w/v, 1.11 mmol) followed by NaCNBH3 (0.04 g, 0.56 mmol). A gelatinous mix formed and after 4 min the mixture became fluid again. After 4 hours, the reaction was quenched with 5 mL of 2N NaOH and the mixture was stirred overnight. The mixture was diluted with EtOAc and stirred until all solid dissolved. The layer was extracted with EtOAc several times, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (0-15% MeOH—CH2Cl2) followed by preparatory HPLC provided the desired product, which was converted to the corresponding HCl salt with HCl (4N in dioxane).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([NH2:12])=[N:10][CH:11]=1.[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH:28]=O)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:13]1([CH2:18][N:19]([CH2:30][CH3:31])[C:20]2[C:21]([CH2:28][NH:12][C:9]3[N:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][S:2][CH3:1])=[CH:11][N:10]=3)=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1C=O
Reactant: CSCCOc1cnc(N)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CNc1ncc(OCCSC)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
A solution of 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.03 g, 5.55 mmol) obtained in Step 1 and 3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypicolinaldehyde (1.60 g, 6.10 mmol) obtained in Step 3 in 1,2-dichloroethane (60 mL) was stirred at room temperature for 10 minutes, and then added with sodium triacetoxyborohydride (1.24 g, 5.83 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain N-({3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (1.60 g, 67%) as pale yellow oil.
Reaction SMILES: CO.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][C:6](=[N:21]O)[C:5]1=[O:23]>[Ni]>[NH2:21][CH:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5]1=[O:23]
Reactant: Cn1c(=O)c(=NO)nc(-c2ccccc2)c2ccccc21
Agent: [Ni]
Solvent: CO
Product: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reaction time: 30 h
Yield: 95 %

Procedure:
A solution of 150 ml of methanol containing 5 g (17.9 mmole) of 1,3-dihydro-1-methyl-3-oximino-5-phenyl-1,4-benzodiazepin-2-one was treated with a slurry of active Raney-nickel catalyst1 (10 g wet weight). The resulting suspension was hydrogenated on a Parr apparatus at 60 psi and 23° C. for 30 hours. The catalyst was removed by filtration and the filtrate was concentrated to afford the title compound in 95% yield. Rf =0.23 (chloroform-ethanol, 95:5), Rf =0.23 (chloroform-methanol-acetic acid-water, 90:10:1:1)
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([OH:30])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])(=[O:3])[CH3:2].N1C=CN=C1.[CH3:37][Si:38](Cl)([CH3:40])[CH3:39]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6](=[O:31])[C@:7]1([O:30][Si:38]([CH3:40])([CH3:39])[CH3:37])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@:21]([F:27])([C@@H:22]([O:26][Si:38]([CH3:40])([CH3:39])[CH3:37])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:28])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)[C@@]1(O[Si](C)(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O[Si](C)(C)C)C[C@@]21C
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
To a solution of (11β,16β)-9-fluoro-11,17-dihydroxy-16-methyl-3,20-dioxopregna-1,4-dien-21-yl acetate (18.79 g, 43.25 mmol) and imidazole (58.89 g, 864.9 mmol) in 200 mL of dry N,N-dimethylformamide was added neat trimethylsilyl chloride (55.0 mL, 433 mmol) dropwise during 15 min. The resulting pale yellow solution was stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate and washed successively with water, sat. NH4Cl, water, sat. NaHCO3, water, and brine. The organic phase was dried over Na2SO4, filtered and evaporated in vacuo to yield 26 g of the title compound as a pale yellow oil.