Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:31])[CH2:7][CH2:8][C@@:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:14][C:13](=[O:15])[N:12]([C@H](C2C=CC(Br)=CC=2)C)[CH2:11][CH2:10]1)(=O)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:2][C:1]1[O:31][C:6]([CH2:7][CH2:8][C:9]2([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:14][C:13](=[O:15])[NH:12][CH2:11][CH2:10]2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: Cc1nnc(CCC2(c3ccccc3)CCNC(=O)O2)o1
Yield: 96.1 %

Procedure:
To a solution of N′-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanehydrazide (0.1 g, 0.21 mmol) in THF (2 mL) was added Burgess Reagent (75 mg, 0.315 mmol). The sealed vial was irradiated in the microwave at 100° C. for 15 min. The mixture was extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC to afford (R)-3-(S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl -1,3-oxazinan-2-one (58 mg, yield: 59%). 1H NMR (CDCl3): δ1.49-1.51 (m, 3H), 2.23-2.26 (m, 2H), 2.30-2.33 (m, 2H), 2.42 (s, 3H), 2.43-2.45 (m, 1H), 2.49-2.54 (m, 1H), 2.87-2.91 (m, 1H), 3.06-3.09 (m, 1H), 5.61-5.63 (m, 1H), 6.76-6.78 (d, 2H), 7.20-7.22 (m, 2H), 7.26-7.33 (m, 2H), 7.35-7.37 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[Cl:11][C:12]1[C:17](Cl)=[N:16][CH:15]=[CH:14][N:13]=1>>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:17]1[C:12]([Cl:11])=[N:13][CH:14]=[CH:15][N:16]=1)([O-:3])=[O:2]
Reactant: Clc1nccnc1Cl
Reactant: Nc1ccccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccccc1Nc1nccnc1Cl
Yield: 67.6 %

Procedure:
Starting with 41.4 g of 2-nitroaniline and 35.0 g of 2,3-dichloropyrazine, 39.8 g of the title compound was obtained by the same method as the one described in Production Example 120.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br:12]Br>CC(O)=O.O>[Br:12][C:6]1[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[NH2:8]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
The title compound was prepared by dissolving 4-Methyl-2-nitro-phenylamine (20.0 g, 131 mmol) in 200 mL of HOAc. The reaction mixture was then heated to 100° C. until reaction mixture was homogeneous. At this point the reaction mixture was cooled to room temperature and Br2 (25.21 g, 157 mmol) was added drop wise over the course of 10 minutes. An orange solid formed, and upon completion of the addition the reaction mixture was diluted with water and the title compound collected by filtration (29 g, 96%).
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:36])([CH:33]=[N:34]O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>N1C=CC=CC=1>[CH2:1]([S:8][C:9]([C:33]#[N:34])([CH3:36])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]([CH3:32])[S:24]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)(=[O:26])=[O:25])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(C=NO)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CN(c1cccc2cc(C(=O)NCC(C)(C#N)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a mixture of N-[2-(benzylthio)-3-(hydroxyimino)-2-methylpropyl]-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (1.00 g) and pyridine (6 ml) was added trifluoromethanesulfonic anhydride (0.40 ml) at 0° C., and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, 10% aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to basic silica gel column chromatography to give the title compound (0.43 g, yield 45%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). melting point 181-182° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:27][C:24]5[CH:25]=[CH:26][S:22][CH:23]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1ccsc1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccsc4)cc3=O)cc21
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (100 mg), 3-thienylmethanol (67 μl) and tributylphosphine (258 μl) in THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (264 mg). The mixture was stirred under sonication at 50° C. for 1 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The crude residue was diluted with DCM (100 ml), and the DCM layer was washed with water (100 ml), brine (30 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (50 mg) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:39][CH3:40])=[C:6]([C:8]([CH3:38])([CH3:37])[CH2:9][C:10]([OH:36])([C:32]([F:35])([F:34])[F:33])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26]([OH:28])=O)[CH:7]=1.Cl.[NH2:42][C@H:43]([C:45]([NH2:47])=[O:46])[CH3:44]>>[NH2:47][C:45](=[O:46])[C@@H:43]([NH:42][C:26](=[O:28])[C:25]1[CH:29]=[CH:30][CH:31]=[C:23]([N:17]2[C:18]3[C:14](=[C:13]([NH:12][CH2:11][C:10]([OH:36])([C:32]([F:34])([F:33])[F:35])[CH2:9][C:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[O:39][CH3:40])([CH3:38])[CH3:37])[CH:21]=[C:20]([CH3:22])[CH:19]=3)[CH:15]=[N:16]2)[CH:24]=1)[CH3:44]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)O)c1)C(F)(F)F
Reactant: C[C@H](N)C(N)=O
Agent: Cl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N[C@@H](C)C(N)=O)c1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from 3-(4-{[4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)benzoic acid and L-alaninamide hydrochloride with System A used for purification by mass directed autopreparation.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[CH2:19][N:18]=[C:17]([C:24]3[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=3)[C:16]=2[CH:34]=1.CC(C1C=C(C(C)C)C(S([N:50]=[N+:51]=[N-:52])(=O)=O)=C(C(C)C)C=1)C.C(O)(=O)C>>[N:50]([CH:19]1[N:18]=[C:17]([C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[N:28][CH:29]=2)[C:16]2[CH:34]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[N:21]([CH3:22])[C:20]1=[O:23])=[N+:51]=[N-:52]
Reactant: COc1ncc(C2=NCC(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ncc(C2=NC(N=[N+]=[N-])C(=O)N(C)c3ccc(Cl)cc32)c(OC)n1
Yield: 94.7 %

Procedure:
As illustrated in the scheme above and following General Procedure 6, KHMDS (7.0 mL of 0.5 M in toluene, 3.5 mmol), 7-chloro-5-(2,4-dimethoxy-5-pyrimidinyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (1.16 g, 3.35 mmol), trisyl azide (2.60 g, 8.40 mmol) and acetic acid (0.85 mL, 14.8 mmol) were combined. After workup, purification of the crude product by silica gel column chromatography (2:3 hexanes:EtOAc) provided the title compound as a pale yellow solid (1.23 g, 95%). 1H-NMR (CDCl3): δ 8.64 (s, 1H), 7.54 (dd, J=2.3 Hz, J=8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.3 Hz, 1H), 4.51 (s, 1H), 4.08 (s, 3H), 3.78 (s, 3H), 3.47 (s, 3H). MS (ESI) (M+H)+388.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:20][C@H:19]3[NH:21]C(=O)OC(C)(C)C)=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.[ClH:31].C(OCC)(=O)C>>[ClH:31].[NH2:21][C@@H:19]1[CH2:20][C@H:18]1[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:9](=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:29])([F:30])[F:1])[CH:4]=2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl {trans-2-[4-({[3-(trifluoromethyl)phenyl]carbonyl}amino)phenyl]cyclopropyl}-carbamate (161 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (130 mg).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S(O[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][C:28]#[N:29])=[CH:23][CH:22]=2)=[C:18]([CH3:30])[N:17]=[C:16]([NH2:31])[N:15]=1)(=O)=O.[CH2:32]([NH2:36])[CH2:33][CH2:34][CH3:35]>O1CCOCC1>[NH2:31][C:16]1[N:15]=[C:14]([NH:36][CH2:32][CH2:33][CH2:34][CH3:35])[C:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]#[N:29])=[CH:25][CH:26]=2)=[C:18]([CH3:30])[N:17]=1
Reactant: CCCCN
Reactant: Cc1cc(C)c(S(=O)(=O)Oc2nc(N)nc(C)c2Cc2ccc(CC#N)cc2)c(C)c1
Solvent: C1COCCO1
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1
Reaction time: 1 h

Procedure:
A mixture of the product from step (iv) (0.3 g) and butylamine (1 ml) in 1,4-dioxane (6 ml) was sealed into a microwave tube and the reaction was performed in the CEM Microwave, at 160° C. and 100 W for 1 h. The solvent was evaporated under reduced pressure and the residue used crude in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2OS(C(F)(F)F)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:28])[CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OS(=O)(=O)C(F)(F)F)C1
Reactant: Cc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cccc(-c2ccc(Cl)cc2OC2CN(C(=O)OC(C)(C)C)C2)c1
Temperature: 100 °C
Yield: 72.3 %

Procedure:
To the title compound of Step A (0.12 g, 0.27 mmol), 3-methylphenylboronic acid (0.08 g, 0.60 mmol), K3PO4 (0.128 g, 0.54 mmol), Pd(dppf)Cl2.CH2Cl2 (0.013 g, 0.017 mmol) and dppf (0.006 g, 0.010 mmol) was added dioxane (3 mL). The flask was heated at 100° C. for 18 h, cooled to rt, diluted with EtOAc and filtered through a small silica pad. Silica gel chromatography (10-40% EtOAc in hexanes) gave 0.073 g (72% yield) of the title compound. 1H NMR (CDCl3): 7.31-7.26 (m, 4H), 7.18-7.15 (m, 1H), 7.05 (dd, J=8.2, 2.0 Hz, 1H), 6.57 (d, J=1.9 Hz, 1H), 4.86-4.81 (m, 1H), 4.30-4.26 (m, 2H), 3.96 (dd, J=10.2, 4.2 Hz, 2H), 2.40 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.N1CCCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A solution of 5-nitro-1H-indole (1 g, 6.17 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.458 g, 12.33 mmol) and pyrrolidine (1.530 mL, 18.50 mmol) were refluxed for 48 hours. The reaction was brought to room temperature, diluted with water (50 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was diluted with isopropanol: hexanes, 1:6 (20 mL). After stirring for 15 minutes, the solid was filtered off, washed with hexanes (2×10 mL), and dried to obtain tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.515 g, 71.5%). 1H NMR (CDCl3) δ 8.83 (d, 1H, J=1.5 Hz), 8.60 (brs, 1H), 8.14 (dd, 1H, J=2.1, 9.0 Hz), 7.42 (d, 1H, J=9.0 Hz), 7.31 (d, 1H, J=2.1 Hz), 6.21 (s, 1H), 4.20-4.16 (m, 2H), 3.70 (t, 2H, J=5.7 Hz), 2.60-2.50 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:6]=2[CH:21]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)[CH2:31][C:32](O)=[O:33])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]3[CH2:15][CH2:14][CH2:13][N:12]([C:32](=[O:33])[CH2:31][C@H:30]([NH:29][C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:35][C:36]4[CH:45]=[CH:44][C:43]5[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=5)[CH:37]=4)[CH2:11]3)[N:7]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:6]=2[CH:21]=1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(Cl)cc21

Procedure:
(R)-6-Chloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole (32D) (0.135 mmol, 0.055 g) was added to a 15 mL round-bottomed flask equipped for stirring under nitrogen. DMF (2 mL), (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid (0.197 mmol, 0.053 g) and N-methylmorpholine (0.706 mmol, 0.079 mL) were then added and the solution was allowed to stir at rt for 5 min. HATU (0.197 mmol, 0.075 g) was added and the resultant solution was stirred at room temperature for 3 hr. The reaction solution was then directly purified by preparative LC/MS (25-85% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording tert-Butyl (R)-4-((R)-3-(6-chloro-1-(3-methoxypropyl)-1H-benz o[d]imidazol-2-yl)piperidine-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (32E) as a clear oil that was used directly onto the next step. ESI-MS: m/z 619.5 (M+H)+,
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[N:16]=[N:15][N:14]([CH2:17][C:18]4[CH:23]=[C:22]([N+:24]([O-])=[O:25])[CH:21]=[CH:20][N:19]=4)[C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CCO.CO.O.[Zn]>[OH:25][NH:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([CH2:17][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:23]=1
Reactant: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cc([N+](=O)[O-])ccn2)o1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cc(NO)ccn2)o1
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A solution of 7-(5-methyl-2-furyl)-3-(4-nitro-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (60 mg, 0.17 mmol) in EtOH (40 mL), MeOH (20 mL) and water (15 mL) was treated with ammonium chloride (280 mg, 5.23 mmol) and zinc (138 mg, 2.05 mmol), stirred for 1 h, filtered through Celite, concentrated in vacuo to ˜20 mL, diluted with brine (20 mL), extracted with EtOAc (3×20 mL) and the combined organic phase dried (MgSO4) and concentrated in vacuo to give the title compound (40 mg, 73%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:17]3[CH2:19][CH2:18]3)=[C:13]([CH:16]=2)[C:14]#[N:15])=[N:6][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:17]3[CH2:19][CH2:18]3)=[C:13]([CH:16]=2)[C:14]#[N:15])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(Nc2ncc(Cl)c(O)n2)ccc1C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: N#Cc1cc(Nc2ncc(Cl)c(Cl)n2)ccc1C1CC1
Yield: 80 %

Procedure:
5-(5-chloro-4-hydroxypyrimidin-2-ylamino)-2-cyclopropylbenzonitrile, containing 1.2 equivalents of p-toluenesulfonic acid (1.00 g, 2.03 mmol) was weighed out and added to a flask with a magnetic stir bar. This was suspended in 11 mL POCl3 and the reaction was heated at reflux for 3 hours. This was evaporated, then quenched with cold 10% aqueous Na2CO3. The mixture was extracted 4 times with ethyl acetate and the combined organic layer was dried over sodium sulfate. This was filtered, concentrated onto a plug of silica, and purified by column chromatography. Pure product was concentrated and dried on the high vacuum to give 493 mg of 5-(4,5-dichloropyrimidin-2-ylamino)-2-cyclopropylbenzonitrile (80% yield, accounting for the mass of p-toluenesulfonic acid present in the starting material).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[N:9][N:10](CC(OCC)=O)[N:11]=2)=[N:4][N:3]=1.BrC1SC(C#N)=NN=1.[N-]=[N+]=[N-].[Na+].Cl>CC(O)C.O.[Zn+2].[Br-].[Br-]>[Br:1][C:2]1[S:6][C:5]([C:7]2[NH:11][N:10]=[N:9][N:8]=2)=[N:4][N:3]=1
Reactant: CCOC(=O)Cn1nnc(-c2nnc(Br)s2)n1
Agent: Cl
Agent: N#Cc1nnc(Br)s1
Agent: [Br-]
Solvent: CC(C)O
Solvent: O
Product: Brc1nnc(-c2nnn[nH]2)s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
Ethyl [5-(5-bromo-1,3,4-thiadiazol-2-yl)-2H-tetrazol-2-yl]acetate To a suspension of 5-bromo-1,3,4-thiadiazole-2-carbonitrile (1 g, 5 mmol) and ZnBr2 (1.1 g, 5 mmol) in i-PrOH (10 mL) and H2O (5 mL) was added NaN3 (0.65 g, 10 mmol) in a sealed tube. The mixture was stirred at 120° C. overnight and then cooled to room temperature. The mixture was adjusted to pH=4 with HCl (2 M) and extracted with EtOAc (3×50 mL). The combined organic layers was dried over Na2SO4, filtered and concentrated in vacuo to afford the crude 5-(5-bromo-1,3,4-thiadiazol-2-yl)-1H-tetrazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=2[F:17])=[C:6]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[N:5]2[N:25]=[CH:26][N:27]=[C:4]2[N:3]=1.O.C(OC)(C)(C)C.[CH3:35][N:36](C)C=O>[C-]#N.C([N+](CC)(CC)CC)C>[C:35]([C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]#[N:16])=[CH:10][C:9]=2[F:17])=[C:6]([N:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)[N:5]2[N:25]=[CH:26][N:27]=[C:4]2[N:3]=1)#[N:36]
Reactant: CC1CCN(c2c(-c3c(F)cc(C#N)cc3F)c(Cl)nc3ncnn23)CC1
Reactant: CN(C)C=O
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: O
Solvent: COC(C)(C)C
Product: CC1CCN(c2c(-c3c(F)cc(C#N)cc3F)c(C#N)nc3ncnn23)CC1

Procedure:
A mixture of 0.1 mol of 5-chloro-6-(2,6-difluoro-4-cyanophenyl)-7-(4-methylpiperidin-1-yl)-[1,2,4]-triazolo-[1,5-a]-pyrimidine (No. I-5) and 0.25 mol of tetraethylammonium cyanide in 750 ml of dimethylformamide (DMF) was stirred at 20–25° C. for 16 hours. After addition of water and methyl tert-butyl ether (MTBE), the organic phase was separated, washed with water, dried and freed from the solvent. After chromatography on silica gel, 6.33 g of the title compound were obtained from the residue.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6](SC)=[N:7][CH:8]=1)#[N:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:3]1[C:4]([NH:11][CH3:12])=[N:5][C:6]([NH:14][NH2:15])=[N:7][CH:8]=1)#[N:2]
Reactant: CNc1nc(SC)ncc1C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNc1nc(NN)ncc1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-cyano-4-methylamino-2-methylsulfanyl-pyrimidine (25.86 g) from Example 3 and hydrazine hydrate (52 mL) in ethanol (250 mL) was heated at reflux with stirring for 3 hours. The reaction mixture was cooled to room temperature and the insoluble product was collected by filtration, washed with cold aqueous ethanol (1:1) to give 23 g of the title compound. Crystallization from ethanol afforded an analytically pure sample of 5-cyano-2-hydrazino-4-methylamino-pyrimidine; mp 247-249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([S:8]([N:11]2[C:15]3[CH:16]=[C:17]([C:24]([OH:26])=O)[CH:18]=[C:19]([C:20]([F:23])([F:22])[F:21])[C:14]=3[O:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1>>[CH2:37]([O:36][C:34](=[O:35])[C:33]1[CH:39]=[CH:40][C:30]([NH:29][C:24]([C:17]2[CH:18]=[C:19]([C:20]([F:22])([F:23])[F:21])[C:14]3[O:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:27][CH3:28])(=[O:9])=[O:10])[C:15]=3[CH:16]=2)=[O:26])=[CH:31][CH:32]=1)[CH3:38]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1COc2c1cc(C(=O)O)cc2C(F)(F)F
Product: CCOC(=O)c1ccc(NC(=O)c2cc3c(c(C(F)(F)F)c2)OCN3S(=O)(=O)c2cc(Cl)ccc2OC)cc1

Procedure:
Reaction of 3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carboxylic acid with ethyl 4-aminobenzoate in analogy with example 30, step 4 gave 4-{[3-(5-chloro-2-methoxy-benzenesulfonyl)-7-trifluoromethyl-2,3-dihydro-benzooxazole-5-carbonyl]-amino}-benzoic acid ethyl ester. Light yellow solid, MS (ISP)=584.9 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C1CCN2C(=NCCC2)CC1.[N+:34]([C:37]1[CH:38]=[C:39](/[CH:43]=[CH:44]\[C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]>C(#N)C>[N+:34]([C:37]1[CH:38]=[C:39]([CH:43]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:44][C:45]#[N:46])[CH:40]=[CH:41][CH:42]=1)([O-:36])=[O:35]
Reactant: N#C/C=C\c1cccc([N+](=O)[O-])c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cccc([N+](=O)[O-])c4)c3)ncnc21
Temperature: 67 °C

Procedure:
To 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.500 g, 0.00158 mol) in 8.0 mL of dry ACN was added DBU (0.24 mL, 0.0016 mol) followed by addition of (2Z)-3-(3-nitrophenyl)acrylonitrile (0.36 g, 0.0021 mol) in 2.0 mL of ACN. The reaction mixture was heated at 67° C. for 18 hours. This was cooled to room temperature, and the mixture was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel using ethyl acetate-hexanes 6:4, to give 3-(3-nitrophenyl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile as a dark orange oil, (688 mg, 88.65%). LCMS (M+1)+:490