Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.S(Cl)([Cl:17])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Product: COc1ccc(C(=O)Cl)c([N+](=O)[O-])c1
Temperature: 75 °C

Procedure:
A mixture of 4-methoxy-2-nitrobenzoic acid 1 (1.0 g) and thionyl chloride (5 mL) was heated at 75° C. for overnight under nitrogen atmosphere. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated at 40° C. under vacuum to give 4-methoxy-2-nitrobenzoyl chloride as a yellow solid which was used in the next step without further purification. To a solution of 4-methoxy-2-nitrobenzoyl chloride (1.0 g) in 10 mL THF was added ammonium hydroxide (5 mL) drop-wise (exothermic). The resulting mixture was stirred at room temperature for 30 min. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated to give 4-methoxy-2-nitrobenzamide 2 which was purified by triturating with methyl tert-butyl ether. Pink solid (1.05 g, 100%). 1H NMR (400 MHz, CDCl3): δ 3.89 (s, 3H); 5.87 (br s, 2H); 7.13-7.15 (m, 1H); 7.25-7.26 (m, 1H); 7.47-7.52 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[CH:21]=[C:20]([S:22]([CH3:23])=[O:30])[N:19]=[C:18]([CH3:24])[N:17]=3)=[N:14][CH:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nccnc2-c2cc(SC)nc(C)n2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1COCCO1
Product: COc1ccc(Nc2nccnc2-c2cc(S(C)=O)nc(C)n2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (11 mg, 0.032 mmol) and 3-chloroperoxybenzoic acid (11.15 mg, 0.065 mmol) in dioxane (1 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was used for the next step reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[C:11](CC(O)=O)[N:12]=2)=[CH:4][CH:3]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1nc(-c2ccc(F)cc2)oc1-c1ccsc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Fc1ccc(-c2ncc(-c3ccsc3)o2)cc1
Yield: 41.3 %

Procedure:
A mixture of 2-(4-fluorophenyl)-5-(3-thienyl)oxazol-4-yl acetic acid (1.5 g), diphenylphosphoryl azide (1.28 ml) and triethylamine (0.83 ml) in t-butanol (30 ml) was refluxed for one day. After cooling the reaction mixture, the solvent was removed under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Chloroform was added to the residue, the mixture was heated and insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: ethyl acetate:n-hexane=1:9→1:7) to obtain 4-(t-butoxycarbonylamino)methyl-2-(4-fluorophenyl-5-(3-thienyl)oxazole (501 mg).
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O>[CH3:13][N:12]([CH3:14])[S:11]([C:10]1[C:2]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:3]([N+:17]([O-:19])=[O:18])[CH:4]=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:16])=[O:15]
Reactant: Oc1ccccc1
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)S(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Temperature: 90 °C

Procedure:
A mixture of 4-chloro-5-dimethylsulphamyl-3-nitro-benzoic acid (3.08 g), phenol (2 g), sodium hydrogen carbonate (3.4 g), and water (20 ml) was heated at 90°C for 8 hours. Then water (40 ml) was added and, after cooling, the 5-dimethylsulphamyl-3-nitro-4-phenoxy-benzoic acid was precipitated by acidification with 4N hydrochloric acid. After isolation by filtration and several recrystallizations from ethanol, the said compound was obtained with a melting point of 224°-226°C.
Reaction SMILES: [C:1](O)(=O)C.FC(F)(F)C(O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][NH2:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C1N2CN3CN(C2)CN1C3>O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:1]=[N:24][CH2:23][CH2:22]2
Reactant: CC(=O)O
Reactant: COc1ccc(CCN)cc1OC
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1OC)CCN=C2
Yield: 95 %

Procedure:
Acetic acid/trifluoroacetic acid (100 mL) was added to a solution of 2-(3,4-dimethoxyphenyl)ethanamine (20 g, 110.38 mmol, 1.00 equiv) and hexamethylenetetramine (31 g, 221.11 mmol, 2.00 equiv). The resulting solution was heated at reflux for about 5 hours in an oil bath. After adding water (100 mL), the solution was extracted with dichloromethane (3×200 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Solids were removed by filtration, and the resulting filtrate was concentrated in vacuo to give the title product as a yellow oil (20 g, yield=95%). LC-MS: m/z=192 (MH)+.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH2:2][CH3:3])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Product: CCO[C@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow oil. IR (liq.) 2973, 2936, 2874, 1606, 1566, 1481, 1441, 1396, 1287, 1230, 1203, 1181, 1124, 1078, 1046 cm−1; OAMS supporting ions at: ESI+ 406.2; MS (EI) m/z 405 (M+); HRMS (FAB) calcd for C21H28CLN3O3+H1 406.1897, found 406.1889.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][C@H:26]([OH:28])[C@H:25]([OH:29])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 71.1 using 5-bromo-6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)nicotinamide (Stage 169.2) and cis-pyrrolidine-3,4-diol (Stage 249.2). After purification by flash chromatography on Silica gel, the oily residue was taken-up in a toluene/MeOH mixture then evaporated to dryness under reduced pressure and dried to yield the title product as a white amorphous solid. UPLC-MS (Condition 3) tR=1.0 min, m/z=477.8-479.9 [M+H], m/z=475.8-477.9 [M−H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28](B1OC(C)(C)C(C)(C)O1)([CH3:30])=[CH2:29].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:28]([CH3:30])=[CH2:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[CH2:10][C@H:9]1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(Br)cc32)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)c1ccc2c(c1)N(C(=O)CN1CCN(C(=O)OC(C)(C)C)[C@H](C)C1)CC2
Temperature: 85 °C
Yield: 80.5 %

Procedure:
Pd(PPh3)4 (32 mg, 0.03 mmol), (R)-4-[2-(6-bromo-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (246 mg, 0.56 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.67 mmol) were dissolved in DMF (1.87 mL). Cs2CO3 (549 mg, 1.7 mmol) dissolved in water (0.37 mL) was added to the DMF solution. The reaction was degassed and heated to 85° C. for 18 h then was filtered and concentrated. Column chromatography on silica gel (gradient elution, 0-100% EtOAc/petrol), gave (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) as a yellow oil. 10% Pd/C (48 mg, 0.05 mmol) and (R)-4-[2-(6-isopropenyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.18 g) were mixed with MeOH (4.5 mL). The reaction was hydrogenated at 1 bar for 30 min at ambient temperature then filtered under vacuum and concentrated, to give the title compound (157 mg, 86%) as a colourless oil. 1H NMR (Me-d3-OD): 8.08 (1H, s), 7.15 (1H, d), 6.95 (1H, d), 4.35-4.18 (3H, m), 3.83 (1H, d), 3.30 (2H, s), 3.25-3.12 (3H, m), 2.97-2.76 (3H, m), 2.33 (1H, dd), 2.20-2.08 (1H, m), 1.48 (9H, s), 1.31 (3H, d), 1.25 (6H, d).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]([F:30])([F:29])[CH2:20]OS(C(F)(F)F)(=O)=O.O>CN1CCCC1=O>[Cl:1][C:2]1[C:9]([O:10][CH2:20][C:19]([F:30])([F:29])[F:18])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1c(Cl)ccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1c(Cl)ccc(OCC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 90 h

Procedure:
To 2,6-dichloro-3-hydroxy-benzaldehyde (114, 2.06 g, 0.0108 mol) in N-methylpyrrolidinone (25.0 mL) were added cesium carbonate (7.02 g, 0.0215 mol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.50 g, 0.0108 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 90 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 100% ethyl acetate in hexane to give a colorless oil (115, 1.00 g, 34.0%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[C:12]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14]2)=[CH:11][CH:10]=[CH:9][C:8]=1[C:24]1[CH:32]=[CH:31][C:30]([C:33]([NH2:35])=[O:34])=[C:29]2[C:25]=1[C:26]1[CH2:39][NH:38][CH2:37][CH2:36][C:27]=1[NH:28]2>>[CH3:6][C:7]1[C:12]([N:13]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[CH:14]2)=[CH:11][CH:10]=[CH:9][C:8]=1[C:24]1[CH:32]=[CH:31][C:30]([C:33]([NH2:35])=[O:34])=[C:29]2[C:25]=1[C:26]1[CH2:39][N:38]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:37][CH2:36][C:27]=1[NH:28]2
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CNCC4)cccc1-n1cnc2ccccc2c1=O
Reactant: CS(=O)(=O)Cl
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4c(c23)CN(S(C)(=O)=O)CC4)cccc1-n1cnc2ccccc2c1=O
Yield: 34 %

Procedure:
Using the procedure of Example 43 but substituting methanesulfonyl chloride in place of acetic anhydride, 9-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-6-carboxamide (20 mg, 0.044 mmol) was converted into the desired product as a white solid (8.0 mg, 34% yield). LCMS (M+H)+ m/z 528.2, (M+Na)+550.2. 1H NMR (400 MHz, DMSO-d6) δ 8.40, 8.15 (1 H, 2s), 8.22 (1 H, ddd, J=13.9, 8.1, 1.3 Hz), 7.92 (1 H, t, J=7.8 Hz), 7.79 (1 H, dd, J=7.6, 4.5 Hz), 7.73 (1 H, t, J=8.3 Hz), 7.54-7.67 (2 H, m), 7.51 (1 H, t, J=7.7 Hz), 7.43 (1 H, dd, J=7.2, 5.6 Hz), 6.83-7.00 (1 H, m), 3.43-3.86 (3 H, m), 3.28-3.34 (3 H, m), 2.89-3.19 (3 H, m), 1.74 (3 H, 2s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[C:27]([O:31][C:32](=[O:38])[N:33]([CH2:35][CH2:36][NH2:37])[CH3:34])([CH3:30])([CH3:29])[CH3:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[CH:20]=[C:21]([C:24]([NH:37][CH2:36][CH2:35][N:33]([CH3:34])[C:32](=[O:38])[O:31][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(C(=O)O)cn34)ccnc2c1
Reactant: CN(CCN)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(C(=O)NCCN(C)C(=O)OC(C)(C)C)cn34)ccnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
3-((7-Methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid (0.072 g, 0.21 mmol) was dissolved in DMF (1.5 mL) then added N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (0.054 ml, 0.31 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.12 g, 0.31 mmol) and triethylamine (0.043 ml, 0.31 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under vacuum. The sample was purified by flash chromatography eluting with 6% 7N ammonia in methanol/dichloromethane to afford tert-butyl 2-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carboxamido)ethyl(methyl)carbamate (0.097 g, 93% yield) as a pale yellow solid. MS (ESI pos. ion) m/z: 507.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:12](OCC)(=O)C>>[N+:8]([C:6]1[CH:7]=[C:2]2[CH:1]=[CH:12][NH:11][C:3]2=[N:4][CH:5]=1)([O-:10])=[O:9]
Reactant: CCOC(C)=O
Reactant: Cc1cc([N+](=O)[O-])cnc1N
Product: O=[N+]([O-])c1cnc2[nH]ccc2c1

Procedure:
5-Nitro-1H-pyrrolo[2,3-b]pyridine 506 of is prepared by reacting 3-methyl-5-nitro-pyridin-2-ylamine 505 with t-butyloxycarbonyl anhydride in an appropriate solvent (e.g. ethyl acetate and hexanes). Concentration and extraction provides a Boc-protected intermediate that is then reacted with 2 equivalents of butyllithium in an appropriate polar solvent (e.g. tetrahydrofuran) with cooling (e.g. 0° C.), followed by the addition of dimethylformamide and stirring for 30 minutes to one hour, followed by addition of 5.5 M HCl. Isolation by conventional means (e.g. extraction and silica gel chromatography) provides 506. (Hands et. al., Synthesis 1996, 877-882.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:17]([O:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[C:23]1[NH:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][C:40]2([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:44][CH2:43][NH:42][CH2:41]2)[CH2:34][CH2:33]1)[CH3:18]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:15][CH2:14][CH2:13][O:12][C:11]=12)[C:6]([N:42]1[CH2:43][CH2:44][C:40]([CH2:39][CH2:38][N:35]2[CH2:36][CH2:37][CH:32]([NH:31][C:23]3[N:22]([CH2:21][CH2:20][O:19][CH2:17][CH3:18])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[N:24]=3)[CH2:33][CH2:34]2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:41]1)=[O:8]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1cc(C(=O)O)cc2c1OCCO2
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-methoxy-4,5-ethylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[CH3:8].[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21](Br)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1>>[N:12]1([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH2:1])[CH:3]=3)=[N:22][CH:23]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: Cc1ccc(B(O)O)cc1N
Product: Cc1ccc(-c2ccc(Cn3ccnc3)cn2)cc1N

Procedure:
Synthesized using 3-amino-4-methylphenylboronic acid (190 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 139 mg, 0.52 mmol, 84%. 1H NMR (500 MHz, CDCl3): δH (ppm): 2.22 (s, 3H), 5.16 (s, 2H), 6.92 (t, J=0.9 Hz, 1H), 7.12 (t, J=0.9 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 7.26 (dd, J=7.9, 1.9 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.45 (dd, J=8.2, 2.2 Hz, 1H), 7.59 (s, 1H), 7.67 (dd, J=8.2, 0.6 Hz, 1H), 8.55 (dd, J=2.2, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=17.2, 48.2, 113.2, 117.1, 119.0, 120.4, 123.9, 129.6, 130.2, 130.9, 135.6, 137.3, 137.4, 145.1, 148.4, 157.8; MS (ESI): m/z=264.25 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl

Procedure:
As described for Reference Example 21, 5.0 g of 2-chloro-5-nitrobenzoic acid is reacted with 50 ml of thionyl chloride to give 5.6 g of the product as an off-white solid.
Reaction SMILES: [Na].CN([CH:5]=[C:6]1[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]1=O)C.Cl.[CH3:15][NH:16][C:17]([NH2:19])=[NH:18]>C(O)C>[CH3:15][NH:16][C:17]1[N:19]=[CH:5][C:6]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][C:7]=2[N:18]=1
Reactant: CNC(=N)N
Reactant: CN(C)C=C1C(=O)CCCC1=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CNc1ncc2c(n1)CCCC2=O
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To anhydrous ethanol (15 mL) was added sodium metal (0.45 g, 19.5 mmol). After complete dissolution of sodium metal in ethanol, 2-((dimethylamino)methylene)cyclohexane-1,3-dione (1 g, 5.5 mmol) and N-methylguanidine hydrochloride (1 g, 9.0 mmol) were added and the reaction was refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ice-cooled water (50 mL) was then added to the residue and the aqueous solution extracted with EtOAc (3×40 mL). The combined organic extract was dried using sodium sulfate and concentrated under reduced pressure to give the desired product (0.6 g, 57%) as a solid. The crude product was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 8.90 and 8.80 (2s, 1H), 5.98 and 5.82 (2s, 1H), 3.11 and 3.09 (2s, 3H), 2.96-2.88 (m, 2H), 2.58 (t, J=6.0 Hz, 2H), 2.10 (quintet, J=6.0 Hz, 2H). LCMS [M+H]: 178.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C(O)(=O)C>[OH:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: COc1cc(C=CC(=O)c2ccccc2)ccc1O
Reaction time: 200 h

Procedure:
3-methoxy-4-hydroxybenzaldehyde (20 gm, 0.132 mol) was added to the solution of acetophenone (20 gm, 0.125 mol) dissolved in acetic acid (20 mL) in a round bottom flask with constant stirring. Temperature of reaction was maintained below 15° C. with Occasional shaking for 200 hrs. Reaction mixture was poured in ice cold water and the product was extracted with chloroform. Chloroform extract was distilled under reduced pressure and the residue was chromatographed on SiO2 gel to obtain 1. m.p. 91° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([C:18]2[CH:23]=[C:22]([C:24]#[C:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:21]=[C:20]([C:33](=[O:45])[NH:34][CH2:35][C:36]3[C:37](=[O:44])[NH:38][C:39]([CH3:43])=[CH:40][C:41]=3[CH3:42])[C:19]=2[CH3:46])[CH2:16][CH3:17])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:42][C:41]1[CH:40]=[C:39]([CH3:43])[NH:38][C:37](=[O:44])[C:36]=1[CH2:35][NH:34][C:33](=[O:45])[C:20]1[CH:21]=[C:22]([C:24]#[C:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:18]([N:15]([CH2:16][CH3:17])[C@H:12]2[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]2)[C:19]=1[CH3:46]
Reactant: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(c1cc(C#CCN2CCOCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)[C@H]1CC[C@H](NC)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl((trans)-4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydro pyridin-3-yl)methyl)carbamoyl)-2-methyl-5-(3-morpholinoprop-1-yn-1-yl)phenyl)(ethyl)amino)cyclohexyl)(methyl)carbamate (1 equiv.) in DCM at 0° C., TFA (3 equiv.) was added and reaction was stirred for 2 h at room temperature. After completion, reaction was concentrated to dryness. The residue was then basified with Na2CO3 (aq.) to pH 8 and the aqueous layer was extracted with 20% methanol in DCM. The combined organic layers were dried over Na2SO4 and solvent was removed under reduced pressure to afford the title compound (99% yield) which was used in the next reaction without further purification.