Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])[CH2:9][C:10](=[O:24])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][CH:19]=[C:13]2[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Br:36]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])[CH2:9][C:10](=[O:24])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:20]([F:22])([F:21])[F:23])=[N:18][C:19]([Br:36])=[C:13]2[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(cnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1)Cc1cc(F)c(F)cc1F
Yield: 86.3 %

Procedure:
(R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1l (20.0 g, 39.6 mmol) was dissolved in 300 mL of anhydrous ethanol under stirring, and 1-bromo-2,5-pyrrolidinedione (14.1 g, 79.2 mmol) was then added to the solution at room temperature. After stirring for an hour, potassium carbonate (10.9 g, 79.2 mmol) and di-tert-butyl dicarbonate (8.6 g, 39.6 mmol) were added to the mixture, and the mixture was stirred for an hour and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was filtered through a pad of coarse silica gel to remove potassium carbonate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1m (20.0 g, yield 86%) as a white solid.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][C:4]2[NH:18][C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:20][C:3]1=2.C1(N(C)C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:38]>CC#N>[Cl:38][C:2]1[C:3]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:18][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]=1
Reactant: CCCCCCCC(=O)Nc1nc2[nH]c(CN3CCCC3)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCCCCCCC(=O)Nc1nc(Cl)c2cc(CN3CCCC3)[nH]c2n1

Procedure:
A solution of octanoic acid (4-oxo-6-pyrrolidin-1-ylmethyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (0.36 g 1 mmol; J. Chem. Soc. Perkin Trans. 1 1998, 1637), BnNEt3Cl (0.70 g, 2 mmol), PhNMe2 (0.25 mL) and POCl3 (0.86 mL, 6 mmol) in CH3CN (5 mL) was heated to 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL×3), and evaporated to give octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide as a crude (0.33 g) which was used without purification. HPLC Rt: 6.737 min. 1H-NMR (CDCl3): δ 11.60 (br s, 1H), 10.20 (br s, 1H), 6.38 (s, 1H), 3.86 (s, 2H), 2.90 (m, 2H), 2.70 9s, 4H), 1.86 (s, 4H), 1.78 (t, 2H), 1.32–1.29 (m, 8H), 0.90 (t, 3H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C:7]3([O:32][C@H:8]3[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=[O:3])[CH3:2].[NH2:33][CH2:34][CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1.C(O)CCC>COC(C)(C)C>[C:1]([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@:7]([OH:32])([C@H:8]([NH:33][CH2:34][CH2:35][C:36]3[N:40]=[CH:39][NH:38][CH:37]=3)[CH2:9][C@@H:10]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H]3OC32C1
Reactant: NCCc1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H](NCCc3c[nH]cn3)[C@@]2(O)C1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
5,6α-epoxicholestan-3β-yl acetate (9.8 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3β-yl acetate as a white solid (7.5 g, 58%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 14% yield.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([N:18]([CH:26]3[CH2:28][CH2:27]3)C(=O)OC(C)(C)C)[N:15]3[N:29]=[CH:30][C:31]([CH:32]=[O:33])=[C:14]3[N:13]=2)[CH:9]=[CH:10][CH:11]=1)(=O)C.Cl.[OH-].[Na+]>O1CCOCC1.O>[NH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[C:16]([NH:18][CH:26]3[CH2:28][CH2:27]3)[N:15]3[N:29]=[CH:30][C:31]([CH:32]=[O:33])=[C:14]3[N:13]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)NCc1cccc(-c2cc(N(C(=O)OC(C)(C)C)C3CC3)n3ncc(C=O)c3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: NCc1cccc(-c2cc(NC3CC3)n3ncc(C=O)c3n2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To tert-butyl 5-(3-(acetamidomethyl)phenyl)-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (50 mg, 0.111 mmol) was added 1 mL of 4M HCl in 1,4-dioxane and 1 mL of H2O. The reaction mixture was stirred at 80° C. for 16 hours then cooled to room temperature and diluted with H2O. To the reaction mixture, 5M NaOH was added to adjust pH to >10 then the mixture was extracted with CH2Cl2. The organic layer was collected, dried over MgSO4, filtered and evaporated to dryness to provide 24 mg of 5-(3-(aminomethyl)phenyl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (70%). LCMS (M+1=308)
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:12][OH:13].[OH-].[Na+]>C(O)C.O.ClCCl>[N+:1]([C:4]1[S:8][C:7]([CH:9]=[N:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=NO)s1
Yield: 79.9 %

Procedure:
A mixture of 5-nitrothiophene-2-carboxaldehyde (10 g, 64 mmol), hydroxylamine hydrochloride (9.4 g, 130 mmol) and sodium hydroxide (4.34 g, 107 mmol) in ethanol/water (150 ml, 2:1) was heated to reflux for 2 hours, then diluted with dichloromethane and washed with water. The organic layer was dried over magnesium sulfate and evaporated to dryness to give 8.8 g of 5-nitro-2-thiophene-carboxaldehyde oxime as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.54 (1H, d), 8.13 (1H, s), 8.16 (1H, d), 13.14 (1H, s).
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:15]2[C:16]3[N:8]([NH:9][CH2:10][C:11]=3[C@H:12]([CH:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:13](=[O:17])[CH:14]=2)[CH:7]=[CH:6][N:5]=1.Br>C(O)(=O)C.CO>[ClH:1].[OH:3][C:4]1[C:15]2[C:16]3[N:8]([NH:9][CH2:10][C:11]=3[C@H:12]([CH:18]3[CH:23]4[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:13](=[O:17])[CH:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: COC1=NC=CN2NCC3=C2C1=CC(=O)[C@H]3C1CN2CCC1CC2
Agent: Br
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: O=C1C=C2C(O)=NC=CN3NCC(=C23)[C@@H]1C1CN2CCC1CC2
Temperature: 100 °C
Yield: 20.5 %

Procedure:
To a solution of (S)-4-methoxy-7-(quinuclidin-3-yl)-8,9-dihydro-[1,4]diazepino[6,7,1-hi]indazol-6(7H)-one (200 mg, 0.6 mmol) from Step K of Example 10 in acetic acid (5 mL) was added 48% aqueous hydrogen bromide (5 ml) and the mixture was heated to 100° C. for 3 days. After cooling to room temperature and diluting with methanol, the pH was adjusted to 8. The solvent was concentrated in vacuo and the residue was purified by prep HPLC. The product was then treated immediately with hydrochloric acid following the procedure described in Step G of Example 8 to afford (S)-4-hydroxy-7-(quinuclidin-3-yl)-8,9-dihydro-[1,4]diazepino[6,7,1-hi]indazol-6(7H)-one hydrochloride (43 mg, 21%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 7.98 (s, 1H), 7.76 (dd, J=2.5 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 4.71-4.60 (m, 3H), 4.12-3.98 (m, 2H), 3.83-3.68 (m, 3H), 3.41-3.34 (m, 3H), 2.54 (d, J=2.5 Hz, 1H), 2.29 (brs 1H), 2.27-2.10 (m, 2H), 2.10-1.99 (m, 1H); MS (ESI+) m/z 313 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[CH3:10][CH2:11][O:12]C(C)=O>>[CH2:7]1[CH2:8][CH2:9][CH:4]([C:2](=[O:3])[CH2:1][C:11](=[O:12])[CH3:10])[CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Reactant: CC(=O)C1CCCCC1
Product: CC(=O)CC(=O)C1CCCCC1

Procedure:
The title compound was prepared as described above from 1.5 g of cyclohexyl methyl ketone and 2.32 mL of EtOAc to yield 1.06 grams of Intermediate 33 as a yellow oil: TLC Rf=0.65 (3/1, hexanes/EtOAc); 1H NMR (400 MHz, CDCl3, enol form) δ5.5 (s, 1H), 2.19-2.12 (m, 1H), 2.08 (s, 3H), 1.85-1.55 (m, 5H), 1.41-1.15 (m, 5H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:11][CH:12]=[CH:13][C:14]=2[F:15])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.FC(F)(F)S(O[Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])(=O)=O>O1CCCC1>[F:3][C:4]1[C:9]([C:10]2[N:11]([Si:37]([CH:44]([CH3:46])[CH3:45])([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])[CH:12]=[CH:13][C:14]=2[F:15])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: Fc1cc[nH]c1-c1cccnc1F
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(F)c1-c1cccnc1F
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of sodium hydride (3.32 g) in tetrahydrofuran (70 mL) was added dropwise a solution of 2-fluoro-3-(3-fluoro-1H-pyrrol-2-yl)pyridine (5.98 g) in tetrahydrofuran (30 mL) under ice-cooling and the mixture was stirred for 30 min. 15-Crown-5 (18.3 g) and tris(1-methylethyl)silyl trifluoromethanesulfonate (25.4 g) were added, and the mixture was stirred for 1 hr. The solvent was evaporated to a half volume under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane hexane-ethyl acetate=19:1) to give the title compound as a pale-yellow oil (yield 10.9 g, 98%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[C:15]([NH:22][CH2:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([O-:29])=[O:28])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(CC)CC)C>C(OCC)(=O)C>[C:15]([NH:22][CH2:23][C:24](=[O:30])[CH2:25][CH2:26][C:27]([O:29][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])=[O:28])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)[O-]
Reactant: O=C(CCCBr)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCC(=O)OCc1ccccc1
Yield: 47.6 %

Procedure:
This compound was prepared from benzyl 4-bromobutanoate (7.2 g; 28.0 mmol), 5-(Boc-amino)-4-oxopentanoate (6.7 g; 29.0 mmol), triethylamine (2.95 mmol), and ethyl acetate (100 mL) as described in Example 1a. The crude product was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2) (750 mL) collecting 6×100 mL fractions. After evaporation of fractions 3 and 4, 5.43 g (46%) product was obtained (yellow oil).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O>CCO>[CH2:15]([N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:14]=2)[C:10]([C:25](=[O:36])[NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=2)=[C:11]1[CH:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
General Procedure F. To a solution of ethyl1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylate (Compound 43, 609 mg, 1.24 mmol) in EtOH (15 ml) was added NaOH (248 mg, 6.21 mmol) and H2O (1 ml). The reaction was stirred at 50° C. for 12 h, concentrated in vacuo to an oil then acidified to PH=5 with 10% HCl, diluted with EtOAc, washed organic with H2O, brine, dried over Na2SO4 and concentrated in vacuo to yield the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:38]3[C:33](=[CH:34][C:35]([C:39](O)=[O:40])=[CH:36][CH:37]=3)[C:32]([CH3:42])=[C:31]2[CH3:43])=[CH:25][CH:24]=1)=[O:16])(C)(C)C>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:39]([C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:18]3[C:17]([C:15]([OH:16])=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:28][CH:27]=1)[C:31]([CH3:43])=[C:32]2[CH3:42])=[O:40]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1cccc(N)c1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc(N)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 3-aminobenzylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](N3CCC(N4CCCC4)CC3)=[C:9]([N+]([O-])=O)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:26]#[N:27].ClC1C=[C:31]([CH:33]=[CH:34][C:35]=1SC1N(C)C=CN=1)[NH2:32].Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[N:32]1([CH:47]2[CH2:48][CH2:49][N:44]([C:4]3[C:3]([C:26]#[N:27])=[CH:2][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[N:5]=3)[CH2:45][CH2:46]2)[CH2:31][CH2:33][CH2:34][CH2:35]1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: N#Cc1cnc2cc(N3CCC(N4CCCC4)CC3)c([N+](=O)[O-])cc2c1Cl
Reactant: c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Product: N#Cc1cc2ccccc2nc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C

Procedure:
A mixture of 0.5 g (1.45 mmol) of 4-chloro-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-yl)quinoline-3-carbonitrile, 0.38 g (1.6 mmol) of 3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]aniline and 0.17 g of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at 105° C. for 1 hour. After cooling to room temperature, the mixture is stirred with 15 mL of saturated solution of sodium bicarbonate. The resulting solid is collected by filtration and washed with water. Some of the product dissolves in water, which is recovered by extracting the aqueous layer with solution of 95:5 methylene chloride/methanol. The organic layer is evaporated to provide crude product. The combined solids are purified by silica gel chromatography (gradient 95:5 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 0.52 g of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-nitro-7-(4-pyrrolidin-1-ylpiperidin-1-ylquinoline-3-carbonitrile as an orange solid, mp 220-230° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]=1[NH2:28])[CH2:2][CH2:3][CH3:4].[C:29](Cl)(=O)[CH3:30].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:6]2[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:7]=2[N:28]=[C:29]1[CH3:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C)nc(N(Cc2ccccc2)Cc2ccccc2)c1N
Reactant: CC(=O)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCn1c(C)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc(C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.6 %

Procedure:
N4 -n-Butyl-6-methyl-N2,N2 -bis(phenylmethyl)pyridine-2,3,4-triamine (0.65 g, 1.7 mmole) was combined with toluene (10 mL) and acetyl chloride (0.12 mL, 1.7 mmole) and stirred at ambient temperature for 15 minutes. Phosphorous oxychloride (0.31 mL) was added and the reaction mixture was heated at reflux overnight. The reaction mixture was evaporated. The residue was purified by silica gel column chromatography eluting with hexane:ethyl acetate (70:30) to provide 0.18 g of the desired product.
Reaction SMILES: COC1C=C(NC2C3C(=C(C)C=C(S(C4C=CC=C(C(=O)NCCCCCCCC=O)C=4)(=O)=O)C=3)N=CC=2C(N)=O)C=CC=1.[OH:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([S:59]([C:62]3[CH:63]=[C:64]4[C:69](=[C:70]([CH3:72])[CH:71]=3)[N:68]=[CH:67][C:66]([C:73]([NH2:75])=[O:74])=[C:65]4[NH:76][C:77]3[CH:82]=[CH:81][CH:80]=[C:79]([O:83][CH3:84])[CH:78]=3)(=[O:61])=[O:60])[CH:54]=2)=[CH:49][CH:48]=1>>[CH:46]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([S:59]([C:62]3[CH:63]=[C:64]4[C:69](=[C:70]([CH3:72])[CH:71]=3)[N:68]=[CH:67][C:66]([C:73]([NH2:75])=[O:74])=[C:65]4[NH:76][C:77]3[CH:82]=[CH:81][CH:80]=[C:79]([O:83][CH3:84])[CH:78]=3)(=[O:60])=[O:61])[CH:54]=2)=[CH:49][CH:48]=1)=[O:45]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCC=O)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(C=O)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 112, using Intermediate 64 as a substrate. ES/MS calcd. for C31H26N3O5S+ 552.2. Found m/z=552.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[CH:20]([Si:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[CH2:21]>C1(C)C=CC=CC=1>[CH3:13][C:2]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH3:1])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:6]=1[CH2:21][CH2:20][Si:22]([O:23][CH2:24][CH3:25])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[O:4]
Reactant: CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Reactant: C=C[Si](OCC)(OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1cc(SC)ccc1C(=O)C(C)(C)N1CCOCC1)(OCC)OCC
Yield: 5.4 %

Procedure:
11.18 g (40 mmol) of 2-methyl-1-(4-methylthiophenyl)-2-morpholino-1-propanone, 735 mg (0.8 mmol) of RuH2 (CO) (PPh3)3 and 10.0 ml (48 mmol) of vinyltriethoxysilane in 60 ml of anhydrous toluene were degase with argon for 1/2 hour and boiled at reflux for 50 hours. Concentration and chromatography (silica gel, CH2Cl2 /ethyl acetate) gave 1.02 g (6%) of a yellowish oil. 1H-NMR (CDCl3): 0.99 ppm (2H, mc, Et-H2); 1.22 ppm (6H, s, CH3); 1.24 ppm (9H, t, CH3 of Si(OEt)3); 2.50 ppm (3H, s, SCH3); 2.59 ppm (4H, mc, morpholine-N--CH2); 2,69 ppm (2H, mc, Et-H1); 3.70 ppm (4H, mc, morpholine-O--CH2); 3.85 ppm (6H, q, SiOCH2, 3JH,H =6.8 Hz); 7.03 ppm (1H, dd, Ph-H5, 3 JH5,H6 =8.2 Hz, 4JH3, H5 =2.0 Hz); 7.13 ppm (1H, d, Ph-H3); 8.40 ppm (1H, d, Ph-H6).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Cl.Cl.[NH:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)[NH2:8]>O>[CH3:16][O:15][C:12]1[N:13]=[CH:14][C:9]([NH:7][NH:8][C:2]([NH2:3])=[O:1])=[CH:10][CH:11]=1
Reactant: COc1ccc(NN)cn1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(NNC(N)=O)cn1
Reaction time: 2 h
Yield: 148 %

Procedure:
Potassium cyanate (8.41 g, 104 mmol) was added to a solution of 5-hydrazino-2-methoxypyridine dihydrochloride (20 g, 94.3 mmol) in water (200 mL). The mixture was stirred for 2 hour and adjusted pH to 7. The solvent was removed under reduced pressure and obtained crude powder to give 2-(6-methoxypyridin-3-yl)hydrazinecarboxamide. (25.4 g, 148% yield).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[C:44](=[O:45])[C:43]4[S:42][C:41]5[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=5[C:35]=4[CH:34]=[N:33]3)[C:27]=2[CH:46]=[O:47])=[CH:3]1.[BH4-].[Na+]>CO>[OH:47][CH2:46][C:27]1[C:28]([N:32]2[C:44](=[O:45])[C:43]3[S:42][C:41]4[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=4[C:35]=3[CH:34]=[N:33]2)=[N:29][CH:30]=[CH:31][C:26]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:20][CH2:21]3)=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A mixture of 4-[1-methyl-5-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl]-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124b (200 mg, 0.31 mmol), NaBH4 (35 mg, 0.92 mmol) and CH3OH (10 mL) was stirred at 25° C. for 1 h. The mixture was then extracted with CH2Cl2 (10 mL×2). The combined CH2Cl2 extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 124 (100 mg, 50%) as a yellow solid. LCMS: [M+H]+ 653. 1H NMR (500 MHz, DMSO) δ 8.64 (d, J=2.0 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.46-8.48 (m, 2H), 7.88 (d, J=3.0 Hz, 1H), 7.54 (d, J=5.0 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.37-7.39 (m, 1H), 7.24 (d, J=9.0 Hz, 1H), 4.85-4.87 (m, 1H), 4.55-4.57 (m, 2H), 4.45-4.47 (m, 2H), 3.67-4.39 (m, 2H), 3.60 (s, 3H), 3.42-3.45 (m, 1H), 3.06-3.08 (m, 4H), 2.95 (s, 2H), 2.87 (s, 2H), 2.38-2.40 (m, 4H), 1.87-1.89 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([N:30]=[CH:31][C:32]=3[C:33]([OH:35])=O)[C:21]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH2:10][CH2:9]1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[CH:17]=[N:18][C:19]3[N:20]([N:30]=[CH:31][C:32]=3[C:33]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:35])[C:21]=2[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH2:12][CH2:13]1
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCN(c3ccccc3Cl)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCN(c4ccccc4Cl)CC3)cnc12
Yield: 19.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(2-chlorophenyl)piperazine-1-carbonyl]-7-(2-methylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.110 g, 0.224 mmol) obtained in step 2 and ethanesulfonamide (0.049 g, 0.448 mmol), the title compound (0.025 g, 19%) was obtained.