Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([CH:25]=[O:26])[C:22]([Cl:27])=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(CC)=C.S(=O)(=O)([OH:35])N.Cl([O-])=O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CS(C)=O.O>[CH2:1]([O:8][C:9]1[C:10]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:21][C:22]([Cl:27])=[C:23]([CH:24]=1)[C:25]([OH:35])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)O
Reactant: O=Cc1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: C=C(C)CC
Product: O=C(O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of benzyl 2-(benzyloxy)-5-chloro-4-formylbenzoate (may be prepared as described in D73) (1.4 g, 3.68 mmol) in tetrahydrofuran (THF) (8 mL) and dimethyl sulfoxide (DMSO) (0.8 mL) were added 2-methyl-1-butene (0.792 mL, 7.35 mmol) and sulfamic acid (1.214 g, 12.50 mmol). The solution was cooled to 0° C. and a solution of sodium chlorite (0.997 g, 11.03 mmol) in water (8 mL) was added. The mixture was stirred for one hour, then saturated sodium thiosulfate solution was added (15 mL) and the mixture was stirred for another 10 minutes. The mixture was extracted with EtOAc (3×20 mL). The organic layer was washed with water (10 mL) and 2M HCl (10 mL), dried over MgSO4 and concentrated in vacuo to give the title product as an off-white solid (1.46 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]2[C:6]3[CH2:20][CH2:19][C:18](=[O:21])[C:7]=3[N:8](C(OC(C)(C)C)=O)[C:9]=2[CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]2[C:6]3[CH2:20][CH2:19][C:18](=[O:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)n1c2c(c3cc(Cl)c(Cl)cc31)CCC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of tert-butyl 6,7-dichloro-3-oxo-2,3-dihydrocyclopenta[b]indole-4(1H)-carboxylate (0.34 g, 1.0 mmol) in CH2Cl2 (10 mL), cooled to 0° C., TFA (1 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 90 min., quenched with saturated NaHCO3 (pH-8) and extracted with DCM (3×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by washing with 5% EtOAc-hexane (3×20 mL) to provide the title compound (200 mg, 83%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.96 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 3.03 (t, J=3.5 Hz, 2H), 2.92 (t, J=4.0 Hz, 2H).
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)[CH3:19].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH2:18]([NH:20][C:21](=[O:34])[C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:29][CH2:30][N:31]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][CH:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:32][CH2:33]2)=[CH:26][CH:27]=1)[CH3:19]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCCC12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)C3CCCCN43)CC2)cc1
Temperature: 90 °C
Yield: 58.4 %

Procedure:
3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (50 mg, 0.214 mmol), N-ethyl-4-(piperazin-1-yl)benzamide (55.0 mg, 0.236 mmol), (cyanomethyl)trimethylphosphonium iodide (67.7 mg, 0.279 mmol) and N,N-diisopropylethylamine (187 μl, 1.072 mmol) were suspended in Propiononitrile (Volume: 644 μl) and heated in a closed vial at 90° C. for 1 h. It was cooled to ambient temperature, the resulting precipitate was filtered, washed with MeCN (5 mL) and dried in vacuum to afford N-ethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (56 mg, 0.125 mmol, 58.2% yield) as a white solid. 1H NMR (DMSO-d6) δ 10.43 (s, 1H), 8.12 (t, J=5.6 Hz, 1H), 7.70 (d, J=9.1 Hz, 2H), 7.66 (d, J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 6.92 (d, J=9.1 Hz, 2H), 4.47-4.55 (m, 1H), 3.83 (dd, J=11.4, 2.8 Hz, 1H), 3.32-3.40 (m, 2H), 3.18-3.28 (m, 6H), 2.61 (td, J=12.6, 2.5 Hz, 1H), 2.43-2.49 (m, 4H), 2.04 (d, J=13.1 Hz, 1H), 1.80-1.91 (m, 2H), 1.64 (d, J=12.6 Hz, 2H), 1.33-1.58 (m, 3H), 1.09 (d, J=14.4 Hz, 3H); [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[NH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH2:40])=[NH:39])=[CH:36][CH:35]=1)[NH2:33]>CCO>[Br:1][C:2]1[C:3]([OH:22])=[C:4]([C:9](=[N:33][NH:32][C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH2:40])=[NH:39])=[CH:41][CH:42]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)c(O)c(C(=O)CCc2ccc([N+](=O)[O-])cc2)c1
Reactant: N=C(N)c1ccc(NN)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)c(O)c(C(CCc2ccc([N+](=O)[O-])cc2)=NNc2ccc(C(=N)N)cc2)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
For example, a solution of 1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-phenyl)-propan-1-one 201 (1.48 g, 0.004 mol), EtOH (30 mL), diisopropylethylamine (Hunigs base)(3 mL), and 4-Hydrazino-benzamidine 200 (0.93 g, 0.004 mol) is heated at reflux for 4 hr. (reaction times can vary between 2 h to 18 h). The solution is cooled to ambient temperature, filtered, washed with 6N HCl (2×25 mL), and dried for 12-18 h in a vacuum oven to give a 90% yield of 4-{N′-[1-(3-bromo-2-hydroxy-5-methyl-phenyl)-3-(4-nitro-phenyl)-propylidene]-hydrazino}-benzamidine 202 as an off-white solid (1.78 g, 0.0036 mol).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=1>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=3[C:12]([OH:14])=[O:13])[CH2:3]2)[N:32]=1
Reactant: Cc1ccccc1-c1nc(CI)c(C)o1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Product: Cc1ccccc1-c1nc(COC2CCCC(OCc3cccc(C)c3C(=O)O)C2)c(C)o1

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(2-methylphenyl)-4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 63 of molecular weight 449.55 (C27H31NO5), MS(ESI): 450.20 (M+H+).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27]([C:29]1[C:37]2[CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH:33]([CH2:47][NH2:48])[C:32]=2[S:31][C:30]=1[NH2:49])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([C:29]1[C:37]2[CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[CH:33]([CH2:47][NH:48][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[S:4](=[O:12])(=[O:11])[N:3]=3)[C:32]=2[S:31][C:30]=1[NH2:49])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC2=NS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
3-Chloro-benzo[d]isothiazole-1,1-dioxide (160 mg, 0.79 mmol) and diisopropylethylamine (1501 μl, 0.86 mmol) were dissolved in dichloromethane (7 ml) at 0° C. 2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (284 mg, 0.70 mmol) was added and the mixture was stirred for 15 minutes at 0° C., diluted with dichloromethane, (10 ml) and washed with water (20 ml) and brine (20 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of hexanes/ethyl acetate (1:1) to pure ethyl acetate as eluent, which afforded 309 mg (77%) of 2-amino-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an foam.
Reaction SMILES: [CH2:1]1[C@H:5]([N:6]2[C:11](=[O:12])[N:10]=[C:9]([NH2:13])[CH:8]=[CH:7]2)[O:4][C@H:3]([CH2:14][O:15][P:16]([OH:19])([OH:18])=[O:17])[C@H:2]1[O:20][P:21]([O:24][CH2:25][C@H:26]1[O:30][C@@H:29]([N:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([NH2:40])[C:34]=3[N:33]=[CH:32]2)[C@H:28]([OH:41])[C@@H:27]1[OH:42])([OH:23])=[O:22].[CH2:43]([S:50][C:51](=[O:67])[CH2:52][C@H:53]([NH:60][C:61](=[O:66])[CH2:62][CH2:63][CH:64]=[CH2:65])[C:54](OCC#N)=[O:55])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.FC(F)(F)C(O)=O>O.O1CCCC1>[CH2:43]([S:50][C:51](=[O:67])[CH2:52][C@@H:53]([NH:60][C:61](=[O:66])[CH2:62][CH2:63][CH:64]=[CH2:65])[C:54]([O:42][C@H:27]1[C@@H:28]([OH:41])[C@H:29]([N:31]2[CH:32]=[N:33][C:34]3[C:35]2=[N:36][CH:37]=[N:38][C:39]=3[NH2:40])[O:30][C@H:26]1[CH2:25][O:24][P:21]([O:20][C@H:2]1[CH2:1][C@H:5]([N:6]2[CH:7]=[CH:8][C:9]([NH2:13])=[N:10][C:11]2=[O:12])[O:4][C@@H:3]1[CH2:14][O:15][P:16]([OH:18])([OH:19])=[O:17])([OH:23])=[O:22])=[O:55])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)OCC#N
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C=CCCC(=O)N[C@H](CC(=O)SCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (200 mg, 0.314 mmol) in water (6.25 ml) and a solution of (S)-cyanomethyl 4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1g-ID) (454 mg, 1.26 mmol) in tetrahydrofuran (3.15 ml) were added to buffer A (113 ml), and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid (2.52 ml, 33.9 mmol) was then added, followed by lyophilization. The resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution=100/0→60/40) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 4-(benzylthio)-4-oxo-2-(pent-4-enamido)butanoate (Compound 1i-ID) (70.9 mg, 24%).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][CH3:11])=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:13][OH:14].[OH-].[K+].N=C=N.NO>CCOCC.CO>[C:1]1([NH:7][C:8]([NH:10][CH3:11])=[N:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CNC(=S)Nc1ccccc1
Agent: Cl
Agent: N=C=N
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: CNC(=NO)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
A mixture of 6.6 g (0.04 mole) of 1-phenyl-3-methylthiourea and 17.3 g (0.08 mole) of yellow mercuric oxide in 50 ml of ether was stirred vigorously at room temperature for 0.5 hour. The thick slurry was diluted with additional ether and filtered. To the filtrate was added all at once a solution of hydroxylamine prepared by treating 3.5 g (0.05 mole) of hydroxylamine hydrochloride in 50 ml of methanol at 0° with 2.8 g (0.05 mole) of potassium hydroxide (filtered after 0.5 hour to remove potassium chloride). The ether-methanol solution of the carbodiimide and hydroxylamine was stirred for 0.5 hour, then the solvent was removed at reduced pressure. The residue was dissolved in dilute hydrochloric acid and extracted with methylene chloride to remove neutral impurities. The aqueous layer was then made basic with sodium hydroxide. Extraction with methylene chloride and removal of the solvent gave the crude product. It was recrystallized from methylene chloride/hexane to give 1.3 g of white 1-phenyl-3-methyl-2-hydroxyguanidine, mp 95°-6°; nmr (CDCl3): δ 2.7 (s, 3); 6.9-7.4 (m, 5); 4-7 (very broad, 3). IR (chloroform solution): both OH and NH present. In the antitetrabenazine test, this compound gave a ptosis ED50 of 12.2 mg/kg and exploratory ED50 of > 81 mg/kg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2
Reactant: O=[N+]([O-])c1cnccc1Nc1ccc2[nH]ccc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1cnccc1Nc1ccc2[nH]ccc2c1
Yield: 110.5 %

Procedure:
To a slurry of 10% Pd/C (1.0 g) in 10 ml of methanol was added N-(3-nitro-4-pyridinyl)-1H-indol-5-amine (4.0 g) in 230 ml methanol and this mixture was hydrogenated at 50 psi on a Parr apparatus. When the reaction was complete, the mixture was filtered through Celite and the filtrate concentrated to yield a solid (3.9 g). This material was eluted with 20% methanol/DCM on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid (2.45 g) which was recrystallized from ethanol/water (10:1) to yield a solid, 1.8 g, m.p. 159°-161° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Sb](F)(F)[F:18]>[Sb](Cl)(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([F:18])=[O:5]
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Reactant: F[Sb](F)F
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: O=C(F)c1ccc(OC(F)(F)F)c(Cl)c1Cl
Yield: 123.2 %

Procedure:
2,3-Dichloro4-trifluoromethoxybenzoyl chloride (17.2 g) was added to a mixture of antimony trifluoride (10.6 g) and antimony pentachloride (1 g). The mixture was heated at reflux for 10 mins then flash distilled to give crude 2,3-dichloro-4-trifluoromethoxybenzoyl fluoride (20 g) as a semi-solid bp 211°-215° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1Cl.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([CH3:11])[N:10]=[C:6]2[C:5]([C:12]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)=[O:13])=[CH:4][CH:3]=1
Reactant: Cc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(CC(C)C)CC3)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cn2c(N)ccc(C(=O)NCC3CCN(CC(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.8 %

Procedure:
A mixture of 5-amino-6-chloro-N-[(1-isobutylpiperidin-4-yl)methyl]-2-methylimidazo[1,2-a]pyridine-8-carboxamide (EXAMPLE 26, Step 6, 134 mg, 0.36 mmol), 10% palladium charcoal (67 mg) and ammonium formate (224 mg, 3.6 mmol) in methanol (5 mL ) was stirred at room temperature for 4 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was treated with 25% aqueous ammonia (10 mL), extracted with dichloromethane (20 mL×2) and washed with brine (20 mL). Removal of the solvent gave 92.4 mg (0.37 mmol, 76%) of the title compound as a yellow amorphous.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=[O:12])[CH3:11].[Cl:19][C:20]1[C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:24][N:23]=[C:22]2[N:32]([CH2:41][C:42](O)=[O:43])[N:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:21]=12.Cl.CN(C)CCCN=C=NCC.OC1C=CC=C[N+]=1[O-]>C(Cl)Cl>[C:10]([N:13]1[CH2:18][CH2:17][N:16]([C:42](=[O:43])[CH2:41][N:32]2[C:22]3=[N:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]([Cl:19])=[C:21]3[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:33]2)[CH2:15][CH2:14]1)(=[O:12])[CH3:11]
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
A solution of diisopropylethylamine (DIPEA) (120 μL, 0.67 mmol) and 1-acetylpiperazine (38 mg, 0.3 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (60 mg, 0.3 mmol) and 2-hydroxypyridine-N-oxide (HOPO) (30 mg, 0.27 mmol). The solution obtained was stirred at room temperature for 18 h then 1-acetylpiperazine (10 mg, 0.08 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.15 mmol) were added. After a further 3.5 h the reaction was purified using chromatography (silica gel, gradient 0 to 5% triethylamine/acetone) followed by preparative HPLC yielding Compound 66 as a white solid (32.2 mg).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[N:31]1([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>C1COCC1>[O:30]=[C:4]1[C:3](=[CH:2][NH:43][C:40]2[CH:39]=[CH:38][C:37]([CH2:36][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:42][CH:41]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(CN2CCCC2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CN4CCCC4)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (43.8 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a yellow precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 15% (0.021 g, 0.067 mmol) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[F:37][C:38]([S:41](O)(=[O:43])=[O:42])([F:40])[F:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:9]2[C:14]([C:15]=1[O:16][S:41]([C:38]([F:40])([F:39])[F:37])(=[O:43])=[O:42])=[CH:13][C:12]([Cl:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCOC(=O)c1c(O)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A solution of 10 (63.0 mg, 0.16 mmol), DMAP (7.0 mg, 0.054 mmol), and diisopropylethylamine (19.0 mg, 0.15 mmol) in anhydrous CH2Cl2 was treated with trifluoromethylsulfonic acid (78.0 mg, 0.28 mmol). The reaction was stirred at room temperature for 30 min and concentrated. Chromatography (SiO2, 3:1 Hex/EtOAc) gave 11 (75.0 mg, 88%) as a amorphous solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2Cl)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([CH:20]=[O:21])=[C:12]2[N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)c1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: CN1CCN(c2c(C=O)c3ccccc3n2-c2ccc(C(C)(C)C)cc2)CC1

Procedure:
1-(4-tert-Butylphenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with 1-methyl piperazine as described in Step 2 of Example 29 to afford 1-(4-tert-butylphenyl)-2-(4-methyl-piperazin-1-yl)-1H-indole-3-carboxaldehyde as a light brown solid. TLC (silica gel, ethyl acetate-16.5% methanol-0.8% 7N methanolic ammonia); Rf=0.23; ESI/MS 376 (M+H), RT=3.4 min; NMR 10.14 (1H, s); 8.12 (1H, d, J=9 Hz); 7.67 (2H, d); 7.45 (2H, d); 7.19 (2H, m); 6.92 (1H, d, J=6 Hz); 3.26 (4H, m); 2.18 (7H, m); 1.37 (9H, s).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([CH2:16][CH3:17])([OH:15])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[OH:14].[CH2:23]([N:27]=[C:28]=[O:29])[CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]([F:21])([F:22])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([CH2:16][CH3:17])([OH:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:28](=[O:29])[NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][C:8]=1[O:14][C:28](=[O:29])[NH:27][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCN=C=O
Reactant: CCC(O)(c1cccc(C(F)(F)F)c1)c1ccc(O)cc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCNC(=O)Oc1ccc(C(O)(CC)c2cccc(C(F)(F)F)c2)c(OC(=O)NCCCC)c1

Procedure:
6.2 g. of 3-trifluoromethyl-2',4'-dihydroxy-α-ethyl-benzhydrol, 4.4 g. of butyl isocyanate and 0.06 g. of 4-dimethylamino-pyridine in 40 ml. of dichloromethane are refluxed for 60 minutes. The reaction mixture is cooled down, and the organic phase is extracted with a 5% aqueous potassium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and solvent is distilled off under reduced pressure. Crystallization of the residue from toluene yields 8.7 g. of the end product, which melts at 110° to 111° C.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][C:7]([S:10]([NH2:12])=[O:11])([CH3:9])[CH3:8].S([O-])([O-])(=O)=O.[Mg+2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[CH:1]1(/[CH:4]=[N:12]/[S:10]([C:7]([CH3:9])([CH3:8])[CH3:6])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=CC1CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/C1CC1
Reaction time: 24 h

Procedure:
To a stirred solution of cyclopropane carboxaldehyde (57.8 g, 825 mmol) in DCM (825 mL) were added 2-methyl-2-propanesulfinamide (50 g, 413 mmol), magnesium sulfate (248 g, 2.06 mol), and PPTS (5.18 g, 20.6 mmol). The reaction mixture was left to stir for 1 day, filtered through a fritted glass, concentrated, and purified by filtration through SiO2 using 40% EtOAc in Hex as an eluent.