Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:8]>C(#N)C.O.O.O.O.O.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:7]#[N:8])[CH:10]=3)[NH:14][CH:13]=2)[CH2:2]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C1C=CCC1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Yield: 69.1 %

Procedure:
2-Cyclopenten-1-one (4.1 g, 4.2 mL, 50 mMol) was added to a stirred solution of 5-cyanoindole (1.42 g, 10 mMol) and ytterbium triflate hexahydrate (124 mg, 0.2 mMol) in acetonitrile (15 mL). After stirring at room temperature for 7d, the reaction was concentrated to an oil and diluted with ether. The red oily mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (35 g) using a gradient of 20–35% ethyl acetate in hexane. Pure product fractions were concentrated and dried under high vacuum to give 3-(3-oxocyclopentyl)-1H-indole-5-carbonitrile (1.55 g, 69%). 1H NMR (500 MHz, CDCl3) δ 8.41 (1 H, bs), 7.99 (1 H, s), 7.45 (2 H, m), 7.12 (1 H, dd, J=2.44, 0.92 Hz), 3.72 (1 H, m), 2.77 (1 H, dd, J=7.63, 18.31 Hz), 2.56 (1 H, m), 2.40 (3 H, m), 2.10 (1 H, m). MS m/e 223.2 (M−H)+. Anal. calcd. for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.75; H, 5.50; N, 12.23.
Reaction SMILES: IC.[OH:3][CH2:4][CH2:5][C:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:12]=2[CH2:13][CH2:14][CH:15]=1>C(O)C.[C].[Pd]>[OH:3][CH2:4][CH2:5][CH:6]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:8][C:7]1=2
Reactant: CCOC(=O)c1ccc2c(c1)CCC=C2CCO
Agent: [Pd]
Solvent: CCO
Solvent: CI
Product: CCOC(=O)c1ccc2c(c1)CCCC2CCO

Procedure:
14.3 g of the above product was allowed to react using procedures analogous to those described in steps (5) and (6) of Referential Example 1 but using iodomethane instead of bromoethane to give an oily product containing a small amount of ethyl 5-(2-hydroxyethyl)-7,8-dihydro-2-naphthalenecarboxylate as a by-product. The product was dissolved in 10 ml of ethanol and 0.5 g of 10% palladium carbon was added thereto. The mixture was catalytically reduced. After absorption of hydrogen gas was completed, the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 1.4 g of ethyl 5-(2-hydroxyethyl)-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as an oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C=O.CC(=O)[O:29]CC>C(Cl)Cl.CO.C(P(CCCC)CCCC)CCC>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:29])[C:13](=[O:17])[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Agent: C=O
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 102 %

Procedure:
To a solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 7, 18 g, 52.71 mmol) in a mixture of DCM (900 mL) and MeOH (350 mL) was added successively formaldehyde (42.8 mL, 527.06 mmol) and tributylphosphine (0.692 mL, 3.16 mmol) at rt. The solution was stirred at room temperature for 2-3 hr until TLC (4:1 Hex/EA) showed that the reaction was complete. It was concentrated under reduced pressure and purified by 120 g silica gel column (0-50% Hex/EA) to afford the title compound (20.00 g, 102%) as an oil.
Reaction SMILES: [I-].[CH2:2]([N+:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[CH3:15])[CH3:3].[C:16](OC(=O)C)(=[O:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:2]([N:4]1[C:8]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=2[S:6]/[C:5]/1=[CH:15]\[C:16](=[O:18])[CH3:17])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC[n+]1c(C)sc2ccc(OC)cc21
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1/C(=C/C(C)=O)Sc2ccc(OC)cc21
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A series of benzothiazole compounds including TG003 were synthesized according to the procedures reported by Gupta et al. (27). In the case of TG003, a mixture of commercially available 5-methoxy-2-methylbenzothiazole (202 mg, 1.12 mmol) and ethyl iodide (2.70 ml, 33.7 mmol) was refluxed for 24.5 h. The precipitate was filtrated, washed with ethyl acetate (20 ml) on a funnel, and dried under reduced pressure to afford 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (270 mg, 0.805 mmol, 71.9%) as a pale green solid. To a suspension of 3-ethyl-5-methoxy-2-methylbenzothiazolium iodide (502 mg, 1.49 mmol) in acetonitrile (2.0 ml), acetic anhydride (330 μl, 3.49 mmol) and triethylamine (490 μl, 3.51 mmol) were successively added at room temperature. After refluxing for 2 h, the mixture was cooled to room temperature and concentrated under reduced pressure. Water (50 ml) was added to the residue, and the mixture was extracted with ethyl acetate (three times with 15 ml). The combined organic extracts were washed with brine (30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (18 g, CH2Cl2/ethyl acetate, 4:1) to afford (Z)-1-(3-ethyl-5-methoxy-2,3-dihydrobenzothiazol-2-ylidene) propan-2-one (TG003) (201 mg, 0.806 mmol, 54.1%) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:16]([C:26]([OH:28])=[O:27])[CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2].[N+](=[CH2:38])=[N-]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:16]([C:26]([O:28][CH3:38])=[O:27])[CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:11][N:10]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:8]=2[CH:35]=1)([O-:3])=[O:2]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(CCCN1CCCCC1)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Product: COC(=O)C(CCCN1CCCCC1)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 14, 7-nitro-2-[(1-carboxy-4-piperidinobutylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-nitro-2[[1-(methoxycarbonyl)-4-piperidinobutylidene]hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([S:3][C:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.O>[CH2:1]([S:3][C:4]1[C:9]2[N:10]=[C:11]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCSc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 3,4 gm (0.01 mol) of 8-ethylthio-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p. 197°-199° C.) in 100 ml of dimethylsulfoxide was slowly poured, while stirring, into a solution of 4.3 gm (0.05 mol) of piperazine in 75 ml of dimethylsulfoxide at 40° C., and the mixture was stirred for 1 hour at 40° C. The reaction mixture was then taken up in about 1 liter of water, whereby the reaction product slowly precipitated in crystalline form. After standing for a short period of time, the precipitate was suction-filtered off, washed with water and dried at about 70° C.
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH2:38])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].O>C1COCC1>[C:20]([C:24]1[CH:25]=[C:26]([CH2:31][CH:32]([NH:38][C:16](=[O:18])[CH:12]([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:13]([CH3:14])[CH3:15])[C:33]2[O:34][CH:35]=[N:36][N:37]=2)[CH:27]=[CH:28][C:29]=1[OH:30])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1cc(CC(N)c2nnco2)ccc1O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1nnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of Z-N-Me-Val-OH (914 mg, 3.45 mmol), 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamine (0.75 g, 2.87 mmol) and CMPI (881 mg, 3.45 mmol) in THF (30 ml), TEA (0.96 ml) was added under cooling with ice and stirred at room temperature for 2 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving 2-benzyloxycarbonylamino-3-methylbutyric acid 2-(3-t-butyl-4-hydroxyphenyl)-1-(1,3,4-oxadiazol-2-yl)ethylamide (1.28 g, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([F:10])[CH:9]=1)[NH2:6])#[CH:2].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[C:8]([F:10])[CH:9]=1)#[CH:2]
Reactant: C#Cc1cc(N)cc(F)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: C#Cc1cc(F)cc(NC(C)c2cc(C(=O)N(C)C)cc3c(=O)cc(N4CCOCC4)oc23)c1
Yield: 86.3 %

Procedure:
3-ethynyl-5-fluoroaniline (165 mg, 1.22 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-ethynyl-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (80 mg, 56%) as a white solid. Mass Spectrum: M+H+ 464. NMR Spectrum (DMSOd6): 1.52 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.50-3.63 (m, 4H), 3.69-3.78 (m, 4H), 4.12 (s, 1H), 4.98-5.07 (m, 1H), 5.66 (s, 1H), 6.31 (d, 1H), 6.40 (d, 1H), 6.46 (s, 1H), 6.81 (d, 1H), 7.54 (d, 1H), 7.80 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16](/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20].C(N(CC)CC)C>ClCCl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:2]([NH:1][S:23](/[CH:22]=[CH:21]/[C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)(=[O:25])=[O:24])[CH:7]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(Cl)ccc1S(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Cl)cc1NS(=O)(=O)/C=C/c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
2-Amino-4-chlorobenzenesulfonamide (100 mg, 0.48 mmol) and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (171 mg, 0.63 mmol) were dissolved in anhydrous dichloromethane (5 mL) and were flushed with argon. Anhydrous triethylamine (0.155 mL, 1.11 mmol) was added and the reaction was stirred at room temperature under an inert atmosphere over night. The reaction was quenched using 2 M hydrochloric acid (20 mL) and extracted with dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated under vacuum to give 194 mg (91% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:4]1([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]#[N:26])=[CH:15][CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].NN.C1COCC1>CCO.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([C:4]1([C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([C:25]#[N:26])=[CH:15][CH:14]=2)[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: C=CCC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Agent: [Cu+2]
Agent: NN
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC1(c2ccc(C#N)cc2-c2ccccc2)CCCc2cncn21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(5-allyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-3-carbonitrile (35 mg, 0.103 mmol) in EtOH (2 mL) at ambient temperature is added H2NNH2/THF (1.0 M, 15 mL, 15 mmol) and saturated aqueous CuSO4 (0.1 mL). The reaction mixture is stirred at ambient temperature overnight. The mixture is concentrated and dissolved in EtOAc, which is washed with water, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 342 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm (HCl salt) 0.95 (t, J=7.2 Hz, 3 H), 1.21-1.33 (m, 2 H), 1.80-1.90 (m, 2 H), 1.90-2.02 (m, 1 H), 2.09-2.37 (m, 3 H), 2.59-2.68 (m, 1 H), 2.71-2.85 (m, 1 H), 6.81-6.88 (m, 1 H), 6.90-6.98 (m, 2 H), 7.19-7.25 (m, 1 H), 7.27-7.39 (m, 3 H), 7.43 (d, J=1.8 Hz, 1 H), 7.71 (dd, J=8.3, 2.0 Hz, 1 H), 8.10-8.18 (m, 1 H).
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:36]([NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C>[CH2:44]([N:43]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:14](=[O:16])[C:13]1[CH:12]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]([Cl:21])=[CH:9][C:8]=1[NH:7][CH2:6][C:3]1[O:4][CH:5]=[CH:1][CH:2]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)N(Cc2ccccc2)Cc2ccccc2)c(NCc2ccco2)cc1Cl

Procedure:
In similar manner to Example 8, furosemide can be reacted with EDC, HOBt and dibenzylamine in DMF to yield N,N-dibenzyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]benzamide.
Reaction SMILES: [Cl:1]C1C2C(=CC=C(N(C)C)C=2)N=CC=1C#N.COC1C=C(C=CC=1)N.[CH3:26][N:27]([CH3:49])[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=1>>[ClH:1].[CH3:26][N:27]([CH3:49])[C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=1
Reactant: CN(C)c1ccc2ncc(C#N)c(Cl)c2c1
Agent: COc1cccc(N)c1
Agent: COc1cccc(Nc2c(C#N)cnc3ccc(N(C)C)cc23)c1
Product: Cl

Procedure:
Prepared from 0.400 g of 4-chloro-6-dimethylaminoquinoline-3-carbonitrile and 0.256 g of 3-methoxyaniline in the same manner as Example 395. The yield of 6-dimethylamino-4-(3-methoxyphenylamino)quinoline-3-carbonitrile was 0.532 g of brown powder: mass spectrum (electrospray, m/e): M+H 318.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])([F:13])[F:12])[C:5](O)=[O:6].[CH2:22]([NH2:32])[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:20]([O:19][P:14]([C:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:6])[NH:32][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:3][C:2]=1[Br:1])([F:13])[F:12])(=[O:15])[O:16][CH2:17][CH3:18])[CH3:21]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C(=O)O)cc1Br
Reactant: NCCCCc1ccccc1
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C(=O)NCCCCc2ccccc2)cc1Br

Procedure:
The 3-bromo-4-[(diethoxyphosphoryl)difluoromethyl)benzoic acid (Compound 35) was coupled to phenbutyl amine following the procedures of Example 39 to give {[2-bromo-4-(4-phenylbutylcarbamoyl)phenyl]difluoromethyl}-phosphonic acid diethyl ester which was treated in a manner similar to Example 40 to give Compound 62. MS (ion spray):m/z 459.98/461.95 (M−H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].Cl[C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:25])[F:24])=[CH:17][N:16]=1>C(O)CCC.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH:5][C:15]1[N:20]=[C:19]([NH:21][CH3:22])[C:18]([C:23]([F:26])([F:24])[F:25])=[CH:17][N:16]=1
Reactant: COc1cc(S(C)(=O)=O)ccc1N
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(Nc2ccc(S(C)(=O)=O)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
To a mixture of 2-methoxy-4-(methylsulfonyl)aniline (0.095 g, 0.47 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in 1-butanol (1.5 mL) was added TFA (0.036 mL, 0.047 mmol). The reaction was stirred in a sealed tube at 100° C. for 1.5 h. The reaction was concentrated and the product was isolated by reverse-phase HPLC to give N2-(2-methoxy-4-(methylsulfonyl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (0.18 g, 20%). 1H NMR (400 MHz, DMSO) δ 8.58 (d, J=12.9, 1H), 8.24 (d, J=5.0, 2H), 7.53 (d, J=10.1, 1H), 7.48 (s, 1H), 7.38-7.29 (m, 1H), 3.99 (s, 3H), 3.20 (s, 3H), 2.94 (d, J=4.3, 3H); LRRK2 Ki=0.002.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[NH:8][C:5]2=[CH:6][N:7]=1.[NH3:15].O>CCO>[CH:11]1([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([NH2:15])[CH:3]=[C:4]3[CH:10]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: Clc1cc2cc(C3CCC3)[nH]c2cn1
Reactant: N
Solvent: O
Solvent: CCO
Product: Nc1cc2cc(C3CCC3)[nH]c2cn1
Temperature: 180 °C
Reaction time: 16 h
Yield: 22 %

Procedure:
To the solution of 5-chloro-2-cyclobutyl-1H-pyrrolo[2,3-c]pyridine (200 mg, 0.97 mmol) in EtOH (10 mL) and NH3.H2O (30 mL) was added CuSO4.5H2O (30 mg, 0.12 mmol). The reaction mixture was stirred under 3 MPa at 180° C. for 16 h. The mixture was extracted with ethyl acetate (3×30 mL). The extract was dried, concentrated in vacuo and purified by chromatography on silica gel (5-10% MeOH in ethyl acetate as eluant) to afford the pure 2-cyclobutyl-1H-pyrrolo[2,3-c]pyridin-5-amine (40 mg, 22% yield). 1H NMR (300 MHz, MeOH) δ: 8.02 (s, 1H), 6.72 (s, 1H), 6.11 (s 1H), 3.72-3.60 (m, 1H), 2.47-1.90 (m, 6H). MS (ESI): m/z [M+H+] 188.1.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=O)=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([CH:14]=[N:17][OH:18])=[CH:12][NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2n[nH]cc2C=NO)o1
Temperature: 0 °C
Yield: 97 %

Procedure:
Stir together 18 g of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde, 6.95 of hydroxylamine hydrochloride and 8.2 g of sodium acetate in 70 ml of water for 1.5 hours at 70° C. Cool the resulting admixture slowly to 0° C. Separate the formed precipitate by vacuum filtration and wash the residue with several portions of ice-cold water to obtain a 97% yield of 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehydeoxime [m.p. 233° to 235° C (with decomposition)].
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[O:26][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[N:28][N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[O:26][C:27]([N:30]5[CH2:31][CH2:32][O:33][CH2:34][CH2:35]5)=[N:28][N:29]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1nnc(N2CCOCC2)o1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3nnc(N4CCOCC4)o3)(CC1)CC2
Yield: 13.7 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(2-amino-1,3,4-oxadiazole-5-yl)morpholine (57.9 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[5-(4-morpholinyl)-1,3,4-oxadiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (10.1 mg).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH3:3].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:3][CH2:2][CH2:1][NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])=[C:20]([CH:21]=[O:22])[CH:23]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCCNCCCC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCNCCCc1ccc(Br)cc1C=O
Temperature: 80 °C
Reaction time: 94 h
Yield: 52.3 %

Procedure:
To a solution of t-butyl 4-propylaminobutyrate (14.2 g, 70.7 mmol) in DMF (20 ml) were added 5-bromo-2-fluorobenzaldehyde (14.4 g, 70.9 mmol) and potassium carbonate (14.7 g, 106 mmol) at room temperature, and the mixture was stirred at 80° C. for 94 hours. The mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=10:1) to give yellow oil of t-but yl 4-(4-bromo-2-formylphenyl)propylaminobutyrate (14.2 g, 52%).
Reaction SMILES: CN(C)[C:3](=O)[CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.ClCC[CH2:50][N:51]([CH3:53])[CH3:52]>>[CH3:50][N:51]([CH3:53])[CH2:52][CH2:3][CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1
Reactant: CN(C)CCCCl
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 3-chloro-N,N-dimethylpropan-1-amine hydrochloride as the alkylating reagent in Step 1. The product was isolated as a white solid (3 mg, 0.85%). LCMS: m/e 615.75 (M+H)+, 2.24 min (method 13). 1H NMR (400 MHz, METHANOL-d4) δ 7.95 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 5.34 (s, 1H), 4.89 (s, 1H), 4.75 (s, 1H), 3.58-3.36 (m, 2H), 3.26 (br. s., 8H), 2.78 (d, J=7.5 Hz, 1H), 2.51-2.26 (m, 3H), 2.26-1.97 (m, 7H), 1.92 (m, 1H), 1.78 (m, 6H), 1.63-1.47 (m, 6H), 1.45-1.36 (m, 2H), 1.32-1.18 (m, 5H), 1.14 (s, 3H), 1.08 (s, 3H), 1.00 (s, 3H), 0.98 (s, 3H)