Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:15][CH2:14][C@@H:4]1[CH2:3][C:2]([F:1])([F:16])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a CH2Cl2 (22 ml) solution of (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.65 g, 11.2 mmol) and Et3N (2.3 ml, 16.8 mmol), at 0° C., methylsulfonyl chloride (0.95 ml, 12.3 mmol) was added dropwise over ˜2 minutes, ice bath was removed after 15 minutes, and stirring was continued at room temperature for another 30 minutes. Reaction went to completion as monitored by LC-MS. The reaction mixture was cooled to 0° C. and was quenched by addition of saturated aqueous solution of NaHCO3 (˜30 ml), stifling was continued at 0° C. for 5 minutes and at room temperature for 15 minutes. Two layers were separated, aqueous layer was extracted with CH2Cl2 (˜30 ml). Organic layers were combined, washed with brine (˜25 ml), dried (Na2SO4), filtered, solvent was removed in vacuo. Compound ((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl methanesulfonate was obtained as a very light yellow oil: 3.40 g (96% crude yield).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[O:22][N:21]=[C:20]([CH:23]([CH3:25])[CH3:24])[N:19]=4)[CH2:14][CH2:13]3)[C:5]=2[N:4]([CH3:26])[CH:3]=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([O-:29])=[O:28].CS(C1C=CC(B(O)O)=CC=1)(=O)=O>>[CH:23]([C:20]1[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([O:11][C:10]3[C:5]4[N:4]([CH3:26])[CH:3]=[C:2]([C:33]5[CH:34]=[CH:35][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=5)[C:6]=4[N:7]=[CH:8][N:9]=3)[CH2:13][CH2:14]2)[O:22][N:21]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1noc(N2CCC(Oc3ncnc4c(Br)cn(C)c34)CC2)n1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)c1noc(N2CCC(Oc3ncnc4c(-c5ccc([N+](=O)[O-])cc5)cn(C)c34)CC2)n1

Procedure:
The procedure of Example 27 was repeated except for using 7-bromo-4-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine and 4-nitrophenylboronic acid instead of 7-bromo-4-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yloxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine and 4-methanesulfonyl-phenylboronic acid in Step 27-2 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:33]([F:34])=[C:32]([F:35])[C:31]([F:36])=[C:30]([F:37])[C:3]=1[O:4][S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14]([CH:18]1[CH2:22][CH2:21][CH2:20][N:19]1C(OC(C)(C)C)=O)=[CH:13][CH:12]=[CH:11]2)(=[O:7])=[O:6].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>C(Cl)Cl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[CH:17][C:8]([S:5]([O:4][C:3]1[C:30]([F:37])=[C:31]([F:36])[C:32]([F:35])=[C:33]([F:34])[C:2]=1[F:1])(=[O:7])=[O:6])=[CH:9]2
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(C3CCCN3)cccc2c1
Yield: 93.6 %

Procedure:
A 25-mL round-bottom flask was charged with tert-butyl 2-(6-((perfluorophenoxy)sulfonyl)naphthalen-1-yl)pyrrolidine-1-carboxylate (674 mg, 1.240 mmol), DCM (4960 μl), and trifluoroacetic acid (2389 μl, 31.0 mmol) to give a clear, very lightly-colored solution After 1 h, the mixture was concentrated, and the residue was taken up in diethyl ether and sonicated, resulting in the formation of a white solid. The mixture was filtered, and the collected solid was washed with diethyl ether, dried over a stream of N2 (g) for 20 min, then dried under vacuum for 30 min to give perfluorophenyl 5-(pyrrolidin-2-yl)naphthalene-2-sulfonate 2,2,2-trifluoroacetate (647 mg, 1.161 mmol, 94% yield) as a white solid: m/z (ESI) 444.2 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[N+](C1C=CC=CC=1S[NH:34][CH2:35][C:36]([O-:38])=[O:37])([O-])=O>ClCCl.C1(S)C=CC=CC=1.C(O)(C(F)(F)F)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:23])[C:9]2[C@@H:15]3[CH:16]=[C:17]([CH3:20])[CH2:18][CH2:19][C@H:14]3[C:13]([CH3:22])([CH3:21])[O:12][C:10]=2[CH:11]=1.[NH2:34][CH2:35][C:36]([O-:38])=[O:37]
Reactant: O=C([O-])CNSc1ccccc1[N+](=O)[O-]
Agent: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(C)=C[C@@H]21
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)[O-]

Procedure:
THC N-(2-nitrophenylsulfenyl)glycinate (6.1 mg, 0.0116 mmol) was dissolved at ambient temperature in dry dichloromethane containing 10% (v/v) of thiophenol and 1.5% (v/v) of TFA (100 μl). After 5 min the mixture was quenched by addition of 120 μL 3% triethylamine in DCM (at 0° C.). The solution of crude product was chromatographed directly on silica gel with dichloromethane-methanol (gradient 1:0, 20:1, 10:1, 5:1). The combined fractions containing the product were diluted with chloroform, concentrated at 25° C. to ˜3 mL, diluted with chloroform and concentrated again to ˜0.5 mL. The solution of product was diluted with chloroform again (˜5 mL) and concentrated to dryness. Remaining oil was immediately dissolved in chloroform, concentrated to dryness (2.49 mg, 58%), and immediately dissolved in chloroform to afford a stock solution of THC glycinate (ALL00130) stored at −20° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]>>[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: N#Cc1cccc(CBr)c1
Agent: Cl
Product: Cc1c(-c2cccnc2)n(Cc2cccc(C#N)c2)c2ccccc12

Procedure:
3-Methyl-2-pyridin-3-yl-1H-indole hydrochloride (Example 1) and 3-bromomethyl-benzonitrile are processed according to the method described in Example 25 to give 3-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile. 1H NMR (400 MHz, MeOD) δ ppm 2.33 (s, 3H), 5.41 (s, 2H), 7.08 (d, J=8.1 Hz, 1H), 7.16 (s, 1H), 7.20 (t, J=7.2 Hz, 1H), 7.27 (ddd, J=7.6, 1.0 Hz, 1H), 7.37 (d, J=5.8 Hz, 1H), 7.38-7.42 (m, 1H), 7.54-7.57 (m, 1H), 7.57 (s, 1H), 7.68 (d, J=7.8 Hz, 1H), 7.85 (dt, J=7.8, 1.9 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.8, 1.5 Hz, 1H). HRMS (ESI) m/z 324.1491 [(M+H)+ Calcd for C22H18N3: 324.1501].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[NH:17][CH:16]=[C:15]([C:18]([OH:20])=O)[C:11]=3[N:12]=[CH:13][N:14]=2)=[C:5]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:4]=1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([NH:39][C:18]([C:15]2[C:11]3[N:12]=[CH:13][N:14]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:21][CH2:22][CH2:23][O:24][CH3:25])[C:10]=3[NH:17][CH:16]=2)=[O:20])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)O)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A74) and commercially available trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound was obtained as colorless solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[C:8]=1[CH3:14].[F:15][CH:16]([F:23])[C:17]1[CH:22]2[CH:20]([CH2:21]2)[O:19][N:18]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.C(OCC)C>[F:15][CH:16]([F:23])[C:17]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[C:8]=2[CH3:14])[CH:22]2[CH:20]([CH2:21]2)[O:19][NH:18]1
Reactant: Cc1c(F)cccc1I
Reactant: FC(F)C1=NOC2CC12
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1c(F)cccc1C1(C(F)F)NOC2CC21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.3 %

Procedure:
To a flame dried RBF was added a solution of n-butyllithium (2.5M in hexanes; 3.01 ml, 7.51 mmol) and diethyl ether (15 ml). The solution was cooled to −78° C., and 2-fluoro-6-iodotoluene (0.981 ml, 7.51 mmol) was added dropwise and the reaction was stirred at −78° C. for 10 minutes. A −78° C. premixed solution of 4-(difluoromethyl)-2-oxa-3-azabicyclo[3.1.0]hex-3-ene (1.00 g, 7.51 mmol) and boron trifluoride diethyl etherate (0.927 ml, 7.51 mmol) in toluene (10 ml) was added to the reaction via syringe. The reaction was stirred at −78° C. for 10 minutes, quenched with saturated ammonium chloride and warmed to RT. The reaction was diluted with water and EtOAc. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-20% ethyl acetate in hexanes to afford 4-(difluoromethyl)-4-(3-fluoro-2-methylphenyl)-2-oxa-3-azabicyclo[3.1.0]hexane (0.81 g, 3.33 mmol, 44.3% yield).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][NH:16][CH2:15]2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[C:50](O)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[C:50]([N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:25])[CH2:8][CH2:9]2)[CH2:15]1)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: Cc1ccccc1C1CCN(CC2CNCC2c2ccccc2)CC1
Reactant: O=C(O)c1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C1CCN(CC2CN(C(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
The title compound was prepared from 3-(SR)-(4-(2-tolyl)-piperidin-1-ylmethyl)-4-(SR)-phenylpyrrolidine (Step A), 0.014 mL of DIEA, 12.5 mg of BOP-Cl and 5 mg of benzoic acid in 0.5 mL of CH2Cl2 using a procedure analogous to that described in Example 63 to provide the title compound. RF : 0.45 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 1.4-4.5 (m, 20H), 7.05-7.6 (m, 14H). Mass Spectrum (CI): 439.4 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=O)[OH:11])[CH3:3].C(Cl)Cl.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:17])[OH:11])[CH3:1]
Reactant: CCNCC
Reactant: CN(C)CC1CCCCC1(O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCN(CC)C(=O)c1cccc(C2(O)CCCCC2CN(C)C)c1
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
A sample of 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-benzoic acid (0.1 g, 0.36 mmol), CH2Cl2 (5 mL), and diethylamine (0.08 mL, 0.36 mmol) was placed into a flask and stirred for 5 min. To the reaction was added HATU (0.13 g, 0.36 mmol) and stirring was continued for 2 h. Water was added and the organic phase was separated, washed again with water, dried (Na2SO4), and filtered. The filtrate was evaporated in vacuo and the residue passed through a silica gel column (90:10:1, CH2Cl2:MeOH:NH4OH) to give 42 mg (35%) of 3-[(1-RS,2-RS)-2-[(dimethylamino)methyl]-1-hydroxycyclohexyl]-N,N-diethyl-benzamide: MS m/z=333 (MH+); 1H NMR (CDCl3) δ 7.7-7.2 (Ar, 4H), 3.6 and 3.2 (bq, 4H), 2.4 (dd, 1H), 2.1 (s, 6H), 2.0-1.5 (m, 10H), 1.1 (bt, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:12]3[CH2:14][CH2:13]3)[O:10][C:3]=12
Reactant: Clc1ccnc2cc(I)oc12
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(C3CC3)oc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
7-Chloro-2-iodofuro[3,2-b]pyridine (0.130 g, 0.47 mmol), cyclopropylboronic acid (0.080 g, 0.93 mmol), and tricyclohexylphosphine (0.026 g, 0.093 mmol) were dissolved in 3 mL toluene and 1 mL water. Potassium phosphate (0.30 g, 1.4 mmol) was added followed by PdOAc2 (0.010 g, 0.047 mmol), the reaction was flushed with argon, and the reaction stirred at 100° C. for 48 h. The reaction was cooled to RT and partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The crude material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chloro-2-cyclopropylfuro[3,2-b]pyridine as an orange oil. MS: M+H+=194.4.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC3CCCCC3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCCC1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(CCC3CCCCC3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(CCC3CCCCC3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.056 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 1-bromo-2-cyclohexylethane (0.053 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-cyclohexyl-ethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H28ClN3, 357.20; found, m/z 358.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.46-7.34 (m, 4H), 4.08 (t, J=7.6 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.94-2.92 (m, 2H), 1.68-1.20 (m, 7H), 1.18-1.05 (m, 4H), 0.93-0.86 (m, 2H).
Reaction SMILES: O.O.[OH-].C[N+](C)(C)C.[C:9]([NH2:17])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]>C1(C)C(C)=CC=CC=1>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:17][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: NC(=O)c1ccccc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Reaction time: 4 h
Yield: 25 %

Procedure:
A solution of tetramethylammonium hydroxide dihydrate (TMA(H)·2H2O) (1.8 g, 14.0 mmole), benzamide (1.2 g., 9.9 mmole) and 10 ml of xylene was stirred under nitrogen at 70° C. The water and xylene was removed by vacuum distillation at 740 mmHg/70° C. Nitrobenzene (1.2 g., 9.7 mmole) was added dropwise and the solution was stirred for 4 hours under nitrogen after which time an aliquot was removed for HPLC analysis. 4'-Nitrobenzanilide was produced in 25% yield based on benzamide. Azoxybenzene was generated in 8% yield in this reaction.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[Cl:29][C:30]1[C:31]2[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:32]=2[N:33]=[CH:34][N:35]=1.[ClH:41].C([O-])(O)=O.[Na+]>CC(O)(C)C.O1CCOCC1>[ClH:29].[ClH:41].[NH2:7][C:8]1[C@:9]([CH3:27])([C:23]([F:24])([F:25])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]3[C:31]4[N:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:32]=4[N:33]=[CH:34][N:35]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Clc1cnc2c(Cl)ncnc2c1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(Nc3ncnc4cc(Cl)cnc34)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 100 °C

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (CAS registry 1262859-70-0) (138 mg, 0.34 mmol) and 4,7-dichloro-pyrido[3,2-d]pyrimidine (CAS registry 917757-12-1) (75 mg, 0.374 mmol) in tBuOH (2 ml) was added 0.1 ml 4N HCl in dioxane and the reaction mixture was heated in a microwave oven for 1 h at 100° C. The reaction mixture was basified with saturated NaHCO3 solution and the product was extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in THF, acidified with 1N HCl in Et2O, and concentrated. The remaining yellow solid was two times triturated with Et2O and subsequently dried to afford the title compound as light yellow amorphous solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9]N[CH2:7][CH2:6]2)OCC1.Cl.Cl[C:13]1[CH:18]=[CH:17]N=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CC(C)C>[CH3:15][CH2:14][CH2:13][CH2:18][CH2:17][CH2:9][CH2:10][CH2:5][CH2:6][CH3:7]
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)CCO
Product: CCCCCCCCCC

Procedure:
A mixture of 1,4-dioxa-8-azaspiro[4,5]decane (51.2 ml), 4-chloropyridine hydrochloride (20 g) and potassium carbonate (18.4 g) in isoamyl alcohol (400 ml) was gently refluxed for 18 hr. The reation mixture was cooled and filtered. The filtrate was evaporated to give a waxy solid which was triturated with hexane to give 8-(4-pyridyl)-1,4-dioxa-8-azaspiro]4,5]decane (24.16 g) as a colourless solid; NMR (d6DMSO) δ 1.65-1.70(4H,m), 3.45-3.55(4H,m), 3.9(4H,s), 6.90(2H,m), 8.15(2H,m); m/Z 221 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:11][CH3:12])[CH2:7][CH:6](OC)[NH:5][C:4]1=[O:10].[C:13]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:19][C@H:18]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[CH:32]1)(=[O:15])[CH3:14]>C1C=CC=CC=1.CC(C)=O>[C:13]([O:16][C@@H:17]1[C@H:21]([O:22][C:23](=[O:25])[CH3:24])[C@@H:20]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:19][C@H:18]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH:36][CH:6]3[NH:5][C:4](=[O:10])[C:3]([O:2][CH3:1])([O:11][CH3:12])[CH2:7]3)[C:34]=2[N:33]=[CH:32]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COC1CC(OC)(OC)C(=O)N1
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: COC1(OC)CC(Nc2ncnc3c2ncn3[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)NC1=O
Temperature: 160 °C
Yield: 73.4 %

Procedure:
3,3,5-Trimethoxy-2-pyrrolidinone (445 mg) was evenly admixed with adenosine 2',3',5'-triacetate (1 g) and the mixture was melted and reacted by heating at 160° C. for 2 hours. The reaction mixture was then allowed to cool and subjected to silica gel column chromatography using benzene-acetone (2:1) as the eluent to give N6 -(3,3-dimethoxy-2-oxo-5-pyrrolidinyl)adenosine 2',3',5'-triacetate (1 g). This product was dissolved in ammonia-saturated methanol (30 ml) and left standing at 5° C. for 17 hours, after which time it was concentrated under reduced pressure. The residue was washed with benzene and the insolubles were subjected to silica gel column chromatography using chloroform-methanol (10:1) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give crystals. Recrystallization from methanol-acetone yielded N6 -(3,3-dimethoxy-2-oxo-5-pyrrolidinyl)adenosine as colorless crystals (680 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.57 g) was dissolved in N,N-dimethylformamide (5 ml), to which were added potassium carbonate (0.24 g) and ethyl bromoacetate (210 ml), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, followed by the extraction with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-[4-(ethoxycarbonylmethoxy)phenyl]isoquinoline (0.57 g) as a pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].O1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17]CC1.CN(C)C=O>O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[N:21]1[CH2:22][CH2:23][C:18](=[O:17])[CH2:19][CH2:20]1
Reactant: Clc1cnccn1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCN(c2cnccn2)CC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 27.1 %

Procedure:
A mixture of 20 g (0.1746 mol) of chloropyrazine, 36 g (0.260 mol) of K2CO3, 76 g (0.5308 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, and 80 ml of dimethylformamide is stirred at 100° C. for 3 days. The reaction mixture is cooled, diluted with water, and extracted with ethyl acetate. The combined extracts are washed with water, dried over Na2SO4 and concentrated in vacuo. The residue, 400 ml of 10% sulfuric acid solution and 100 ml of tetrahydrofuran are stirred at ambient temperature for 4 days, diluted with water, basified (NaOH) and extracted with methylene chloride. The extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. Trituration with ether gives 8.4 g of title compound: IR (KBr) 1720 and 1580 cm-1 ; NMR (CDCl3) δ 8.24-7.88 (m, 3H), 3.98 (t, 4H), and 2.56 (t, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CC(C)c1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(NN(C)C(=O)OC(C)(C)C)c1
Temperature: 50 °C
Yield: 26.7 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 300 mg, 2.05 mmol), 2-isopropylphenylboronic acid (Lancaster; 330 mg, 2.01 mmol), copper(II) acetate (373 mg, 2.05 mmol) and triethylamine (287 μL, 2.05 mmol) in 1,2-dichloroethane (4 mL) was heated in an oil bath at 50° C. for 3 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5% ethyl acetate/hexanes, to give N′-(3-isopropyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (142 mg, 26%) as an oil.