Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])/[C:6]/2=[CH:15]/OC.[N:18]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][NH:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:30][CH:29]=1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(OC)cc21
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=CNc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 77.7 %

Procedure:
A mixture of (4E)-6-methoxy-4-methoxymethylene-4H-isoquinoline-1,3-dione (117 mg, 0.50 mmole), N,N-dimethylformamide (1 mL) and 4-piperidin-1-ylmethyl-phenylamine (95 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator overnight. The reaction mixture is evaporated to dryness, taken up in 7.5% methanol in chloroform and passed through a short pad of Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated in vacuo, treated with acetonitrile, filtered and dried to give a yellow solid 152 mg (78%), mp 272-5° C. dec; MS (ESI): m/z 392.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[NH:12]1[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[NH2:12][CH2:13][CH2:14][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C1CN1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(OCCN)cc1

Procedure:
Methyl p-hydroxybenzoate (7.6 g) was dissolved in 50 ml of chloroform with heating, 2.15 g of aziridine was dropped in with stirring, and the mixture was heated to refluxed for 8 hours. The reaction solution was concentrated in vacuo and the residue was purified by a silica gel column chromatography (200 g of silica gel C-200; the eluting solvent used was a 9:1 mixture of chloroform and methanol).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br>>[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27]
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(Br)c1

Procedure:
The title compound was prepared in a similar manner to that described in Example 11 using 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-5-trifluoromethyl-1H-pyrazole and using 3-bromobenzyl bromide instead of benzyl bromide.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][CH:11]=2)[C:6]([OH:21])=[C:5]([C:22](OCCCC)=[O:23])[N:4]=1)#[N:2].OC(C(F)(F)F)=O.[NH2:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40].C[O-].[Na+]>CCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])=[CH:10][CH:11]=2)[C:6]([OH:21])=[C:5]([C:22]([NH:36][CH2:37][C:38]([CH3:43])([CH3:42])[C:39]([OH:41])=[O:40])=[O:23])[N:4]=1)#[N:2]
Reactant: CC(C)(CN)C(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3C)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Cc1ccccc1Oc1ccc2c(C#N)nc(C(=O)NCC(C)(C)C(=O)O)c(O)c2c1

Procedure:
Butyl 1-cyano-4-hydroxy-6-(o-tolyloxy)isoquinoline-3-carboxylate (11 mg, 0.03 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (27.1 mg, 0.12 mmol) and NaOMe (12.3 mg, 0.23 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 90 minutes. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-25% MeOH/CH2Cl2) to give the title compound in 7 mg. MS: (−) m/z 417.94 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]#[N:31]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:29][C:30]#[N:31])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(O)cn2)CC1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncc(OCC#N)cn2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a stirred solution of 4-(5-hydroxy-pyrimidin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.74 g, 2.5 mmol, 1.0 equiv; intermediate C31/step 2) in DMF (10 mL) was added potassium carbonate (1.05 g, 7.5 mmol, 3.0 equiv), followed by bromoacetonitrile (0.21 mL, 0.37 g, 3.0 mmol, 1.2 equiv). After 90 min, the reaction mixture was poured into ice water and extracted twice with diethylether. The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 0.70 g (84%) of the title compound as a light yellow solid. MS (ISP): 334.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[N:7][CH:8]=1.C(N(CC)CC)C.[C:18]1([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][NH:30][CH2:31]3)=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH3:9][C:6]1[N:5]=[C:4]([NH2:10])[C:3]([CH2:2][N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:25][CH:26]=3)[CH2:31]2)=[CH:8][N:7]=1
Reactant: c1ccc(-c2ccc3c(c2)CNCC3)cc1
Reactant: Cc1ncc(CCl)c(N)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CCc3ccc(-c4ccccc4)cc3C2)c(N)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A suspension of 0.17 g (0.00088 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine in 10 ml of dimethylformamide was treated with 0.30 ml (0.0021 mol) of triethylamine and 0.184 g (0.00088 mol) of 7-phenyl-1,2,3,4-tetrahydro-isoquinoline and the mixture was stirred at room temperature under argon for 18 hours. The solvent was distilled off in a high vacuum. The residue was partitioned between dichloromethane/water, extracted and dried over MgSO4. After removing the solvent the residue was chromatographed over silica gel with ethyl acetate as the eluent. 0.22 g (76%) of 2-methyl-5-(7-phenyl-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-pyrimidin-4-ylamine was obtained as a light yellowish solid; m.p. 147°-149°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Br.[Br:16][CH2:17][CH2:18][CH2:19][NH2:20].C(=O)([O-])O.[Na+]>CC(C)=O.O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9]([NH:20][CH2:19][CH2:18][CH2:17][Br:16])(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NCCCBr)cc1
Temperature: 2.5 °C
Yield: 166.7 %

Procedure:
To a stirred solution of N-acetylsulfanilyl chloride (57.15 g, 0.244 mol) in acetone (500 mL) and H2O (187.5 mL) at 0° C. was added 3-bromopropylamine hydrobromide (25.0 g, 0.114 mol). When a clear solution was obtained, a solution of sodium hydrogencarbonate (44.15 g, 0.526 mol) in H2O (550 mL) was added dropwise, maintaining the internal temperature at 0-5° C. When the addition was completed, the reaction mixture was heated at 50° C. for 5 h, then cooled to room temperature and poured into ice H2O with stirring. After stirring at 5° C. for 4 h, the suspension was filtered and the filter cake was washed with H2O and dried in vacuo to give 34.6 g (90%). An additional reaction was performed to give an additional 63.7 g of similar material.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24]1[CH:25]=C([CH:29]=[CH:30][CH:31]=1)CN>>[CH3:22][O:23][C:24]1[CH:25]=[C:2]([CH:29]=[CH:30][CH:31]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6]
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using 3-methoxybenzylamine instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 379 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (1H, br. s.) 10.48 (1H, br. s.) 10.24 (1H, br. s.) 8.17 (1H, br. s.) 8.02 (1H, d, J=5.47 Hz) 7.79 (1H, d, J=5.27 Hz) 7.44-7.54 (1H, m) 7.31 (1H, d, J=2.73 Hz) 6.82 (1H, br. s.) 6.41 (1H, br. s.) 3.93 (1H, br. s.) 3.39 (1H, br. s.) 3.23 (2H, br.s.) 1.67-1.88 (4H, m) 1.39 (9H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17]C)=O)=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:26]=1.[CH3:27][N-:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:28]([CH3:29])[CH3:27])=[O:17])=[C:10]3[CH2:9][C:8](=[O:19])[N:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:6]=2[CH:26]=1
Reactant: C[N-]C
Reactant: COC(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2
Product: CN(C)C(=O)c1ncn2c1CC(=O)N(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
As described in previous example, 8-chloro-4,6-dihydro-6-phenyl-5-oxo-5H-imidazo[1,5-a][1,5]benzodiazepine-3-carboxylic acid, methyl ester was converted to the dimethylamide, mp. 255°-257°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12].[C:15](N1C=CN=C1)([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:14])([CH3:13])[CH2:11][NH:12][C:15]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)=[O:16]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(CN)c1cc2ccccc2[nH]1
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)n1ccnc1)c1cc2ccccc2[nH]1
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 2-(indol-2-yl)-2-methylpropylamine (363.2 mg) in tetrahydrofuran (10 ml) was added 1,1'-carbonyldiimidazole (340 mg) in small portions at room temperature. After stirring for 3 hours, the reaction mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography (3% methanol-chloroform) to give N-[2-(indol-2-yl)-2-methylpropyl]-1-imidazolecarboxamide (395 mg) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>[Ni].CN(C=O)C>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:10]([CH3:22])([CH3:23])[CH2:9][O:8][C:7]2[CH:24]=[CH:25][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: CC(C)(COc1ccc([N+](=O)[O-])cc1)COc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(C)(COc1ccc(N)cc1)COc1ccc(N)cc1

Procedure:
1949 g 1,3-bis(4-nitrophenoxy)-2,2-dimethylpropane were hydrogenated as in Example 10 in 10 1 DMF in the presence of 300 g Raney nickel. The crude product was recrystallized from ethanol/isopropanol (1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[CH:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11])([O-])=O.[H][H]>O1CCCC1.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([CH2:12][Si:13]([CH3:15])([CH3:14])[CH3:16])[CH3:11]
Reactant: CC(=C[Si](C)(C)C)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C[Si](C)(C)C)c1ccccc1N
Yield: 74.1 %

Procedure:
The reaction product of step A [7.2 g] was hydrogenated in tetrahydrofurane over palladium on charcoal at atmospheric pressure and room temperature until the uptake of hydrogen ceased. The catalyst was filtered off and, after evaporation of the solvent, the product was chromatographed on silacagel (eluent: 10% ethylacetate in hexane) to yield 2-(2-aminophenyl)-3-(trimethylsilyl)-propane [4.7 g; 88% purity according to NMR]. This product was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-])=O)=[CH:15][C:10]=3[S:9](=[O:20])(=[O:19])[C:8]=2[CH:21]=1)([O-])=O.CN(C)C=O.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[C:11]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][C:10]=3[S:9](=[O:20])(=[O:19])[C:8]=2[CH:21]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1cc([N+](=O)[O-])ccc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)S(=O)(=O)c1cc(N)ccc1-2
Yield: 97.7 %

Procedure:
A mixture of 10.0 g of 3,7-dinitrodibenzothiophene S,S-dioxide, 180 ml of dimethylformamide, 20 ml of glacial acetic acid and 1.0 g of 5% palladium on carbon was hydrogenated in a Parr apparatus until hydrogen uptake ceased. The mixture was then filtered through diatomaceous earth, the filtrate poured into 1 liter of ice water, the solid collected by filtration, washed with ethanol and ether and dried at 110° C., giving 7.86 g of the desired product as a solid mp 320°-330° C.(dec.).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:31]=[CH:30][C:29](=[O:32])[N:28]([CH2:33][CH:34]=O)[C:27]=2[N:36]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:8][N:7]([CH2:34][CH2:33][N:28]2[C:29](=[O:32])[CH:30]=[N:31][C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[N:36][C:27]2=3)[CH2:6][CH:5]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])[CH2:4]1
Reactant: CO[C@H]1CNC[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Reactant: COc1ccc2ncc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CC(CN4C(=O)c5ccccc5C4=O)CC(OC)C3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To cis-2-{[(3RS,5SR)-5-(methyloxy)-3-piperidinyl]methyl}-1H-isoindole-1,3(2H)-dione (125 mg, 0.43 mmol) in MeOH (1 ml) and CHCl3 (5 ml) was added [6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]acetaldehyde (for a preparation see Example 126(e)) (100 mg; 0.50 mmol) and the reaction was allowed to stir at room temperature under N2 for 4 hours. Na(OAc)3BH (210 mg; 1.0 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The reaction was partitioned between saturated aqueous NaHCO3 (5 mL) and CH2Cl2 (20 mL), the aqueous layer was further extracted with CH2Cl2 (20 mL), and the combined organic layers were dried over Na2SO4. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (10 mg; 55%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.C([O-])(O)=O.[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:7]([O:6][C:4]([CH:3]1[CH2:9][CH2:10][CH2:11][N:1]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:2]1)=[O:5])[CH3:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a room temperature solution of 4.05 g (25.8 mmoles) of ethyl nipecotate and 4.33 g (51.5 mmoles) of NaHCO3 in water (26 mL) was added benzyl chloroformate (4.1 mL, 28.3 mmol). The reaction mixture was stirred at 23° C. under an atmosphere of N2 overnight. The crude products were diluted with water, extracted with Et2O, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→70:30 hexane:EtOAc) to yield the title compound as a clear colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:16].[B-](F)(F)(F)F.C1[N+]2(O)CC[N+](F)(CC2)C1>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([F:16])[CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)c1ccc2c(c1)CCC2=O
Agent: O[N+]12CC[N+](F)(CC1)CC2
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC(F)C2=O

Procedure:
5-tert-butyl-indan-1-one (7.53 g, 40 mmol) was dissolved in methanol (400 ml). Accufluor (32.18 g) was added, and the reaction heated to reflux for 2 hours. After cooling and removing the solvent under vacuum, the residue was taken in methylene chloride and filtered. The filtrate was washed with water, dried with magnesium sulfate, and filtered, and the solvent removed under vacuum to give 5-tert-Butyl-2-fluoro-indan-1-one, which was used without further purification. 1H NMR (300 MHz, CDCl3) 7.73 (d, 1H), 7.48 (d, 1H), 7.45 (s, 1H), 5.18-5.35 (m, 1H), 3.54-3.65 (m, 1H), 3.12-3.29 (m, 1H), 1.36 (s, 9H). MS (CSI) m/e 224 (M+NH4)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:35]1[CH2:42][S:41][CH2:40][C@H:36]1[C:37]([OH:39])=[O:38]>>[CH3:1][O:2][C:3]1[C:4](=[O:34])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:35]2[CH2:42][S:41][CH2:40][C@H:36]2[C:37]([OH:39])=[O:38])=[O:24])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: O=C(O)[C@@H]1CSCN1
Reactant: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)N2CSC[C@H]2C(=O)O)=C(C)C1=O
Yield: 32.1 %

Procedure:
Using p-nitrophenyl 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoate (474 mg, 1 mmol) and L-thioproline (266 mg, 2 mmol) and following the procedure of Example 13, there was obtained 10-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)decanoyl-L-thioproline (150 mg) as an oil.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][CH2:22][O:23][CH3:24])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:25][CH3:26])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][CH2:22][O:23][CH3:24])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COCCc1cc(Cl)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Solvent: CO
Solvent: CN(C)C=O
Product: COCCc1cc(N)n2nc(SC)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.50 g (1.25 mmol) of 3-benzenesulphonyl-7-chloro-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]-pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 10:1) and crystallization from EtOH yielded 0.30 g (63%) of 3-benzenesulphonyl-5-(2-methoxy-ethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 186-187°.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.C1N=C[N:19]([C:22](N2C=NC=C2)=[O:23])C=1.N>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH2:19])=[O:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(I)cc1F
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NC(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Yield: 99.4 %

Procedure:
Under argon atmosphere, to a solution of 2-fluoro-4-iodoaniline 47 (20.0 g) and triethylamine (23.6 ml) in chloroform (200 ml) was added N,N-carbonyldiimidazole (27.4 g) with stirring under ice-cooling. After the completion of the addition, the mixture was stirred under ice-cooling for 15 min and at room temperature for 4 hrs. The reaction mixture was ice-cooled, and 28% aqueous ammonia (100 ml) was added dropwise. The mixture was stirred at room temperature for 1.5 hrs. The precipitated crystals were collected by filtration, washed with water and dried to give (2-fluoro-4-iodophenyl)-urea 78 (23.5 g, yield 98.8%) as pale-pink crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:13][CH2:14][O:15][CH3:16])/[C:9](/[F:12])=[CH:10]\[F:11])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1>O1CCCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:13][CH2:14][O:15][CH3:16])/[C:9](/[F:12])=[C:10](\[F:11])/[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: COCCC(/C(F)=C\F)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
To a stirred solution of 1-chloro-4-[(2E)-2,3-difluoro-1-(2-methoxyethyl)-2-propenyl]benzene (0.87 g, 3.52 mmol) in tetrahydrofuran (10 ml) under nitrogen at −65° C. was added n-butyllithium (1.1 ml of a 2.5 M solution in hexane, 2.75 mmol). To this mixture was added zinc chloride (5.3 ml of 0.5 M in tetrahydrofuran, 2.65 mmol) and the resulting mixture was stirred for one hour. Tetrakis(triphenyl-phosphine)palladium (0.066 g, 0.057 mmol) in tetrahydrofuran (1 ml) was added, followed by α-bromo-3-phenoxytoluene (0.70 g, 2.66 mmol) in tetrahydrofuran (2 ml), and the resulting mixture was stirred and allowed to warm to room temperature over four hours and was then stirred for another sixteen hours. The reaction mixture was then quenched with water, diluted with 10% hydrochloric acid and thoroughly extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to a brown oil (1.378 g). Chromatography of this oil on silica gel eluting with ethyl acetate:hexane (5:95) afforded the title compound as a yellow syrup (0.359 g) which was characterized by IR, 1HNMR, 19FNMR and mass spectral analysis.