Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:16])[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CN(Cc2ccc(Br)cc2)C(=O)N1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CN(Cc2ccc(Br)cc2)C1=O
Temperature: 50 °C
Reaction time: 48 h
Yield: 83.2 %

Procedure:
1-(4-Bromobenzyl)imidazolidine-2,4-dione (1B4) (1.86 mmol, 500 mg) was dissolved in DMF (7 ml) and potassium carbonate (5.57 mmol, 770 mg) and iodomethane (1B5) (1.86 mmol, 0.116 ml, 264 mg) were added and the reaction mixture was stirred at 50° C. under nitrogen. The reaction was monitored by TLC and after 48 h of heating some starting material remained. An additional 2 equivalents of iodomethane (3.72 mmol, 0.232 ml, 528 mg) was added and the mixture stirred at 75° C. under nitrogen overnight. The reaction mixture was cooled to room temperature, filtrated and concentrated, then purified on silica eluting with heptane/EtOAc/EtOH 5/4/1 to give 1-(4-bromobenzyl)-3-methylimidazolidine-2,4-dione (1B6) 438 mg, (83%); 1H NMR (400 MHz, CDCl3) 7.51 (d, 2H) 7.15 (d, 2H) 4.53 (s, 2H) 3.74 (s, 2H) 3.06 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccc([N+](=O)[O-])cc4)c3C2=O)C(=O)N1
Yield: 74 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (2.2 g, 8.0 mmol) and 4-nitrobenzoyl chloride (3.0 g, 16.0 mmol) in THF (80 mL) was heated to reflux for 15 h. To the mixture was added methanol (20 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-Dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-4-nitro-benzamide as a white solid (2.5 g, 73% yield): mp, 298-300° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.98 (m, 1H, CHH), 5.18 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.73 (d, J=7.2 Hz, 1H, Ar), 7.93 (t, J=8.0 Hz, 1H, Ar), 8.19-8.22 (m, 2H, Ar), 8.42-8.47 (m, 3H, Ar), 10.65 (s, 1H, NH), 11.18 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 48.99, 119.30, 119.56, 124.06, 127.49, 129.01, 131.58, 135.77, 136.23, 138.96, 149.69, 163.65, 166.57, 167.48, 169.68, 172.72; Anal Calcd for C20H14N4O7: C, 56.88; H, 3.34; N, 13.27. Found: C, 57.15; H, 3.02; N, 13.22.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>C1COCC1.[Cu]I>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:14]([OH:15])[CH2:16][CH:17]=[CH2:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CO2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CC[C@H](O)C(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
(2R)-2-benzhydryl-oxirane (0.5 g, 2.38 mmol) 23a was dissolved in dry THF (5 ml) and was added into a dry THF solution at −78° C. containing CuI (0.045 g, 0.24 mmol) and vinylmagnesium bromide (5.95 ml of 1.0M solution in THF, 5.95 mmol). The reaction mixture was stirred and allowed to reach room temperature over a period of 2 h, and then quenched with saturated NH4Cl solution. The aqueous phase was extracted with ethyl acetate (3×30 ml). The combined organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by flash chromatography on silica gel (Hexane/Ethyl Ether=4:1) to give 0.4 g (2S)-1,1-diphenyl-pent-4-ene-2-ol (70%, [α]D=(−)25, c=1, MeOH).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][C:19]2[C:24](Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[C:26]([O:28]C)=[O:27])=[C:8](/[CH:30]=[C:31](\[CH2:37][C:38]2[C:46]([O:47][CH3:48])=[CH:45][C:41]3[CH2:42][CH2:43][O:44][C:40]=3[CH:39]=2)/[C:32]([O:34]CC)=[O:33])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].CCOC(C)=O.CCCCCC>CC(O)=O>[CH2:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:26]([OH:28])=[O:27])=[C:8](/[CH:30]=[C:31](\[CH2:37][C:38]2[C:46]([O:47][CH3:48])=[CH:45][C:41]3[CH2:42][CH2:43][O:44][C:40]=3[CH:39]=2)/[C:32]([OH:34])=[O:33])[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)OCC)c1-c1ccc(Cl)cc1OCc1c(Cl)cccc1C(=O)OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCn1ncc(/C=C(\Cc2cc3c(cc2OC)CCO3)C(=O)O)c1-c1ccc(Cl)cc1OCc1ccccc1C(=O)O
Yield: 90 %

Procedure:
Following the procedure of Example (1u) except substituting Ethyl (E)-3-[1-n-Butyl-5-[2-(2-methoxycarbonyl)phenylmethoxy-4-chlorophenyl]- 1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate for ethyl (E)-[1-n-butyl-5-[2-(2-(methoxycarbonyl)-6-chlorophenylmethoxy]-4-chlorophenyl]-1H-pyrazol-4-yl]-2-[(5-methoxy-2,3-dihydrobenzofuran-6-yl)methyl]-2-propenoate, the title compound was prepared in 90% yield as a white solid: Rƒ0.58 (1:1 EtOAc/hexane with 1% AcOH); 1H NMR (400 MHz CDCl3) d 8.19 (d, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.49 (t, 1H), 7.30 (m, 2H), 7.13 (m, 3H), 6.77 (s, 1H), 6.48 (s, 1H), 5.52 (bs, 2H), 4.45 (t, 2H), 3.92 (m, 2H) 3.82 (s, 3H), 3.80 (bs, 2H), 3.12 (t, 2H), 1.65 (m, 2H), 1.12 (m, 2H), 0.76 (t, 3H); MS(ESI) m/e 618 [M+H]+; mp: 116-118° C. Anal. (C34H33ClN2O7.0.5H2O) calcd: C, 65.22; H, 5.47; N, 4.47, found: C, 65.03; H, 5.33; N, 4.37.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:27]>O>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Ag+:27]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
7.5 g of stearic acid and 1.2 g of sodium hydroxide were added to 300 ml of water and sufficiently stirred until they were completely dissolved. 5.2 g of silver nitrate was added thereto, and the result was stirred for 3 hours. White powder on the surface of the result was collected and washed three times each with distilled water and with methanol to obtain silver stearate. An anode active material was prepared as in Example 1, except that silver stearate was used instead of nickel stearate, the molar ratio of silver to silicon was 0.2:1, the weight ratio of silicon to graphite was 0.5:1, and the carbon layer was 5.2 wt % of the anode active material.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[C:8]([OH:11])[CH:9]=2)[CH2:4][CH2:3]1.[Br:14]Br.C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[Br:14][C:9]1[C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=[C:5]2[C:10]=1[C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4]2
Reactant: BrBr
Reactant: Cc1cc2c(cc1O)C(C)(C)CC2
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc2c(c(Br)c1O)C(C)(C)CC2
Temperature: 0 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a 25 mL one necked round bottom flask, 3,3,6-trimethylindan-5-ol was dissolved in acetic acid (10 mL). The solution was cooled down to 0° C. followed by slow addition of bromine (290 μL, 5.65 mmol). The reaction was slowly warmed up to room temperature. After 3 h of stirring, the reaction was completed. Excess acetic acid was removed by rotavap, and the residue was quenched with ascorbic acid solution. The content was extracted with sodium bicarbonate and brine. Plugged column with silica gel 5:95 ethyl acetate:hexane gave colorless oil, 4-bromo-3,3,6-trimethylindan-5-ol (82% yield). 1H NMR (300 MHz, CDCl3): δ 1.42 (s, 6H), 1.98(dd, 2H, J=15.11, 7.55 Hz), 2.24 (s, 3H), 2.54 (s, 3H), 2.57 (s, 3H), 2.85(d, 2H, J=7.55 Hz), 3.89 (s, 3H), 5.12(d, 1H, J=3.40 Hz), 6.31 (s, 1H), 6.95(m, 1H), 7.01 (s, 1H), 7.12(d, 1H, J=3.40) 8.34 (bs, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[I-:14].[Na+]>C(C(C)=O)C>[I:14][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(CCCI)c1ccc(F)cc1
Yield: 96.2 %

Procedure:
20 g of 1-chloro-3-(p-fluorophenylcarbonyl)propane dissolved in 100 cm3 of methyl ethyl ketone are refluxed for 24 hours in the presence of 18.5 g of sodium iodide. After treatment, 28 g of the desired compound are isolated.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:32]([CH:29]3[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]3)=[O:33])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.5 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (100 mg, 0.41 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (94 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated using rotary evaporator to obtain 14 mg of tert-butyl 4-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethylcarbamoyl)piperidine-1-carboxylate after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0. 05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). The compound obtained was taken in 3 ml of HCl in dioxane and stirred for 1 h to obtain 5 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)piperidine-4-carboxamide as HCl Salt. 1H NMR (DMSO) 10.78 (bs, 1H), 8.1 (bs, 1H), 7.40 (d, 1H), 7.2 (s, 1H), 7.05 (d, 1H), 4.6-4.2 (m, 1H), 4.3-4.2 (m, 1H), 4.2 (m, 2H), 4.0-3.8 (m, 3H), 3.35-3.05 (m, 4H), 3.0 (s, 3H), 2.95-2.8 (m, 2H), 2.4 (s, 3H), 2.3-2.2 (m, 1H), 2.1-2.00 (m, 1H), 1.8-1.6 (m, 4H).
Reaction SMILES: C([O:8][C:9](=[O:22])[C@H](CCCNC(=N)N)N[N+]([O-])=O)C1C=CC=CC=1.C(OC(=O)[C@H](C)N)C1C=CC=CC=1.C([O:43][C:44](=[O:67])[C@H:45]([CH2:60][CH2:61][CH2:62][NH:63][C:64](=[NH:66])[NH2:65])[N:46]([N+]([O-])=O)[C:47](=[O:56])[CH:48]([CH3:55])[CH2:49][CH2:50]C(OC)=O)C1C=CC=CC=1.COC(CCC(C)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)=O.C(CCC(C)C(N[C@H](C(O)=O)CCCNC(=N)N)=O)(O)=O>>[C:9]([CH:61]([CH2:62][NH:63][C:64](=[NH:66])[NH2:65])[CH2:60][C@@H:45]([C:44]([OH:43])=[O:67])[NH:46][C:47](=[O:56])[CH:48]([CH3:55])[CH2:49][CH3:50])([OH:22])=[O:8]
Reactant: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)OCc1ccccc1
Reactant: COC(=O)CCC(C)C(=O)N([C@@H](CCCNC(=N)N)C(=O)OCc1ccccc1)[N+](=O)[O-]
Agent: CC(CCC(=O)O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: COC(=O)CCC(C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: C[C@H](N)C(=O)OCc1ccccc1
Product: CCC(C)C(=O)N[C@@H](CC(CNC(=N)N)C(=O)O)C(=O)O

Procedure:
By substituting nitro-L-arginine benzyl ester for the L-alanine benzyl ester in the procedure of Example 23, and then treating the product by the procedures of Examples 24 and 26, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-nitro-L-arginine benzyl ester, Nα -(4-methoxycarbonyl-2-methylbutanoyl)-L-arginine, and Nα -(4-carboxy-2-methylbutanoyl)-L-arginine are obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][C:40](=[O:44])[NH:41]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([C:35]2[CH:43]=[C:42]3[C:38]([CH2:39][C:40](=[O:44])[NH:41]3)=[CH:37][CH:36]=2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3c(c2)NC(=O)C3)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4c(c3)NC(=O)C4)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.187 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-indol-2-one (63.1 mg, 0.243 mmol), DMSO(1.5 mL), sodium carbonate (0.281 mL, 0.562 mmol), and bis(triphenylphosphine)palladium(II) chloride (10.51 mg, 0.015 mmol). The final product was collected as 10 mg (11%). LCMS E-S (M+H)=471.1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.8 Hz, 6 H), 2.13 (s, 3 H), 2.22 (s, 3 H), 3.58 (s, 2 H), 4.41 (d, J=4.8 Hz, 2 H), 5.31 (quin, J=6.6 Hz, 1 H), 5.91 (s, 1 H), 7.38 (d, J=7.6 Hz, 1 H), 7.73 (d, J=1.0 Hz, 1 H), 7.87 (dd, J=7.8, 1.5 Hz, 1 H), 8.12 (s, 1 H), 8.37 (s, 1 H), 9.00 (t, J=4.8 Hz, 1 H), 10.55 (s, 1 H), 11.58 (s, 1 H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]2[C:7]([CH3:10])=[CH:8][O:9][C:5]=2[CH:4]=1.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1>O1CCOCC1>[Cl:13][C:12]1[C:3]([N:2]2[CH:16]=[CH:20][CH:19]=[CH:18]2)=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1coc2cc(N)c(Cl)cc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1coc2cc(-n3cccc3)c(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7 ml of 5N hydrochloric acid are added to a mixture of 9.1 g (50 mmole) of 6-amino-5-chloro-3-methylbenzofuran, 10 ml (78 mmole) of 2,5-dimethoxytetrahydrofuran and 200 ml of dioxane and the whole is stirred at room temperature for 16 hours. The whole is subsequently concentrated by evaporation in vacuo and the residue is chromatographed over silica gel with petroleum ether/methylene chloride. Crystallisation of the resulting product from petroleum ether yields 5-chloro-3-methyl-6-(pyrrol-1-yl)-benzofuran having a melting point of 49°-52°.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[CH2:12][C:11](=[O:13])[NH:10][N:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[CH2:12][C:11](=[O:13])[NH:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC2=NNC(=O)C2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CC(Cc2ccc(O)cc2)=NN1
Temperature: -78 °C
Reaction time: 12 h

Procedure:
A stirred suspension of 3-(4-methoxybenzyl)-2-pyrazolin-5-one 2.5 mmol in dichloromethane 100 ml cooled at −78° C., was treated with boron tribromide 7.5 ml (1M in dichloromethane). After 1 hour at −78° C. the reaction mixture was stirred at room temperature for 12 hours. The mixture was quenched with water 50 ml. The aqueous phase was separated out, and basified with 5% sodium bicarbonate solution. The formed precipitate was filtered and crystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][N:22]=1)=[S:32]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(N2CCOCC2)cc1NC(=O)c1ncc[nH]1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(N2CCOCC2)cc1NC(=S)c1ncc[nH]1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a suspension of 1.0 g of imidazole-2-carboxylic acid (8.9 mmol) in 15 ml DMF was added 1.6 g of CDI (9.8 mmol) and stirred at ambient temperature for 1 h. Then the mixture was refluxed for 30 min. After cooling to ambient temperature, 2.0 g of 2-methoxy-5-morpholin-4-yl-phenylamine (9.8 mmol) were added and the reaction mixture was heated to reflux for 16 h. The mixture was evaporated and the residue taken up in water (40 ml) and extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 2:1). 0.25 g 1H-imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (9%) were obtained as a white solid; M.p.: 227–230° C. 0.2 g of 1H-Imidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (0.66 mmol) were taken up in toluene (8.0 ml) and treated with 0.8 g of Lawesson reagent (2.0 mmol). The reaction mixture was heated to reflux for 22 h. After cooling to ambient temperature, water (25 ml) was added and the mixture was extracted 3 times with ethyl acetate. The combined organic phases were dried on sodium carbonate, evaporated and the residue subjected to column chromatography (silica gel, ethyl acetate/hexanes 1:1). 0.125 g of 1H-imidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (59%) was obtained as a yellow foam; MS (ISP): m/e=319 (M+H+).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([CH2:39][S:40][C:41]2[C:46]([C:47]([OH:49])=O)=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:36]=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:50][C:51]1[CH:56]=[C:55]([CH3:57])[CH:54]=[C:53]([CH3:58])[CH:52]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:25]([O:29][C:30]([NH:32][C:33]1[CH:38]=[C:37]([CH2:39][S:40][C:41]2[C:46]([C:47]([NH:50][C:51]3[CH:56]=[C:55]([CH3:57])[CH:54]=[C:53]([CH3:58])[CH:52]=3)=[O:49])=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:36]=[CH:35][N:34]=1)=[O:31])([CH3:27])([CH3:28])[CH3:26]
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(CSc2ncccc2C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC(=O)OC(C)(C)C)c2)c1

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (630 mg, 1.7 mmol) was added to a solution of 2-(2-tert-butoxycarbonylaminopyridin-4-ylmethylthio)pyridine-3-carboxylic acid (Reference compound No. 9-1, 500 mg, 1.4 mmol), 3,5-xylidine (180 mg, 1.5 mmol) and N,N-diisopropylethylamine (0.72 mL, 4.1 mmol) in N,N-dimethylformamide (7 mL) at room temperature, and the mixture was stirred for 12 hours. Ethyl acetate (30 mL) was added to the reaction mixture, then the whole was washed with brine (50 mL) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure, then the resulting residue was purified by silica gel column chromatography to give 670 mg of the target compound quantitatively as a colorless solid.
Reaction SMILES: [CH:1]([CH:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[N-:11]=[N+:12]=[N-:13].[Na+].CN(C)C=O>C(OCC)C>[CH:1]([CH:3]([N:11]=[N+:12]=[N-:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2]
Reactant: C=CC(Cl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CC(N=[N+]=[N-])c1ccccc1
Yield: 100.7 %

Procedure:
A mixture of 100 grams (655 mmol.) of vinylbenzyl chloride (mixture of m- and p-isomers), 42.6 grams (655 mmol.) of sodium azide and 500 mi. of dimethylformamide was stirred at room temperature for 24 hours. Ethyl ether, 500 mi., was then added and the mixture was extracted with two 300-mi. portions of water. The combined aqueous phases were extracted with 500 mi. of ethyl ether, and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to yield 105 grams (100% of theoretical) of vinylbenzyl azide. The structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy and infrared spectroscopy.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:14]([O:16]C(C)(C)C)=[O:15]>Cl>[ClH:1].[CH3:2][C:3]1[N:7]2[CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][N:11]=[C:6]2[S:5][C:4]=1[C:14]([OH:16])=[O:15]
Reactant: CC1=C(C(=O)OC(C)(C)C)SC2=NCC(C)(C)CN21
Agent: Cl
Product: CC1=C(C(=O)O)SC2=NCC(C)(C)CN21
Temperature: 25 °C
Reaction time: 7 h
Yield: 78.9 %

Procedure:
In 100 ml of 2N hydrochloric acid was suspended 2.0 g of tert-butyl 3,6,6-trimethyl-6,7-dihydro-5H-thiazolo[3,2-a]-pyrimidine-2-carboxylate hydrochloride obtained in Example 119, followed by stirring at room temperature for 7 hours. The precipitated crystals were collected by filtration and washed with diethylether and acetone to obtain 1.3 g of the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:33]>C(O)(C(F)(F)F)=O.CO.C(Cl)Cl.CCOCC>[ClH:33].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C@@H:14]4[CH2:18][CH2:17][CH2:16][O:15]4)=[O:13])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4CCCO4)c23)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4CCCO4)c23)C1
Yield: 82.4 %

Procedure:
A solution of tert-butyl (R)-1-(5-bromo-3-((S)-tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.295 mmol) in neat TFA (3 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo. The resulting residue was purified by C-18 reverse phase flash chromatography (Biotage C-18, 12M+) on Biotage SP4 unit eluting with a gradient of 1-50% CH3CN/water gradient (14 CV). The product obtained was dissolved in minimal MeOH, diluted with CH2Cl2 (1 mL), and treated with 1M HCl in ether (3 mL). The resulting suspension was concentrated in vacuo and evaporated from CH2Cl2 (3×5 mL). The solid obtained was dried under high vacuum to provide (S)-N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetra-hydrofuran-2-carboxamide hydrochloride (117 mg, 0.243 mmol, 82.4% yield) as a solid. NMR (400 MHz, (CD3)2SO) δ 11.72 (s, 1H), 9.82 (s, 1H), 8.29 (br s, 3H), 8.21 (s, 1H), 7.89 (s, 1H), 4.39 (t, 1H), 4.02-3.97 (m, 1H), 3.85-3.79 (m, 2H), 3.63-3.55 (m, 1H), 3.42-3.35 (m, 1H), 3.33-3.21 (m, 2H), 2.97-2.89 (m, 1H), 2.27-2.19 (m, 1H), 2.17-2.09 (m, 1H), 1.97-1.92 (m, 1H), 1.89-1.83 (m, 2H), 1.79-1.73 (m, 1H), 1.49-1.40 (m, 1H); LCMS (APCI+) m/z 408, 410.1 (M+H)+; Retention time=2.18 minutes (Method 2).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]#[N:12])[NH:6]2.[O-:13][S:14]([C:17]([F:20])([F:19])[F:18])(=O)=[O:15]>>[C:11]([C:5]1[NH:6][C:7]2[C:3]([CH:4]=1)=[C:2]([O:1][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:15])=[O:13])[CH:10]=[CH:9][CH:8]=2)#[N:12]
Reactant: N#Cc1cc2c(O)cccc2[nH]1
Reactant: O=S(=O)([O-])C(F)(F)F
Product: N#Cc1cc2c(OS(=O)(=O)C(F)(F)F)cccc2[nH]1

Procedure:
4-Hydroxy-1H-indole-2-carbonitrile was made as described by Estep, K. G., Synth. Comm. 25: 507-14 (1995). It was converted to the triflate by the procedure in Example 21.