Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.[Cl:29][C:30]1[CH:31]=[C:32]([CH:39]=[CH:40][C:41]=1F)[C:33]([N:35]1[CH2:38][CH2:37][CH2:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:35]1([C:33]([C:32]2[CH:39]=[CH:40][C:41]([O:27][C:25]3[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=3)[C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])=[C:30]([Cl:29])[CH:31]=2)=[O:34])[CH2:38][CH2:37][CH2:36]1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: O=C(c1ccc(F)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 50.6 %

Procedure:
To a mixture of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (215 mg, 0.53 mmol) and 1-(3-chloro-4-fluorobenzoyl)azetidine (135 mg, 0.63 mmol) in DMF (2.0 mL) was added potassium carbonate (146 mg, 1.06 mmol) and the stirred mixture heated at 160° C. in a ‘Smith Creator Microwave’ for 120 minutes. The mixture was allowed to reach ambient temperature and pressure then reduced in volume. Purification by column chromatography, eluting with 0-20% methanol in DCM, afforded the title compound (130 mg).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([Cl:21])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(NC(=O)c2ccccc2)c1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1.5 g of 3-(benzoylamino) benzoic acid suspended in 10 ml of toluene was added 2 ml of thionyl chloride, and the resulting mixture was stirred under a reflux condition for 2 hours. The reaction solution was returned to room temperature, and then the solvent was removed under a reduced pressure to obtain 1.53 g of the desired product (Yield: 95%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]([CH3:24])([C:21](O)=[O:22])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:54][C:55]1[C:63]([NH2:64])=[CH:62][CH:61]=[CH:60][C:56]=1[C:57]([NH2:59])=[O:58]>CN(C=O)C>[NH2:54][C:55]1[C:56]([C:57](=[O:58])[NH2:59])=[CH:60][CH:61]=[CH:62][C:63]=1[NH:64][C:21]([C:20]1([CH3:24])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[O:22]
Reactant: CC1(C(=O)O)Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2cccc(C(N)=O)c2N)Cc2ccccc2CN1C(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Step-4: To a solution of 2-((benzyloxy)carbonyl)-3-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (620 mg, 1.91 mmol) in anhydrous DMF (5 ml) was added EDC.HCl (1.098 mg, 5.73 mmol), HOAt (390 mg, 2.87 mmol) and triethylamine (0.4 ml, 2.87 mmol) at RT and the mixture was stirred for 10 min. To this reaction mixture, 2,3-diaminobenzamide (346 mg, 2.29 mmol) was added and heated to 55° C. for 3 days. The reaction mixture was poured into ice cold water and stirred for 30 min. The precipitate formed was filtered and dried under vacuum and purified by preparative TLC using ethyl acetate as eluent to afford benzyl 3-((2-amino-3-carbamoylphenyl)carbamoyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 481.2 [M+Na]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH:10]=1)[NH2:5].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:21])[O:22][CH2:23][C:24]2[CH:4]=[CH:3][CH:2]=[CH:8][CH:7]=2)[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:18][CH2:17][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:11][CH2:10]1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(C2=CCC3(CC2)OCCO3)c(Cl)c1
Agent: O=[Pt]
Product: O=C(Nc1ccc(C2CCC3(CC2)OCCO3)c(Cl)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Platinum oxide (250 mg) was added in one portion to a stirred solution of 3-chloro-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)aniline (3.4 g, 12.8 mmol) in ethyl acetate (50 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 9 h. A further portion of platinum oxide (250 mg) was added in one portion and the mixture was stirred for 8 h at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated in vacuo to leave the cyclohexane-aniline product (2.1 g) as a solid, which was used with no further purification.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:7][CH2:6]1)=[N+]=[N-].Cl.[H][H]>[Pd].C(O)C.O>[NH2:1][CH2:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[CH2:9][CH2:10]1
Reactant: CCCCOC(=O)[C@H]1CC[C@@H](CN=[N+]=[N-])CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCOC(=O)[C@H]1CC[C@@H](CN)CC1

Procedure:
A mixture of butyl cis-4-(azidomethyl)cyclohexanecarboxylate (27.85 g, 116 mmol), 6N hydrochloric acid (39 ml, 234 mmol) and 10% palladium on carbon (3.78 g) in ethanol (500 ml) was hydrogenated (hydrogen balloon) for 2.5 days. The catalyst was removed by filtration through Celite. The filter cake was washed with ethanol (3×50 ml) and the filtrate was concentrated under reduced pressure to give a gum. The gum was taken up in water (250 ml) and washed with ether (250 ml). The aqueous layer was basified to pH 10 with 10N sodium hydroxide solution and extracted with ethyl acetate (3×250 ml). The ethyl acetate layer was washed with water (100 ml) and brine (100 ml), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give butyl cis-4-(aminomethyl)cyclohexanecarboxylate (15.25 g, 62%) as a gum: 1H NMR (CDCl3) 4.08 (2H, t, J 7 Hz), 2.57 (2H, d, J 8 Hz), 2.02 (2H, m), 1.66-1.51 (6H, m), 1.45-1.23 (5H, m), 0.94 (3H, t, J 7 Hz). MS: 214.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(O)(C)C.CCOC(C)=O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[C:11]=1[CH3:12]
Reactant: CN1CCNCC1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1c(N2CCN(C)CC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (300 mg, 1.20 mmol) and 1-methylpiperazine (140 μL, 1.20 mmol) were slurried in isopropanol (2.4 mL) and heated in a microwave reactor at 100° C. for 6 h. The reaction was cooled to rt and the resulting plug was slurried in EtOAc and filtered to give 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpiperazin-1-yl)quinoline. Mass Spectrum (ESI) m/e=312.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: BrCC1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2ccc(OCC3CCC(CBr)CC3)cc2N1
Yield: 30.8 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (196 mg, 1.2 mmol), 1,4-bis(bromomethyl)cyclohexane (972 mg, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give 7-((4-(bromomethyl)cyclohexyl)methoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 49) (130 mg, 30%) as a white solid.
Reaction SMILES: CN1CC[CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)(=O)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]([O:29]C)=[O:28])=[C:21]([NH:31][C:32]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[Cl:44])=[O:33])[CH:20]=1>O>[C:3]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[C:21]([NH:31][C:32]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=2[Cl:44])=[O:33])[CH:20]=1)(=[O:7])[CH3:4]
Reactant: COC(=O)C=Cc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reactant: CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)Nc1ccc(C=CC(=O)O)c(NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
6 ml of N-methylpyrrolidone, 1.11 g (3.4 mmol) of cesium carbonate and 0.27 g (3.4 mmol) of acetyl chloride were added to 0.70 g (1.7 mmol) of methyl 3-{4-amino-2-[3-(2-chloro-4,5-difluorobenzoyl)ureido]phenyl}acrylate and the mixture was stirred at room temperature for 30 minutes. It was then diluted with H2O and extracted with ethyl acetate. The organic phase was washed with H2O, dried and concentrated. 0.65 g (85%) of the desired product was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1>>[CH3:24][O:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2([C:25]3[CH:26]=[CH:27][C:28]([C:40]4[CH:41]=[N:42][NH:43][CH:44]=4)=[CH:29][CH:30]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:19][CH:18]=1
Reactant: COCCOc1ccc(C2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COCCOc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1

Procedure:
4-(4-Bromo-phenyl)-4-[4-(2-methoxy-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 1H-pyrazole following the procedure set out in Example 1, substituting tetrakis triphenylphosphine palladium (0) as catalyst, the title compound was obtained. LC/MS: (PS-A2) Rt 3.27 [M+H]+ 478.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[C:21]([NH:25][NH2:26])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([NH:25][NH:26][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc2c(NNC(C)(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To 6 ml of a solution of 438 mg (2.0 mol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 249 mg (2.0 mmol) of t-butylhydrazine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 16 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:2) to give 314 mg (yield: 58.0%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[CH3:13].[Br:14]Br>C(O)(=O)C.[Cl-].[Na+].O>[Br:14][C:8]1[CH:7]=[C:6]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:4]([CH3:13])[C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COc1ccc(CC(=O)O)cc1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(C)cc(CC(=O)O)cc1Br

Procedure:
To a solution of 4-methoxy-3-methylphenylacetic acid (0.43 g) in glacial acetic acid (7 mL) was added 0.2 mL of neat bromine carefully while stirring. The mixture was stirred in dark at ambient temperature for 27 h. The resulting mixture was diluted with brine, extracted with ethyl acetate, dried and concentrated in vacuo to afford 3-bromo-5-methyl-4-methoxyphenylacetic acid. This crude product was dissolved in methanol (30 mL), treated with concentrated sulfuric acid (1 mL) carefully, stirred at reflux for 16 h. Cooled reaction mixture was concentrated under reduced pressure, diluted with brine, extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was dissolved in dichloromethane (10 mL), treated-with boron tribromide (1 M, 2 mL) under nitrogen and stirred at ambient temperature for 1 h. The reaction mixture was poured to stirring water and extracted with ethyl acetate from 1 N HCl. The combined organic layers were dried and concentrated. Flash column chromatography on silica gel with ethyl acetate/hexane (0-50% gradient elution) afforded 3-bromo-5-methyl-4-hydroxyphenylacetic acid methyl ester (0.21 g, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 80 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-((S)-1,1-diethoxy-propan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8].C(N(CC)CC)C.[Br:25][C:26]([CH3:31])([CH3:30])[C:27](Br)=[O:28]>ClCCl>[Br:25][C:26]([CH3:31])([CH3:30])[C:27]([NH:1][C:2]1[S:3][C:4]([CH3:17])=[C:5]([CH3:16])[C:6]=1[C:7](=[O:8])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:28]
Reactant: Cc1sc(N)c(C(=O)c2ccc(Cl)cc2)c1C
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc(NC(=O)C(C)(C)Br)c(C(=O)c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottomed flask was charged with (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone (2 g, 7.53 mmol) and a stirbar. Dichloromethane (75 mL, 0.1 M) was added, followed by triethylamine (1.573 ml, 11.29 mmol, 1.5 equiv). The solution was cooled to 0° C. for the addition of 2-bromo-2-methylpropanoyl bromide (1.163 ml, 9.41 mmol). The solution was stirred at room temperature 1 h, at which point LC/MS analysis showed complete conversion of the starting material. The solution was washed successively with water and brine before being dried with sodium sulfate and concentrated to give a quantitative yield of 2-bromo-N-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-2-methylpropanamide as a yellow amorphous solid (m/z=414/416), which was used crude in the subsequent reaction.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([CH:25]=[CH:26][C:27]#[N:28])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([CH:25]=[CH:26][C:27]2[NH:31][N:30]=[N:29][N:28]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: C(=Cc1cn(Cc2ccccc2)c2ccc(OCc3ccccc3)cc12)c1nnn[nH]1

Procedure:
Following the procedure of Example 56, N-benzyl-5-benzyloxy-3-(2-cyanovinyl)indole is reacted with the sodium azide to give N-benzyl-5-benzyloxy-3-(2-tetrazol-5-ylvinyl)indole. (m.p. 178°-180° C. (dec.))
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)(N)C(C)(C)N.[CH2:34](Br)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].P(=O)(O)(O)O>O1CCCC1.CCCCCC>[CH3:25][O:24][C:14]1[C:15]([CH3:23])=[C:16]([CH3:22])[C:17]([O:20][CH3:21])=[C:18]([CH3:19])[C:13]=1[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: COc1c(C)c(C)c(OC)c(Cc2ccccc2)c1C
Reactant: CCCCCCBr
Agent: CC(C)(N)C(C)(C)N
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC(c1ccccc1)c1c(C)c(OC)c(C)c(C)c1OC
Reaction time: 0.42 h
Yield: 77.3 %

Procedure:
A 3.1 ml (5.0 mmole) portion of n-butyllithium.hexane solution was added dropwise to 1.35 g (5.0 mmole) of 1-benzyl-2,5-dimethoxy-3,4,6-trimethylbenzene and 0.83 ml (5×1.1 mmole) of 1,1,2,2-tetramethylethylenediamine dissolved in anhydrous tetrahydrofuran (15 ml), under an atmosphere of argon at 50° C. over the period of 5 miniutes, followed by stirring at 50° to 55° C. for 25 minutes. Then, a solution of 0.83 g (5.0 mmole) of n-hexyl bromide in tetrahydrofuran (5 ml) was added dropwise to the mixed solution over the period of 5 minutes, followed by stirring at 50° C. for further 10 minutes. The reaction solution was cooled with ice and made acid by adding a 10% aqueous phosphoric acid solution, and the product was extracted with isopropyl ether. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to effect purification (elution with hexane/isopropyl ether) to thereby give 1.37 g (77%) of 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptane. Its typical physical properties and nuclear magnetic resonance specrum data are shown in Table 14.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[I-].[Na+].[OH-].[Na+].Cl[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>C(O)(CC)(C)C.C1(C)C=CC=CC=1>[C:14]1([C:12](=[O:13])[CH2:11][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: c1c[nH]nn1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Product: O=C(Cn1ccnn1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
1,2,3-Triazole (1689 mg, 24.45 mmol), sodium iodide (2443 mg, 16.3 mmol) and sodium hydroxide (978 mg, 24.45 mmol) were added to t-amyl alcohol (6.5 ml), and the mixture was refluxed under stirring for 1 hour. 2-Chloro-1-phenylethanone (2520 mg, 16.3 mmol) was dissolved in t-amyl alcohol (13 ml) and added dropwise over 1 hour. The mixture was refluxed under stirring for 1 hour. The mixture was cooled to room temperature, toluene (50 ml) was added. The mixture was washed with water (50 ml×2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/2→1/4) to give 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone (1.38 g) as brown crystals (yield 45%). 1-Phenyl-2-(2H-1,2,3-triazol-2-yl)ethanone (550 mg) was obtained as yellow crystals (yield 18%). 1-phenyl-2-(1H-1,2,3-triazol-1-yl)ethanone
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4]O.S(=O)(=O)(O)O.[ClH:14].CO>O>[ClH:14].[Cl:14][CH2:4][CH2:3][CH:2]([NH2:1])[C:6]([OH:8])=[O:7]
Reactant: N[C@@H](CCO)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: NC(CCCl)C(=O)O
Temperature: 70 °C

Procedure:
Approximately 1 equivalent of homoserine, 0.01 equivalent of sulfuric acid may be combined with water in a reactor. The reactor may be sealed and 1.1 equivalent of anhydrous HCl (gas) may be may be added to the reactor. The reaction mixture may be heated to about 70° C. and maintained at about 80 psi for about 24 hours. The reaction mixture may be cooled and about 10 equivalents of methanol may be added, such that the product precipitates. The product (i.e., 4-chloro-2-aminobutanoic acid hydrochloride) may be isolated by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([NH:56][C:57]2[CH:61]=[C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])[O:59][N:58]=2)=[O:55])=[CH:49][CH:48]=1.O>CN(C=O)C>[C:62]([C:60]1[O:59][N:58]=[C:57]([NH:56][C:54](=[O:55])[NH:53][C:50]2[CH:49]=[CH:48][C:47]([NH:46][C:21]([C:17]3[CH:16]=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]4)[CH:20]=[CH:19][N:18]=3)=[O:22])=[CH:52][CH:51]=2)[CH:61]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)O)c2)CC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
4-(1-(tert-Butoxycarbonyl)piperidin-4-yloxy)picolinic acid from Step 2 (188 mg, 0.58 mmol) was stirred in 3 mL of DMF. TBTU (244 mg, 0.76 mmol) was added, followed by TEA (82 μL, 0.058 mmol). After 10 min, 1-(4-aminophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (Ref: Milanov, Zdravko V. et al. WO2005/48948 A2, 2005 Jun. 2) (160 mg, 0.58 mmol) was added, followed by TEA (82 μL, 0.058 mmol). The resulting mixture was stirred at rt for 3 h. LC-MS indicated that the reaction was complete. Water (20 mL) was then added, the precipitates were collected by filtration and washed with cold water, dried in vacuum oven to give tert-butyl 4-(2-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenylcarbamoyl)pyridin-4-yloxy)piperidine-1-carboxylate (280 mg, 83%) as an off-white solid. LC-MS (ESI) m/z 579 (M+H)+.