Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][N:13]2[CH2:17][CH2:16][NH:15][C:14]2=[N:18][N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:15]2[CH2:16][CH2:17][N:13]([CH:12]=[CH:11][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:10][CH:9]=3)[C:14]2=[N:18][N+:19]([O-:21])=[O:20])=[CH:27][N:26]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=[N+]([O-])N=C1NCCN1C=Cc1ccc(OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])N=C1N(C=Cc2ccc(OCC(F)(F)F)cc2)CCN1Cc1ccc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A mixture comprising 5.0 g of 1-{4-(2,2,2-trifluoroethoxy)phenylvinyl}-2-nitroiminoimidazolidine, 5.8 g of 2-chloro-5-chloromethylpyridine, 8.4 g of potassium carbonate and 30 ml of dimethylsulfoxide was stirred at 60° C. for one hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried (with anhydrous MgSO4) and concentrated to give an oily residue. This was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=4/1) to give 4.9 g of 1-(2-chloropyridin-5-ylmethyl)-2-nitroimino-3-{4-(2,2,2-trifluoroethoxy)phenylvinyl}-imidazolidine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[S:17])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4].[C:18]([O-])([O-])=O.[K+].[K+].CI>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([S:17][CH3:18])[NH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:4]
Reactant: COC(=O)c1[nH]c(=S)[nH]c1-c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: COC(=O)c1nc(SC)[nH]c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a stirred solution of compound 7 (18 g, 71.0 mmol) in MeOH (200 mL) was added K2CO3 (12.0 g, 85.0 mmol), followed by the dropwise addition of a solution of MeI (8.9 mL, 143 mmol) in MeOH (200 mL) at rt. The resulting mixture was stirred at rt for 2 h and then concentrated under reduced pressure. The residue was treated with water (200 mL) and extracted with ethyl acetate (150 mL×3). The combined extracts were washed with brine (50 mL×2), dried over anhydrous MgSO4, filtered, and evaporated to afford product 8 (19.0 g, 100%) as a white solid. ESI MS m/z 267.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:24][CH2:23][C@@H:19]3[CH2:20][NH:21][CH2:22][C@H:18]3[C@@H:17]2[C:25]2[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=2[CH3:33])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([N:21]1[CH2:22][C@H:18]2[C@H:17]([C:25]3[CH:30]=[C:29]([I:31])[C:28]([F:32])=[CH:27][C:26]=3[CH3:33])[C@@H:16]([O:15][C@@H:13]([C:5]3[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:4]=3)[CH3:14])[O:24][CH2:23][C@@H:19]2[CH2:20]1)(=[O:38])[CH3:37]
Reactant: Cc1cc(F)c(I)cc1[C@@H]1[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC[C@@H]2CNC[C@H]21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1C[C@H]2CO[C@H](O[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3cc(I)c(F)cc3C)[C@@H]2C1

Procedure:
The title compound was prepared from (3aS,6R,7R,7aR)-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluoro-5-iodo-2-methylphenyl)octahydropyrano[3,4-c]pyrrole and acetic anhydride according to the procedures used for example 19. MS: (MH)+660.
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][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[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]([C:18]2[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:26])[F:25])=[CH:22][C:17]=2[CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1cc(C(F)(F)F)ccc1B(O)O
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(F)(F)F)ccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methyl-4-(trifluoromethyl)phenylboronic acid (0.411 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 3 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-methyl-4-(trifluoromethyl)phenyl)quinoline as a yellow oil. Mass Spectrum (ESI) m/e=372.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl-].[Na+].Cl.[C:21](Cl)(=[O:23])[CH3:22]>O>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([C:21](=[O:23])[CH3:22])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(=O)c1c(O)ccc2c(C)cc(=O)oc12
Temperature: 150 °C

Procedure:
4-Methyl-7-hydroxy-coumarin (26.4g), aluminum chloride (76.1g) and sodium chloride (9.5g) were placed in a flask and shaken to effect reasonable mixing. The flask was then immersed in an oil bath, and the temperature raised to 150° C. Hydrogen chloride evolution commenced at about 100°-110° C. After maintaining the temperature at 150° C for 15 minutes, the melt produced was heated to 160° C and stirred until evolution of hydrogen chloride ceased. Stirring was continued while acetyl chloride (11.8 ml) was added to the melt over a period of about 30 minutes. After maintaining the melt at 160° to 165° C for a further 15 minutes, it was poured with stirring into water (1000 ml). The solid produced was filtered off, washed free of chloride, and dried. On analysis, it was found that the solid contained about 70% by weight of 4-methyl-7-hydroxy-8-acetyl-coumarin and about 30% by weight of 4-methyl-7-hydroxy-6-acetyl-coumarin. The latter isomer was removed by recrystallisation of the product three times from 85% IMS to yield 20.4g of a 4-methyl-7-hydroxy-8-acetyl-coumarin, mpt 167°-169° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]([CH2:12][CH:13]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])C(=O)C(F)(F)F.Cl.[OH-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:34])[CH2:4][NH:5][CH2:12][CH:13]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][CH2:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: COC(=O)CN(CC(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C)C(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CNCC(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C
Yield: 44.2 %

Procedure:
To a solution of N-[2-(5-chloro-2-neopentylamino phenyl)-2-(2-chlorophenyl)ethyl]-N-trifluoroacetylglycine methyl ester (0.2 g) in methanol (3 ml) was added conc. hydrochloric acid (0.6 ml), which was heated under reflux for one day. To the reaction mixture was added a 1N aqueous solution of sodium hydroxide (8ml), followed by extraction with dichloromethane. The extract solution was washed with water, then the solvent was distilled off to leave 72 mg of an oily compound.
Reaction SMILES: [C:1]1([N:7]([CH2:9][CH2:10][OH:11])N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:14]([CH2:28][CH3:29])[C:15]([CH:17]1[CH2:26][C:25](=O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:18]1)=[O:16])[CH3:13].S(=O)(=O)(O)O>C(O)C>[CH2:28]([N:14]([CH2:12][CH3:13])[C:15]([CH:17]1[C:26]2[C:6]3[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=3)[N:7]([CH2:9][CH2:10][OH:11])[C:25]=2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[S:18]1)=[O:16])[CH3:29]
Reactant: CCN(CC)C(=O)C1CC(=O)c2ccccc2S1
Reactant: NN(CCO)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCN(CC)C(=O)C1Sc2ccccc2-c2c1c1ccccc1n2CCO
Temperature: 25 °C
Yield: 85.8 %

Procedure:
To a solution of 2-(N-phenyl-hydrazino)-ethanol (ii) (0.59 g, 1.9 mmol) and 4-oxo-thiochroman-2-carboxylic acid diethylamide (iii) (0.5 g, 1.9 mmol) in ethanol 10 ml was added conc. sulfuric acid 0.5 ml. The reaction mixture was stirred and refluxed for 20 hours. It was then cooled to room temperature and poured onto water 50 ml. The resulting precipitate was collected by filtration and washed with water (3×30 ml). It was then dried in desiccators under vacuum with P2O5 as the drying agent to give the product 11-(2-Hydroxy-ethyl)-6,11-dihydro-5-thia-11-aza-benzo[α]fluorene-6-carboxylic acid diethylamide (iv) as a yellow solid 0.62 g, which was used to next step without further purification. Yield: 86%.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH3:16])[NH2:12]>N1C=CC=CC=1>[CH3:8][C:9]1[CH:10]=[C:11]([NH:12][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(N)cc1C
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C)c(C)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (38.9 mL, 412 mmol) was added to a stirred solution of 3,4-dimethylaniline 1-5 (10.0 g, 82.5 mmol) in pyridine (150 mL) at ambient temperature. After stirring at approximately 60° C. for 2 h, the volatiles were removed in vacuo, and the residue was partitioned between diethyl ether and aqueous 1 N hydrochloric acid. The organic phase was separated and washed with saturated aqueous sodium bicarbonate, brine, dried (sodium sulfate) and concentrated in vacuo to afford 1-6 as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[C@H:3]1([CH2:11][OH:12])[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH2:13]([O:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:11][OH:12])[CH2:4][CH2:5]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC[C@H]1CC[C@H](CO)CC1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a slurry of NaH (440 mg, 11 mmol) in THF (22 mL) is added trans-1,4-cyclohexanedimethanol (1.44 g, 10 mmol) at 0° C., and the mixture is stirred for 1 hour while warming to room temperature. Benzyl bromide (1.2 mL, 10 mmol) is added dropwise followed by TBAI (185 mg, 0.5 mmol). The reaction is heated to 60° C. for 15 hours. After cooling to room temperature, H2O is added, and the mixture is extracted with EtOAc. The combined organic layer after dried over MgSO4 is concentrated to obtain (4-benzyloxymethyl-cyclohexyl)-methanol as clear oil (1.40 g, 60%) after purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=4[CH:29]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=3[CH:29]=2)[CH2:15][C:14]2[CH:30]=[CH:31][C:11]([C:10]#[C:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:12][CH:13]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(C#Cc2ccc(CNc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: COc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The title compound was prepared following the procedure B using 7-({4-[(4-methoxyphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropionyl chloride as a beige solid (63%). 1H NMR (CDCl3) δ 7.91 (d, J=8.3 Hz, 1H), 7.41 (m, 4H), 7.12 (d, J=8.1 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.76 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 4.87 (s, 2H), 3.80 (s, 3H), 2.15 (t, J=6.9 Hz, 2H), 1.70 (s, 6H), 1.40-1.61 (m, 9H), 0.95 (m, 2H). HPLC, Rt: 5.78 min (purity: 99.3%).
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7]>C1COCC1>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][S:6]([NH2:1])(=[O:8])=[O:7]
Reactant: CN(C)CCS(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: CN(C)CCS(N)(=O)=O

Procedure:
Ammonia was cautiously added to a cooled solution of the subtitle product of step ii) in THF (50 ml) and stirring maintained until all of the ammonia had evaporated before filtering off the product as a white solid. Yield: 0.88 g.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([NH:30][C:31]([N:37]([CH3:39])[CH3:38])=[N:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:25]=[C:26]([NH:30][C:31]([N:37]([CH3:39])[CH3:38])=[N:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:27]=[C:28]([CH3:29])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(NC(=NS(C)(=O)=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(C)cc(NC(=NS(C)(=O)=O)N(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1d from methyl 4'-[[2-ethyl-4-methyl-6-(3,3-dimethyl-2-methylsulphonyl-guanidino) -1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and 2N sodium hydroxide solution in ethanol.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[CH:8]1([C:14]([NH2:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[CH:8]1([C:14]([NH:16][CH:3]([OH:4])[C:2]([Cl:7])([Cl:6])[Cl:1])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NC(=O)C1CCCCC1
Solvent: c1ccccc1
Product: O=C(NC(O)C(Cl)(Cl)Cl)C1CCCCC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 80.9 %

Procedure:
First, cyclohexyl-N-(2,2,2-trichloro-1-hydroxyethyl)carboxamide 3 was synthesized as follows. A mixture of chloral hydrate (9.0 g, 54,5 mmol) and cyclohexane carboxamide (5.0 g, 49.5 mmol) in dry benzene (30 ml) was heated at 80° C. in an oil bath. The initial suspension eventually became a clear solution (reaction time depends on the amount of starting materials, in this example it took about 6 hours). The mixture was stirred for an additional 30 minutes, then removed from the oil bath, and left at room temperature. Upon cooling, the crystalline solid formed was filtered and washed with hexanes to give the product cyclohexyl-N-(2,2,2-trichloro-1-hydroxyethyl)carboxamide 3 (11.0 g). NMR (1H, CDCl3): δ 6.23 (d, J=8.4 Hz, 1H), 5.9 (dd, 1H), 4.35 (broad s, 1H), 2.16 (t, 1H), 1.90-1.22 (m, 10H).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[C:6](O)=[O:7])(=[O:3])[CH3:2].[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH2:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH3:17][O:18][C:19](=[O:30])[CH:20]([NH:29][C:6](=[O:7])[CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1
Reactant: COC(=O)C(N)Cc1ccc(O)cc1
Reactant: CC(=O)NC(Cc1ccc(O)cc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc(O)cc1)NC(=O)C(Cc1ccc(O)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-acetylamino-3-(4-hydroxy-phenyl)-propionic acid 20 (13.4 grams, 60.09 mmol) and 2-amino-3-(4-hydroxy-phenyl)-propionic acid methyl ester 1 (11.7 grams, 60.00 mmol) in anhydrous dichloro methane (100 mL) under a nitrogen atmosphere at 0° C. is added dropwise to a solution of 1,3-dicyclohexyl carbodiimide (31 grams, 150.24 mmol) in dichloro methane (75 mL). The mixture is stirred at room temperature for 6 hours. The resulting solids are filtered off. The organic phase is washed with 5% sodium bicarbonate (2×25 mL) and water (2×25 mL), dried over sodium sulphate, and distilled to give crude 21, which can be purified in appropriate solvent.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>C(O)C>[N:14]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=2)=[CH:2][N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=12
Reactant: Nc1ccccn1
Reactant: N#CCc1ccc(C(=O)CCl)cc1
Solvent: CCO
Product: N#CCc1ccc(-c2cn3ccccc3n2)cc1
Yield: 62.3 %

Procedure:
A mixture of 28 g of 4-(chloroacetyl)phenylacetonitrile, 70 ml of ethanol and 24 g of 2-aminopyridine is heated under reflux for 2 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The crystalline precipitate is filtered off and recrystallized from methanol to give 21 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetonitrile as colorless crystals melting at 175°-177°C with decomposition.
Reaction SMILES: C([O:20][NH:21][C:22](=[O:63])[C@H:23]([N:44]([S:52]([C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]3[O:41][CH2:42][O:43][C:36]=23)=[O:31])[CH2:26][CH2:25]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([SiH](CC)CC)C.[F:71][C:72]([F:77])([F:76])[C:73]([OH:75])=[O:74]>C(Cl)Cl>[F:71][C:72]([F:77])([F:76])[C:73]([OH:75])=[O:74].[OH:20][NH:21][C:22](=[O:63])[C@H:23]([N:44]([S:52]([C:55]1[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=1)(=[O:54])=[O:53])[CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[CH:24]1[CH2:25][CH2:26][N:27]([C:30]([O:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]3[O:41][CH2:42][O:43][C:36]=23)=[O:31])[CH2:28][CH2:29]1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C2CCN(C(=O)OCCc3cccc4c3OCO4)CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccncc2)[C@@H](C(=O)NO)C2CCN(C(=O)OCCc3cccc4c3OCO4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of N-(trityloxy)-2-(R)-[(4-methoxybenzenesulfonyl) (4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxyphenyl)-ethoxycarbonyl))-4-piperidinyl]acetamide (468 mg, 0.54 mmol) in methylene chloride (10 ml) cooled to 0° C. is added triethyl silane (0.17 ml, 1.08 mmol) followed by slow addition of trifluoroacetic acid (0.33 ml, 4.31 mmol). After stirring at 0° C. for 5 minutes, the solvent is removed in vacuo, at room temperature. The resulting white solid is dried on high vacuum for 1 hour and dissolved in the minimum amount of methylene chloride (ca. 2.5 ml). A mixture of diethyl ether (ca. 5 ml) and pentane (ca. 2.5 ml) is slowly added and the resulting white precipitate is triturated, filtered and washed with pentane (Note: this precipitation process must be repeated a second time if high purity is not obtained after the first attempt), to provide N-hydroxy-2-(R)-[(4-methoxybenzenesulfonyl)(4-picolyl)amino]-2-[(N-(2-(2,3-methylenedioxyphenyl)-ethoxycarbonyl))-4-piperidinyl]acetamide trifluoroacetic acid salt.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Br>CN(C=O)C>[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:1]1[C:5]2=[CH:6][N:7]=[C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CCOC(=O)c1cc2cc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccn(Cc3ccc(F)cc3F)c2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.1 %

Procedure:
To a stirred solution of ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate (0.50 g, 2.63 mmol) in DMF (10 mL) under a nitrogen atmosphere was added sodium hydride (0.087 g, 80% in mineral oil, 2.89 mmol) and 2,4-difluorobenzyl bromide (0.60 g, 2.89 mmol). The resulting mixture was stirred for 16 hours at ambient temperature. It was quenched with water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with water (2×30 mL), dried over sodium sulfate, concentrated in vacuo, and purified by flash chromatography. Elution with hexane/ethyl acetate (1:1) provided the title compound as a light yellow solid (0.40 g, 48% yield). 1H NMR (CD3OD) δ ppm. 8.86 (s, 1H), 8.47 (s, 1H), 7.71 (d, 1H, J=3.2 Hz), 7.31 (dd, 1H, J=6.3 Hz), 6.94-7.05 (m, 2H), 6.79 (d, 1H, J=3.2 Hz), 5.63 (s, 2H), 4.46 (q, 2H, J=7.3 Hz), 1.45 (t, 3H, J=7.3 Hz). LCMS (API-ES, M+H+): 317.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>[Cl:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 50 °C

Procedure:
To a stirred solution of 375.2 g (2 mole) of N-(4-chloro-2-fluorophenyl)acetamide in 600 mL of concentrated sulfuric acid and 400 mL of oleum (30%) was added 166 mL of a 1:1 mixture of nitric acid (100%) and concentrated sulfuric acid at 0° C. over a period of 1.5 hours. After the addition was complete, the reaction mixture was poured into 11 L of ice water. The precipitate was filtered and the filter cake suspended in 200 mL of water. The solid was redissolved by the addition of 2 L of ethyl acetate and neutralized with aqueous NaOH to pH 7. The two phase mixture was heated to 50° C. and separated. The organic layer was washed with 150 mL of water. 200 mL of ethyl acetate were distilled off and the remaining solution was treated with 12 g of Celite® at 70° C., filtered and washed with another 200 mL of ethyl acetate.
Reaction SMILES: Cl.O1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[C:33]([C:36]1[CH:37]=[CH:38][C:39]([CH3:50])=[C:40]([NH:42][C:43]([C@@H:45]2[CH2:49][CH2:48][CH2:47][NH:46]2)=[O:44])[CH:41]=1)(=[O:35])[CH3:34].[CH3:51][O:52][C:53]([NH:55][C@H:56]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:57](O)=[O:58])=[O:54].CCN(C(C)C)C(C)C>CO.CN(C)C=O>[C:33]([C:36]1[CH:37]=[CH:38][C:39]([CH3:50])=[C:40]([NH:42][C:43]([C@@H:45]2[CH2:49][CH2:48][CH2:47][N:46]2[C:57](=[O:58])[C@H:56]([NH:55][C:53](=[O:54])[O:52][CH3:51])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:44])[CH:41]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)c1ccc(C)c(NC(=O)[C@@H]2CCCN2)c1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C(C)=O)ccc1C)c1ccccc1
Reaction time: 18 h
Yield: 81.6 %

Procedure:
Example J.38 (3 g, 83 mmol) was dissolved in methanol (30 mL) and 4N HCl/dioxane (50 mL) was added and the reaction was stirred 18 hr. The solvents were removed in vacuo, and (S)—N-(5-acetyl-2-methylphenyl)pyrrolidine-2-carboxamide HCl salt was exposed to vacuum. LC (Cond-J1): 0.9 min. HATU (1.4 g, 3.5 mmol) was added in one portion to a stirred solution of (S)—N-(5-acetyl-2-methylphenyl)pyrrolidine-2-carboxamide HCl (1.0 g, 3.5 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (740 mg, 3.5 mmol), and Hunig's base (2.9 mL) in dimethylformamide (25 mL) and the reaction mixture was stirred 18 h. The solvent was removed in vacuo and the residue was applied to a 40 M Biotage SiO2 column, and eluted by gradient 50%-100% B (500 mL); A=hexanes; B=ethyl acetate to give J.39, methyl (R)-2-((S)-2-(5-acetyl-2-methylphenylcarbamoyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate 1.25 g (87%). 1H NMR (300 MHz, DMSO-d6) δ: 9.42 (s, 1H), 7.95 (s, 1H), 7.75-7.69 (m, 2H), 7.43-7.19 (m, 6H), 5.50/5.40 (d, J=7.7 Hz, 1H), 4.49-4.47 (m, 1H), 3.87-3.81 (m, 1H), 3.58-3.54 (m, 1H), 3.50 (s, 3H), 2.54 (s, 3H), 2.27 (s, 3H), 1.99-1.83 (m, 4H). LC (Cond.-J1): 1.65 min; LRMS: Anal. Calcd. for [M+H]+ C24H28N3O5: 438.20; found 438.20.