Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:10][C:9]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:7]=[C:6]([C:19]3[N:20]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([C:28](O)=[O:29])[CH:22]=4)[C:5]=2[CH2:4][CH2:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:63][CH:64]([CH3:67])[CH2:65][OH:66]>CN(C)C=O.C(OCC)(=O)C.O>[OH:66][CH2:65][CH:64]([NH:63][C:28]([C:23]1[CH:22]=[C:21]2[C:26]([CH:27]=[C:19]([C:6]3[C:5]4[CH2:4][CH2:3][C:2]([CH3:39])([CH3:1])[CH2:10][C:9]=4[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[N:7]=3)[N:20]2[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])=[CH:25][CH:24]=1)=[O:29])[CH3:67]
Reactant: CC1(C)CCc2c(-c3cc4ccc(C(=O)O)cc4n3COCC[Si](C)(C)C)nn(COCC[Si](C)(C)C)c2C1
Reactant: CC(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CO)NC(=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(C)C4)n(COCC[Si](C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
To a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid obtained in Example 1, Step 4 (500 mg, 0.88 mmol) in N,N-dimethylformamide (5 ml) were added 1-hydroxybenzotriazole monohydrate (161 mg, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.1 mmol) and 2-amino-1-propanol (84 mg, 1.1 mmol) at room temperature, and the mixture was stirred at room temperature for 7 hr. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (511 mg, yield 93%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=O.[OH2:12].O[NH2:14].O>CC(O)C>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[N:14][OH:12]
Reactant: O
Reactant: NO
Reactant: O=Cc1c(F)cc(Cl)cc1Br
Solvent: CC(C)O
Product: ON=Cc1c(F)cc(Cl)cc1Br
Temperature: 40 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of 2-bromo-4-chloro-6-fluoro-benzaldehyde (15 g, 63.16 mmol) in 2-propanol (130 ml) was added hydroxyl amine hydrate (50% solution in water, 4.55 g, 68.90 mmol) at 25° C. and the mixture was warmed to 40° C. for 2 h. Water (55 ml) was then added slowly to this mixture and the slurry was aged for 1 h at 20° C. The reaction mixture was filtered and the remaining solid was washed with a mixture of 2-propanol and water (1.5:1) and dried under vacuum to yield the title compound as white solid (12.5 g, 77%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[OH:20][CH2:21][CH2:22][NH2:23]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([S:9]([NH:23][CH2:22][CH2:21][OH:20])(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cncc(Br)c1

Procedure:
A cooled (0° C.) solution of 5-bromopyridine-3-sulfonyl chloride hydrochloride (3.00 g, 10.2 mmol) in DCM (50 ml) was slowly treated with triethylamine (4.3 ml) and stirred until a clear solution was obtained. This solution was treated dropwise with 2-hydroxyethylamine (0.68 g, 0.68 mL) and stirred at RT for 16 hours. The reaction mixture was washed successively with water and brine, the organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography (silica) eluting with 20% ethyl acetate in petroleum ether, to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:29])([CH2:14][NH:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[CH3:28][O:27][C:25]([C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:15][CH2:14][C:11]3([F:29])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:17][C:18]=2[CH:24]=1)=[O:26]
Reactant: COC(=O)c1ccc2nc(NCC3(F)CCN(C(=O)OC(C)(C)C)CC3)[nH]c2c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc2nc(NCC3(F)CCNCC3)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-fluoro-4-({[5-(methoxycarbonyl)benzimidazol-2-yl]amino}methyl)piperidinecarboxylic acid tert-butyl ester (1.2 g, 2.95 mmol) in MeOH (6 ml), a 4N hydrogen chloride/1,4-dioxane solution (3.7 ml, 14.7 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated to obtain 2-{[(4-fluoro-4-piperidyl)methyl]amino}benzimidazole-5-carboxylic acid methyl ester hydrochloride. The compound was identified by LC-MS.
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(S)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br.BrCCN.C(CC(=O)C)C(C)=O>C(O)(=O)C.C(N(CC)CC)C>[C:1]1([S:7][CH2:8][CH2:9][N:10]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:16]2[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCSc1ccccc1
Reactant: Sc1ccccc1
Agent: Br
Agent: CC(=O)CCC(C)=O
Agent: NCCBr
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1ccc(C)n1CCSc1ccccc1
Yield: 70 %

Procedure:
Phenylthioethylamine (5.00 g, 32.68 mmoles) prepared by reacting thiophenol and β-bromoethylamine hydrobromide in the presence of triethylamine and 3.74 g (32.68 mmoles) of acetonylacetone were heated under reflux for 4 hours in 80 ml of acetic acid. The acetic acid was distilled off under reduced pressure, and toluene was added to the residue. The mixture was distilled under reduced pressure. The resulting crude product was chromatographed on a column of silica gel using hexane/benzene as an eluent to afford 2,5-dimethylpyrrol-1-yl-ethyl phenyl sulfide (5.32 g, 22.88 mmoles, 70%).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.C1COCC1.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[N:21]1([S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[C:10]3=[O:11])(=[O:14])=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3)cc2C1=O
Reaction time: 1 h
Yield: 38.6 %

Procedure:
To a cold solution of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride (2.00 g, 8.14 mmol) in a 1:1 mixture of THF: CHCl3 (96 mL) was added drop-wise via syringe pump over a period of 1 hr a solution of pyrrolidine (0.885 mL, 10.6 mmol) and N,N-diisopropylethyl amine (2.84 mL, 16.3 mmol, 2 eq) in chloroform (16 mL) under a dry N2 atmosphere with cooling in an ice bath. After stirring for 1 h., the reaction was concentrated. The crude product was purified on Biotage KP silica gel eluting with 80/20 CH2Cl2/EtOAc to give the title compound as a greenish-yellow solid (0.88 g, 39% yield). NMR (300 Mz, DMSO-d6): consistent. MS: (ES−) m/z 279 [M−H].
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][C:12]([OH:18])([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.OS([O-])(=O)=O.[K+]>C(Cl)Cl.C(O)C>[C:19]([O:18][C:12]1([C:15]([OH:17])=[O:16])[CH2:11][CH2:10][N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)C1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1(C(=O)O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
A mixture of 9.4 g 1-benzyl-4-hydroxy-piperidine-4-carboxylic acid, hydrochloride, 3.62 g (35 mmol) acetic anhydride, 11.89 mL pyridine in 40 mL DCM was stirred for 1 h at room temperature. KHSO4 (10%) and ethanol were added and filtered. The filtrate was evaporated and the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and HCOOH. The product containing fractions were evaporated to yield 4.2 g (52%) of the title compound as light yellow solid. MS (m/e): 278.1 [(M+H)+].
Reaction SMILES: [CH2:1]([S:7][CH2:8][C:9](=[O:34])[C@@H:10]([NH:15][C:16](=[O:33])[CH2:17][CH2:18][C@H:19]([CH3:32])[CH2:20][NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:11][CH2:12][CH2:13][CH3:14])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[CH2:1]([S:7]([CH2:8][C:9](=[O:34])[C@@H:10]([NH:15][C:16](=[O:33])[CH2:17][CH2:18][C@H:19]([CH3:32])[CH2:20][NH:21][C:22](=[O:31])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:11][CH2:12][CH2:13][CH3:14])=[O:36])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCC[C@H](NC(=O)CC[C@H](C)CNC(=O)COc1ccccc1)C(=O)CSCc1ccco1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCC[C@H](NC(=O)CC[C@H](C)CNC(=O)COc1ccccc1)C(=O)CS(=O)Cc1ccco1
Yield: 36.3 %

Procedure:
(s)-1-Furfurylthio-3-((s)-4-methyl-2-phenoxyacetylaminovalerylamino)-2-heptanone (176 mg) obtained in Example 3 was dissolved in methanol (10 ml) and water (10 ml). To the solution was added sodium metaperiodate (82 mg), and the mixture was reacted at room temperature for 48 hours. Then, methanol was removed in vacuo, saturated brine was added to the residue, and the resultant mixture was extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and filtered. The filtrate was concentrated and chromatographed on a silica gel column, eluting with hexane:ethyl acetate (1:1) to give the titled product (66 mg).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[C:20]([CH:29]3[CH2:31][CH2:30]3)=[CH:19][N:18]=2)=[O:16])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[CH:1]1([CH2:4][C:5]([NH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][C:25]([F:26])([F:27])[F:28])[C:20]([CH:29]3[CH2:31][CH2:30]3)=[CH:19][N:18]=2)=[O:16])([CH3:13])[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(C)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 105.5 %

Procedure:
To a solution of tert-butyl 3-cyclopropyl-2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-methyl-propanoate (example 186c, 103 mg, 233 μmol) in dichloromethane (0.5 ml) was added TFA (159 mg, 108 μl, 1.4 mmol). The reaction mixture was stirred at room temperature for 14 hours. Volatiles were removed in vacuo and the residue was dissolved in a mixture of dichlormethane and toluene followed by evaporation to dryness. The procedure was repeated twice until a precipitate formed. The precipitate was dried under high vacuum to yield the title compound (95 mg) as a crude solid which was used without any purification. MS (ESI, m/z): 387.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].Cl[C:36](OC1C=CC([N+]([O-])=O)=CC=1)=[O:37].N1C=CC=CC=1.C([O:56][P:57]([CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][NH2:67])(=[O:61])[O:58]CC)C.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:36](=[O:37])[NH:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][P:57](=[O:61])([OH:56])[OH:58])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: CCOP(=O)(CCCCCN)OCC
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCCP(=O)(O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.2 %

Procedure:
{[4-(6′-Amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.100 g, 0.204 mmol), (Example 25: step c), 4-nitrophenyl chloroformate (0.041 g, 0.204 mmol), pyridine (0.018 g, 0.224 mmol), DCM [3 mL] were added to a flask containing a stirbar. This solution was stirred at room temperature for 2.5 hours. To this solution was added (5-Amino-pentyl)-phosphonic acid diethyl ester (0.136 g, 0.611 mmol) and Triethylamine (0.062 g, 0.611 mmol). Solution was stirred at room temperature for 18 hours. Reaction was concentrated in vacuo followed by chromatography (50%–100% EtOAc/Hx) to yield title compound (0.138 g, 88%). ESI-MS (m/z): Calcd. for C34H47N4O8PS3: 767.93 (M+H); found 667.1.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6].[CH3:33]I>O>[CH2:3]([O:7][C:8]1[C:13]([CH2:14][O:15][CH3:33])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (11 mg 4.5 mMol) is added to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-3-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]pyridine (50 mL). After 1 hour, methyl iodide (85 mg, 0.6 mMol) is added and the reaction mixture is stirred for 20 hours at room temperature. Water (1 mL) is added dropwise and the mixture is concentrated to an oily solid. The titled material is purified by silica gel chromatography.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH2:32]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (100 mg, 0.23 mmol) in DMF (3 mL) were added benzyl bromide (39 mg, 0.23 mmol) followed by DIPEA (40 μL, 0.23 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel prep TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 8 mg of the title compound, m/z 531.6 [M+1]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([N:15]1[CH:20]=[C:19]([C:21]([OH:23])=O)[C:18](=[O:24])[C:17]2[CH:25]=[C:26]([I:28])[S:27][C:16]1=2)[CH3:14].[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=1.CC(O)=O>CN(C=O)C>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][NH:35][C:21]([C:19]2[C:18](=[O:24])[C:17]3[CH:25]=[C:26]([I:28])[S:27][C:16]=3[N:15]([CH2:13][CH3:14])[CH:20]=2)=[O:23])=[CH:32][CH:31]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(I)sc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 53 %

Procedure:
Carbonyldiimidazole (0.290 g) is added to a solution of 7-ethyl-2-iodo-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (Eur. J. Med. Chem. 1987, 22, 139) (0.520 g) in DMF (13 mL). The reaction is heated to 60° C. and stirred for 18 h. The reaction mixture is cooled to rt, and 4-chlorobenzylamine (0.22 mL) is added. The reaction is stirred at rt for 7 h. The reaction mixture is poured into 20% aqueous HOAc (50 mL), and the resulting off-white solid is filtered off. This material is recrystallized twice from methanol to yield 0.372 g (53%) of the title compound as an off-white, crystalline solid.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[C:15]1[S:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:19]=1.C(=O)(O)[O-].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O1CCOCC1>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[S:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:19]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(-c2ccc([N+](=O)[O-])cc2)s1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Water (5 mL) and 1,4-dioxane (5 mL) were added to 4-nitrophenylboronic acid (667 mg, 4 mmol), ethyl 2-bromo-1,3-thiazole-5-carboxylate (448 μL, 4 mmol), sodium bicarbonate (1.01 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (462 mg, 0.4 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for 1.5 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 0.6 g of the title compound as a colorless solid (54%).
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C[N:22]([CH:24]=O)C.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:32][CH:31]=1)=O>O.CCOC(C)=O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:14]=[CH:13][C:11]([N:12]3[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])=[CH:32][CH:31]=4)[N:22]=[C:24]3[CH2:6][CH2:1][CH2:2][CH3:3])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 13 %

Procedure:
To a stirred solution of 4-(biphenyl-4-oxy)aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was purified by chromatography (Silica gel). Pure product obtained from 2–4% MeOH/DCM (yield˜13%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][CH2:23][C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][CH2:23][C@H:24]([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: NC[C@H](O)c1ccccc1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNC[C@H](O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (R)-(−)-2-amino-1-phenylethanol.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5](=O)[C:6]([OH:8])=[O:7].CC1[N:18]=CC(COP(O)(O)=O)=C(C=O)C=1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C@@H:5]([NH2:18])[C:6]([OH:8])=[O:7]
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Reactant: O=C(O)C(=O)CCC(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](CCC(F)(F)F)C(=O)O

Procedure:
A solution containing 5,5,5-trifluoro-2-oxopentanoic acid (100 mg, 0.588 mmoles), R,S-alanine (200 mg, 2.244 mmoles), and 0.02 mM pyridoxal phosphate, in 0.1 M potassium phosphate buffer, pH 7.5, was incubated with R-transaminase AT-103 from Biocatalytics (5 mg, 44 units) or cloned R-transaminase from Bacillus thuringiensis SC16569 (0.5 mL, 10 units, BMS transaminase) at 30° C. in a total volume of 5 mL in 15 mL tubes for 44 h. Reaction yields of (R)-5,5,5-trifluoro-2-aminopentanoic acid of 49% and 48% were obtained with AT-103 and BMS transaminases, respectively. Ee was 100% in both cases.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])[C@@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.[Si]([O:42][CH:43]1[CH2:49][C:48](=[O:50])[O:47][C:45](=[O:46])[CH2:44]1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])[C@@H:12]([NH:14][C:48]([CH2:49][CH:43]([OH:42])[CH2:44][C:45]([OH:47])=[O:46])=[O:50])[CH3:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)OC(=O)C1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)c1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)CC(O)CC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 71.1 %

Procedure:
129 mg of (1S,2R)-3-(3,4-dichlorophenyl)-1-methyl-2-(2-naphthoyloxy)propylamine hydrochloride and 120 μl of triethylamine were dissolved in 15 ml of methylene chloride, and 82 mg of 3-(tert-butyldimethylsilyloxy)glutaric anhydride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was extracted by an addition of 1N hydrochloric acid and methylene chloride. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in a liquid mixture of 10 ml of tetrahydrofuran and 5 ml of 1N hydrochloric acid, and the solution was left to stand at room temperature overnight. The reaction solution was extracted by an addition of water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent is separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (Kieselgel™ 60F254, Art 5744, manufactured by Merck Co.; chloroform/methanol=6/1) to obtain 112 mg (yield: 71%) of the above-identified compound as white powder.