Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]([OH:14])[OH:13])=[CH:8][CH:7]=1.O[C:16]([C:19](O)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:14][C:19]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[O:13]2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(OCCCBr)cc1
Reactant: CC(C)(O)C(C)(C)O
Solvent: CCOCC
Product: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Reaction time: 18 h
Yield: 112.8 %

Procedure:
To a solution of 4-(3-bromopropoxy)phenylboronic acid (1.0 g, 3.9 mmol) in diethyl ether (40 mL) was added pinacol (1.4 g, 12 mmol) and the reaction mixture was stirred for 18 h and concentrated to afford the desired product (1.5 g, crude) as a light brown oil which carried onto the next step without further purification: ESI MS m/z 247 [C15H22BBrO3−94]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=O.Cl.CO.P(Br)(Br)[Br:16]>ClCCl>[Br:16][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([S:2][CH3:1])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: CSc1cccc(C(=O)O)c1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CSc1cccc(CBr)c1
Reaction time: 8 h

Procedure:
A solution of 1.50 g (8.92 mmol) 3-(methylthio)benzoic acid (Aldrich) in 20 mL of dry dichloromethane is cooled to 0° C. and 1.86 mL (19.6 mmol) borane-methylsulfide complex (Aldrich) is added. The solution is allowed to reach room temperature and stirred overnight, then hydrochloric acid (4 M, 50 mL) is added and the resulting mixture is stirred for additional 2 h. The reaction mixture is extracted with ethyl acetate (50 mL, 3 times) and the collected organic phases are washed with 10% NaHCO3 solution and brine and volatiles evaporated under vacuum to yield 3-methylsulfanyl-phenyl)-methanol (1.20 g, content ca. 75%), which is directly used in the next step. Step B: A solution of 3-methylsulfanyl-phenyl)-methanol (1.20 g, content ca 75%) in dichloromethane (25 mL) and phosphorus tribromide (1 M in dichloromethane, 6.42 mL) is stirred for 3 h at room temperature. The reaction mixture is washed with NaHCO3 solution (10%, 10 mL, 2 times) and the remaining organic phase is dried (MgSO4) and volatiles are evaporated under reduced pressure to yield the title compound (1.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][NH:12]2)[CH2:9]1)=[O:7].C(N(CC)CC)C.N1C=CC=CC=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:10]([CH2:11][N:12]2[S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])[CH2:9]1)=[O:7]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CNC2C1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CC2CN(S(=O)(=O)c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of rac-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide (150 mg, 270 μmol) in dichloromethane (6 mL) were added triethylamine (82 mg, 810 μmol), pyridine (1 mL) and benzenesulfonyl chloride (52 mg, 297 μmol). The reaction mixture was stirred at ambient temperature overnight before concentrating in vacuo. Purification by chromatography (SiO2; dichloromethane:methanol 1:0 to 19:1) afforded the title compound (56 mg, 47%) as a colorless solid. MS (EI) m/e: 440.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:58][C:59]1([CH3:62])[CH2:61][O:60]1>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:58][C:59]([OH:60])([CH3:62])[CH3:61])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCC(C)(C)O)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]-amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.1 M) was added cesium carbonate (2.5 eq.) and 2,2-dimethyloxirane (15 eq.). The reaction was stirred for 18 h at 50° C., then added more 2,2-dimethyloxirane (10 eq.). The reaction was heated to 80° C. and stirred for 4.5 h. After cooling to rt, the reaction was diluted with ether. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 45%→55% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: CO.[OH-].[Na+].[CH2:5]([O:7][C:8]1[C:9]([N:41]2[CH2:46][CH2:45][CH:44]([C:47]([O:49]CC)=[O:48])[CH2:43][CH2:42]2)=[C:10]([F:40])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[C:14]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:28]=1[CH3:38])=[O:24])[C:13]2=[O:39])[CH3:6].Cl>O.CN(C=O)C>[CH2:5]([O:7][C:8]1[C:9]([N:41]2[CH2:42][CH2:43][CH:44]([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]2)=[C:10]([F:40])[CH:11]=[C:12]2[C:17]=1[N:16]([CH2:18][C:19]([F:22])([F:21])[F:20])[CH:15]=[C:14]([C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:29][C:28]=1[CH3:38])=[O:24])[C:13]2=[O:39])[CH3:6]
Reactant: CCOC(=O)C1CCN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(OC(F)(F)F)cc4C)cn(CC(F)(F)F)c3c2OCC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
2 ml of methanol, 2.5 ml of DMF and 2 ml of a sodium hydroxide solution (2N) are added to 85 mg (0.126 mmol) of the compound of Example 78. The mixture is stirred for 1 h at room temperature, acidified with 1N-HCl to pH 1, diluted with water and extracted three times with ethyl acetate. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under high vacuum. 81 mg of the title compound are obtained (96% of theory).
Reaction SMILES: N.[NH2-].[Na+].[Na].[N:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C.O.[N+]([O-])([O-])=O.[Fe+2].[N+]([O-])([O-])=O>[CH3:13][C:6]1[CH:7]=[C:8]([CH2:12][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[C:10]([CH3:11])[N:5]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: ClCc1ccccc1
Agent: [Fe+2]
Agent: N
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(CCc2ccccc2)cc(C)n1
Reaction time: 1 h

Procedure:
Liquid ammonia (150 ml) was introduced into a 250 ml three-necked round bottomed flask equipped with a mechanical stirrer, dropping funnel and outlet tube and immersed in a dry ice/ethanol bath. Sodium amide was generated by addition of 20 mg of iron nitrate (Fe3+) followed by metallic sodium (2.09 g, 0.09 mol). The deep blue solution was stirred for one hour and a solution of collidine (1) (10.06 g, 0.083 mol) in 20 ml of dry diethylether was introduced into the reaction by addition over a period of 15 min. The resultant yellow suspension was stirred for an additional 45 min, followed by the addition or benzylchloride (6.33 g, 0.05 mol) dissolvedin 10 ml of dry diethylether. The reaction mixture was stirred for 45 min and excess sodium amide was neutralized by addition of ammonium chloride (4.82 g, 0.09 mol) dissolved in 20 ml of H2O. Ammonia was evaporated and the residue was partitioned between water and diethylether. The collected etheral phase was dried over sodium sulfate and evaporated. The brown residual oil was fractionated, and a fraction distilling at 130° C./0.1 mmHg was colelcted.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH:13]([OH:15])[CH:12]([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:19]=[C:20](F)[CH:21]=[CH:22][CH:23]=1>CS(C)=O>[Cl:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][CH:19]=1)[O:15][C@H:13]1[CH2:14][N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:11][C@H:12]1[OH:16]
Reactant: Fc1cccc(Cl)c1
Reactant: OC1CN(Cc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@@H]1Oc1cccc(Cl)c1
Temperature: 95 °C

Procedure:
A slurry of 1.2 g. (50 mmoles) of sodium hydride (2.1 g. of 57% oil dispersion, washed with ether to remove the oil) in 25 ml. of dimethyl sulfoxide was stirred while 9.6 g. (50 mmoles) of 1-benzyl-3,4-dihydroxypyrrolidine, cis isomer, in 25 ml. of dimethyl sulfoxide was added. The mixture was stirred at ambient temperature for one hr., then 50 ml. of dimethyl sulfoxide was added and the temperature was raised to 95° C. for 0.5 hr. Mechanical stirring of the thick slurry was necessary while 13 g. (100 mmoles) of m-chlorofluorobenzene was added. During the heating period of 1 hr. at 95° C., all precipitate dissolved. The reaction mixture was concentrated by vacuum distillation of the dimethyl sulfoxide and excess m-chlorofluorobensene. The residue was poured into water and extracted with hot cyclohexane. The organic extracts were combined, dried over anhydrous sodium sulfate and concentrated to give 7.5 g. (49%) of off-white crystals, m.p. 86-87.5° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[O:8]=[C:9]1[C@H:13](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:12][CH2:11][O:10]1>C1COCC1>[OH:5][CH2:4][CH2:3][CH2:2][S:1][C@H:13]1[CH2:12][CH2:11][O:10][C:9]1=[O:8]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2=O)cc1
Reactant: OCCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCC[C@@H]1SCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
A solution of 3-mercaptopropan-1-ol (360 mg, 3.90 mmol) in THF (8 mL) cooled to 0° C. was treated with 60% NaH (86 mg, 2.15 mmol). After warming to room temperature and stirring for 30 minutes, a solution of (R)-toluene-4-sulfonic acid 2-oxotetrahydrofuran-3-yl ester (500 mg, 1.95 mmol) in THF (2 mL) was added. After stirring at room temperature for 60 hours, the reaction mixture was quenched with saturated NaHCO3 and diluted with EtOAc. The organic layer was washed with saturated NH4Cl, saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated under reduced pressure. The residue was chromatographed (2:1 EtOAc/hexanes) to provide the product as colorless oil (155 mg, 45%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([N:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C:24]2=[O:36])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][C:24]2=[O:36])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(C1CCN(C(=O)OCc2ccccc2)CC1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)CC(C1CCN(C(=O)OCc2ccccc2)CC1)N1CCNCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
To a solution of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)-3-[4-(tert-butoxycarbonyl)-2-oxopiperazine-1-yl]propionate (4.78 g) in ethyl acetate (15 ml) was added 4N hydrochloric acid in ethyl acetate (15 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was diluted with water, made basic with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The extract was washed with saturated brine, dried and concentrated to give pale yellow amorphous of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)-3-(2-oxopiperazine-1-yl)propionate (2.34 g).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][O:6][N:5]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C(N(CC)C(C)C)(C)C>C(O)C.C(#N)C>[Br:16][C:17]1[CH:18]=[C:19]([NH:20][C:3]([C:4]2[C:8]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[N:7][O:6][N:5]=2)=[N:2][OH:1])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: ON=C(Cl)c1nonc1N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CC#N
Product: ON=C(Nc1ccc(F)c(Br)c1)c1nonc1N1CCOCC1
Reaction time: 62 h
Yield: 48.7 %

Procedure:
A solution of N-Hydroxy-4-morpholin-4-yl-1,2,5-oxadiazole-3-carboximidoyl chloride (40 mg, 0.17 mmol) and 3-bromo-4-fluoroaniline (49 mg, 0.26 mmol) in ethanol (1 mL) was treated with a solution of N,N-diisopropylethylamine (45 μL, 0.26 mmol) in acetonitrile (1 mL) and stirred for 62 h. The reaction mixture was purified by preparative HPLC to give the desired product (32 mg, 48%). LCMS for C13H14BrFN5O3 (M+H)+: m/z=386.0, 388.0.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8]2)[CH:4]=[N:3][CH:2]=1.[OH-].[K+].Cl>O.CO>[N:3]1[CH:4]=[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH:6]=[N:1][CH:2]=1
Reactant: COC(=O)c1cn(-c2cncnc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(-c2cncnc2)c2ccccc12
Temperature: 80 °C

Procedure:
To a solution of methyl 1-(pyrimidin-5-yl)-1H-indole-3-carboxylate (16 mg, 0.063 mmol) in water MeOH (316 μl) was added 2M KOH (158 μl, 0.316 mmol). The mixture was heated at 80° C. for 4 h then neutralized with 1M HCl. The precipitate was collected by filtration to afford the title compound as a white solid, which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12]C(=O)C)=[CH:7][CH:6]=2.[CH3:16][N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:16][N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([OH:12])=[CH:7][CH:6]=3)[CH:19]=[N:18]1
Reactant: CC(=O)Oc1ccc2ncc(Br)cc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(O)cc3c2)cn1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of acetic acid 3-bromo-quinolin-6-yl ester (108 g, 0.406 mol), 1-methyl-4-pyrazoleboronic acid pinacol ester (169 g, 0.752 mol), Na2CO3 (129 g, 1.28 mol), Pd(dppf)Cl2 (32.8 g, 0.0406 mol), H2O (607 mL) and 1,4-dioxane (1000 mL) was heated to 100° C. overnight. After cooling down to room temperature, most of the dioxane was removed under vacuo. The mixture was partitioned between ethyl acetate (500 mL) and brine (500 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2*500 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 54 g of 3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-ol as a yellow solid (59% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]#[N:34]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:32][C:33]#[N:34])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[C:4]([CH3:18])=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(O)cc3)cc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC#N)cc3)cc12
Yield: 91.2 %

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(1,3-dimethyl-2-phenyl-1H-indol-5-yl)-phenol (0.353 g, 1.126 mmol) was reacted with K2CO3 (0.189 g, 1.352 mmol) and bromoacetonitrile (0.162 g, 1.352 mmol) in acetone (15 ml) to give the desired product (0.362 g, 1.027 mmol, 91%) as a white solid, mp 177-179° C. 1H NMR (DMSO-d6) δ 2.25 (s, 3H), 3.61 (s, 3H), 5.21 (s, 2H), 7.15 (d, J=8.7 Hz, 2H), 7.45-7.52 (m, 5H), 7.55 (t, J=7.5 Hz, 2H), 7.72 (d, J=8.9 Hz, 2H), 7.78 (s, 1H); [EI], m/z 352 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](F)[C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[F:11][C:10]([F:13])([F:12])[C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[NH2:14]
Reactant: N
Reactant: Fc1cc(F)c(C(F)(F)F)c(F)c1
Solvent: C1CCOC1
Product: Nc1cc(F)cc(F)c1C(F)(F)F
Temperature: 120 °C

Procedure:
200 ml of tetrahydrofuran and 50 g of 2,4,6-tri-fluorobenzotrifluoride are initially introduced into a stainless steel autoclave, and 30 ml of liquid ammonia are injected. The batch is then heated to 120° C. for 6 hours and with stirring. The reaction mixture is cooled,the pressure is released and the reaction mixture subjected to fractional distillation. At a boiling point of 57° C.-58° C./12 mbar, 15 g of 2-trifluoromethyI-3,5-difluoroaniline are obtained. After a small intermediate fraction 32 g of 3,5-difluoro-4-trifluoromethylaniline distil over at a boiling point of 103° C.-105° C./16 mbar (melting point: 66° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]2([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:21])[C:11]([O:13][C:14]2([CH3:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C(=O)OC1(C)CCCCC1)c1ccc(N)cc1
Yield: 67.1 %

Procedure:
A stirred solution of 34.9 g of 1-methylcyclohexyl 2-(p-nitrophenyl)-propionate in 250 ml of absolute ethanol was hydrogenated at atmospheric pressure in the presence of 10% palladium on carbon catalyst. After the uptake of hydrogen gas was complete, the catalyst was filtered off through celite and the filtrate was evaporated to dryness. Trituration of the residue with petroleum ether gave 21.02 g (67% yield) of 1-methylcyclohexyl 2-(p-aminophenyl)-propionate as creamy white crystals melting at 85°-87° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].[C:12](O)(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(#N)C>C(O)C(N)(CO)CO.Cl>[C:12]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([C:9]([OH:11])=[O:10])[NH2:2])(=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 88 %

Procedure:
Ten (10) U of the enzyme of the present invention was added in 100 mM Tris-HCl buffer (pH 7.0) to L-lysine hydrochloride (final concentration of 1 M) and lauric acid (final concentration of 15 mM), and reacted for 3 hours at 45° C. The reaction solution was analyzed by HPLC (YMC-Pack ODS 150×4.6 mm, eluent: 35% acetonitrile solution, pH 2.8, flow rate: 0.8 mL/min). The synthesis yield was about 88% based on fatty acids.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].C(O)(=O)C.[C:10]([O:14][C:15](=[O:36])[CH2:16][NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:20][C:19]=1[NH2:35])([CH3:13])([CH3:12])[CH3:11]>CCO>[C:10]([O:14][C:15](=[O:36])[CH2:16][N:17]1[C:18]2[CH:23]=[CH:22][C:21]([NH:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])=[CH:20][C:19]=2[N:35]=[C:1]1[CH2:2][CH2:3][CH3:4])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)CNc1ccc(NS(=O)(=O)c2ccc(F)cc2)cc1N
Reactant: CCCC=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Butyraldehyde (3.8 mL, 41.8 mmol) and acetic acid (1.4 mL) were added to a solution of [2-amino-4-(4-fluoro-benzenesulfonylamino)-phenylamino]-acetic acid tert-butyl ester (12.5 g, 26.8 mmol) in EtOH (135 mL), and stirred overnight at 70° C. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give the crude sub-titled compound that was used without further purification. MS calculated for C22H26FN3O4S—H: 446, observed: 446.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([C:9](Cl)=[O:10])[S:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:12][C:13]1[C:18]([Cl:19])=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH3:23].O>O1CCOCC1>[C:22]([C:14]1[C:13]([NH:12][C:9]([C:6]2[S:7][CH:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:5]=2)=[O:10])=[C:18]([Cl:19])[C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:24])[CH3:23]
Reactant: O=C(Cl)c1nc(C2CC2)cs1
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C3CC3)cs2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of compound 267a (3.4 g, 1.2 eq.) in dioxane (60 mL) was added 6-acetyl-2-chloro-3-methoxy aniline 201d (3.01 g, 1 eq.) in dioxane. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate) to yield compound 268a as a brown solid in 66% yield. 1H NMR (CDCl3, 400 MHz): δ (ppm) 1-1.06 (m, 4H), 2.08-2.15 (m, 1H), 2.58 (s, 3H), 3.99 (s, 3H), 6.87 (d, J=8.78 Hz, 1H), 7.16 (s, 1H), 7.67 (d, J=8.78 Hz, 1H), 10.27 (br s, 1H); MS (ESI, EI+): m/z=351 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:7]=1.[N:16]1([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:29]([O:28][C:26]([N:24]1[CH2:25][CH:22]([N:16]2[CH2:21][CH2:20][N:19]([C:10](=[O:12])[CH2:9][CH2:8][C:6]3[CH:7]=[C:2]([Br:1])[C:3]([Cl:15])=[CH:4][C:5]=3[O:13][CH3:14])[CH2:18][CH2:17]2)[CH2:23]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CC(N2CCNCC2)C1
Reactant: COc1cc(Cl)c(Br)cc1CCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Cl)c(Br)cc1CCC(=O)N1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred solution of 3-(5-bromo-4-chloro-2-methoxyphenyl)propanoic acid (350 mg, 1.2 mmol) in DMF (30 mL) at RT, tert-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (317 mg, 1.3 mmol), BOP (731 mg, 1.4 mmol) and DIEA (461 mg, 3.6 mmol) were added and the mixture was stirred at RT for 1 h. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (285 mg, 46% yield).