Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C@:13]12[CH2:30][CH2:29][C@H:28]3[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@:26]3([CH3:27])[CH2:25][CH2:24][C@H:23]([OH:31])[CH2:22]4)[C@@H:17]1[CH2:16][CH:15]=[CH:14]2.C[C@]12CC[C@H]3[C@@H](CC[C@@H]4[C@]3(C)CC[C@H]([OH:51])C4)[C@@H]1CCC2=O.O>N1C=CC=CC=1>[CH3:12][C@:13]12[CH2:30][CH2:29][C@H:28]3[C@@H:18]([CH2:19][CH2:20][C@@H:21]4[C@:26]3([CH3:27])[CH2:25][CH2:24][C@H:23]([OH:31])[CH2:22]4)[C@@H:17]1[CH2:16][CH:15]=[CH:14]2.[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])(=[O:51])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C[C@]12CC[C@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 1 h

Procedure:
4-Methylbenzenesulphonyl chloride (20 g) was added to a stirred solution of (3β, 5α)-androst-16-en-3-ol (20 g), which was prepared from (3β, 5α)-androstan-3-ol- 17-one in a similar way as described in Examples 1 and 2, in pyridine (100 ml) at °C. The mixture was stirred at 0°-5° C. for 1 h., then set aside in a refrigerator for 3 d. Water was added to precipitate the product as off-white prisms. Recrystallisation from diethyl ether-methanol gave colourless prisms of (3β, 5α)-androst-16-en-3-ol 4-methylbenzenesulphonate, Which Was treated as described in Example 3.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(O)[CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24]O)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:48])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:22](\[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[CH2:23][CH2:24][Cl:48])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC(c1ccccc1)C(O)(c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: ClCC/C(=C(\c1ccccc1)c1ccc(OCCOCCOCc2ccccc2)cc1)c1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1-{4-[2-(2-Benzyloxy-ethoxy)ethoxy]phenyl}-1,2-diphenyl-butane-1,4-diol (10.0 g, 19.5 mmol) is dissolved in toluene (50 ml). Triethylamine (2.17 g, 21.4 mmol) is added to the solution and the mixture is cooled to −10° C. Thionyl chloride (6.9 g, 58.5 mmol) is added to the mixture at −10-±0° C. The mixture is stirred for 1 hour at 0-5° C., warmed up to 70° C. and stirred at this temperature for 4 hours. Solvent is evaporated, the residue is dissolved to toluene, washed three times with 1M HCl solution and twice with water. The Z-isomer of the product is crystallized from isopropanol-ethyl acetate. Yield 3.0 g. The filtrate is purified by flash chromatography to give E-isomer.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)CC4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]([CH3:54])[C:47]1[CH:52]=CC(N)=[CH:49][CH:48]=1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:52][C:47]([N:46]([CH3:54])[CH3:45])=[CH:48][CH:49]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH3:34])[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN(C)c1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CN(C)c1ccc(NC(=O)Nc2ccc(-c3nc(N4CC5CCC(C4)O5)c4cnn(C)c4n3)cc2)cc1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing N,N-dimethyl-1,4-phenylenediamine as the aniline component. (24%, MS=499.2 (M+H))
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[Br:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:16][CH2:15][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[N:8]=3)[CH2:10][CH2:11]2)=[CH:20][CH:19]=1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(Br)cc3)CC2)n1
Yield: 42.3 %

Procedure:
4-{[(4-Bromophenyl)oxy]methyl}-1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]piperidine (322 mg, 42%) was prepared from {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 450 mg, 2.0 mmol), 4-bromophenol (346 mg, 2.0 mmol) and Ph3P (629 mg, 2.4 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.512 mL, 2.6 mmol) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 2H, J=9.1 Hz), 6.76 (d, 2H, J=8.9 Hz), 4.28-4.18 (m, 2H), 3.79 (d, 2H, J=6.2 Hz), 3.14-3.04 (m, 2H), 2.94-2.82 (m, 1H), 2.10-1.94 (m, 1H), 1.97-1.87 (m, 2H), 1.49-1.36 (m, 2H), 1.28 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 380/382 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([O:22]CC)=[O:21].[I-].[Li+]>N1C=CC=CC=1>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:5][CH:4]=[C:3]1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1cnc(-c2cccnc2)n(-c2ccccc2)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1cnc(-c2cccnc2)n(-c2ccccc2)c1=O
Temperature: 127.5 °C

Procedure:
A suspension of ethyl 1,6-dihydro-6-oxo-1-phenyl-2-(3-pyridinyl)-5-pyrimidinecarboxylate (i.e. the product from Example 7, Step B) (5.0 g, 15.5 mmol) and lithium iodide (powder, 5.2 g, 38.8 mmol) in pyridine (15 mL) was heated to 125-130° C. for 12 h. After cooling to ambient temperature, excess solvent was removed under reduced pressure. The resulting residue was dissolved in water (100 mL) and acidified with hydrochloric acid (6 N) to pH 7. The resulting dark brown solution was extracted with ethyl acetate (1×100 mL) to remove the non polar impurities. The aqueous layer was again extracted with dichloromethane/methanol (95:5) (2×50 mL). After initial extractions, the aqueous layer was slowly acidified to pH 4 and further extracted with dichloromethane/methanol (95:5) (3×50 mL). The combined neutral and acidic extracts were washed with brine and dried over anhydrous Na2SO4. The residue obtained after removal of the solvent was dried under high-vacuum to obtain 3.4 g of the title compound as a light brown solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:36])[CH2:16][NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([OH:35])=[O:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:11][C:10]=1[NH:37][S:38]([CH3:41])(=[O:40])=[O:39])C1C=CC=CC=1>CN(C)C(=O)C.[C].[Pd]>[OH:36][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[CH:29][C:30]([C:33]([OH:35])=[O:34])=[CH:31][CH:32]=2)=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CNCCOc2ccc(-c3ccc(C(=O)O)cc3)cc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCOc2ccc(-c3ccc(C(=O)O)cc3)cc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of the crude 4′-{2-[(R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-hydroxyethylamino]ethoxy}biphenyl-4-carboxylic acid and 10% palladium-carbon (0.03 g) in N,N-dimethylacetamide (5 mL) was stirred at room temperature for 2 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was triturated in methylene chloride, and then dissolved by addition of acetonitrile (5 mL) and water (5 mL) The insoluble materials were removed by filtration, and the solvent was evaporated under reduced pressure to afford the title compound (0.045 g).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[CH2:18](OC1C=CC(C(C)CC(OCC)=O)=CC=1)C=C>>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(C(C)CC(=O)OCC)cc1
Reactant: C=CCc1cc(CCC(=O)OCC)ccc1O
Product: C=CCc1cc(C(C)CC(=O)OCC)ccc1O

Procedure:
Ethyl 3-(3-allyl-4-hydroxyphenyl)butanoate was prepared as for ethyl 3-(3-allyl-4-hydroxyphenyl)propionate as in Example 1 but using ethyl 3-(4-allyloxyphenyl)butanoate in place of ethyl 3-(4-allyloxyphenyl)propionate; microanalysis: found: C, 72.6; H, 7.80%; C15H20O3 requires C, 72.6; H, 8.12%; m/z 249(M+H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([CH:14]2[CH2:16][O:15]2)[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>CO>[F:23][C:24]1[CH:25]=[C:26]([S:30][CH2:16][CH:14]([OH:15])[CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][C:4]=2[C:19]([F:22])([F:21])[F:20])[C:10]([O:12][CH3:13])=[O:11])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C1CO1
Reactant: Fc1cccc(S)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CSc1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
480 mg (1.5 mmol) of methyl (4-fluoro-2-trifluoromethylbenzoylamino)oxiranylacetate were dissolved in methanol, and 215 mg (1.5 mmol) of 3-fluorothiophenol and 280 mg (3.8 mmol) of triethylamine were then added. The mixture was then stirred at RT for 15 h, and the solvent was then removed. This gave 760 mg of diasteromerically pure crude product which was used for the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:26]([CH2:33][CH2:34]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:34][CH2:33][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOc2ccccc2)c(=O)c2c1ncn2Cc1ccccc1
Reaction time: 1 h

Procedure:
2.6 g (18.72 mmol) of potassium carbonate were added at 60° C. to a suspension of 3.0 g (11.7 mmol) of 7-benzyl-3-methylxanthine (prepared according to Example 1a) in 70 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 3.1 g (15.21 mmol) of 2-phenoxyethyl bromide were then added dropwise and the mixture was stirred at 80° C. for 5 hours. The crude mixture was then filtered, the filtrate was concentrated under reduced pressure, the residue was taken up in dichloromethane and the solution was washed once with 1 N sodium hydroxide solution and twice with water. The organic phases were dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, heptane/ethyl acetate (1/2).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]C)=[O:37])[CH:30]=2)=[CH:25][CH:24]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC=C[C:56]=1[NH:61][C@@H:62](CC1C=CC(C2C=CC=C(NC)C=2)=CC=1)C(OCC)=O)(=O)C1C=CC=CC=1.C(N(CC)C1C=CC(N=C=O)=CC=1)C>>[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C@@H:16]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]([CH3:46])[C:36]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([N:61]([CH3:62])[CH3:56])=[CH:43][CH:44]=3)=[O:37])[CH:30]=2)=[CH:27][CH:28]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](Nc3ccccc3C(=O)c3ccccc3)C(=O)OCC)cc2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(NC)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: CCN(CC)c1ccc(N=C=O)cc1
Product: CCOC(=O)[C@H](Cc1ccc(-c2cccc(N(C)C(=O)Nc3ccc(N(C)C)cc3)c2)cc1)Nc1ccccc1C(=O)c1ccccc1
Yield: 75 %

Procedure:
In a manner similar to the preparation of the ethyl (S)-2-(2-benzoylphenylamino)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionate (Example 1h), using 1.0 g (2.1 mmol) of ethyl (S)-2-(2-benzoylphenylamino)-3-(3′-methylaminobiphenyl-4-yl)propionate (Example 1g) and 0.40 g (2.47 mmol) of 4-(diethylamino)phenyl isocyanate, 0.86 g of ethyl (S)-2-(2-benzoylphenylamino)-3-{3′-[3-(4-dimethylaminophenyl)-1-methylureido]biphenyl-4-yl}propionate is isolated with a 75% yield.
Reaction SMILES: [C:1]([C:3]1[C:12](I)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:14])[CH:4]=1)#[N:2].C1(P(C2C=CC3OC4C(=CC=CC=4)CC=3C=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:61][C@@H:62]([NH2:65])[CH2:63][CH3:64]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C@H:62]([NH:65][C:12]1[C:3]([C:1]#[N:2])=[CH:4][C:5]([CH3:14])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])([CH2:63][CH3:64])[CH3:61]
Reactant: COC(=O)c1cc(I)c(C#N)cc1C
Reactant: CC[C@@H](C)N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC[C@@H](C)Nc1cc(C(=O)OC)c(C)cc1C#N
Temperature: 95 °C
Reaction time: 16 h
Yield: 73.4 %

Procedure:
To a solution of methyl 4-cyano-5-iodo-2-methylbenzoate (500 mg, 1.66 mmol) in 1,4-dioxane (25 mL) was added 9,9-dimethyl-4,5-(bis(diphenylphosphino)xanthene (96 mg, 0.166 mmol), tris(dibenzylideneacetone)-dipalladium (76 mg, 0.083 mmol), cesium carbonate (1.08 g, 3.32 mmol) and (R)-butan-2-amine (506 μL, 4.98 mmol). The reaction mixture was heated to 95° C. and stirred for 16 h, at which time it was cooled to room temperature. The heterogeneous mixture was filtered through a bed of celite, and the filter cake rinsed with ethyl acetate. The filtrate was concentrated, and the residue was purified by flash chromatography (100% hexanes to 5% ethyl acetate in hexanes) to afford (R)-methyl 5-(sec-butylamino)-4-cyano-2-methylbenzoate (300 mg, 73%) as a bright yellow oil. MS (EI) for C14H18N2O2: 247 (MH+).
Reaction SMILES: C=O.C(O)=O.[Br:6][C:7]1[CH:13]=[CH:12][C:10](N)=[C:9](C)[C:8]=1[N+:15]([O-:17])=[O:16].[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[CH3:18][N:19]([CH3:20])[C:21]1[CH:12]=[CH:13][C:7]([Br:6])=[C:8]([N+:15]([O-:17])=[O:16])[C:9]=1[CH3:10]
Reactant: CN(C)C=O
Reactant: Cc1c(N)ccc(Br)c1[N+](=O)[O-]
Agent: C=O
Solvent: O=CO
Product: Cc1c(N(C)C)ccc(Br)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
5.8 g of paraformaldehyde and 15 ml of formic acid are dissolved in 15 ml of DMF and heated to 90° C.-100° C. A solution of 18 g of 4-bromo-2-methyl-3-nitroaniline in 15 ml of DMF is added dropwise within 10 minutes. After 2 hours, the mixture is added to about 600 ml of ice water and the aqueous phase is extracted with 300 ml of ether. The organic phase is washed with Na2CO3 (1M), filtered and evaporated down. The product is purified by chromatography (silica gel, eluant: petroleum ether/ethyl acetate (40/60). 15 g of N,N-dimethyl-4-bromo-2-methyl-3-nitroaniline is obtained as a brownish-orange oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][C:18](Br)=[O:19].O>ClCCl>[Br:16][CH2:17][C:18]([NH:4][C:3]1[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=1[F:9])=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 2,6-difluoroaniline (1.12 g) and potassium carbonate (1.8 g) in 50 mL dichloromethane was added bromoacetyl bromide (1.5 mL) and the mixture was stirred at room temperature for 17 h. Water was added and the mixture stirred for several hours then the phases were separated on a hydrophobic frit and the organic layer was evaporated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane to give the sub-titled compound (0.92 g) as a white solid.
Reaction SMILES: O.[CH3:2][N:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([OH:7])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:53]/[C:54](=[CH:60]\[C@@H:61]([N:65]([CH3:74])[C:66](=[O:73])[C@H:67]([C:69]([CH3:72])([CH3:71])[CH3:70])[NH2:68])[CH:62]([CH3:64])[CH3:63])/[C:55]([O:57]CC)=[O:56].[OH-].[Li+]>ClCCl.CO.ClCCl.O.O1CCCC1.O>[CH3:2][N:3]1[CH2:10][CH2:9][CH2:8][C@H:4]1[C:5]([NH:68][C@H:67]([C:66]([N:65]([C@@H:61]([CH:62]([CH3:64])[CH3:63])/[CH:60]=[C:54](/[C:55]([OH:57])=[O:56])\[CH3:53])[CH3:74])=[O:73])[C:69]([CH3:71])([CH3:72])[CH3:70])=[O:7]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)(C)C
Reactant: CN1CCC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H]1CCCN1C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
To a solution of N-methyl-L-proline monohydrate (0.26 g, 1.79 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (1.4 g, 2.69 mmol) in anhydrous dichloromethane (3.0 ml) at 25° C. is added diisopropylethylamine (0.63 ml, 3.62 mmol) under an inert atmosphere. To this solution is added a solution of ethyl (2E,4S)-2,5-dimethyl-4-[methyl(3-methyl-L-valyl)amino]hex-2-enoate (0.39 g, 1.27 mmol, WO 99/32509) in anhydrous dichloromethane (2.0 ml). The resulting reaction mixture is stirred at room temperature overnight. The reaction mixture is evaporated in vacuo. The residue (300 mg, 0.78 mmol) is dissolved in methanol (6.85 ml), water (1.8 ml) and tetrahydrofuran (3.25 ml). To this reaction mixture is added aqueous lithium hydroxide solution (3.54 ml, 3.54 mol) The resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane/water. The organic layer is washed with citric acid, brine, dried over sodium sulfate and filtered. The solvent is removed in vacuo, and the residue is chromatographed by HPLC (0.01% trifluoroacetic acid in water/acetonitrile) to give the product as a yellow oil, 0.08 g (28% yield). MS: m/z 396.28 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[OH-].[Na+].C1(C)C=CC=CC=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)n1ccc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.9 %

Procedure:
A mixture of 5-fluoroindole (1.0 g, 7.4 mmole), 4-chlorobenzenesulfonyl chloride (1.6 g, 7.6 mmole), tetra-n-butylammonium hydrogen sulfate (0.05 g), 4N sodium hydroxide (5 mL, 20 mmol), and toluene (6 mL) was stirred at room temperature for 15 h. The mixture was diluted with 10 mL water and extracted with 25 mL ethyl acetate. The organic phase was washed with 10 mL water, 10 mL saturated sodium chloride, and then dried (anhydrous magnesium sulfate). The solution was concentrated under reduced pressure. The residue was recrystallized from ethyl ether/hexane to provide 1-(4-Chlorobenzenesulfonyl)-5-fluoro-1H-indole (1.74 g) m.p. 108–109°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([CH:32](O)[CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].[SiH](CC)(CC)CC.B(F)(F)F.CCOCC>CC#N>[CH2:1]([O:3][C:4](=[O:35])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])=[C:20]([CH2:32][CH3:33])[CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(C(C)O)c1)NC(=O)c1c(Cl)cccc1Cl
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)[C@H](Cc1ccc(-c2ccccc2OC)c(CC)c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-3-(1-hydroxyethyl)-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester (0.08 g) in CH3CN (3 mL) at 0° C. was added Et3SiH (0.075 mL) followed by BF3.Et2O (0.0197 mL). The mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with CH3OH/H2O and the mixture was extracted with CH2Cl2. The organic layer was dried (MgSO4), filtered and evaporated. The residue was purified by preparative TLC (silica gel; eluent: EtOAc/hexane 1/2) to give 39 mg of N-(2,6-dichlorobenzoyl)-3-ethyl-4-(2-methoxyphenyl)-L-phenylalanine ethyl ester. ESMS: m/z 500 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=O.O.[NH2:19][NH2:20]>C1(C)C=CC=CC=1.CN(C=O)C>[N+:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:20][N:19]=[C:11]2[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: NN
Reactant: O=C(c1ccc[nH]1)c1cc([N+](=O)[O-])ccc1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Temperature: 120 °C
Yield: 77 %

Procedure:
A mixture of (2-chloro-5-nitro-phenyl)-(1H-pyrrol-2-yl)-methanone (600 mg) and hydrazine hydrate (0.5 mL) in toluene (20 mL) and DMF (3 mL) was heated at 120° C. for 2 hours. The reaction was concentrated, the residue was washed with water and recrystallized to give 0.42 g (77%) of the titled compound as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24]OS(C)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:24][C:20]3[S:19][CH:23]=[CH:22][CH:21]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: CS(=O)(=O)OCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (1.63 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) and 385 mg (2.00 mmol) methanesulfonic acid thiophen-2-ylmethyl ester in 20 mL DMF is added 451 mg (3.26 mmol) potassium carbonate at RT. The reaction mixture is stirred overnight at RT and is diluted with 60 mL of EtOAc. The organic phase is washed three times with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).