Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[C:23]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=5[Cl:37])=[N:24][O:25][C:26]=4[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=3[CH3:38])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[OH-].[Na+].CO.C1COCC1>O>[Cl:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:37])[C:30]=1[C:23]1[C:22]([CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:10]3[CH:9]=[C:8]4[C:13]([C:5]([C:3]([OH:4])=[O:2])=[CH:6][NH:7]4)=[CH:12][CH:11]=3)=[C:15]([CH3:38])[CH:16]=2)=[C:26]([CH:27]([CH3:29])[CH3:28])[O:25][N:24]=1
Reactant: COC(=O)c1c[nH]c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1-c1ccc2c(C(=O)O)c[nH]c2c1
Temperature: 85 °C
Yield: 52.3 %

Procedure:
A mixture of 6-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-ylmethoxy]-2-methyl-phenyl}-1H-indole-3-carboxylic acid methyl ester (80 mg, 0.15 mmol), 5 N sodium hydroxide (150 μL, 0.750 mmol), methanol (2 mL) and THF (1 mL) is heated at 85° C. for five hours. The mixture is cooled and 5 mL of water is added and the volatile solvents are evaporated under reduced pressure. The basic layer is washed with ether and then acidified with 1 N HCl and extracted with ether. The second ether layers are dried over anhydrous magnesium sulfate, are concentrated, and are crystallized from ether-hexane to provide 42 mg (54%) of the title compound. LC-ES/MS m/e 535.0 (M+1), 93.2% purity.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[N:20]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[N:20]=2)[CH:14]=1)[S:28]([CH3:27])(=[O:30])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 2 from above was treated with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 456.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]2[C@@H:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=3)[C:14](=[O:15])[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9].[C:27]1(=[O:33])[O:32][C:30](=[O:31])[CH2:29][CH2:28]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]2[C@@H:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=3)[C:14](=[O:15])[O:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[OH:9].[C:27]([O-:32])(=[O:33])[CH2:28][CH2:29][C:30]([O-:2])=[O:31]
Reactant: O=C1CCC(=O)O1
Agent: COc1cc(C[C@H]2COC(=O)[C@@H]2Cc2ccc(O)c(OC)c2)ccc1O
Solvent: c1ccncc1
Product: O=C([O-])CCC(=O)[O-]
Reaction time: 24 h

Procedure:
Matairesinol (500 mg, 1.4 mmol) was dissolved in 30 ml pyridine. To the solution succinic anhydride (700 mg, 7 mmol) was added in small portions. The temperature was adjusted to 50° C. and the mixture was stirred for 24 h. The solvent was removed under reduced-pressure and the residue dissolved in dichloromethane and extracted first with slightly basic water. The water phase was then acidified with 10% HCl and extracted with dichloromethane. The organic phases were combined, concentrated and chromatographed on a silica column using CHCl3:EtOAc (1:1) as eluent. The fractions containing the product were combined and the solvents were removed.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[S:9](=[O:11])(=[O:10])[N:8](C(SC1NN=NN=1)C1C=CC=CC=1)[C:7]2=[O:28])([O-])=O>C1COCC1.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:12](=[CH:13][CH:14]=1)[S:9](=[O:11])(=[O:10])[NH:8][C:7]2=[O:28]
Reactant: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1C(Sc1nnn[nH]1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(=O)NS2(=O)=O
Reaction time: 60 h

Procedure:
5-Nitro-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin (4 g, 9.56 mmol) (Example 11) was dissolved in THF (250 ml) and placed in a Parr shaker bottle. Two spatulas of 10% palladium-on-charcoal catalyst were added under nitrogen, and the mixture was shaken under hydrogen (55 psi) for 2.5 days. The reaction mixture was filtered through Celite diatomaceous earth and filtrate mixed with water and extracted with MDC. The organic layer was dried (Na2SO4), freed of solvent under vacuum, and the resultant yellow foam was sonicated with warm ethanol, cooled and filtered. The desired 5-aminosaccharin derivative, 0.5 g, was isolated as a cream colored solid. FDMS: m/e 388 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[C:6]2[CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)=[C:6]2[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1c(-c2ccc(F)cc2)[nH]c2ccc(OC)cc12
Reactant: BrCc1ccccc1
Product: COC(=O)Cc1c(-c2ccc(F)cc2)n(Cc2ccccc2)c2ccc(OC)cc12

Procedure:
Prepare by a method similar to Example 48 using methyl [5-methoxy-2-(4-fluorophenyl)-indol-3-yl]-acetate and benzyl bromide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O>CC(O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]2[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][O:9]2)[CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccccc1CO
Reactant: O=Cc1cccc(Br)c1
Solvent: CC(C)O
Product: Brc1cccc(C2Nc3ccccc3CO2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.5 %

Procedure:
A mixture of 2-amino-benzenemethanol (0.073 mol) and 3-bromo-benzaldehyde (0.073 mol) in 2-propanol (100 mL) was stirred for 3 hours at rt. The solvent was evaporated. Part (3 g) of the residue (20.5 g) was crystallized from hexane. The precipitate was filtered off and dried, yielding 1.37 g of the desired product.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH2:20][C:19](=[O:22])[NH:18][C:17]=2[CH:23]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[N+:1]([C:14]1[C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:23][C:17]2[NH:18][C:19](=[O:22])[CH2:20][O:21][C:16]=2[CH:15]=1)([O-:4])=[O:2]
Reactant: O=C1COc2ccc(OCc3ccccc3)cc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=C1COc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2N1
Reaction time: 1 h

Procedure:
Aqueous 65% nitric acid (5.04 g, 0.052 mole) was added under stirring at room temperature to the oxazinone ((d), 12 g, 0.047 mole) in acetic acid (ml 30). After 1 hour, the separated solid was filtered and washed with acetic acid to give the nitroxazinone ((e), 9 g, 64%) as yellow prisms. The product structure was confirmed by NMR analysis.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.CCOC(C)=O>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OCC2CO2)cc1
Temperature: 100 °C
Yield: 48 %

Procedure:
A solution of NaOH (0.35 g) in 10 mL of water was added to a mixture of 4-methoxyphenol (1.10 g, 8.5 mmol) and epichlorohydrin (0.80 mL, 10.2 mmol). The mixture was heated at 100° C. for 3 h. After cooling, the mixture is taken up with AcOEt (50 mL). The organic phase was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 4:1, as eluent) to afford pure compound in 48% yield. 1H NMR (CDCl3): δ 2.73-2.75 (m, 1H), 2.89 (app t, 1H), 3.31-3.36 (m, 1H), 3.76 (s, 3H), 3.88-3.93 (m, 1H), 4.14-4.20 (m, 1H), 6.81-6.88 (m, 4H).
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.O[CH2:48][C@H:49]([CH2:62][CH2:63][O:64][C:65](=[O:83])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH2:50][N:51]1[CH:59]=[N:58][C:57]2[C:56](=[O:60])[NH:55][C:54]([NH2:61])=[N:53][C:52]1=2>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:8][C@H:9]([C:13]([O:15][CH2:48][C@H:49]([CH2:62][CH2:63][O:64][C:65](=[O:83])[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH3:82])[CH2:50][N:51]1[CH:59]=[N:58][C:57]2[C:56](=[O:60])[NH:55][C:54]([NH2:61])=[N:53][C:52]1=2)=[O:14])[CH:10]([CH3:11])[CH3:12]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCC(=O)OCC[C@@H](COC(=O)[C@@H](N)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 45.7 %

Procedure:
A mixture of N-Boc-L-valine (528 mg; 2.1 mmol) and N,N′-dicyclohexyl carbodiimide (250 mg; 1.21 mmol) in dichloromethane (20 ml) was stirred over night at room temperature dicyclohexylurea filtered off and extracted with a small volume of dichloromethane, and the filtrate evaporated in vacuo to a small volume. (R)-9-[2-Hydroxymethyl-4-(stearoyloxy)butyl]guanine (340 mg; 0.654 mmol), 4-dimethylaminopyridine (25 mg; 0,205 mmol and dry N,N-dimethylformamide (15 ml) were added and the mixture was stirred for 4 h at 50° C. under N2. The solvent was evaporated in vacuo to a small volume. Column chromatography on silica gel, their on aluminum oxide (ethyl acetate:methanol: water 15:2:1 as eluent) gave 185 mg (39%) pure title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[C:12](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.[Cl-].[NH4+].O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:25]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[N:14]=[C:13]([C:15]([O:17][CH3:18])=[O:16])[C:12]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:10]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)/C=C/c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1C(=O)OC
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: COC(=O)CCc1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1C(=O)OC
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
To a solution of methyl 6-(dibenzylamino)-3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]pyridine-2-carboxylate (2.60 g, 6.24 mmol) and nickel(II) chloride hexahydrate (891 mg, 3.75 mmol) in methanol (62 mL) was added sodium tetrahydroborate (472 mg, 12.5 mmol) under ice-cooling, and the mixture was stirred for 5 min. The reaction solution was diluted with saturated aqueous ammonium chloride solution, and the organic solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (2.24 g, yield 86%).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH:27]=O)[CH:23]=[CH:22][CH:21]=[N:20]1>>[N:19]1([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: O=Cc1cccc(-n2cccn2)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-n2cccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(1H-pyrazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.76 min.; [M+H]+: 378.17 g/mol.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:29](Cl)=[O:30].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:29]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:30]
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4ccc(Cl)c(Cl)c4)C3)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, (60 mg, 0.13 mmol), 3,4-dichloro benzoyl chloride (Aldrich, 27 mg, 0.13 mmol) and Et3N (76 uL, 0.54 mmol) in DCM (4 mL) was stirred at room temperature for 1 hour followed by aqueous workup with sat NaHCO3 and DCM. The organic layer was dried (Na2SO4) and concentrated in vacuo followed by column chromatography purification (5% NH3 in MeOH mixed with EtOAc) resulting in the title compound as a white solid.
Reaction SMILES: O.[NH2:2][C@H:3]([C:14]([NH:16][C@H:17]([C:20]([NH:22][C@H:23]([C:32]([OH:34])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:21])[CH2:18][OH:19])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CC(O)=O.C([O-])(O)=O.[Na+].C1C(=O)N([O:51][C:52]([O:54][CH2:55][CH:56]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[C:62]3[C:57]2=[CH:58][CH:59]=[CH:60][CH:61]=3)=O)C(=O)C1>O1CCOCC1>[NH:2]([C:52]([O:54][CH2:55][CH:56]1[C:57]2[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:63]2[C:68]1=[CH:67][CH:66]=[CH:65][CH:64]=2)=[O:51])[C@H:3]([C:14]([NH:16][C@H:17]([C:20]([NH:22][C@H:23]([C:32]([OH:34])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:21])[CH2:18][OH:19])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reaction time: 4 h

Procedure:
To a mixture of 50 ml of water and 50 ml of dioxane, 19.96 g (38.8 mmol) of H-Trp-Ser-Tyr-OH acetate, 6.52 g (77.6 mmol) of NaHCO3 and 14.2 g (42 mmol) of Fmoc-OnSu are added successively. After allowing to stand for 4 hours at room temperature, insoluble material is filtered off and discarded next day. The filtrate is concentrated. The residue is triturated with petroleum ether, filtered off with suction and dried.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:20]=[C:19]2[C:9]([NH:10][CH:11]=[C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:8][CH:7]=1)=[O:4].[Br:21]N1C(=O)CCC1=O.[OH-].[Na+]>C(O)(=O)C.CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[NH:5][C:6]1[CH:20]=[C:19]2[C:9](=[CH:8][CH:7]=1)[NH:10][C:11]([Br:21])=[C:12]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17]
Reactant: COC(=O)Nc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)Nc1ccc2[nH]c(Br)c(CCNC(C)=O)c2c1

Procedure:
A solution of 5-methoxycarbonylamino-N-acetyltryptamine (0.05 mmol) in acetic acid (0.5 mL) is treated with N-bromosuccinimide (0.05 mmol) 3.5 h at 25° C. The solution is next neutralized with 50% sodium hydroxide solution and extracted with ethyl acetate. The organic extract is evaporated and the purified product obtained following chromatography on silica gel with 2% methanol-chloroform as eluent.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:5]=[C:4]([Cl:12])[N:3]=1.[Na].[CH2:14]([O:16][CH2:17][CH2:18][OH:19])[CH3:15]>>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([Cl:11])([Cl:10])[Cl:9])[CH:7]=[C:2]([O:19][CH2:18][CH2:17][O:16][CH2:14][CH3:15])[N:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Reactant: CCOCCO
Agent: [Na]
Product: CCOCCOc1cc(C(Cl)(Cl)Cl)cc(Cl)n1

Procedure:
To a solution of 26.54 grams (0.1 mole) of 2,6-dichloro-4-(trichloromethyl)pyridine dissolved in 150 ml of 2-ethoxyethanol was added over a 35 minute period, a solution of 2.53 grams (0.11 mole) of sodium metal dissolved in ~100 ml of 2-ethoxyethanol. The mixture was heated for 5 hours at 65°-75° C. The insoluble by-products were filtered off and the 2-ethoxyethanol was removed by evaporation under reduced pressure. The residue which remained was diluted with water and extracted with methylene chloride and the extract dried with sodium sulfate. The extract was filtered and the methylene chloride evaporated off leaving the 2-chloro-6-(2-ethoxyethoxy)-4-(trichloromethyl)pyridine product as an oil. The product had a refractive index of n 25/d = 1.5395 and was recovered in a yield of 23.8 grams (75 percent of theoretical). Upon analysis, the compound was found to have carbon, hydrogen, nitrogen and chlorine contents of 37.72, 3.25, 4.55 and 44.61 percent, respectively, as compared with the theoretical contents of 37.64, 3.48, 4.39 and 44.45 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]1[NH:10][CH2:9]1>>[C:2]1([NH:1][CH2:8][CH2:9][NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C1CN1
Product: NCCNc1ccccc1
Yield: 13 %

Procedure:
It is known to produce certain unsymetrically substituted 1,2-ethanediamines. Current processes, however, have proven unacceptable. For example, G. I. Braz et al. disclosed that the aminoethylation of aniline with ethyleneimine afforded only a 13 percent yield of N-phenyl-1,2-ethanediamine. The remaining product comprised polyamino ethyl compounds of high molecular weight. Dokl. Akad. Nauk., 59, 489 (1948), Chem. Abstr., 42, 6747 (1948).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:11][O:10][C:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:20])=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ncccc1C
Solvent: ClCCl
Product: COC(=O)c1c(C)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
A mixture of methyl 3-methylpicolinate (2 g, 14.8 mmol) and m-CPBA (3 g, 17.8 mmol) in DCM (35 mL) was stirred at RT overnight. Then the mixture was washed with NaHSO3 (a.q.) and concentrated in vacuum. The residue was purified by column chromatography (DCM:MeOH=200:1) to give the product of 2-(methoxycarbonyl)-3-methylpyridine 1-oxide (1.89 g, yield: 79%). 1H-NMR (CDCl3, 400 MHz) δ 8.05 (d, J=6.0 Hz, 1H), 7.18 (t, J=8.4 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 3.95 (s, 3H), 2.23 (s, 3H). MS (M+H)+: 168.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH2:24][CH2:25][C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[CH3:34][CH:35](O)[CH3:36]>>[CH:35]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]([NH:14][C:5]2([C:3]([OH:2])=[O:4])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)=[O:33])=[CH:17][C:18]=1[O:23][CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1)([CH3:36])[CH3:34]
Reactant: CC(C)O
Reactant: COC(=O)C1(NC(=O)c2ccc(O)c(OCCc3cccc(C)c3)c2)Cc2ccccc2C1
Product: Cc1cccc(CCOc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2OC(C)C)c1

Procedure:
The compound of step 1 of example 254 was reacted with 2-propanol in analogy to step 1 of example 1 and the obtained ester hydrolyzed in analogy to example 2.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[N:16]12[CH2:24][C@H:20]([C:21](=O)[CH2:22]1)[CH2:19][CH2:18][CH2:17]2.C(N(CC)CC)C.[C:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[N:33].[ClH:40]>O.C1(C)C=CC=CC=1>[ClH:40].[N:16]12[CH2:24][C@H:20]([C:21](=[C:34]([C:32]#[N:33])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:22]1)[CH2:19][CH2:18][CH2:17]2
Reactant: CCOC(=O)CC#N
Reactant: O=C1CN2CCC[C@@H]1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CN2CCC[C@@H]1C2
Temperature: 25 °C
Reaction time: 144 h

Procedure:
(5R)-1-Azabicyclo[3.2.1]octan-6-one (−) camphorsulfonate (61.8 g, 135.0 mmol) and triethylamine (20.4 g, 202 mmol) and ethyl cyanoacetate (61.8 g, 547 mmol) were mixed and stirred at room temperature for 6 days. Toluene (120 ml) and water (120 ml) were added to the reaction mixture and the pH was adjusted to 2 with concentrated hydrochloric acid. The phases were separated and the water phase extracted with toluene (30 ml). The combined organic phases were washed with water (20 ml). The combined water phases were adjusted to pH=9.4 with NH3 (25% in water) and extracted with toluene (1×120 ml, 1×60 ml). The combined toluene extracts were evaporated. The residue was dissolved in ethanol (120 ml) and concentrated hydrochloric acid (16 ml) was added. The title compound precipitated in 22 g yield. Upon evaporation of the mother liquor and crystallization from ethanol (40 ml) further 14.6 g of the title compound was isolated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:8])[C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(F)cccc1F
Agent: O=S(=O)(O)O
Product: Cc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 1,3-difluoro-2-methyl-benzene (15 g, 0.12 mol) in H2SO4 (100 mL) was treated dropwise with 65% HNO3 (11.4 g, 0.12 mol) at −10° C. and the resultant mixture was stirred for about 30 min. The mixture was poured into ice-water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo to give 1,3-difluoro-2-methyl-4-nitro-benzene (16 g, 78% yield). 1H NMR (400 MHz, CDCl3): δ 7.80 (m, 1H), 6.95 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=2)[NH:19][C:18]([C:30]([NH2:32])=O)=[CH:17]3)=[CH:9][CH:8]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:20](=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=2)[NH:19][C:18]([C:30](=[S:42])[NH2:32])=[CH:17]3)=[CH:9][CH:8]=1
Reactant: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCCOCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 96.5 %

Procedure:
To a solution of 5-({6-[(2-methoxyethoxy)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (1.1 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (1.1 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.1 g, yield 96%) as a yellow amorphous solid.