Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=1)(=[O:24])=[O:23].C1C(=O)N([I:42])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([I:42])=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=1)(=[O:24])=[O:23]
Reactant: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)ccc2n1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a CH2Cl2 (20 mL) solution N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (315.0 mg, 619.0 μmol) was added n-iodosuccinimide (195.0 mg, 866.6 μmol, Alfa Aesar, Ward Hill, Mass.) as a solid in a single portion. The solution turned dark brown and was maintained at rt for 1 h. The solution was concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The crude residue was taken up in minimal CH2Cl2/MeOH and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (80 g) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (370.0 mg, 94.16% yield) as a brown solid. LCMS (ESI positive ionization) m/z: 635 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[NH2:16]OS(O)(=O)=O>CN(C)C=O.O>[NH2:16][N:11]1[CH:12]=[CH:13][C:9]([C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:8])=[CH:10]1
Reactant: O=C(c1ccccc1)c1cc[nH]c1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nn1ccc(C(=O)c2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-benzoylpyrrole (4.92 g) in 50 ml of dry dimethylformamide was added milled potassium hydroxide (8.06 g). Hydroxylamine-O-sulfonic acid (4.23 g) was added to the suspension in 4 portions over a period of 1 hour with stirring at room temperature. After the addition was completed the reaction mixture was stirred for 30 minutes at room temperature, and subsequently diluted with 50 ml of water and extracted with DCM. The combined organic layers were washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, DCM/ethyl acetate, 5:1), affording starting material (1.44 g) and the desired product as the second fraction. Recrystallization from ethyl ether/hexane gave the product as crystals (1.80 g), which was combined with material obtained from a 36.9 mmol scale reaction and recrystallized from DCM/hexane affording 3.20 g of crystals, m.p. 82°-83° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:16]([O-])([OH:18])=[O:17]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])([C:12]([O:14][CH3:15])=[O:13])[CH2:11][C:2]=1[OH:1]
Reactant: COC(=O)c1ccc(C(=O)OC)c(O)c1
Reactant: O=[N+]([O-])O
Product: COC(=O)C1=C(O)CC(C(=O)OC)([N+](=O)[O-])C=C1

Procedure:
Dimethyl hydroxyterephthalate (3.00 g, 14.3 mmol) was cooled to 5° C. and mixed with 7 mL fuming nitric acid for 40 min. The reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with pH 7 phosphate buffer, saturated NaCl, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to yield crude 3.0 g dimethyl-2-hydroxy-4-nitroterephthalate. IR: 1739, 1688, 1549, 1442, 1338 and 1254 cm−1
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([N:13]([CH2:28][CH3:29])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:26]=O)=[CH:23][C:24]=1[CH3:25])=[O:19])[CH3:12].C(OC(C1C(C=O)(C)C=CN1)=O)C>>[CH2:28]([N:13]([CH2:11][CH3:12])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([C:20]1[NH:21][C:22]([CH:26]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:23][C:24]=1[CH3:25])=[O:19])[CH3:29]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Agent: CCOC(=O)C1NC=CC1(C)C=O
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccccc32)cc1C
Yield: 21 %

Procedure:
Oxindole (66.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide (prepared from 3-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester by method B then C) to give 39 mg (21%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:15])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(F)cc1
Reaction time: 2 h
Yield: 104.1 %

Procedure:
To a solution of 4-fluorophenylacetic acid (1, scheme 1) (26.5 g, 172 mmol) in DCM (93 mL) was added oxalyl chloride (2 eq., 30.1 mL, 344 mmol) over 5 min and DMF (0.005 eq., 0.067 mL, 0.86 mmol) over 1 min. The reaction mixture was stirred at r.t for 2 h then concentrated. The residual DCM was removed as an azeotrope with toluene (2×20 mL) to afford intermediate 2-(4-fluorophenyl)acetyl chloride (1a) (30.85 g, 179 mmol, assumed quantitative yield) as yellow oil. Part of that material was used as is in the next step.
Reaction SMILES: C(Cl)Cl.[CH:4]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5]1.C[Si]([N:14]=[C:15]=[O:16])(C)C>CO>[CH:4]1([NH:9][C:15]([NH2:14])=[O:16])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C[Si](C)(C)N=C=O
Reactant: NC1CCCC1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)NC1CCCC1
Reaction time: 8 h

Procedure:
To a CH2Cl2 solution of cyclopentylamine was added trimethylsilyl isocyanate. The reaction mixture was stirred overnight. To this was added 200 ml of CH3OH, and the mixture was stirred for another 2 hrs. The reaction mixture was concentrated and was titrated using diethyl ether to give an off-white precipitate. The precipitate was filtered through a Buchner funnel to give cyclopentyl urea Compound 30a as a white crystalline solid compound (13.0 g, 86%). To this urea Compound 30a (5.0 g, 38.7 mmol) in acetic acid (11 mL), was added malonic acid (4.0 g, 38.7 mmol) followed by acetic anhydride (18 mL) and the reaction was stirred at 70° C. for 12 hrs. The reaction mixture was concentrated, cooled in an ice bath and titrated using 4/1 EtO2/EtOAc. A pale yellow crystalline solid precipitated out. The precipitate was filtered and washed 2-3 times using cold diethyl ether to obtain a pale yellow solid Compound 30b (2.5 g, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl:9][C:10]1[C:11](F)=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25]CC)=[O:24])=[CH:15][C:14]=2[CH:28]=1>>[Cl:9][C:10]1[C:11]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:12][C:13]2[O:18][CH:17]([C:19]([F:21])([F:22])[F:20])[C:16]([C:23]([OH:25])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccccc1Cl
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccccc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 199.0-199.1° C. 1H NMR (acetone-d/300 MHz) 7.94 (s, 1H), 7.76 (s, 1H), 7.65 (m, 1H), 1.51 (m, 1H), 7.38 (m, 1H), 7.32 (m, 1H), 6.44 (s, 1H), 5.85 (q, 1H, J=7.0 Hz). 13F NMR (acetone-d6 /28; MHz) -79.5 (d, J=6.5 Hz). ESHRMS m/z 402.9752 (M-H, Calc'd 402.9751). Anal. Calc'd for C17H9Cl2F3O4 : C, 50.40; H, 2.24; Cl, 17.50. Found: C, 50.42; H, 2.12; Cl, 17.72.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:19][CH3:20]
Reactant: CCCBr
Reactant: Oc1cccc2ccoc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cccc2ccoc12
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 7-hydroxybenzofuran (2.60 g) in DMF (30 ml) was added potassium carbonate (3.75 g) and then was added dropwise bromopropane (2.87 g) under nitrogen atmosphere, and the mixture was stirred overnight. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (three times) and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give brown oil of 7-propoxybenzofuran (2.73 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]([CH2:22]Cl)[N:19]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18][C@H:17]1[CH3:31])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][C@H:20]([CH2:22][N:3]2[CH2:7][CH2:6][CH2:5][C:4]2=[O:8])[N:19]([CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:18][C@H:17]1[CH3:31])=[O:15])([CH3:10])([CH3:11])[CH3:12]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: O=C1CCCN1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 187.7 %

Procedure:
Three separate reaction flasks were each charged with sodium hydride (60% in mineral oil, 0.486 g, 12.16 mmol) and anhydrous DMF (40.5 mL). To these, pyrrolidinone (0.924 mL, 12.16 mmol) was added dropwise. After stirring at this temperature for 30 minutes, (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.74 g, 8.11 mmol) was added to each at room temperature. The reactions were stirred at 80° C. for 4 h. The reactions were combined and saturated aqueous sodium bicarbonate was added and the mixture extracted with diethyl ether (3×). The combined organic layers were washed with brine, dried with sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-100%, EtOAc in petrol 40-60) gave the title compound (5.9 g), MS: [M+H]+=388.
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C@H:6]1[C@H:11]([OH:12])[CH2:10][C@H:9]2[C@H:13]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C:21]1[CH:20]=[CH:19][C:18]([OH:25])=[CH:17][C:16]=1[CH2:15][CH2:14]3)=[O:4].CC(C)=O.O.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>[OH-].[Na+]>[C:31]([O:25][C:18]1[CH:19]=[CH:20][C:21]2[C@@H:22]3[C@H:13]([C@H:9]4[C@@:7]([CH2:24][CH2:23]3)([CH3:8])[C@@H:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:1])[C@H:11]([OH:12])[CH2:10]4)[CH2:14][CH2:15][C:16]=2[CH:17]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCC(=O)N[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@@]21C
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)N[C@H]1[C@H](O)C[C@H]2[C@@H]3CCc4cc(OC(=O)c5ccccc5)ccc4[C@H]3CC[C@@]21C
Reaction time: 0.17 h

Procedure:
17β-Methylacetamido-oestra-1,3,5(10)-triene-3,16α-diol (13.1 g) was dissolved in aqueous sodium hydroxide solution (260 ml; 2 N), acetone (260 ml) and water (260 ml). Benzoyl chloride (6.5 ml) was added and the mixture stirred vigorously for 10 min.; a further 6.5 ml of benzoyl chloride was added and the mixture was stirred vigorously for a further 10 min. Water (5 l) was added and the precipitated product was filtered, washed with water and dissolved in dichloromethane. The dichloromethane solution was washed with water, dried (Na2SO4) and evaporated to give a white froth (6.8 g), which was crystallised from dichloromethane-ether-light petroleum to give impure product (6.0 g). Acidification of the aqueous mother liquors provided unreacted starting material (7.8 g), which was treated as above to give a further quantity of impure product (2.3 g). Recrystallisation of the combined products from dichloromethane-ether afforded an isomeric mixture of 17β-methylacetamido-oestra-1,3,5(10)-triene-3,16α-diol 3-benzoates (4.68 g; 27%).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][N:38]=1>>[Cl:36][C:37]1[N:38]=[CH:39][C:40]([C:2]2[CH:35]=[CH:34][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]5)=[CH:22][CH:21]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:4][CH:3]=2)=[CH:41][CH:42]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: OB(O)c1ccc(Cl)nc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nc4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure G using 2-chloro-5-pyridine-boronic acid (315 mg, 2 mmol) to give 5-{4-[2-[4-(6-chloro-pyridin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[CH:16])[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.C[Si](C)(C)C#CC=C1CCNCC1.Br[C:34]1[CH:35]=[C:36]([C:40]2[O:44][N:43]=[C:42]([CH3:45])[N:41]=2)[CH:37]=[CH:38][CH:39]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[C:16][C:38]3[CH:39]=[CH:34][CH:35]=[C:36]([C:40]4[O:44][N:43]=[C:42]([CH3:45])[N:41]=4)[CH:37]=3)[CH2:10][CH2:9]2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2cccc(Br)c2)n1
Reactant: C#CC=C1CCN(c2nc(C)ccc2[N+](=O)[O-])CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#CC=C1CCNCC1
Agent: [F-]
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(N2CCC(=CC#Cc3cccc(-c4nc(C)no4)c3)CC2)n1
Yield: 61 %

Procedure:
The title Compound was prepared from Compound 274c following the procedure described for the compound of Example 274 using 5-(3-bromophenyl)-3-methyl-1,2,4-oxadiazole instead of 1-bromo-3,5-difluorobenzene and adding 1 molar equivalent of tetrabutylammonium fluoride monohydrate to the starting reaction mixture. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from 9:1 to 7:3 affording the title product. Yellow oil. Yield: 61%.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[NH2:17].[N:20]#[C:21]Br.Cl>C(O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:7]2[C:8](=[CH:9][C:10]=1[O:15][CH3:16])[NH:17][C:21]1=[N:20][CH:3]=[CH:4][N:5]1[CH2:6]2
Reactant: COc1cc(N)c(CNCC(OC)OC)cc1OC
Reactant: N#CBr
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)Nc1nccn1C2
Reaction time: 2 h

Procedure:
1.1 g of N-(2,2-dimethoxyethyl)-2-amino-4,5-dimethoxybenzylamine and 0.5 g of cyanogen bromide are heated under reflux over-night in 10 ml of 95% ethanol. 5 ml of 5 N hydrochloric acid are then added, and the solution is left to stand at room temperature for 2 hours. After the reaction solution is concentrated in a vacuum it is made alkaline with dilute caustic soda. The little compound is obtained in crystalline form, and is crystallised from ethyl acetate. M.p. 215°-217° (from ethanol).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:9]=[CH:10]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2Cc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 25 °C
Yield: 9 %

Procedure:
A solution of 1-benzyl-5-nitroindole (0.51 g, 0.02 mol) in a mixture of ethyl acetate (25 ml) and methanol (25 ml) was carefully added to 10% palladium on charcoal (45 mg). The resulting suspension was stirred at room temperature under an atmosphere of hydrogen. When the reaction was complete (indicated by tlc or calculated uptake of hydrogen) the suspension was filtered through a pad of Harbolite™, and the filtrate evaporated to dryness to give 5-amino-1-benzylindole (0.40 g, 91%) as an off-white solid; m.p. 66-68° C.; δH [2H6]-DMSO 7.30-7.12 (6H, m, 2-H, 2″-H, 3″-H, 4″-H, 5″-H, 6″-H), 7.08 (1H, d, J 8, 7-H), 6.70 (1H, s, 4-H), 6.49 (1H, d, J 8, 6-H), 6.18 (1H, s, 3-H), 5.28 (2H, s, CH2), 4.38 (2H, br s, NH2).
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:22]=1>C1(C)C=CC=CC=1>[C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1cccnc1
Reactant: c1ccc(C(CC2CCNCC2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(CCCc1cccnc1)N1CCC(CC(c2ccccc2)c2ccccc2)CC1

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 10 starting with 5.3 g of 4-(2,2-diphenylethyl)piperidine free base and the acid chloride prepared from 5.0 g of 3-pyridine butanoic acid, there was obtained 7.0 g of oil from the toluene extracts. Crystallization from methylene chloride/ether provided 6.3 g (76%) of 4-(2,2-diphenylethyl)-1-[1-oxo-4-(3-pyridinyl)butyl]piperidine, mp 98°-100° C. Analysis Calculated for C28H32N2O: C, 81.51; H, 7.82; N, 6.79. Found: C, 81.43; H, 7.88; N, 6.53.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14](=[O:16])[CH3:15])=[CH:3][C:4]=1[F:12])(=[O:11])[CH3:10]
Reactant: CC(=O)Nc1ccc(N)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(NC(C)=O)c(F)c1
Temperature: 15 °C

Procedure:
134.5 g (0.8 mol) of the 1-amino-4-acetylamino-3-fluorobenzene prepared above under A. are heated at 85° C. together with 800 ml of water and 34 g of acetic acid. 86.5 g of acetic anhydride are added to this mixture in the course of one hour. The reaction mixture is subsequently stirred at the same temperature for a further hour and cooled to 15° C. The product which has precipitated is then filtered off, washed twice with 150 ml of water each time and dried.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][S:4]([CH2:7][CH:8]([NH:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29])[C:9](=[O:26])[NH:10][CH:11]([C:14]([C:16]1[O:20][N:19]=[C:18](C2SC=CC=2)[N:17]=1)=[O:15])[CH2:12][CH3:13])(=[O:6])=[O:5].C1C=CC2N(O)N=NC=2C=1.N[C@@H](CC)C(C1ON=[C:53]([C:56](C)([CH3:58])[CH3:57])N=1)O>ClCCl>[C:56]([C:18]1[N:17]=[C:16]([CH:14]([OH:15])[CH:11]([NH:10][C:9]([CH:8]([NH:27][C:28]([N:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[O:29])[CH2:7][S:4]([CH2:3][CH:2]([CH3:36])[CH3:1])(=[O:5])=[O:6])=[O:26])[CH2:12][CH3:13])[O:20][N:19]=1)([CH3:58])([CH3:57])[CH3:53]
Reactant: CC[C@H](N)C(O)c1nc(C(C)(C)C)no1
Reactant: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(=O)c1nc(-c2cccs2)no1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCC(NC(=O)C(CS(=O)(=O)CC(C)C)NC(=O)N1CCOCC1)C(O)c1nc(C(C)(C)C)no1
Reaction time: 0.33 h
Yield: 104.7 %

Procedure:
N-Cyclohexylcarbodiimide-N′-methylpolystyrene (0.526 g, 1 mmol, loading 1.9 mmol/g) was suspended in dichloromethane (20 mL). 3-(2-methyl-propane-1-sulfonyl)-2-[(morpholine-4-carbonyl)-amino]-propionic acid (0.242 g, 0.6 mmol, reference Example 5) and HOBt (0.114 g, 0.85 mmol) were added and the reaction mixture was stirred for 20 minutes. (2S)-2-Amino-1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-butan-1-ol (0.107 g, 0.5 mmol, Reference Example 6) was added and stirring continued for 5 hours. Silicycle Triamine (1.27 g, 5 mmol) was added and the mixture stirred for 15 hours. The reaction mixture was filtered under suction and the filtrate concentrated to give morpholine-4-carboxylic acid [1-{1-[(3-tert-butyl-1,2,4-oxadiazol-5-yl)-hydroxy-methyl]-propylcarbamoyl}-2-(2-methyl-propane-1-sulfonyl)-ethyl]-amide (0.271 g), [LC/MS m/z=518(M+H+)].
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH2:15])[CH3:14])=[CH:9][CH:8]=1.Cl([O-])(=O)(=O)=O.[Li+].CCOCC>C(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][CH2:4][C:2]([CH3:3])([OH:5])[CH3:1])[CH3:14])=[CH:9][CH:8]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC1(C)CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C[C@H](NCC(C)(C)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Isobutylene oxide (1.0 g) and (S)-1-(4-fluorophenyl)ethylamine (2.25 mL) were added to a solution of lithium perchlorate (14.8 g) in an ether (27.8 mL) at room temperature, and the reaction solution was stirred at room temperature for 1.5 hours. Isobutylene oxide (0.5 mL) was added to the reaction solution, which was then stirred overnight. Ice water and chloroform were added to the reaction solution, and the organic layer was separated. Thereafter, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (chloroform:2-propanol=100:1 to 1:1) to obtain 2.13 g of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH2:15][C:16]#N)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](=O)([O:21]C)[O:19]C.C([O-])([O-])=O.[K+].[K+]>>[OH:21][C:18]([CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH:10]=1)[CH3:16])=[O:19]
Reactant: COC(=O)OC
Reactant: N#CCc1cccc(C(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Yield: 80 %

Procedure:
A mixture of (3-benzoylphenyl)acetonitrile (1 g), dimethyl carbonate (15 ml) and K2CO3 (3 g) in the 1:40:5 molar ratio, is reacted in a steel autoclave at the temperature of 140° C. for 10 hours and 30 minutes. After recovering DMC, 0.85 g of the title product are obtained, with a monomethylation selectivity >99% (80% yield), which is hydrolyzed to obtain ketoprofen by known methods.