Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[CH:6]2C)#[N:2].[NH4+].[Cl-].C([O:18]CC)C>C1COCC1.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:18])[CH2:6]2)#[N:2]
Reactant: CCOCC
Reactant: CC1C(=S)Nc2ccc(C#N)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CC(=O)N2
Reaction time: 18 h

Procedure:
A solution of 5-cyano-3-methylthiooxindole (6.0 g, 29 mmol) in THF (100 mL) was stirred at room temperature and a saturated aqueous solution of NH4Cl (100 mL) added followed by activated zinc (25 g, 0.38 mol). The resulting mixture was stirred for 18 hours. The mixture was filtered through a pad of diatomaceous earth and the pad washed with THF (20 mL). The organic phase was separated, dried over anhydrous MgSO4 and the solvent evaporated to leave a tan solid. Trituration of this solid with diethyl ether gave 5-cyanooxindole a white solid, (4.1 g, 88%). 1H NMR (DMSO-d6) δ7.63 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 6.93 (d, 1H, J=8.4 Hz), 3.55 (s, 2H). MS (−ve ES) 157 (100), (M−H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[N:10]=1)[C:5](O)=[O:6].Cl.[O:29]([NH2:31])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:15][CH2:16]2)[N:10]=1)[C:5]([NH:31][O:29][CH3:30])=[O:6]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1

Procedure:
The title compound was synthesised by an analogous method to Example 45 starting from 2-chloro-6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinic acid (Example 153) and methoxylamine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](Cl)=[N:6][CH:7]=1.[O:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:12]2[CH2:13][CH2:14][CH2:15][O:9][CH2:10][CH2:11]2)=[N:6][CH:7]=1
Reactant: Clc1ccc(Br)cn1
Reactant: C1CNCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Brc1ccc(N2CCCOCC2)nc1
Yield: 92.7 %

Procedure:
The solution of 5-bromo-2-chloropyridine (1.5 g, 7.8 mmol), 1,4-oxazepane (1.29 g, 9.36 mmol) and K2CO3 in 15 mL of NMP was stirred at 120° C. overnight. The mixture was added to 150 mL of water, washed with EA, dried over Na2SO4, and the volatiles were removed in vacuo to give 1.86 g of 4-(5-bromopyridin-2-yl)-1,4-oxazepane. MS(m/z)=259 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:27]([OH:29])=O)[C:14]3[C:19]([CH3:20])=[N:18][N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[C:15]=3[N:16]=2)=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.[CH2:39]([N:46]1[CH2:51][C:50]([CH3:53])([CH3:52])[NH:49][CH2:48][C:47]1([CH3:55])[CH3:54])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.O>[CH2:39]([N:46]1[C:47]([CH3:55])([CH3:54])[CH2:48][N:49]([C:27]([C:13]2[CH:12]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=3)[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]=23)=[O:29])[C:50]([CH3:53])([CH3:52])[CH2:51]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)CN(Cc2ccccc2)C(C)(C)CN1
Reactant: COCOc1ccc(-c2cc(C(=O)O)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(-c2cc(C(=O)N3CC(C)(C)N(Cc4ccccc4)CC3(C)C)c3c(C)nn(C4CCCCO4)c3n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a suspension of 1.24 g of 6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid in 15 ml of DCM were added 2.1 ml of Hünig's base, 1.03 g of BEP and 0.87 g of 1-Benzyl-2,2,5,5-tetramethyl-piperazine. The reaction was stirred at r.t. for 3 h. For workup it was diluted with water and DCM and the layers were separated. The organic layer was washed with water twice, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc gradient) to obtain 1.54 g (81%) of the title compound.
Reaction SMILES: [N:1]1([CH2:4][C@@H:5]([OH:15])[CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1.[BrH:16]>CC(C)=O>[BrH:16].[Br:16][CH2:3][CH2:2][NH:1][CH2:4][C@@H:5]([OH:15])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1nccn1C[C@H](O)CN1CC1
Agent: Br
Solvent: CC(C)=O
Product: O=[N+]([O-])c1nccn1C[C@H](O)CNCCBr

Procedure:
In another alternate procedure, treatment of (R)-(-)-α-(1-aziridinylmethyl)-2-nitro-1H-imidazole-1-ethanol, synthesized as described in Example 2(e), with aqueous hydrogen bromide in acetone, as described in The Journal of Medicinal Chemistry, 33, 2608 (1990), gives the product, mp 149°-150.5° C. (decomposition), 99.3% optically pure by chiral HPLC.
Reaction SMILES: [C:1]([N:5]1[CH2:40][CH2:39][CH2:38][CH2:37][C:8]2[C:9]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20]#[C:21][CH2:22][C@@H:23]5[CH2:27][O:26]C(C)(C)[O:24]5)[C:16]([O:30][CH3:31])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:41])([CH3:4])([CH3:3])[CH3:2].[OH2:42].N>C(O)(=O)C>[C:1]([N:5]1[CH2:40][CH2:39][CH2:38][CH2:37][C:8]2[C:9]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([C:20](=[O:42])[CH2:21][CH2:22][C@@H:23]([OH:24])[CH2:27][OH:26])[C:16]([O:30][CH3:31])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1C#CC[C@@H]1COC(C)(C)O1)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O
Agent: N
Solvent: CC(=O)O
Product: COc1cc2c(cc1C(=O)CC[C@@H](O)CO)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3

Procedure:
A solution of 40 mg of 28a in 1 mL 80% acetic acid was stirred at room temperature for 16 h. Then water was added and the mixture was made alkaline with ammonia. The mixture was extracted with 2×ethyl acetate. The combined organic phases were dried and concentrated. The crude product was purified by preparative HPLC on a reversed phase C18 column to give 8.8 mg of compound 28b.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Yield: 42.9 %

Procedure:
In 20 ml of tetrahydrofuran was dissolved 10 ml of a 65% toluene solution of sodium dihydrobis-(2-methoxyethoxy)-aluminate. To the solution was added dropwise 20 ml of tetrahydrofuran solution and 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine while stirring and cooling with ice. The mixture was stirred at room temperature for two hours. After addition of 5% hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was crystallized from ethyl acetate-petroleum ether to give 410 mg of N-(cyclohexylmethoxycarbonyl)-tyrosinol.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxyacetophenone (25 g, 184 mmol) in acetone (500 ml) were added potassium carbonate (50.7 g, 367 mmol) and benzyl bromide (32 g, 187 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water (500 ml) and extracted with ethyl acetate (500 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the objective substance (36.8 g, 89%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].S(O)(O)(=O)=O.[NH2:15]O.[OH-].[Na+].C(OC(=O)C)(=O)C>O.C1(C)C=CC=CC=1>[C:1](#[N:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCC=O
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCCCCC#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 150 %

Procedure:
Into a nitrogen-substituted 500 mL volume flask, toluene (200 g) and the crude 7-octenal (30.5 g) (90.0% in gas chromatography simple area %, net: 27.5 g, 0.22 mol; cis-6-octenal: 6.3% in gas chromatography simple area %, tras-6-octenal: 4.0% in gas chromatography simple area %) obtained by the technique of Synthesis Example 1 were charged. An aqueous solution of 35.5% by mass hydroxylamine sulfate (55.5 g; net: 19.7 g, 0.12 mol) was added thereto, and then the mixture was cooled to 0° C. An aqueous solution of 18% by mass sodium hydroxide (53.3 g; net: 9.6 g, 0.24 mol) was added thereto at a temperature in a range of 10 to 20° C. over 1.0 hour. After completion of the reaction, water (100 g) was added and the resulting two layers were separated. After acetic anhydride (24.5 g, 0.24 mol) was added to the organic layer, azeotropic dehydration was carried out by heating at an internal temperature of 120° C. for 3 hours. The organic layer was separated, and the obtained organic layer was distilled under a reduced pressure of 670 Pa, to obtain crude 7-octenonitrile (25.0 g) (90.2% in gas chromatography simple area %, 22.5 g, 0.18 mol; cis-6-octenonitrile: 3.9% in gas chromatography simple area %, tras-6-octenonitrile: 3.4% in gas chromatography simple area %) as a distillate.
Reaction SMILES: [C:1](OC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].CCCCCCC.C(C([C:27]1[C:35]2[C:30](=[N:31][CH:32]=[CH:33][N:34]=2)[NH:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:38][CH:37]=1)(C)C(OC)=O)(=O)C>CN1CCCC1=O.[OH-].[Na+].CO.O1CCCC1.C(OCC)(=O)C>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([C:28]2[NH:29][C:30]3=[N:31][CH:32]=[CH:33][N:34]=[C:35]3[C:27]=2[CH2:1][CH2:2][C:3](=[O:4])[CH3:5])=[CH:37][CH:38]=1)([CH3:44])([CH3:43])[CH3:45]
Reactant: COC(=O)C(C)(C(C)=O)c1c(-c2ccc(C(C)(C)C)cc2)[nH]c2nccnc12
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCc1c(-c2ccc(C(C)(C)C)cc2)[nH]c2nccnc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl acetoacetate (1.35 mL) in N-methylpyrrolidone (15 mL), cooled to 0° C., was treated portionwise with sodium hydride (0.33 g, 60% dispersion in mineral oil) and after stirring at 0° C. for 30 minutes this mixture was then treated with a solution of [6-(4-tert-butylphenyl-5H-pyrrolo[2,3-b]pyrazin-7-yl]methyltrimethylammonium iodide [2 g, Reference Example 45(a)] in N-methylpyrrolidone (100 mL). After stirring at room temperature overnight the reaction mixture was subjected to chromatography on silica eluting with a mixture of heptane and ethyl acetate. The resulting 2-acetyl-[6-(4-tert-butyl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]propionic acid, methyl ester (1.2 g) was dissolved in a mixture of sodium hydroxide (250 mL, 2N), methanol (25 mL) and tetrahydrofuran. This solution was then heated at 50° C. for 1 hour, then evaporated, then acidified by addition of hydrochloric acid (25 mL, 2N) and then extracted with ethyl acetate. The organic extract was dried over sodium sulfate and then evaporated to give the title compound (1 g). MS: 322 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][OH:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.O=[Mn]=O>[C:1]1([C:7]2[N:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1nc(-c2ccccc2)cs1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.5 %

Procedure:
To (4-phenylthiazol-2-yl)methanol (900 mg, 4.7 mmol) in DCM (10 mL) was added MnO2 (4 g, 47 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then filtered, washed with water, extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was concentrated under vacuum to give a crude product, which was purified by column chromatography to afford the title compound as a yellow solid (360 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][C:5]2[C:9]([NH:17]C(=O)C)=[CH:10][CH:11]=[C:12]([C:13]([O:15]C)=[O:14])[C:4]=2[O:3]1.[OH-].[Na+]>CO>[CH3:1][C:2]1([CH3:21])[CH2:8][CH2:7][CH2:6][C:5]2[C:9]([NH2:17])=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:4]=2[O:3]1
Reactant: COC(=O)c1ccc(NC(C)=O)c2c1OC(C)(C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCCc2c(N)ccc(C(=O)O)c2O1

Procedure:
To a solution of 5.5 g (19.0 mmol) of methyl 2,2-dimethyl-6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate in 10 ml of methanol is added 10 ml of a 10% aqueous sodium hydroxide solution in a single portion at room temperature. The reaction mixture is heated to reflux and maintained at that temperature for 2 hours. After cooling, methanol is removed in vacuo and the residue is diluted with water. The pH of the solution is adjusted to 7 with 1N HCl and the solution is extracted with CH2Cl2. The combined organic extracts are dried over MgSO4, filtered and concentrated. Flash chromatography (30% EtOAc/hexanes) gives 2,2-dimethyl-6-amino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: C([O:5][C:6](=[O:26])[NH:7][CH:8]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[CH2:9][CH:10](O)[CH:11]=[CH2:12])(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.CCOCC>[C:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:8]2[CH2:9][CH:10]([CH:11]=[CH2:12])[O:26][C:6](=[O:5])[NH:7]2)=[CH:20][CH:19]=1)([CH3:23])([CH3:24])[CH3:25]
Reactant: C=CC(O)CC(Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC1CC(Cc2ccc(OC(C)(C)C)cc2)NC(=O)O1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To a solution of 46 (20.0 mg, 0.056 mmol) in dry THF (1.2 mL) under N2 at room temperature was added KHMDS solution (0.5 M, 0.12 mL, 0.060 mmol). After the addition, the reaction mixture was stirred for 45 min. and diluted with ether. The solution was washed with 1 N HCl (aq), H2O, saturated NaHCO3 (aq), and brine and dried over Na2SO4. The solvent as removed under reduced pressure and the residue was purified by flash chromatography (hexanes:ethyl acetate 2:1) to afford 47 as a pale yellow oil.
Reaction SMILES: CCN(CC)CC.[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[C:19](=O)[CH3:20].[CH2:22]([O:24][C:25](=[O:30])[CH2:26][C:27](Cl)=[O:28])[CH3:23].CCOC(C)=O.CCCCCC>C(Cl)Cl.O>[CH2:22]([O:24][C:25]([C:26]1[C:27]([OH:28])=[N:8][C:9]2[C:10]([C:19]=1[CH3:20])=[CH:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)=[O:30])[CH3:23]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
12.6 ml (0.09 mol) NEt3 was added to a solution of 16.6 g (0.08 mol) 1-(2-amino-4-(trifluoromethyl)phenyl)ethanone in DCM (170 ml) and cooled to 0° C. 13.4 ml (0.11 mol) 3-chloro-3-oxo-propanoic acid ethyl ester was subsequently added in drops and the mixture was then stirred for 16 h at RT. The mixture was then diluted with water and extracted with DCM (3×). The combined organic phases were dried over Na2SO4 and concentrated in a vacuum. After CC (EtOAc/hexane 2:3) of the residue, 18.1 g (0.07 mol, 87%) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was obtained.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[C:11]=1[C:12]([NH2:14])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].CO>[C:1]([NH:6][C:7]1[NH:8][CH:9]=[C:10]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[C:11]=1[C:12]([NH2:14])=[O:13])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCC(=O)Nc1[nH]cc(-c2ccc([N+](=O)[O-])cc2)c1C(N)=O
Agent: [Pd]
Solvent: CO
Product: CCCC(=O)Nc1[nH]cc(-c2ccc(N)cc2)c1C(N)=O
Yield: 118.5 %

Procedure:
0.195 g (0.61 mmol) of 2-butyrylamino-4-(4-nitrophenyl)-1H-pyrrole-3-carboxamide is added at a temperature in the region of 25° C. to a suspension of 0.068 g (0.064 mmol) of 10% palladium on carbon in 20 cm3 of methanol. After hydrogenating for 5 hours in an autoclave under 2 bar of hydrogen, at a temperature in the region of 25° C., the reaction mixture is filtered, the catalyst is rinsed with twice 10 cm3 of methanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.207 g of 2-butyrylamino-4-(4-aminophenyl)-1H-pyrrole-3-carboxamide, in the form of a cream solid. 1H NMR (400 MHz, (CD3)2SO, —δ in ppm) 0.94 (t, J=7.5 Hz, 3H); 1.63 (m, 2H); 2.37 (t, J=7.5 Hz, 2H); 5.11 (broad s, 2H); from 6.05 to 8.45 (very broad m, 2H); 6.24 (d, J=2.5 Hz, 1H); 6.60 (d, J=8.5 Hz, 2H); 6.99 (d, J=8.5 Hz, 2H); 10.8 (broad s, 1H); 11.3 (broad s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH2:19][C:20]([O-:22])=[O:21])O)=[CH:11][CH:10]=1.[Li+]>ClCCl>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=C([O-])CC1(O)CCc2ccc(F)cc21
Agent: [Li+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1\CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
Trifluoroacetic acid (1.5 mL) was added to a stirred, chilled (ice-methanol bath) suspension of lithium 2-(6-fluoro-1-hydroxy-1-indanyl)acetate (0.5 g, 2.3 mmol) in dichloromethane (13.5 mL). After 15 min, the mixture was concentrated in vacuo and the resulting white solid was recrystallized from aqueous acetone to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as white crystals (0.32 g, 73%) identical to compound of Example 1i by mixed m.p., (203°-205° C.) and NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=2)[C:3]=1[C:16]([OH:18])=O.C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[CH3:14][C:12]1[C:13]2[C:16](=[O:18])[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:8]=2[CH:9]=[C:10]([CH3:15])[CH:11]=1
Reactant: Cc1cc(C)cc(-c2cccc(C)c2C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C)c2c(c1)-c1cccc(C)c1C2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.6 %

Procedure:
In a 250 ml 1-necked round bottom flask the biphenyl-carboxylic acid 52 (3.0 g, 12.9 mmol) was treated with concentrated sulphuric acid (40 ml) at 0° C. (ice bath). The resulting dark brown solution was stirred for 15 min at 0° C., then for additional 1 h at ambient temperature. The reaction mixture was poured in ice (100 g) whereupon the color changes to a bright yellow. The suspension was neutralized with K2CO3 and extracted with Et2O (3×100 ml). The combined organic phases were washed with brine (75 ml), dried over MgSO4, filtered and the volatiles removed in vacuo to afford 53 (2.8 g, 98%) as yellow crystals. Rf 0.52 (cyclohexane:ethylacetate 10:1). The product was used without any further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:26])([F:25])[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1>C(Cl)Cl>[F:26][C:9]([F:8])([F:25])[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)COC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (1.15 mL) was added dropwise to a solution of tert-butyl 4-(2,2,2-trifluoroethoxy)piperidine-1-carboxylate (prepared in an analogous manner to Intermediate 203, 1.14 g, 4.0 mmol) in DCM (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The mixture was then concentrated under vacuum, the crude residue was dissolved in water and product was extracted with diethylether (2 times). The aqueous phase was basicified to pH 10 using solid potassium carbonate and extracted with DCM (4 times). The organic extracts were combined, dried over sodium sulfate and concentrated under vacuum to afford the title compound (610 mg, 83%). 1H NMR (300 MHz, CDCl3) δ ppm 3.84 (2H, q), 3.53 (1H, m), 3.10 (2H, m), 2.61 (2H, m), 1.76 (2H, m) and 1.54 (2H, s).
Reaction SMILES: C1(S([C:10](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])(=O)=O)C=CC=CC=1.[N-:31]=[N+:32]=[N-:33]>>[CH3:30][C:27]([C:18]1[CH:17]=[C:16]([C:15]2[NH:31][N:32]=[N:33][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]=1[OH:26])([CH3:28])[CH3:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)S(=O)(=O)c1ccccc1
Product: CNC(=O)c1nn[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
reacting 2-(benzenesulfonyl)-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methylacrylamide with a metal azide to yield 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-3H-[1,2,3]triazole-5-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH:28]([C:29]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: O=C=Nc1ccccc1
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccccc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and phenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:27]I>CN(C=O)C>[CH3:27][O:16]/[C:15](/[C:17]1[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=1)=[CH:14]\[N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:24][CH2:23][C:5]1=2
Reactant: CI
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)c2ccncc2)CCN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanone (100 mg) was dissolved in DMF (5 mL). Sodium hydride was added at once under nitrogen atmosphere followed by addition of methyl iodide. The contents were stirred at RT overnight. The reaction was monitored by LCMS. The reaction mixture was poured into 25 mL ice cold water and extracted with EtOAc (20 mL×3). The combined organic layers were given water washing (30 mL×2), dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by reverse phase column chromatography to get 2 mg product as the TFA salt. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.78 (d, 2H), 8.22 (d, 2H), 7.70 (s, 1H), 7.34 (m, 2H), 7.18 (d, 1H), 4.80 (m, 1H), 4.40 (m, 2H), 3.80 (m, 1H), 3.60 (m, 1H), 3.40 (s, 3H), 3.26 (m, 2H), 3.16 (s, 3H), 2.44 (s, 3H).