Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH2:45])[CH3:38]>O1CCCC1>[CH2:37]([O:39][C:40](=[O:49])[C@H:41]([CH3:48])[NH:42][C:43](=[O:47])[N:44]([CH3:46])[NH:45][C:16](=[O:18])[C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:10]([CH3:11])[NH:9][C:7](=[O:8])[C@H:5]([CH3:6])[NH:4][C:1](=[O:3])[CH3:2])[CH3:38]
Reactant: CCOC(=O)[C@H](C)NC(=O)N(C)N
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(C)=O
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To a solution of acetylalanylalanylproline (3 mmole) and N-methylmorpholine (3 mmole) in dry tetrahydrofuran (110 ml) at -20° to -25° C. is added isobutyl chloroformate (3 mmole) and stirred at -20° C. for 10 minutes. A solution of 2-azaalanylalanine ethyl ester (3 mmole) in tetrahydrofuran (15 ml) is added dropwise. The resulting mixture is allowed to warm to room temperature over a period of 1 hour and stirred overnight. The precipitate is filtered off and the filtrate is concentrated to dryness. Chromatography on silica gel (70 gm) and elution with 8% methanol in chloroform gives acetylalanylalanylprolyl-2-azaalanylalanine ethyl ester.
Reaction SMILES: [NH2:1][C:2]1([C:15]([F:18])([F:17])[F:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([CH:30]=O)[CH:28]=[CH:29][C:23]=2[S:22][CH2:21]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>CN(C=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][C:2]([NH:1][CH2:30][C:27]2[CH:28]=[CH:29][C:23]3[S:22][CH2:21][C:20](=[O:19])[NH:25][C:24]=3[CH:26]=2)([C:15]([F:18])([F:16])[F:17])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(F)(F)F)CC1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc3c(c2)NC(=O)CS3)(C(F)(F)F)CC1

Procedure:
A mixture of 4-amino-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine (3 e) (1 equiv.), 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (1n) (1.1 equiv.), and Na2SO4 in DMF is stirred until the imine has formed, then is filtered through a sintered glass funnel. The filtrate is concentrated to dryness in vacuo, and the residue is dissolved in EtOH. NaBH4 (1 equiv.) is added, and the reaction is stirred until the imine is consumed. The solvent is removed in vacuo and the residue is taken up in dilute HCl. The mixture is neutralized with dilute NaOH and extracted with CH2Cl2. Drying (Na2SO4), concentration, and flash chromatography on silica gel gives the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH2:18])[S:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][O:24][CH2:25][C:26]#[C:27][C:28]1[S:32][C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:30][C:29]=1[C:39](O)=[O:40]>>[CH3:23][O:24][CH2:25][C:26]#[C:27][C:28]1[S:32][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:30][C:29]=1[C:39]([NH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=1[C:14]1[S:13][C:10]2[C:9]([N:15]=1)=[CH:8][C:7]([CH2:6][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[CH:12][N:11]=2)=[O:40]
Reactant: COCC#Cc1sc(-c2ccccc2)nc1C(=O)O
Reactant: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Product: COCC#Cc1sc(-c2ccccc2)nc1C(=O)Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Yield: 30 %

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 5-(3-methoxyprop-1-ynyl)-2-phenylthiazole-4-carboxylic acid. The product was isolated using workup 2 and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2) followed by recrystallization from MeOH to give the title compound (111 mg, 30% yield). MS Calcd for C31H27N5O2S2: 565.16. Found (M+H)+ m/z=566.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18]CC)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O

Procedure:
A mixture of 3.11 g (9.72 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 10 ml of ethanol, 2 ml of water and 400 mg of sodium hydroxide is heated to boiling under reflux for 1 hour. After evaporation of the ethanol, the residue is treated with 10 ml of 1 N hydrochloric acid. The colourless material obtained is filtered off under suction, washed with water and dried. There is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid with a decomposition point of 283°-284°.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:15][C:14]2[NH:13][C:12]3[CH2:11][C:10]([CH3:17])([CH3:16])[CH2:9][C:8](=[O:18])[C:7]=3[CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)[C:5]=2[C:4](=[O:28])[CH2:3]1.[H][H]>C(O)C.Cl.[Pd]>[CH3:16][C:10]1([CH3:17])[CH2:11][C:12]2[NH:13][C:14]3[CH2:15][C:2]([CH3:1])([CH3:29])[CH2:3][C:4](=[O:28])[C:5]=3[CH:6]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)[C:7]=2[C:8](=[O:18])[CH2:9]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1(C)CC(=O)C2=C(C1)NC1=C(C(=O)CC(C)(C)C1)C2c1cccc(N)c1
Yield: 97.4 %

Procedure:
A solution of 10 g of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-nitrophenyl)-1,8(2H,5H)-acridinedione in 190 ml of ethanol and 100 ml of 1M hydrochloric acid was hydrogenated at atmospheric temperature and pressure in the presence of 0.5 g of 10% palladium on carbon catalyst. When hydrogen uptake had ceased, the catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in water (20 ml) and the solution made alkaline by addition of excess 1M sodium carbonate solution. The precipitated solid was filtered off, washed with water and dried giving 9.0 g of 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-(3-aminophenyl)-1,8(2H,5H)-acridinedione as a pale brown solid; mass spectrum (ESP) m/e 365 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([CH3:31])=[CH:6]2.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:7]([CH3:31])=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(NS(C)(=O)=O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(NS(C)(=O)=O)cc2)c1-c1ccccc1
Temperature: -20 °C
Reaction time: 0.02 h
Yield: 62.3 %

Procedure:
A stirring solution of 269 (0.27 g, 0.62 mmol) in CH2Cl2 (10 mL) chilled to −20° C. under N2 was added BBr3 (0.47 g, 1.86 mmol), dropwise, via syringe, over 1 minute. The resulting yellow/orange r×n was stirred for 2 h at −20° C. and then poured over 50 g ice followed by addition of EtOAc (50 mL). The resulting slurry was transferred to a separatory funnel and the organic layer washed with brine (50 mL), dried (Na2SO4) and concentrated to a pale yellow foam. The crude product was purified by silica gel column chromatography with 2% MeOH: CH2Cl2 to yield 162 mg (63%) of the title compound 270, as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 2.13 (s, 3H), 2.83 (s, 3H), 6.55 (d, J=9.0 Hz, 2H), 6.97 (d, J=8.3 Hz, 2H), 6.96 (dd, J1=2.3 Hz, J2=9.1 Hz, 1H), 7.12 (d, J=2.3 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 7.21-7.30 (m, 4H), 7.54 (d, J=8.5 Hz, 1H), 7.55 (s, 1H), 9.33 (s, 1H), 9.84 (s, 1H). Anal. Calc for C29H26O3.0.5H2O: C, 67.27; H, 5.18; N, 3.27. Found: C, 67.13; H, 5.04; N, 3.27.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:16]1([CH2:15][O:14][C:12]2[C:11]([C:19]([F:22])([F:20])[F:21])=[CH:10][C:9]3[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[CH:28]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(OCC3CC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-cyclopropylmethoxy-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M176) (275 mg, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (170 mg, 78%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:31]1[CH2:32][CH2:33][CH:28]([NH:27][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:30]1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC2CCOCC2)nn1
Yield: 62 %

Procedure:
As described for example 81, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, using 4-aminotetrahydropyran instead of aminomethylcyclopropane, to the title compound (64 mg, 62%) which was obtained as a white foam. MS: m/e=412.5 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[CH3:32][N:33]([CH3:39])[C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1.[Li+].[Cl:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]2[CH:48]=[C:49]([C:51]([O-])=[O:52])[S:50][C:43]=12>CN(C=O)C>[Cl:41][C:42]1[CH:47]=[CH:46][N:45]=[C:44]2[CH:48]=[C:49]([C:51]([N:36]3[CH2:37][CH2:38][C@@H:34]([N:33]([CH3:39])[CH3:32])[CH2:35]3)=[O:52])[S:50][C:43]=12
Reactant: CN(C)[C@@H]1CCNC1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 32.1 %

Procedure:
HATU (4.99 g, 26.25 mmol) and Et3N (7.23 mL, 52.50 mmol) was added to a solution of (3R)-N,N-dimethylpyrrolidin-3-amine (1.0 g, 17.5 mmol) and 7-chlorothieno[3,2-b]pyridine-2-carboxylic acid lithium salt (3.85 g, 17.5 mmol) in 30 mL DMF at 0° C. The reaction mixture was stirred at 0° C. for 15 min and solvent was concentrated. The residue was partition between H2O and 10% CH3OH in EtOAC. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (5-7% CH3OH in CH2Cl2) to give a white solid (1.74 g, 32%). 1H NMR (CD3OD) δ 8.57 (1H, d, J=5.2 Hz), 7.90 (1H, d, J=7.9 Hz), 7.48 (1H, d, J=5.2 Hz), 4.11-3.97 (1H, m), 3.90-3.36 (3H, m), 2.99-2.90 (1H, m), 2.30 (3H, s), 2.26 (3H, s), 1.97-1.72 (2H, m). ESIMS (MH+): 310.10.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(N(C(C)C)C(C)C)C>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Brc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.5 g (50 mmol) 4-bromobenzylbromide is slowly added dropwise to a solution of 4.52 mL (55 mmol) pyrrolidine and 10.3 mL (60 mmol) ethyldiisopropylamine in 100 mL THF and stirred overnight at RT. The precipitate is filtered off and the solvent is eliminated i.vac. The product is obtained as a light-brown liquid which is further reacted without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[N+:15]([O-])=O)=[C:6]([N+:18]([O-])=O)[CH:5]=[CH:4][CH:3]=1.O.NN.NN>C(O)C.[Ni]>[CH3:14][C:13]1[C:8]([C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[NH2:18])=[C:9]([NH2:15])[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc([N+](=O)[O-])c1-c1c(C)cccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cccc(N)c1-c1c(C)cccc1N

Procedure:
The atmosphere of a 500 ml eggplant flask equipped with a three-way cock at the top and an Allihn condenser was dried under reduced pressure and displaced with nitrogen. In the flask was charged 13.6 g (50 mmole) of 6,6'-dimethyl-2,2'-dinitro-1,1'-biphenyl (7) as obtained in Preparation Example 4 and dissolved in 120 ml of warm 99% ethanol having been previously displaced with nitrogen, followed by stirring. To the mixture was added 35 ml (0.7 mole) of hydrazine hydrate having been displaced with nitrogen. A suspension of 3 ml of a Raney nickel W2 type catalyst in ethanol was slowly added thereto by means of a syringe while maintaining the activity. Thereafter, the mixture was heated at reflux in an oil bath until the whole of the hydrazine was consumed.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:17][NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][CH:21]=3)[CH3:16])[C:11]([C:31]([F:34])([F:33])[F:32])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].Cl.O>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:17][NH:18][C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][CH:21]=3)[CH3:16])[C:11]([C:31]([F:33])([F:32])[F:34])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1ccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(NNC(=O)c1ccc(C(=O)O)cc1)=C1C(=O)N(c2ccc(C)c(C)c2)N=C1C(F)(F)F
Temperature: 0 °C
Yield: 88.9 %

Procedure:
4-Methoxycarbonylbenzoic N′-(1-(1-(3,4-dimethylphenyl)-3-trifluoromethyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide (0.107 mmol, 50.7 mg) was dissolved in methanol (2 ml) and stirred with 1M aqueous sodium hydroxide (0.534 mmol, 0.534 ml) at room temperature for 2 hours and at 60° C. for 1.5 hours. Then, the reaction vessel was cooled to 0° C., and 1M hydrochloric acid (0.534 mmol, 0.534 ml) and water were added. The precipitated solid was collected by filtration with water and dried to obtain 4-carboxybenzoic N′-(1-(1-(3,4-dimethylphenyl)-3-trifluoromethyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl)-hydrazide as a yellow solid (43.8 mg, 89%).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([NH:27][C:28]([NH2:30])=[O:29])=[C:12]([CH2:25][CH3:26])[N:13]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:25]([C:12]1[N:13]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]2[C:10]([C:11]=1[NH:27][C:28]([NH2:30])=[O:29])=[C:9]([O:8][CH2:7][C:6]([OH:31])=[O:5])[CH:17]=[CH:16][CH:15]=2)[CH3:26]
Reactant: CCc1c(NC(N)=O)c2c(OCC(=O)OC(C)(C)C)cccc2n1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1c(NC(N)=O)c2c(OCC(=O)O)cccc2n1Cc1ccccc1
Yield: 46.1 %

Procedure:
A solution of [[2-ethyl-1-(phenylmethyl)-3-ureido-1H-indol-4-yl]oxy]acetic acid tert-butyl ester (0.2 g) and trifluoroacetic acid (0.3 mL) in 5 mL of methylene chloride was stirred at room temperature for 18 hours. After concentrating to dryness, the resulting solid was slurried in ether, filtered and air dried to give 0.08 g of titled compound. Mass spectrum: 368.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[OH:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:8]=1[C:9](OC)=[O:10]>O.O1CCOCC1>[NH2:4][OH:1].[OH:6][C:7]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:8]=1[C:9]([NH:4][OH:1])=[O:10]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: [OH-]
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NO)c(O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 123.5 %

Procedure:
An hydroxylamine solution was prepared by addition of aqueous sodium hydroxide (393 mg, 9.82 mmol)/water (1.6 ml) to a stirred solution of hydroxylamine hydrochloride (292 mg, 4.21 mmol) in water (3.5 ml). Immediately slowly added a solution of methyl 2-hydroxy-4-methoxybenzoate (511 mg, 2.81 mmol) in 1,4-dioxane (1.5 ml). The resulting reaction mixture was stirred at room temperature for 18 hours, under an argon atmosphere. The reaction mixture was concentrated on a rotary evaporator to half the original volume, and the product precipitated by addition of concentrated hydrochloric acid, keeping flask cool in an ice bath. Filtered the suspension to give 2-hydroxy-4-methoxybenzohydroxamic acid (476 mg, 92%) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:17]1([N:23]=[C:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=2[NH:1][C:24]([NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:25])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1[nH]c2ccccc2c1-c1ccccc1
Product: O=C(Nc1ccccc1)Nc1[nH]c2ccccc2c1-c1ccccc1

Procedure:
The compound is obtained according to Example 34 by reacting 2-amino-3-phenylindole (m.p. 220°-223° C) with phenylisocyanate. M.p. 210°-212° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C@H:8]2[CH2:10][C:11](=O)[CH2:12][C@H:7]2[CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:5]1[CH2:9][C@H:8]2[CH2:10][C:11](=[N:15][OH:16])[CH2:12][C@H:7]2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C[C@H]2CC(=O)C[C@H]2C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCN1C[C@H]2CC(=NO)C[C@H]2C1

Procedure:
A suspension of (3aS,6aR)-2-butylhexahydrocyclopenta[c]pyrrol-5-one (0.467 g, 2.58 mmol), hydroxylamine hydrochloride (0.430 g, 6.19 mmol) and sodium acetate (0.842 g, 6.19 mmol) in ethanol (21 ml) and water (7 ml) is heated to reflux for 1 hour. The ethanol is evaporated and the residue partitioned between saturated aqueous NaHCO3 and EtOAc. The organic phase is washed with brine, dried (MgSO4) and evaporated to afford (3aS,6aR)-2-butylhexahydrocyclopenta[c]pyrrol-5-one oxime, MH+197.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:43])[NH:7][C:8]1[C:9]([C:22]2[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:26][C:27]=2[Cl:28])=[CH:10][C:11]2[CH:16]=[N:15][C:14](S(C)(=O)=O)=[N:13][C:12]=2[N:21]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:55]([N:57]([CH2:68][CH3:69])[CH2:58][CH2:59][O:60][C:61]1[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=1)[CH3:56]>CN(C=O)C>[C:1]([NH:5][C:6](=[O:43])[NH:7][C:8]1[C:9]([C:22]2[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:26][C:27]=2[Cl:28])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([NH:67][C:64]3[CH:63]=[CH:62][C:61]([O:60][CH2:59][CH2:58][N:57]([CH2:68][CH3:69])[CH2:55][CH3:56])=[CH:66][CH:65]=3)=[N:13][C:12]=2[N:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CC(C)(C)NC(=O)Nc1nc2nc(S(C)(=O)=O)ncc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(-c4c(Cl)ccc(NC(=O)c5cccc(C(F)(F)F)c5)c4Cl)c(NC(=O)NC(C)(C)C)nc3n2)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
This compound is prepared using a similar procedure to the one described above except that in step D the following procedure is used. To a solution of N—{3-[7-(3-tert-butyl-ureido)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-6-yl]-2,4-dichloro-phenyl}-3-trifluoromethyl-benzamide (50 mg, 0.08 mmol) in DMF (2 ml) is added p-toluenesulfonic acid (15 mg, 0.08 mmol) and 4-(2-diethylamino-ethoxy)-phenylamine (21 mg, 0.1 mmol). The reaction is stirred at 80° C. for 4 hours. The crude product is purified by RP-HPLC to give the title compound as yellow solid: 1H NMR 400 MHz (DMSO) δ 10.46 (s, 1H), 10.09 (s, 1H), 9.30 (s, 1H), 9.05 (s, 1H), 8.28 (s, 1H), 8.24 (d, 1H, J=7.6 Hz), 8.05 (m, 2H), 7.95 (m, 3H), 7.76 (m, 3H), 7.67 (d, 2H, J=8.8 Hz), 4.24 (t, 2H, J=4.6 Hz), 3.45 (m, 2H), 3.15 (m, 4H), 1.39 (s, 9H), 1.18 (t, 6H, J=7.2 Hz); MS m/z 783.3 (M+1).
Reaction SMILES: ClCCl.B(Br)(Br)Br.[CH3:8][O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([CH3:34])=[C:28]3[N:27]=[C:26]2[CH2:35][O:36]C)=[CH:20][CH:19]=1)=[O:11]>CO>[OH:36][CH2:35][C:26]1[N:25]([CH2:24][C:21]2[CH:22]=[CH:23][C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:10]([O:9][CH3:8])=[O:11])=[CH:19][CH:20]=2)[C:29]2=[N:30][CH:31]=[CH:32][C:33]([CH3:34])=[C:28]2[N:27]=1
Reactant: COCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc(Cn2c(CO)nc3c(C)ccnc32)cc1
Yield: 75.5 %

Procedure:
50 ml (50 mmol) of a dichloromethane solution of 1M boron tribromide was added little by little dropwise to 100 ml of a dichloromethane solution of 3.3 g (8.2 mmol) of 3-[(2'-methoxycarbonyl-biphenyl-4-yl) methyl]-2-methoxymethyl-7-methyl-3H-imidazo[4,5-b]pyridine, while stirred and cooled with ice. The mixture was further stirred at a room temperature for 12 hours. Methanol was added dropwise to the product mixture, while stirred and cooled with ice, and the solvent was distilled out at a reduced pressure. The residue was mixed with water and neutralized with sodium bicarbonate. It was weakly acidified with acetic acid and decanted to remove the water. Methanol was added to the residue and distilled out at a reduced pressure. It was re-crystallized from ethanol-isopropylether to obtain 2.4 g of the intended compound.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:11][CH:10]=2)([O:3]CC)=[O:2].Cl>C(O)C.[OH-].[Na+].O>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:1]([OH:3])=[O:2]
Reactant: CCOC(=O)c1cnc2ccc(C3CCCCC3)cc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc2ccc(C3CCCCC3)cc2c1O

Procedure:
A solution of 11 g of 3-carboethoxy-4-hydroxy- 6-cyclohexyl-quinoline in 300 ml of ethanol and 50 ml of 10 N sodium hydroxide solution is heated for 3 hours on a water bath. It is then diluted with 200 ml of water and the clear solution is acidified with concentrated hydrochloric acid, whereupon a solid precipitate results. This is filtered off and recrystallised from ethanol or dimethylformamide, and gives 4-hydroxy-6-cyclohexyl-quinoline-3-carboxylic acid in the form of pale yellow crystals of melting point 263°-265°C.