Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[CH:25]=[CH:26][CH:27]=[C:18]([C:19]=45)[S:17]3(=[O:29])=[O:28])[CH2:9][CH2:8]2)[C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[NH:3]1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[C:34]([N:3]1[C:4]2[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=2[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[CH:25]=[CH:26][CH:27]=[C:18]([C:19]=45)[S:17]3(=[O:29])=[O:28])[CH2:11][CH2:12]2)[C:2]1=[O:1])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCN(CCCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1c(=O)n(C2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 15 h
Yield: 51.5 %

Procedure:
The experiment is carried out as in Example 44, starting with 2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) in dimethylformamide (20 cc) and benzoyl chloride (1.4 g) in tetrahydrofuran (20 cc) and sodium hydride (0.48 g) as a 50% dispersion in vaseline oil. The mixture is stirred for 15 hours at a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a dichloromethanemethanol (90-10 vol) mixture as eluant, and then recrystallization from a boiling acetone/ethanol (90-10 vol) mixture (60 cc), 2-{3-[4-(3-benzoyl-2-oxo-1-benzimidazolinyl)piperidino]propyl}naphto [1,8-cd]isothiazole 1,1-dioxide (2.9 g) is obtained, m.p. 133° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH2:11]([O:13][C:14]([C:16]1[C:20](CBr)=[C:19]([S:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[N:18]([CH:32]([CH3:34])[CH3:33])[N:17]=1)=[O:15])[CH3:12].O>CN(C=O)C>[CH2:11]([O:13][C:14]([C:16]1[C:20]([CH2:2][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[C:19]([S:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)[N:18]([CH:32]([CH3:33])[CH3:34])[N:17]=1)=[O:15])[CH3:12]
Reactant: OCc1ccncc1
Reactant: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1Cc1ccncc1
Yield: 35.2 %

Procedure:
To a solution of 55 mg of 4-(hydroxymethyl)pyridine in DMF at 0° C. was added 20 mg sodium hydride (60% in oil). To the mixture was added dropwise a solution of 229 mg of 4-bromomethyl-5-(3,5-dichlorophenylthio)-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 2 ml of N,N-dimethylformamide. After 15 min water was added and the mixture was extracted with dichloromethane (×3). The combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography using ethyl acetate/iso-hexane for the elution to give 80 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3carboxylic acid ethyl ester as a colourless gum. Mass spectrum (ESI) m/z 480 [M]+.
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:46][N:45]=[C:44]([CH3:47])[C:43]=2[CH:48]=O)=[CH:38][CH:37]=1>C1COCC1.Cl>[Br:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[O:46][N:45]=[C:44]([CH3:47])[C:43]=2[CH:48]=[CH:10][CH2:9][CH2:8][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:40][CH:41]=1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3-phenylpropyl)triphenylphosphonium bromide (0.956 g, 2.07 mmol) in THF (5 mL) at −78° C. was slowly added n-butyllithium (2.5M in hexanes; 0.83 mL, 2.07 mmol), and the mixture was stirred for 15 minutes. 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.500 g, 1.88 mmol) in THF (3 mL) was added, and the reaction was warmed to 0° C. and stirred for 1 hour. The solution was diluted with 1N aqueous HCl and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, decanted, and concentrated. The residue was purified by silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40](O)=[O:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([C:40]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:22])[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:41])[CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC1(CC)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Product: CCC1(CC)C(=O)N(C2CCN(C(=O)c3cc(OCc4ccccc4)ccc3C)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B7) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclohexane/EA=1:1) to yield the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11](=O)[CH3:12].N1CCCCC1.Cl.[Cl-].[Na+]>C(OCC)(=O)C>[CH:11](=[C:4]([C:3](=[O:10])[CH2:2][Cl:1])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:12]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CC=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: CC=C(C(=O)CCl)C(=O)OCC
Temperature: -75 °C
Reaction time: 2 h

Procedure:
50 parts by weight of ethyl 4-chloroacetoacetate and 76 parts by volume of ethyl acetate are taken, covered with a layer of nitrogen and cooled to -75° C. 33 parts by weight of acetaldehyde are added to the cold solution and a solution of 0.43 part by volume of piperidine in 3 parts by volume of ethyl acetate is then allowed to run in over a period of 50 minutes. The solution is now warmed to 0° C. in the course of 40 minutes and is stirred at this temperature for 2 hours. After addition of 121 parts by volume of 1N hydrochloric acid and 16 parts by weight of sodium chloride, the mixture is worked up. The organic phase is separated off and the aqueous phase is extracted again with 45 parts by volume of ethyl acetate. The combined organic phases are extracted twice with a solution of in each case 16 parts by weight of sodium chloride in 55 parts by volume of water and dried. After the solvent has been stripped off, 51.9 parts by weight of product remain, which can be further processed in the crude form.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:10]#[N:11]>>[N+:1]([C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:7]([O:6][CH3:5])=[CH:8][C:9]=1[C:10]#[N:11])([O-:4])=[O:2]
Reactant: COc1ccc(C#N)cc1OC
Reactant: O=[N+]([O-])O
Product: COc1cc(C#N)c([N+](=O)[O-])cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a nitric acid (40 mL) in ice bath was added 3,4-dimethoxybenzonitrile (5.0 g, 30.6 mmol) and was allowed to stir for 2 hours. Then the solution was gradually returned to room temperature. To this solution was added ice (200 mL) to get light yellow precipitate which was then collected by filtration to give 6.25 g (98%) of 2-nitro-4,5-dimethoxybenzonitrile. 1H NMR (100 MHz, DMSO-d6): δ3.69 (s, 3H, CH3), 3.90 (s, 3H, CH3), 7.53 (s, 1H, Ar--H), 7.75 (s, 1H, Ar--H). ms: m/z 208 (M+), 192 (M+ -16), 178 (M+ -30), 162 (M+ -46).
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[SH:8][CH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@H:14]([CH2:18][S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:15]([OH:17])=[O:16])=[O:12].O.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[SH:8][CH2:9][C@@H:10]([CH3:28])[C:11]([NH:13][C@@H:14]([CH2:18][S:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)[C:15]([O:17][CH3:30])=[O:16])=[O:12]
Reactant: Cc1ccc(CSC[C@H](NC(=O)[C@H](C)CS)C(=O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)[C@H](C)CS

Procedure:
Anhydrous sodium sulfate (3 g) is added to a solution of (2R)-2-[(2S)-3-mercapto-2-methylpropionylamino]-3-(4-methylbenzylthio)propionic acid (compound No. 1-1, 300 mg) and p-toluenesulfonic acid monohydrate (240 mg) in methanol (10 ml), and the mixture is refluxed for three hours and 30 minutes. Sodium sulfate is filtered out, and the filtrate is concentrated under reduced pressure. A 5% aqueous sodium hydrogencarbonate solution is added to the obtained residue, and the whole is extracted with ethyl acetate. The organic layer is washed with a 5% aqueous sodium hydrogencarbonate solution, a 5% aqueous citric acid solution and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the titled compound. The following compound is obtained by a method similar to Example 5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14]3[CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)([C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)O)[CH:17]=[CH:18][C:13]=3[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][S:9]2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:39])=O>>[Cl:39][C:19]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)([C:21]1[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=1)[C:16]1[CH:17]=[CH:18][C:13]2[N:12]3[N:34]=[N:35][N:36]=[C:11]3[CH2:10][S:9][CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:14]=2[CH:15]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Reactant: O=S(Cl)Cl
Product: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCc1nnnn1-2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(3-chlorophenyl)-α-(4-chlorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-4 H,6H-tetrazolo[1,5-a][4,1]benzothiazepine-8-methanol (described in Example B15b) (0.0032 mol) in thionyl chloride (40 ml) was stirred at room temperature for 30 min and at 40° C. for 1 hour. The solvent was evaporated till dryness. The product was used without further purification, yielding (quant.) of 8-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophenyl)-4H,6H-tetrazolo[1,5-a ][4,1]benzothiazepine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][CH:35]=1)(C)(C)C.C(=O)(OC(C)(C)C)N.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].ClCCl>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[NH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:41][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[O:24])(=[O:42])=[O:43])=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Agent: CC(C)(C)OC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccc(CN)cc4)oc3C)cc2)cc1

Procedure:
4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with (4-sulphamoyl-benzyl)-carbamic acid tert-butyl ester (85 mg) in an analogous manner to that described in Example 2A. The intermediate tert-butyl carbamate was hydrolysed with 1% trifluoroacetic acid/dichloromethane over 24 hours, then concentrated in vacuo to give compound 12 as a white solid (10 mg). LC/MS System C: Rt=4.67 mins, m/z (ES−)=493 (M− 1 for C27H26N2O6S).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([C@H:13]3[CH2:15][C@H:14]3[C:16](O)=[O:17])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:22][NH2:23]>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]3[CH:13]4[CH:14]([C:16](=[O:17])[NH:22][N:23]=3)[CH2:15]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)[C@H]1C[C@H]1C(=O)O
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1NN=C(c2ccc(C3CCCCC3)cc2)C2CC12
Yield: 92.5 %

Procedure:
8.0 g (29.4 millimoles) of cis-2-(p-cyclohexylbenzoyl)-cyclopropanecarboxylic acid, 1.6 g (32.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 8 hours. The product is filtered off at 0° C. and dried under reduced pressure at 50° C. 7.3 g (93% of theory) of 2-(p-cyclohexylphenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are obtained as almost colorless crystals, of melting point 211°-212° C. after recrystallization from isopropanol.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27].[C:30](Cl)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:39]1[CH:46]=[CH:45][C:42]([O:43][CH3:44])=[CH:41][CH:40]=1)[C:31]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[CH:33][CH:32]=1.CO>N1C=CC=CC=1>[NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:2][CH2:3][C:4]([O:6][C:30]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:39]1[CH:46]=[CH:45][C:42]([O:43][CH3:44])=[CH:41][CH:40]=1)[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[CH:37][CH:38]=1)=[O:5].[NH2:24][CH:25]([CH2:28][OH:29])[CH2:26][OH:27]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: NC(CO)CO
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(OC(=O)CCNC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 0.25 h

Procedure:
N-Fmoc-β-Ala-Serinol (1, 93 g, 242 mmol) is co-evaporated 2×400 mL anh. pyridine, and then dissolved in 300 mL of the same solvent with magnetic stirring. The mixture is cooled in a ice bath, and DMT-Cl (86.1 g, 254 mmol) in 465 mL pyridine is added dropwise over a period of 1.5 hours. The ice bath is removed and the mixture is allowed to react for another hour at room temperature. Methanol (100 mL) is added and stirred for 15 min. to quench the remaining DMT-Cl. After evaporation in vacuo, the residue co-evaporated 3×400 mL with toluene. Silica gel column purification using ethyl acetate/methanol/triethylamine (95:5:0.25) as mobile phase yielded 90.6 g (55%) grams of isolated product 2.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]=[CH:6][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:8]([C:7]1[C:2](=[O:1])[C:3]2[C:4](=[N:16][N:17]([CH3:19])[CH:18]=2)[N:5]([CH3:22])[CH:6]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc2c(O)c(C(=O)c3ccccc3)cnc2n1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc2c(=O)c(C(=O)c3ccccc3)cn(C)c2n1

Procedure:
25.3 g. of (4-hydroxy-2-methyl-2H-pyrazolo[3,4-b]pyridin-5-yl)phenylmethanone (0.1 mol.), 15.5 g. of methyl iodide (0.11 mol.) and 21 g. of potassium carbonate (0.15 mol.) are heated in 150 ml. of dimethylformamide with stirring at 80° for 10 hours. After this time, the inorganic precipitate is filtered off and the filtrate evaporated to dryness. The remaining 5-benzoyl-2,7-dihydro-2,7-dimethyl-4H-pyrazolo[3,4-b]pyridin-4-one is recrystallized from butanol, yield 18 g. (67%); m.p. 272°-274°.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1B(O)O>>[Cl:10][C:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:12]=2[F:11])[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: COc1ccc(F)c(-c2cc(F)c(N)c(Cl)c2)c1
Yield: 59 %

Procedure:
The title compound (70 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.44 mmol) and 2-fluoro-5-methoxyphenylboronic acid (98 mg, 0.58 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.30-7.24 (m, 2H), 7.17 (t, J 9.1, 1H), 7.02-6.97 (m, 1H), 6.90-6.84 (m, 1H), 5.61 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(O)CCC>[CH:3]1([CH2:2][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrCC1CCCCCC1
Reactant: c1c[nH]cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1cn(CC2CCCCCC2)cn1
Reaction time: 7 h

Procedure:
Bromomethylcycloheptane (5.3 g, 0.0278 mol) was added dropwise to a stirred solution of potassium t-butoxide (3.1 g, 0.0277 mol) and imidazole (1.9 g, 0.0279 mol) in dry n-butanol (50 ml) maintained at 100° and under dry nitrogen. After the addition (~20 mins) the temperature of the reaction mixture was raised to boiling. The reaction mixture was then stirred and boiled for 7 h and then cooled.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[NH:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[N:20]([O-])=[O:21].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:18])[CH:15]=3)[N:10]([N:20]=[O:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)CC(c1ccc(F)cc1)CN2N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a stirred solution of 3-(4-fluorophenyl)-6-methyl-1,2,3,4-tetrahydroquinoline (0.28 g, 0.00166 mol) in ethanol (1 mL) was added 1N hydrochloric acid (1 mL), and the reaction mixture was cooled to 0° C. Sodium nitrite (0.160 g, 0.00232 mol) in water (3 mL) was added at 0° C., and the mixture stirred for 1 h at RT. The reaction was monitored by TLC. After completion, solvent was removed under reduced pressure to obtain product as a brown colored oil (0.28 g, 89% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]([CH2:14][OH:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:15][CH2:14][CH:13]1[CH2:12][CH:11]2[CH:9]([CH2:10]2)[N:8]1[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:26])=[O:25]
Reactant: OCC1CC2CC2N1c1cncc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CC2CC2N1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice-cold solution of [2-(5-Bromopyridin-3-yl)-2-azabicyclo[3.1.0]hex-3-yl]methanol (462 mg, 2.43 mmol) in dry dichloromethane (10 mL) was added triethylamine (0.51 mL, 3.6 mmol) followed by methanesulfonyl chloride (334 mg, 2.92 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The volatiles were removed under reduced pressure and the crude product was purified by flash column chromatography to obtain title compound of 586 mg as gummy liquid. Yield: 90%.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:12])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:19].[Na+].O>O1CCOCC1>[NH2:3][C:4]1[C:5]([S:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:19])=[O:1]
Reactant: [OH-]
Reactant: O=C1Cc2cccc(S(=O)c3ccccc3)c2N1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1c(CC(=O)O)cccc1S(=O)c1ccccc1
Yield: 42.4 %

Procedure:
A mixture of 2-oxo-7-phenylsulfinylindoline (4.3 g.), sodium hydroxide (1.2 g.), water (10 ml.) and dioxane (10 ml.) was refluxed for 6 hours with stirring. The reaction mixture was evaporated under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. The aqueous solution was adjusted to pH 4 with 5% sulfuric acid and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride twice, dried over magnesium sulfate and evaporated under reduced pressure. The residue was washed with a mixture of ethanol and diisopropyl ether to give crystals of 2-(2-amino-3-phenylsulfinylphenyl)acetic acid (1.95 g.).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[F:9][C:10]1[CH:11]=[C:12]([N+:20]([CH3:23])([CH3:22])[CH3:21])[CH:13]=[CH:14][C:15]=1[C:16]([O:18]C)=[O:17].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:16]([C:15]1[CH:14]=[CH:13][C:12]([N+:20]([CH3:22])([CH3:21])[CH3:23])=[CH:11][C:10]=1[F:9])([OH:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](C)(C)C)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[N+](C)(C)c1ccc(C(=O)O)c(F)c1

Procedure:
A solution of 2.50 g (6.92 mmol) 4b, 60 ml dest. water and 60 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude product 4c was obtained in 100% yield (2.40 g; 6.92 mmol) and crude compound 4c was used for the next step without purification.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:28]5[CH2:29][CH2:30][O:26][C:27]5=[O:31])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1NCCO1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCOC3=O)nc2)CC1
Yield: 25 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (525 mg) described in Preparation Example 106 and oxazolidin-2-one (183 mg), the title compound (133 mg) was obtained.