Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([N:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:12])[CH:10]=1)=O.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH2:33])[CH3:32].C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[CH:31]([NH:33][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH:8]=[C:9]([N:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[CH3:12])[CH:10]=1)=[O:2])[CH3:32]
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)cc(N(C)C(=O)C(C)C)c1
Reactant: CC(N)c1cnccn1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)NC(C)c3cnccn3)cc(N(C)C(=O)C(C)C)c2)cc1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
5-(Isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (67 mg, 0.22 mmol) was added to methylene chloride (3 mL) and stirred at room temperature. TEA (0.87 g), 1-pyrazin-2-yl-ethylamine (32 mg, 0.25 mmol), HOBt (29 mg) and ECDI (54 mg) were added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was placed directly onto a silica column and eluted with 50% ethyl acetate/hexanes to give 32 mg of 5-(isobutyryl-methyl-amino)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide as a white solid, MS (M+H)=417.
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[N:14]1[CH:19]=[C:18](B(O)O)[CH:17]=[N:16][CH:15]=1>>[CH3:11][O:10][C:5]1[CH:4]=[C:3]([O:12][CH3:13])[C:2]([C:18]2[CH:19]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1cncnc1
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1cc(OC)c(-c2cncnc2)cc1C=O
Yield: 98 %

Procedure:
Ex-31A: 2,4-Dimethoxy-5-pyrimidin-5-yl-benzaldehyde was prepared from 5-bromo-2,4-dimethoxybenzaldehyde and pyrimidine-5-boronic acid in a similar manner as described in Ex-3A, 98% yield. 1H-NMR (CDCl3) δ 10.37 (s, 1H), 9.15 (s, 1H), 8.87 (s, 2H) 7.86 (s, 1H), 6.57 (s, 1H), 4.03 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[C:15]3[C:20]([CH:21]=2)=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.O.[Sn](Cl)(Cl)(Cl)[Cl:40].Cl.[OH-].[Na+]>C(O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:14]([CH2:25][C:26]3[CH:30]=[C:29]([C:31]4[S:32][C:33]([Cl:36])=[CH:34][CH:35]=4)[O:28][N:27]=3)[C:15]3[C:20]([CH:21]=2)=[C:19]([Cl:40])[C:18]([NH2:22])=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NC(=O)c2cc3cc([N+](=O)[O-])ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)N1CCC(NC(=O)c2cc3c(Cl)c(N)ccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
24.4 mg 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-nitro-1H-indole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were added to a solution of 58.5 mg tin chloride dihydrate in 1 ml ethanol. 0.5 ml 12 N aqueous hydrochloric acid was added and the mixture was stirred at room temperature for 16 hours. After cooling of the reaction mixture it was basified to pH 12 with saturated aqueous solution of sodium hydroxide and the product isolated by filtration. The product was obtained as a white solid which was dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH3:18])[C:9]=2[CH3:19])[CH:5]=[CH:6][CH:7]=1.[CH2:20]([O:22][C:23](=[O:28])[C:24](Br)([CH3:26])[CH3:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:28])[C:24]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:18])[C:9]([CH3:19])=[C:8]2[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)([CH3:26])[CH3:25])[CH3:21]
Reactant: Cc1c(-c2cccc(Cl)c2)c2cc(O)ccc2n1C
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)c(-c1cccc(Cl)c1)c(C)n2C

Procedure:
The above compound was prepared from 3-(3-chlorophenyl)-1,2-dimethyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester analogously to Example 10.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)(C)[CH2:9][C:10]2C=CC=C[CH:11]=2)=[CH:4][CH:3]=1.O[C:25]1[CH:30]=CC(C(C2C=CC(O)=CC=2)(CC)C)=C[CH:26]=1>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)([CH2:26][CH2:25][CH3:30])[CH2:9][CH2:10][CH3:11])=[CH:22][CH:21]=1
Reactant: CCC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(Cc1ccccc1)(c1ccc(O)cc1)c1ccc(O)cc1
Product: CCCC(CCC)(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
2,2-bis(4-hydroxyphenyl)-1-phenylpropane; 2,2-bis(4-hydroxyphenyl)butane;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][C:37]1[C:38]([CH:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)=[CH:39][C:40]([O:44][CH3:45])=[C:41]([CH:43]=1)[NH2:42].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:42][C:41]3[CH:43]=[C:37]([CH3:36])[C:38]([CH:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]4)=[CH:39][C:40]=3[O:44][CH3:45])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCCN1CCC(c2cc(OC)c(N)cc2C)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: CCCN1CCC(c2cc(OC)c(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)cc2C)CC1
Temperature: 120 °C
Yield: 69.4 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 5-methyl-2-(methyloxy)-4-(1-propyl-4-piperidinyl)aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (90 mg, 0.125 mmol, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.38 (d, J=6.41 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.01 Hz, 1H), 7.69 (d, J=8.97 Hz, 1H), 7.52 (s, 1H), 7.41-7.46 (m, 1H), 7.33-7.40 (m, 1H), 7.27 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.95 (t, J=6.68 Hz, 1H), 6.89 (s, 1H), 6.57 (d, J=5.13 Hz, 1H), 3.97 (s, 3H), 3.80 (s, 3H), 2.91-3.01 (m, 2H), 2.58-2.67 (m, 1H), 2.20-2.30 (m, 2H), 2.18 (s, 3H), 1.92-2.03 (m, 2H), 1.62-1.73 (m, 4H), 1.40-1.49 (m, J=7.33, 7.33, 7.33, 7.33 Hz, 2H), 0.85 (t, J=7.33 Hz, 3H). MS (ESI): 718 [M+H]+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12](=[NH:14])[NH2:13])[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].CN(C)[CH:18]=[C:19]([Br:22])[CH:20]=O.CCO>CO>[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12]2[N:13]=[CH:20][C:19]([Br:22])=[CH:18][N:14]=2)[CH2:11][CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Reactant: CN(C)C=C(Br)C=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ncc(Br)cn2)CC1
Temperature: 80 °C

Procedure:
(1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (1.0 g, 4.2 mmol) (prepared according to the procedure described in patent application WO 2009/070485 A1) and 3-dimethylamino-2-bromo-propenal (1.1 g, 6.4 mmol) are added to EtOH (2 mL) in a pressure tube. The reaction vessel is capped and the mixture is heated at 80° C. for 24 hours. The mixture is cool to room temperature and methanol (20 mL) is added. The resulting solids are filtered and the filtrate is concentrated in vacuo. The residue is dissolved with CH2Cl2 (50 mL) and the solids are filtered. The filtrate is concentrated and the residue is purified by silica gel chromatography using a gradient of 0-50% EtOAc in hexanes to afford [1-(5-bromo-pyrimidin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[F:25])(O)[CH2:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)C>[F:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[F:1])=[CH:10][C:11]1[N:15]([CH3:16])[N:14]=[N:13][N:12]=1
Reactant: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(C(=Cc2nnnn2C)c2ccc(C)cc2F)c(F)c1

Procedure:
A suspension of 1,1-bis(2-fluoro-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanol (7.3 g, 21.0 mmoles) in toluene (200 mL) with p-toluene sulfonic acid (3 g) and the mixture heated at reflux for 14 hours. After cooling, the mixture was diluted with diethyl ether and extracted with saturated sodium bicarbonate solution and water. The organic layer was dried (MgSO4) and evaporated. The residue was triturated with isopropyl ether to give the title compound; m.p.=58°-60° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:20]=[CH:19][C:18]=3[CH3:33])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:34]([CH2:36][NH2:37])[OH:35]>CS(C)=O>[OH:35][CH2:34][CH2:36][NH:37][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:20]=[CH:19][C:18]=3[CH3:33])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4cccc(Cl)c4)ccc3C)csc12
Solvent: CS(C)=O
Product: Cc1ccc(NC(=O)c2cccc(Cl)c2)cc1OCc1csc2c(C(=O)NCCO)cncc12
Temperature: 135 °C

Procedure:
A mixture of 3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (315 mg, 0.65 mmol) (from Example 24 supra) in methyl sulfoxide (3 mL) and ethanolamine (9 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. After cooling to room temperature, the precipitate was filtered off, washed thoroughly with MeOH and dried to give 3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide as a white solid. (Yield 267 mg, 82.8%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19](O)=[O:20])=[N:8][C:9]=2[O:10][C@@H:11]([C:15]([F:18])([F:17])[F:16])[CH2:12][CH2:13][OH:14])[CH2:3][CH2:2]1.[NH2:22][C:23]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:24]([NH:26][CH3:27])=[O:25]>>[CH2:28]([C:23]([NH:22][C:19]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[C:9]([O:10][C@@H:11]([C:15]([F:16])([F:18])[F:17])[CH2:12][CH2:13][OH:14])[N:8]=1)=[O:20])([C:24](=[O:25])[NH:26][CH3:27])[CH2:30][CH3:31])[CH3:29]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(C2CC2)c(O[C@H](CCO)C(F)(F)F)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(O[C@H](CCO)C(F)(F)F)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-((R)-3-hydroxy-1-trifluoromethyl-propoxy)-pyridine-2-carboxylic acid (Example 313a) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials; MS (EI) 432.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH3:17][C:18]1[C:19](=O)[CH2:20][CH2:21][C:22]=1[O:23][Si](C)(C)C.Cl.N>O1CCCC1>[CH3:17][C:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1cccc2cccnc12
Reactant: CC1=C(O[Si](C)(C)C)CCC1=O
Agent: Cl
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(c2cccc3cccnc23)CCC1=O
Temperature: -80 °C
Yield: 74.9 %

Procedure:
A mixture of 38.7 g (186 mmol) of 8-bromoquinoline in 250 ml of tetrahydrofuran was cooled to −80° C. and 74.4 ml of n-butyllithium (2.5 M in hexane, 186 mmol) were subsequently added while stirring. The mixture was stirred for a further 15 minutes and, while stirring, 49.9 g (186 mmol) of 2-methyl-3-(trimethylsilyloxy)cyclopent-2-enone were added. The mixture was allowed to warm to room temperature while stirring and was stirred for a further one hour. The reaction mixture was then hydrolyzed by means of a mixture of 40 g of ice and 30 ml of concentrated hydrochloric acid and the mixture obtained in this way was refluxed for 3 hours. The mixture was allowed to cool to room temperature while stirring and ammonia solution was added until the pH was 12. The aqueous phase was then separated off from the organic phase and the aqueous phase was extracted twice with diethyl ether. The organic phases were combined, dried over magnesium sulfate, filtered and the solvent was distilled off. The residue obtained in this way was distilled at 119-139° C. and 2×10−2 mbar to give 31.1 g (139.3 mmol, 74.9%) of 2-methyl-3-(8-quinolyl)cyclopent-2-enone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:22]=[C:21]([C:23](=[O:28])N(OC)C)[S:20][C:19]=2[CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[F:14][C:15]1[CH:16]=[CH:17][C:18]2[CH:22]=[C:21]([C:23]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=3)=[O:28])[S:20][C:19]=2[CH:29]=1
Reactant: Brc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cc2ccc(F)cc2s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1cccc(Br)c1)c1cc2ccc(F)cc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 2,4-difluorobenzaldehyde (5.0 g) in dimethylsulfoxide (100 ml) were added methyl thioglycolate (3.45 ml) and triethylamine (10 ml), and the mixture was stirred at 80° C. overnight. The reaction mixture was poured into ice-cold water. The mixture was extracted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give 6-fluoro-2-methoxycarbonylbenzo[b]thiophene (1.32 g) as colorless powder. GC-EI-Mass m/Z 210 (M). (2) The above 6-fluoro-2-methoxycarbonylbenzo[b]thiophene was treated in a manner similar to Reference Example 4-(1) to give 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid as colorless powder. ESI-Mass m/Z 195 (M−H). (3) The above 6-fluorobenzo[b]thiophen-2-ylcarboxylic acid was treated in a manner similar to Reference Example 4-(2) to give 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene as colorless powder. APCI-Mass m/Z 240 (M+H). (4) A solution of 1,3-dibromobenzene (493 mg) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (2.44 M hexane solution, 0.86 ml). The reaction mixture was stirred at the same temperature for 30 minutes, and thereto was added dropwise a solution of the above 6-fluoro-2-(N-methoxy-N-methylcarbamoyl)benzo[b]thiophene (500 mg) in tetrahydrofuran (3 ml). The mixture was warmed to room temperature, and added thereto was a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to give 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone (479 mg) as a pale yellow solid. APCI-Mass m/Z 335/337 (M+NH4). (5) The above 3-bromophenyl 6-fluorobenzo[b]thiophen-2-yl ketone was treated in a manner similar to Reference Example 5-(2) to give 3-bromo-1-(6-fluorobenzo[b]thiophen-2-ylmethyl)benzene as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9][C:8](=[O:14])[C:7]=2[CH:15]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][N:12]1[C:6]2[CH:5]=[C:4]([O:16][CH3:17])[C:3]([O:2][CH3:1])=[CH:15][C:7]=2[C:8](=[O:14])[CH2:9][CH2:10][C:11]1=[O:13]
Reactant: COc1cc2c(cc1OC)C(=O)CCC(=O)N2
Reactant: ClCCCCBr
Product: COc1cc2c(cc1OC)N(CCCCCl)C(=O)CCC2=O
Yield: 36.1 %

Procedure:
Analogously to Example 1, reaction of 7,8-dimethoxy-3,4-dihydro-1H-1-benzazepine-2,5-dione (1.70 mmol, 0.40 g, preparation according to Arch. Pharm. 1991, 324, 579) and bromo-4-chlorobutane (2.04 mmol, 0.35 g) afforded 0.20 g of the contaminated title compound. The compound is reacted further without purification.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32])([O-:24])=[O:23]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N+:22]([O-:24])=[O:23])(=[O:32])=[O:33])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and 2-nitrobenzenesulphonic acid chloride analogously to Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41](O)[CH2:42]C>>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH2:41][CH3:42])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCO
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 0.60 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.13 g of sodium carbonate, and 7.0 ml of n-propanol was stirred under reflux for 2 hours. After cooling to room temperature, the solvent was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography to give propyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-14).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][C:3]1=[O:33].Cl.[NH2:35][OH:36].C([O-])(O)=O.[Na+]>>[OH:36]/[N:35]=[C:8](/[C:6]1[CH:5]=[CH:4][C:3](=[O:33])[N:2]([CH3:1])[CH:7]=1)\[CH2:9][CH:10]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[O:25])=[CH:22][CH:23]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N2CCOCC2)cc1

Procedure:
In analogy to example 151, step 3, 1-methyl-5-{3-[4-(morpholine-4-carbonyl)-phenyl]-3-o-tolyl-propionyl}-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=460.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:9])#[N:2].[OH-:27].[Na+]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:22][C@H:23]([CH3:26])[CH2:24][OH:25])=[C:7]([CH:21]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]2[O:16][CH2:17][O:18][C:14]=2[CH:13]=1)=[O:9])(=[O:27])[NH2:2]
Reactant: C[C@H](CO)Nc1ccc(C#N)cc1C(=O)NCc1ccc2c(c1)OCO2
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CO)Nc1ccc(C(N)=O)cc1C(=O)NCc1ccc2c(c1)OCO2

Procedure:
To a solution of (R)-5-cyano-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (76 mg) in ethanol (6 mL) was added 1N-sodium hydroxide (0.65 mL), and the mixture was heated for 6 hours under reflux. The solvent was evaporated in vacuo. The residue was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (9:1) to give (R)-5-carbamoyl-2-(2-hydroxy-1-methylethylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (27 mg) as a solid substance.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[C:6]([F:8])[CH:7]=1.I[CH3:11]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:9][CH3:11])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CI
Reactant: O=c1[nH]cc(F)cc1Br
Solvent: Cc1ccccc1
Product: COc1ncc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
3-Bromo-5-fluoropyridin-2(1H)-one (10.0 g, 52.1 mmol) and Ag2CO3 (10.0 g, 36.5 mmol) were combined in toluene (100 mL) and iodomethane (3.89 mL, 62.5 mmol) was added drop-wise. The reaction was stirred at ambient temperature overnight, filtered through Celite and the solids were washed with toluene. The filtrate was concentrated and the residue was purified on a silica gel column (5-25% EtOAc/hexanes) to afford 3-bromo-5-fluoro-2-methoxypyridine (4.70 g, 43.8%) as a clear oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>CN1C(=O)CCC1>[OH:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]([CH3:23])[CH:13]=2)[CH2:26][CH2:27]1
Reactant: Cn1cc(-c2cc(S(C)(=O)=O)ccc2F)c2ccccc2c1=O
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2N[C@H]2CC[C@H](O)CC2)c2ccccc2c1=O
Temperature: 250 °C

Procedure:
A mixture of 4-(2-fluoro-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one (150 mg, 0.45 mmol) and trans-4-aminocyclohexan-1-ol (417 mg, 3.62 mmol) in NMP (0.2 mL) was heated for 20 min at 200-300° C. The cooled brownish residue was purified by prep-HPLC to give the title compound (55.64 mg, 28.8%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.54 (d, J=8.0 Hz, 1H), 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.60-7.55 (m, 2H), 7.15-7.13 (m, 2H), 6.79 (d, J=8.8 Hz, 1H), 3.91-3.85 (m, 1H), 3.67 (s, 3H), 3.63-3.55 (m, 1H), 3.37-3.34 (m, 1H), 3.06 (s, 3H), 2.04-1.92 (m, 5H), 1.44-1.35 (m, 2H), 1.11-1.02 (m, 2H). LCMS (M+H)+=427.1 (M+H)+