Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(C)(C)C.[K+]>CS(C)=O>[CH2:12]([C:19]1[CH:20]=[CH:21][C:22]([NH:23][C:2]2[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=[CH:6][C:7]=2[CH3:8])=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(Cc2ccccc2)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cccc([N+](=O)[O-])c1Nc1ccc(Cc2ccccc2)cc1

Procedure:
The product (1.01 g) is obtained according to the method of stage 1 of Example 4, by using 1.13 g of 2-fluoro-3-methyl-nitrobenzene and 2 g of 4-benzyl-aniline in the presence of 1.31 g of potassium tert-butanolate in 30 mL of DMSO.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].O>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CCc1ccc(Br)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1ccc(Br)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a solution of 1-bromo-4-ethylbenzene (7 g, 37.8 mmol) in 9 mL concentrated H2SO4 at −20° C. was added a mixture of H2SO4 (3.74 g, 41.9 mmol) and HNO3 (2.64 g, 41.9 mmol). The mixture was stirred at −20° C. for 2 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography to give that tile compound (3 g, 34%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl.[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][NH:29]N>CCO>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[N:29]([CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Reactant: NNCCC(F)(F)F
Agent: Cl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccnn1CCC(F)(F)F
Temperature: 80 °C
Yield: 76 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 1.73 g, 5.41 mmol, 1 eq.) in EtOH (10 mL) was added (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.30 g, crude above, 6.49 mmol, 1.2 eq.) at RT. The mixture was heated at 80° C. for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g; 76% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=4.7, 1.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.29 (dd, J=7.9, 4.7 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 4.62 (s, 2H), 4.45-4.33 (m, 2H), 2.82-2.61 (m, 2H), 0.85 (s, 8H), −0.00 (s, 5H). MS (ESI) m/z 386.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].I[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[N:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Ic1ccncc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccncc4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-iodopyridine [CAS 15854-87-2; commercially available] (225 mg, 1.1 mmol) according to general procedure II. Obtained as a yellow solid (92 mg, 21%). MS (ISP) 433.2 [(M+H)+]; mp 252-256° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][CH:13]=1.Br[C:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[N:30]([CH:37]([CH3:39])[CH3:38])[N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:39][CH:37]([N:30]1[C:31]2[C:32](=[N:33][CH:34]=[CH:35][CH:36]=2)[C:28]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:17][CH:16]=2)=[N:29]1)[CH3:38]
Reactant: CC(C)n1nc(Br)c2ncccc21
Reactant: Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2cccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)n1nc(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc21
Yield: 95.6 %

Procedure:
A mixture of 3-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-3H-imidazo[4,5-b]pyridine (215 mg), 3-bromo-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (147 mg), Pd(PPh3)4 (21 mg) and Na2CO3 (227 mg) in DME (5 mL) and water (1 mL) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (225 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ccn(-c3ccc([N+](=O)[O-])cc3)c(=O)c2cc1F
Temperature: 120 °C
Reaction time: 6 h
Yield: 67.5 %

Procedure:
To a solution of 11.0 g of 7-Fluoro-6-methoxy-2H-isoquinolin-1-one (57 mmol) in DMF (108 mL) was added potassium carbonate (11.8 g), followed by 10.6 g of 1-fluoro-4-nitrobenzene (75 mmol). The reaction mixture was stirred at 120° C. for 6 hr then poured onto ice water. The slurry was extracted with ether to remove excess pFPhNO2. The precipitate was collected by filtration, washed with ether and dried in vacuo to give 12.1 g (68%) of the product asa yellow solid. RP-HPLC: 4.79 min; ES-MS (M+H)+=315.0; 1H-NMR (DMSO-d6) δ (ppm): 4.0 (3H, s), 6.76 (1,d), 7.48 (d, 1), 7.53 (d, 1), 7.83 (d,2), 7.92 (d, 1), 8.38 (d, 2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[N:6][C:5]=1[CH2:12][O:13][CH3:14].[N+:16]([O-])([OH:18])=[O:17].O>CC(O)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([OH:10])=[C:8]([N+:16]([O-:18])=[O:17])[C:7]([OH:11])=[N:6][C:5]=1[CH2:12][O:13][CH3:14]
Reactant: O=[N+]([O-])O
Reactant: COCc1nc(O)cc(O)c1C(=O)OC
Solvent: O
Solvent: CC(=O)O
Product: COCc1nc(O)c([N+](=O)[O-])c(O)c1C(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4,6-Dihydroxy-2-methoxymethyl-nicotinic acid methyl ester (15.9 g, 74.75 mmol) is dissolved in AcOH (60 mL) and cooled to 0° C. in an ice bath. Nitric acid (70%, 4.73 mL) is added dropwise. The resulting solution is stirred at room temperature overnight. Water (200 mL) is added to the mixture and a white precipitate forms. The precipitate is collected and dried in a vacuum oven to afford the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2C=CC(O)=CC=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[C-]#[N:19].[C-]#N.[Na+]>>[C:11]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)([CH3:9])[CH3:10])#[N:19]
Reactant: [C-]#N
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [Na+]
Product: CC(C)(C#N)c1ccc(O)cc1
Temperature: 185 °C

Procedure:
A process wherein a solventless mixture of Bisphenol A and cyanide ion in the form of sodium cyanide is heated in a closed vessel to about 185° C. and maintained at that temperature for about 20 hours to produce 4-(1-cyano-1-methylethyl)phenol with a conversion of about 100 percent and a selectivity of about 80 percent based on Bisphenol A.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[S:18][C:19]([C:44]3[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:45]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([S:32]([C:35]4[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=4[F:42])(=[O:34])=[O:33])[CH2:29][O:30][CH3:31])[C:23]=3[F:43])[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[C:54]([O:53][C:51](=[O:52])[NH:50][C:46]1[CH:45]=[C:44]([C:19]2[S:18][C:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[N:21][C:20]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]([S:32]([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[F:42])(=[O:33])=[O:34])[CH2:29][O:30][CH3:31])[C:23]=2[F:43])[CH:49]=[CH:48][N:47]=1)([CH3:57])([CH3:55])[CH3:56]
Reactant: COCN(c1cccc(-c2nc(C3CCN(C(=O)OCc4ccccc4)CC3)sc2-c2ccnc(NC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COCN(c1cccc(-c2nc(C3CCNCC3)sc2-c2ccnc(NC(=O)OC(C)(C)C)c2)c1F)S(=O)(=O)c1cc(F)ccc1F
Yield: 83.6 %

Procedure:
Benzyl-4-[5-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-4-(3-{[(2,5-difluorophenyl)sulfonyl]-(methoxymethyl)amino}-2-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (prepared as described in Example 10, 110 mg, 0.13 mmol) was dissolved in absolute ethanol (10 mL) under nitrogen atmosphere. Ammonium formate (440 mg, 7 mmol) and palladium on charcoal 5% (150 mg portionwise) were then added. The mixture was refluxed for 2 days, then filtered on a celite pad and evaporated to dryness. The residue was taken up with DCM and washed with water. The organic layer was dried over Na2SO4 and evaporated, affording 75 mg (84%) of tert-butyl-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]-(methoxymethyl)amino}-2-fluorophenyl)-2-(piperidin-4-yl)-1,3-thiazol-5-yl]pyridin-2-yl}carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.Cl.[NH2:13][OH:14].N1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:13][OH:14])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCC(=NO)c1ccc(Cl)cc1
Yield: 54.5 %

Procedure:
1-(4-Chlorophenyl)propan-1-one (8.4 g, 50 mmol) was combined with hydroxylamine hydrochloride (4.0 g, 58 mmol), pyridine (4.6 g, 58 mmol), and ethanol (75 mL). The mixture was refluxed for 3 h. Solvent was evaporated and the residue diluted with water and extracted into diethyl ether/hexane (1:1). The organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. Crystallization from cold hexane gave 5.0 g of 1-(4-chlorophenyl)propan-1-one oxime.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:13][C:14]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:31][CH3:32])[C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C(Cl)Cl>[CH3:13][C:14]1[CH:36]=[CH:35][C:34]([NH:37][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([N:2]([CH3:12])[CH3:1])[CH:4]=2)=[CH:33][C:15]=1[NH:16][C:17]1[C:26]2[C:21](=[C:22]([O:31][CH3:32])[C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1
Reactant: COc1cc2c(Nc3cc(N)ccc3C)ncnc2c(OC)c1OC
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Solvent: ClCCl
Product: COc1cc2c(Nc3cc(NC(=O)c4cccc(N(C)C)c4)ccc3C)ncnc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 11.6 %

Procedure:
3-Dimethylaminobenzoyl chloride (105 mg) was added to a suspension of 4-(2-methyl-5-aminoanilino)-6,7,8-trimethoxyquinazoline (180 mg) in dry methylene chloride (4 ml) and the resulting mixture was stirred at ambient temperature for 18 hours. Methylene chloride (100 ml) was added and the mixture washed with aqueous sodium hydroxide solution (100 ml), water and brine, dried over sodium sulphate, filtered and evaporated give a yellow gum. This was purified by silica column chromatography, eluting with 2% methanol in methylene chloride to yield the title compound as a solid (30 mg, 12%); NMR (CDCl3) 2.22 (s, 3H), 2.97 (s, 6H), 3.96 (s, 3H), 4.06 (s, 3H), 4.13 (s, 3H), 6.84 (dd, 1H), 7.05 (m, 2H), 7.18 (m, 2H), 7.28 (t, 1H), 7.42 (m, 1H), 7.92 (s, 1H), 7.95 (s, 1H), 8.61 (s, 1H); m/s: M+H+ 488.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:25][CH2:26][N:27]([CH2:35][CH2:36]Cl)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:25][CH2:26][N:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH2:36]1)=[O:23])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Product: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 16.9 mmol) and bis-(2-chloro-ethyl)-benzyl amine (6.44 g, 24 mmol). Yield 2.21 g (25%); yellow oil; MS: 513.9 (M+H)+
Reaction SMILES: [N+](=[C:3]([CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH2:16]=[CH:17]/[CH:18]=[CH:19]\[CH3:20]>CCCCC>[CH3:20][C@@H:19]1[CH:18]=[CH:17][CH2:16][C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C@H:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=C/C=C\C
Reactant: COC(=O)C(C=Cc1ccccc1)=[N+]=[N-]
Solvent: CCCCC
Product: COC(=O)C1=C[C@@H](c2ccccc2)[C@H](C)C=CC1
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of (E) Methyl 2-diazo-4-phenyl-3-butenoate (0.26 g, 1.3 mmol) in dry pentane (20 mL) is added dropwise to a stirred solution of Rh2 (TBSP)4 (0.0195 g, 13.5 mmol) and cis-1,3-pentadiene (0.45 g, 6.7 mmol) in dry pentane (50 mL) under an argon atmosphere at room temperature. After stirring for 2 hours the solvent is removed under reduced pressure. Purification by silica gel column chromatography (1/99; diethyl ether/petroleum ether, Rf =0.05) gave the product as a yellow oil (0.25 g, 79%). IR (neat) 3025.0, 2952.4, 2872.3, 1712.2, 1652.4, 1455.8, 1435.7, 1240.3; 1H NMR (CDCl3)d 7.43-7.21 (m, 5H), 7.05 (d, 1H, J=5.1 Hz), 5.82 (dp, 1H, J=5.7, 2.0 Hz), 5.58 (dd, 1H, J=5.3, 3.8 Hz), 3.74 (s, 3H), 3.60 (dd, 1H, J=9.8, 5.2 Hz), 3.29 (d, 1H, J=5.7 Hz), 2.90-5.70 (m, 1H), 0.83 (d, 3H, J=7.0 Hz); 13C NMR (CDCl3)d 168.0, 146.3, 143.5, 136.7, 131.9, 128.6, 128.2, 126.7, 126.6, 51.9, 51.0, 36.3, 25.3, 20.8; MS m/z (relative intensity) 242 (100), 91 (70); HRMS calcd for C16H18O2 : 242.1307. Found: 242.1314.
Reaction SMILES: [S:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:15]([OH:17])=O.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[NH:21][CH3:22]>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[N:21]([CH3:22])[C:15]([C:2]1[S:1][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1)=[O:17]
Reactant: O=C(O)c1cc2c(s1)-c1ccccc1OCC2
Reactant: CNc1ccccc1Cl
Product: CN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl

Procedure:
Following General Procedure C, 157 is prepared from 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid and 2-chloro-N-methylaniline. MS: (ESI+) 370.1
Reaction SMILES: FC1C=CC=CC=1C1N(C(=O)CNC(N[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)=O)C(C(=O)NCC(C)C)CC1S(C1C=CC=C(OC)C=1)(=O)=O.[OH-].[K+]>CO.O>[C:25]([OH:27])(=[O:26])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3cccc(OC)c3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1

Procedure:
A The process is performed as described in Example 1A, but starting with 3 g of (2RS,4SR,5RS)-5-(2-fluorophenyl)-2-isobutylcarbamoyl-1-{2-[3-(3-methoxycarbonylphenyl)ureido]acetyl}-4-(3-methoxyphenyl)sulphonylpyrrolidine and 0.245 g of potassium hydroxide in a mixture of 60 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.5 g of (2RS,4SR,5RS)-3-(3-{2-[5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(3-methoxyphenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido!benzoic acid is obtained [Rf=0.4; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 383 K, δ in ppm): 0.95 (d, J=6.5 Hz, 6H: C (CH3)2); 1.86 (mt, 1H: CH); from 2.35 to 2.55 and 2.86 (2 mts, 1H each: CH2 at 3); 3.08 (mt, 2H: NCH2); from 3.60 to 3.80 and 3.90 (mt and d respectively, (J=17 Hz), 1H each: COCH2N); 3.91 (s, 3H: OCH3); 4.09 (mt, 1H: H4); 4.81 (t, J=7 Hz, 1H: H2); 5.72 (very broad s, 1H:H5); from 6.95 to 7.65 (mt, 10H: aromatic H); 8.00 (mt, 1H: aromatic H (H2 : ortho to the COOH)); 8.20 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6))].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1nccnc1C1CCNCC1
Yield: 245.6 %

Procedure:
To a well stirred solution of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (92 g, 0.309 mol, 1 eq.) in dichloromethane (1 L) was added trifluoroacetic acid (119 mL, 1.545 mol, 5 eq.). The resulting mixture was heated to reflux overnight (16 h). The mixture was concentrated and the resulting TFA salt was dried with toluene (500 mL) azetropically to give 150 g 2-chloro-3-(piperidin-4-yl)pyrazine. This was used in the next step without further purification.
Reaction SMILES: C(OC(C1N=CC2NC3C(C=2C=1C)=C(C=O)C=CC=3)=O)C.[N+](CC)([O-])=O.[CH2:27]([O:29][C:30]([C:32]1[N:33]=[CH:34][C:35]2[NH:36][C:37]3[C:42]([C:43]=2[C:44]=1[CH3:45])=[C:41]([CH:46]=[C:47]([N+:49]([O-])=O)[CH3:48])[CH:40]=[CH:39][CH:38]=3)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1[N:33]=[CH:34][C:35]2[NH:36][C:37]3[C:42]([C:43]=2[C:44]=1[CH3:45])=[C:41]([CH2:46][CH:47]([NH2:49])[CH3:48])[CH:40]=[CH:39][CH:38]=3)=[O:31])[CH3:28]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(C=C(C)[N+](=O)[O-])c3c2c1C
Agent: CCOC(=O)c1ncc2[nH]c3cccc(C=O)c3c2c1C
Solvent: CC[N+](=O)[O-]
Product: CCOC(=O)c1ncc2[nH]c3cccc(CC(C)N)c3c2c1C

Procedure:
The production takes places analogously to example 9 by condensation of 5-formyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester with nitroethane and hydrogenation of the resulting 4-methyl-5-(2-nitropropenyl)beta-carboline-3-carboxylic acid ethyl ester.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:24][OH:25])[CH3:8].[CH:27](Br)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>CN(C)C=O.CCOCC>[CH2:7]([O:9][C:10](=[O:26])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:24][O:25][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:8]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1CCCC2CCO
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1cccc2c1CCCC2CCOC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium t-butoxide (810 mg) was added to a solution of [1-(2-hydroxyethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy]acetic acid ethyl ester (2.11 g, prepared by the same procedure as in reference example 1) in dimethylformamide (50 ml) at 0° C. The reaction mixture was stirred for 1 hr at room temperature. Benzhydryl bromide (2.15 g) was added to the mixture at 0° C. The mixture was stirred for 1 hr at room temperature. To the mixture, a saturated aqueous solution of ammonium chloride and ether were added. The extract was washed with water and saturated brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate=8: 2) to give the title compound (257 mg).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)=[CH:35][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:12]
Reactant: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3ccncc3)ccc2OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(-c3ccncc3)ccc2O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate (0.094 g) in ethyl acetate (2.5 mL) and methanol (3.5 mL), 10% palladium-carbon (19 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. To the reaction mixture, 10% palladium-carbon (19 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and the residue was washed with ethyl acetate and tetrahydrofuran. The filtrate and the washing liquid were combined, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), PSQ100B(spherical), eluent: 65-45% hexane/ethyl acetate] to obtain tert-butyl 2-(2-hydroxy-5-(pyridin-4-yl)benzamido)-4-(2-methoxyphenyl)benzoate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([Br:11])[CH:5]=1.O.[NH2:14][NH2:15]>CO>[Br:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([NH:14][NH2:15])=[O:2]
Reactant: COC(=O)c1ccc(C)c(Br)c1
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)NN)cc1Br
Temperature: 80 °C
Yield: 50.1 %

Procedure:
A mixture of methyl-3-bromo-4-methylbenzoate (5.0 g, 21.8 mmol, 1.0 eq) and hydrazine hydrate (5 mL, 99 mmol, 4.5 eq) in methanol (50 mL) was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated under vacuum. The residue was taken in ethyl acetate (100 mL) and washed with water (2×50 mL), brine (50 mL), dried (Na2SO4) and filtered. The filtrate was evaporated under reduced pressure to afford 2.5 g (50%) of the desired product as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H, D2O exchangeable), 8.01 (d, J=2.0 Hz, 1H), 7.74 (dd, J=8.0, 2.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 4.50 (s, 2H, D2O exchangeable), 2.37 (s, 3H); ESI-MS (m/z) 229, 231 [(MH)+, Br79,81].