Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:25]1[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]1)=[O:13])[CH2:8]2
Reactant: OC1CCNCC1
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCC(O)CC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and 4-hydroxypiperidine (0.31 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-(4-hydroxy-piperidin-1-yl)-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (87 mg, 81%) as an off-white powder. ES-HRMS m/e calcd for C20H31N4O2 (M+H+) 359.2442, found 359.2437.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.S([O-])([O-])(=O)=[O:11].[Na+].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N+:3]=1[O-:11]
Reactant: O=S(=O)([O-])[O-]
Reactant: COc1ccc(C)nc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.2 %

Procedure:
To a solution of 2-methyl-5-methoxy-pyridine (2.93 g, 24 mmol) in DCM (100 mL) was added sodium sulphate (5 g, 35 mmol), followed by m-chloro-peroxy-benzoic acid (10 g, 58 mmol), and mixture was stirred at room temperature for ˜48 hours. The reaction mixture was filtered, and the white solid was washed with DCM. The filtrate was concentrated and purified by normal phase chromatography eluting with a gradient of 1:1 EtOAc/heptane to EtOAc to give 2-methyl-5-methoxy-pyridine-N-oxide (2.41 g, 72%).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH2:34].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:34][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a suspension of 3.00 g of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 2.01 g of L-histidine methyl ester dihydrochloride in 24 ml of N,N-dimethylformamide were added successively 2.16 ml of diphenylphosphoryl azide and 3.81 ml of triethylamine under ice-cooling, and the mixture was stirred for 16 hours under ice-cooling. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Diethyl ether was added to the residue, the precipitated crystals were collected by filtration to obtain 4.08 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine methyl ester as a white powder. To a solution of 4.00 g of the ester compound obtained in 25 ml of methanol was added 2.75 g of hydrazine monohydrate, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether, and dried under reduced pressure below 40° C. to obtain 3.90 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide as a white powder. In 5 ml of methanol was dissolved 2.20 g of the hydrazide compound obtained with heating at 40° C., and insoluble materials were filtered off. The filtrate was allowed to stand overnight at room temperature, and then precipitated crystals were collected by filtration to obtain 0.70 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide as a white powder.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][P:10](=[O:17])([O:14]CC)[O:11]CC)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:18][Si:19](Br)([CH3:21])[CH3:20]>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][CH2:9][P:10](=[O:17])([O:14][Si:19]([CH3:21])([CH3:20])[CH3:18])[O:11][Si:19]([CH3:21])([CH3:20])[CH3:18])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C[Si](C)(C)Br
Reactant: C=C(C)C(=O)OCCCP(=O)(OCC)OCC
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCP(=O)(O[Si](C)(C)C)O[Si](C)(C)C

Procedure:
To a solution of diethyl 3-methacryloyloxypropylphosphonate (28.2 g; 0.107 moles) in CH2Cl2 (60 g) is added dropwise a solution of trimethylsilyl bromide (34.4 g; 0.225 moles) in CH2Cl2 (22 g) at room temperature. The mixture is refluxed for 5 hours. The solvent is evaporated under vacuum to give di(trimethylsilyl) 3-methacryloyloxypropylphosphonate as a clear, colorless liquid (37.9 g). 1H NMR (CDCl3, δ ppm) 0.01 (s, 9H, CH3—Si), 1.41-1.55 (m, 2H, CH2—P), 1.59-1.73 (m, 2H, CH2—CH2—P), 1.66 (d, 3H, CH3), 3.90 (t, 2H, CH2—O), 5.28 (s, 1H, CH═), 5.82 (s, 1H, CH═). 31P NMR (CDCl3, δ ppm) 13.6.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[S:25])[NH:16]C(=O)C3C=CC=CC=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>C(O)C.O>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH2:16])=[S:25])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(c2ccc(NC(=S)NC(=O)c3ccccc3)cc2)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=S)Nc1ccc(C2=NNC(=O)CC2)cc1
Yield: 81.1 %

Procedure:
To a suspension of 0.7 g of N-[[[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]amino]thioxomethyl]benzamide in 7 ml of ethanol is added 1.6 ml of 10% ethanolic sodium hydroxide followed by heating for two hours. The reaction mixture is cooled, diluted with water, and filtered to give 0.4 g of the product, N-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]thiourea mp 234°-235° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH:11]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH:11]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(N[C@@H]1C[C@H]1c1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroform (5 mL) was added to a 200 mL round-bottomed flask containing 1,1-dimethylethyl 4-(1-{[trans-2-phenylcyclopropyl]amino}ethyl)-1-piperidinecarboxylate (67 mg, 0.194 mmol) to give a suspension. HCl/1,4-Dioxane (1.5 mL, 6.00 mmol) was added and the mixture stirred 18 hours at room temperature. The Upon completion, the solvents were removed, MeOH (1 mL) added and the mixture purified via reverse phase column chromatography on Gilson ((C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) affording the title compound as a white solid LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, MeOD-d4) δ ppm 1H NMR (400 MHz, MeOD) d 7.93 (s, 1H), 7.31-7.39 (m, 2H), 7.17-7.30 (m, 3H), 3.46-3.59 (m, 3H), 2.95-3.14 (m, 3H), 2.50-2.63 (m, 1H), 2.17-2.28 (m, 1H), 1.94-2.05 (m, 3H), 1.59-1.76 (m, 3H), 1.48 (t, J=7.71 Hz, 1H), 1.39 (d, J=6.82 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[C:24]([CH3:29])[CH:23]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CCO.C1COCC1>[CH3:29][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[C:3]([OH:30])=[O:2])=[CH:15][CH:16]=2)[CH:27]=[CH:26][C:25]=1[CH3:28]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCc2ccc(C)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(CCc2ccc(Nc3ccc([N+](=O)[O-])cc3C(=O)O)cc2)cc1C
Yield: 95.3 %

Procedure:
The title compound was prepared 2-{4-[2-(3,4 dimethyl-phenyl)-ethyl]phenylamino}-5-nitrobenzoic acid methyl ester (1.12 g, 2.76 mmol), 1N NaOH (50 mL) in EtOH (50 mL) and THF (50 mL) using the procedure described in Example 2. This procedure yielded a yellow solid, 1.03 g (2.63 mmol, 81%) of the desired product. mp 214-216° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:21]1[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.5 %

Procedure:
To a solution of 1H-indole-2,5-dicarboxylic acid 2-ethyl ester (3.08 g, 13 mmol) and tert-butyl 1-homopiperazine-carboxylate (1 eq., 2.657 g) in DMF (50 ml) was added N-hydroxybenzotriazole (0.2 eq., 360 mg). After a five minutes, N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (1.2 eq., 3.05 g) was added and the mixture stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (3:1 heptane/ethyl acetate eluant) to afford the product as a light-brown solid (5.21 g, 94%). MS (m/z): 416.4 (M+H)+.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=2[F:23])=[C:13]([CH3:24])[C:12](=[O:25])[N:11]2[CH2:26][CH2:27][O:28][C:10]=12.C(OC(=O)C)C>N1C=CC=CC=1>[F:23][C:17]1[CH:18]=[C:19]([I:22])[CH:20]=[CH:21][C:16]=1[NH:15][C:14]1[C:9]([NH:8][S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:6])=[O:5])=[C:10]2[O:28][CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]=1[CH3:24]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCO2
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
Cyclopropane sulfonyl chloride (50 mg, 0.35 mmol) was added to a solution of 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (I-7f: 80 mg, 0.199 mmol) in dry pyridine (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1.5% MeOH in DCM) afforded 3 mg of the product (3% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[CH3:19])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Product: CCOc1cc(CN2CCC(NC(=O)c3ccccc3C)CC2)ccc1Cl
Yield: 63 %

Procedure:
The title compound (24 mg, 63%) was prepared analogously to example 7 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 2-methylbenzoyl chloride. MS:387.4 (MH+).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:26])([F:25])[CH2:22][NH:23][NH2:24]>>[CH3:16][C:15]1[CH:14]=[C:13]([C:10]2[C:9]([CH3:19])=[N:8][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:11]=2[OH:12])[N:23]([CH2:22][C:21]([F:26])([F:25])[F:20])[N:24]=1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Reactant: NNCC(F)(F)F
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(CC(F)(F)F)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and 2,2,2-trifluoro-ethyl hydrazine (70% in water) according to the procedure of Example 28.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH:12]([C:19]2[N:20]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[N:21]=[C:22]3[C:27]=2[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([C:36]([F:39])([F:38])[F:37])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([N:20]2[C:19]([CH:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:40])=[O:2])=[CH:5][C:6]=3[C:36]([F:38])([F:37])[F:39])=[O:35])=[C:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N:21]2)=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(C(F)(F)F)c1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-acetylamino}-3-trifluoromethyl-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as brown solid. MS: m/e=558.2 [M+H+].
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:50]([O:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=1)=[O:56])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[C:58]1[C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:67]=1)=[O:56])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cc5ccccc5n4C(=O)OC(C)(C)C)c3)c(=O)oc12
Temperature: 25 °C
Yield: 72.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2-(3-Amino-phenyl)-indole-1-carboxylic acid tert-butyl ester (0.02 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 76% yield: LCMS (ESI) m/z 511 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)Cn1c(C(F)F)cc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, methyl bromoacetate (2 eq) and Cs2CO3 (2 eq): MS (ES) m/z 299 (M+1).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.C([O:19][C:20](=[O:30])[C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:10]([N:4]1[CH2:3][C:22]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[C:21]([C:20]([OH:30])=[O:19])[CH2:5]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (116.8 g, 0.49 mol) in CH2Cl2 (260 ml) was added dropwise over 90 min to a stirred solution of (4-chloro-phenyl)-propynoic acid ethyl ester (72.0 g, 0.34 mol) and trifluoroacetic acid (2.5 ml, 0.03 mol) in CH2Cl2 (350 ml). The reaction mixture was stirred at 25° C. overnight and afterwards evaporated to dryness. The residue was dissolved in dioxane (0.8 l); an aqueous solution of NaOH (91.0 ml, 1.02 mol, 3 eq.) was added, and the resulting emulsion was stirred at r.t. for 48 h. The low boiling organic solvent was removed under vacuum, water (0.9 l) was added, and the aqueous layer was separated and washed with TBME (1 l). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was stirred overnight; the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 62.0 g (60%) of IIa as a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].ClS(C1C=CC=CC=1C(O)=O)(=O)=[O:16].[OH-].[Na+:28]>O.ClC1C=CC=CC=1>[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O-:10])=[O:9])([OH:16])(=[O:4])=[O:3].[Na+:28]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cl
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: O
Product: O=C([O-])c1cccc(S(=O)(=O)O)c1
Temperature: 100 °C
Yield: 93.3 %

Procedure:
273.6 g of 3-(chlorosulfonyl)benzoic acid containing 28.6% water (corresponding to 195.3 g (0.89 mol) of 100% chlorosulfonylbenzoic acid) are admixed with 50 g of water and 500 g of chlorobenzene and heated in a water separator. A total of 106 ml of water are expelled. After cooling the reaction mixture to 100° C., 108 g (0.89 mol) of 33% strength sodium hydroxide solution are added dropwise over 30 minutes. Subsequently a further 90 ml of water are expelled. After cooling, the precipitated product is filtered off with suction. After drying at 100° C./100 torr (13.16 kPa) 190.4 g of sodium 3-sulfobenzoate are obtained, the purity determined by titration being 97.3%; this corresponds to a yield of 93.3%.
Reaction SMILES: [C:1]([C:9]1[C:17]([N+:18]([O-])=O)=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:18][C:17]1[C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCOc1cc(C(=O)O)cc(N)c1C(=O)c1ccccc1

Procedure:
To a stirred mixture of 4-benzoyl-3-n-butoxy-5-nitrobenzoic acid (5.1 g), pyridine (25 ml), and water (25 ml), sodium dithionite (10.2 g) is added in portions. The mixture is heated on a steam bath for 1 hour and is then evaporated in vacuo. The remaining material is dissolved in water (about 50 ml) and the solution is acidified with conc. hydrochloric acid (about 15 ml). After cooling, the resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from ethanol, 5-amino-4-benzoyl-3-n-butoxybenzoic acid is obtained with a melting point of 202.5° -203.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1cn[nH]c1
Reactant: Brc1ccccc1
Product: c1ccc(-n2cccn2)cc1

Procedure:
Following General Procedure A (90° C., 30 hours), 1H-pyrazole (205 mg, 3.0 mmol) is coupled with bromobenzene (212 μL, 2.0 mmol). The crude brown oil is purified by flash chromatography on silica gel (eluent: dichloromethane/hexanes=50/50) to provide 270 mg (94% isolated yield) of the desired product as a light yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5](=[O:24])[NH:6][CH:7]1[CH2:16][C:15]2[C:10](=[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]1=[O:23].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][CH:2]([CH3:33])[CH2:3][C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[C:5](=[O:24])[NH:6][CH:7]1[CH2:16][C:15]2[C:10](=[C:11]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])[CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:8]1=[O:23]
Reactant: BrCc1ccccn1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2NC1=O
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccccn2)C1=O
Reaction time: 1 h

Procedure:
tert-Butyl (2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylcarbamate (320 mg) was dissolved in N,N-dimethylformaldehyde (4.0 mL), and 2-bromomethylpyridine hydrobromide (216 mg) and sodium hydride (67 mg) were added thereto under cooling on ice, followed by stirring for one hour. The resultant mixture was subjected to extraction with saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (ethyl acetate:methanol=20:1), whereby the title compound (315 mg) was yielded.
Reaction SMILES: [CH2:1]([O:4][CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)[CH:2]=[CH2:3].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:19]([NH:26][C@H:10]1[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C@H:5]1[O:4][CH2:1][CH:2]=[CH2:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C=CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Yield: 83.7 %

Procedure:
The same operation as in Example (90c) was performed using tert-butyl 3-allyloxy-4-oxopiperidine-1-carboxylate obtained in Example (113b) (4.37 g, 17.1 mmol), benzylamine (2.02 g, 18.9 mmol), sodium (triacetoxy)borohydride (6.36 g, 30 mmol) and 1,2-dichloroethane (40 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 4.96 g of the title compound as a colorless oily substance (84%).