Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[C:21]2[CH:20]=[CH:19][S:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)=[O:11])(=O)C1C=CC=CC=1.C([NH:30][C:31]([NH:33][CH:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][CH2:35]1)=[O:32])(=O)C1C=CC=CC=1>>[S:18]1[CH:19]=[CH:20][C:21]2[CH:13]([NH:12][C:10]([NH2:9])=[O:11])[CH2:14][CH2:15][CH2:16][C:17]1=2.[CH:34]1([NH:33][C:31]([NH2:30])=[O:32])[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37][CH2:36][CH2:35]1
Reactant: O=C(NC(=O)c1ccccc1)NC1CCCc2ccccc21
Reactant: O=C(NC(=O)c1ccccc1)NC1CCCc2sccc21
Product: NC(=O)NC1CCCc2ccccc21
Product: NC(=O)NC1CCCc2sccc21

Procedure:
In the manner described in Example 60, 1-benzoyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea and 1-benzoyl-3-(1,2,3,4-tetrahydro-1-naphthyl)urea are hydrolyzed to afford 4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea, m.p. 204.5° C. to 208.5° C., and 1,2,3,4-tetrahydro-1-naphthylurea, m.p. 212° C. to 214° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][N:21]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[CH:14][N:15]=2)[CH2:22][CH2:23]1)=[O:26])[CH3:29]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Reactant: CCOC(=O)C1CCNCC1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cn2)CC1

Procedure:
5′-(3-tert-Butyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-30% EtOAc in hexanes gradient. FIRMS m/z calcd for C24H31N3O3 [M+H]+: 410.2438. Found: 410.2436
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[CH3:10][O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:12]([O:11][CH3:10])=[O:13])=[CH:15][CH:16]=2)[CH:3]=1
Reactant: Cc1ccc(N)cc1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: [Cs+]
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Temperature: 90 °C
Yield: 51.8 %

Procedure:
3-Bromo-4-methylaniline (744 mg, 4.0 mmol), (4-methoxycarbonylphenyl)boronic acid (864 mg, 4.8 mmol), tetrakis(triphenylphosphine)palladium (100 mg, 0.087 mmol) and caesium carbonate (2.4 g, 7.37 mmol) were mixed in DME (30 ml) and heated at 90° C. for 20 h. The reaction was absorbed onto silica applied to a silica SPE (10 g) and eluted with ethyl acetate/cyclohexane (0-100% ethyl acetate). The solvent was evaporated from the product fractions under vacuum to give methyl 5′-amino-2′-methyl-1,1′-biphenyl-4-carboxylate (500 mg, 43%). NMR; δH CDCl3 8.07,(2H, d), 7.38,(2H, d), 7.07,(1H, d), 6.67,(1H, dd), 6.60,(1H, d), 3.94,(3H, s), 2.14,(3H, s).
Reaction SMILES: N1([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)CCCCC1.C(OCC)(=O)C1C(=CC=CC=1)C(OCC)=[O:19].C(N(CC)CC)C.[F:38][C:39]1[CH:48]=[CH:47][C:42]([C:43](=[O:46])[CH2:44]Br)=[CH:41][CH:40]=1.Cl>O1CCCC1>[F:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([CH2:44][CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:7]=[O:19])=[O:46])=[CH:41][CH:40]=1
Reactant: CCOC(=O)c1ccccc1C(=O)OCC
Reactant: C(=CN1CCCCC1)c1ccccc1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=CC(CC(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
4.68 g of the β-piperidinostyrene/diethyl phthalate mixture were dissolved in 70 ml of anhydrous tetrahydrofuran, and 1.01 g (10 mmol) of triethylamine were added to the resulting solution. 2.60 g (12 mmol) of 4-fluorophenacyl bromide were then added to the resulting mixture, which was then stirred at room temperature for 3 hours. At the end of this time, 30 ml of 1N aqueous hydrochloric acid were added to the reaction mixture, and the mixture was stirred at room temperature for a further 1 hour. It was then extracted with diethyl ether. The organic extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure and the residue was applied to a silica gel chromatography column and eluted with a 95:5 by volume mixture of hexane and ethyl acetate, to give 0.50 g of the title compound as a slightly yellow oily substance.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([OH:27])[C:23]3[C:24]4[N:15]([C:16](=[O:26])[CH:17]=[N:18][C:19]=4[CH:20]=[CH:21][C:22]=3[F:25])[CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.CN(C)C=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]2[N:18]=[CH:17][C:16](=[O:26])[N:15]3[CH2:14][C:13]([CH2:12][N:28]4[CH2:29][CH2:30][CH:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:32][CH2:33]4)([OH:27])[C:23]=1[C:24]=23
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)cnc4ccc(F)c2c43)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(CC2(O)Cn3c(=O)cnc4ccc(F)c2c43)CC1
Temperature: 50 °C

Procedure:
A mixture of (7-fluoro-6-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[1,2,3-de]quinoxalin-6-yl)methyl 4-methylbenzenesulfonate (3.64 g, 9.3 mmol) (for a preparation, see Example 9(f)), 1,1-dimethylethyl 4-piperidinylcarbamate (2.0 g, 10.2 mmol) and sodium carbonate (2.9 g, 27.9 mmol) in ethanol (110 mL) and dimethylformamide (10 mL) was heated at 50° C. for 6 h. The mixture was evaporated to remove ethanol and the residue was partitioned between dichloromethane and half-saturated brine (200 mL each).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH:29]=[CH2:30])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.O1CCOCC1>C1COCC1>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH2:29][CH2:30][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)(=[O:28])=[O:27])[CH2:24][CH2:25]3)[N:11]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:13]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: C=CS(=O)(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCN3CCN(C)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.1 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and 1-methylpiperazine (0.16 mL, 1.44 mmol) in THF (20 mL) was refluxed for 5 hrs and then stirred at room temperature for 3 days. Additional 1-methylpiperazine (0.16 mL, 1.44 mmol) and 1,4-dioxane (20 mL) were added and the reaction mixture was refluxed for 20 hrs. The mixture was cooled to room temperature and the solvents were removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (100:0 to 95:5) followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-{[2-(4-methyl-1-piperazinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (116 mg, 65%).
Reaction SMILES: B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[Br:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C:31](=[O:33])[CH3:32].N(CCO)CCO>O1CCCC1>[Br:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]([OH:33])[CH3:32]
Reactant: CC(=O)c1cccc(C)c1Br
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: Cc1cccc([C@@H](C)O)c1Br
Temperature: -20 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
(+)-B-chlorodiisopinocampheylborane (8.46 g, 26.4 mmol) was dissolved in tetrahydrofuran (150 mL), cooled to −20° C., slowly added dropwise with a solution of 1-(2-bromo-3-methylphenyl)ethanone (4.30 g, 20.3 mmol) described in US 2007/167506 in tetrahydrofuran (50 mL), and stirred for 18 hours. The reaction solution was added with diethanolamine (6.38 g, 60.8 mmol), cooled to room temperature, and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and added with n-hexane (100 mL). The precipitated solids were filtered off and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a white solid (4.30 g, yield 99%, 95.6% ee).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[H][H]>CCO.[Pd].[C]>[N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccc2c(n1)NCCC2

Procedure:
A mixture of 11-6 (4.0 g, 13.9 mmol) and 10% Pd/carbon (4.0 g) in EtOH (100 mL) was stirred under a balloon of hydrogen for 4 h. Following filtration and evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol) to give 11-7 as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:34][C:35]#[CH:36])[C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14](CC2C=CC=CC=2)[CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[ClH:37]>CC(O)C.[Pd].ClCCl.CCOCC>[ClH:37].[CH3:1][N:2]([CH2:34][C:35]#[CH:36])[C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][NH:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:11]=1
Reactant: C#CCN(C)C(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(C)O
Product: C#CCN(C)C(=O)COc1ccc(CCNCC(O)COc2ccccc2)cc1

Procedure:
A solution of N-methy-N-propargyl 4-[2-(N-benzyl-N-(2-hydroxy-3phenoxypropyl)amino)ethyl]phenoxyacetamide (1.0 g) was dissolved in propan-2-ol (70 ml). 10% Palladium on carbon catalyst (0.2 g) was added and the mixture hydrogenated overnight under an atmosphere of hydrogen. The catalyst was separated by filtration through Keiselguhr and the filtrate evaporated under reduced pressure to give an oil. This residue was dissolved in dichloromethane (70 ml) and the pH (as indicated on moist test paper) was adjusted to 3 by adding a saturated solution of HCl in ether. The solvent was evaporated and this process was repeated as described in Example 26. The final residual oil (0.9 g) was suspended in a minimum amount of propan-2-ol from which it crystallised. A small amount of methyl acetate was added before the solid was filtered off and air-dried to give N-methyl-N-propargyl-4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]-phenoxyacetamide hydrochloride salt (0.3 g) mp 105°-107° C.. NMR: 0.73-0.92[m,3 H, hindered rotamers CH2CH3 ]; 1.35-1.67[m,2H, hindered rotamers, NCH2CH2CH3 ]; 2.80 and 2.96[pr.s,3H, hindered rotamers, N-CH3 ]; 2.84-3.02[m,2H,CHHD 2C6H4 ]; 3.02-3.30[m,4H,CH2NHCHHD 2]; 3.98[m,2H, OCH2CHOH]; 4.20[m,1H,CHOH]; 4.74[s,2H,OCH2CO]; 6.80-6.98[m,5H, aromatic H]; 7.10-7.34[m,4H, aromatic H].
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].C[O:9][C:10](=O)[CH2:11][S:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>ClCCl.CO.CCN(CC)CC>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:10](=[O:9])[CH2:11][S:12][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCCCCCN
Reactant: COC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: NCCCCCC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 56 %

Procedure:
1,5-Diaminopentane (0.75 g, 7.21 mmol) was stirred while tritylsulfanyl-acetic acid methyl ester (2.53 g, 7.27 mmol) was added slowly. The mixture was heated at 100° C. for 2 h while methyl alcohol escaped. The product was isolated by column chromatography (dichloromethane/MeOH/Et3N=10/1/0.1) to provide 7-Amino-1-tritylsulfanyl-heptan-2-one (1.63 g, 54%). 1H NMR (300 MHz, CD3OD) δ 7.42-7.36 (m, 6H), 7.31-7.18 (m, 9H), 3.00 (t, J=6.9 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H), 1.42 (m, 4H), 1.27 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 171.1, 145.8, 130.9, 129.2, 128.2, 68.4, 42.5, 40.8, 37.4, 33.4, 30.1, 25.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[N:11]([O-])=O.[Na+].[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([N:11]=[N:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1)[CH3:17]
Reactant: O=N[O-]
Reactant: CNC
Reactant: COC(=O)c1cc(N)cs1
Agent: [Na+]
Product: COC(=O)c1cc(N=NN(C)C)cs1

Procedure:
Diazotization of methyl 4-aminothiophene-2-carboxylate with sodium nitrite followed by treatment with dimethylamine provides methyl 4-[(dimethylamino)diazenyl]thiophene-2-carboxylate. Treatment of the ester with ammonia gave the required 4-[dimethylamino)diazenyl]thiophene-2-carboxamide (compd. No. 12). The precursor compound, methyl 4-aminothiophene-2-carboxylate is produced from the commercially available thiophene-2-carboxylic acid. The nitration of thiophene-2-carboxylic acid provides an inseparable mixture of 4-nitrothiophene-2-carboxylic acid and 5-nitrothiophene-2-carboxylic acid, which is esterified to get the corresponding esters. The nitro functionality is then reduced to amines using iron powder and the mixture separated by silica gel column chromatography to obtain methyl 4-aminothiophene-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2cc(OCCCCBr)ccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 475.3 %

Procedure:
9.41 g (40 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 90 ml acetone were treated with 16.6 g (6 mmol) K2CO3 (powdered) and 17.3 g (5 mmol) 1,4-dibromobutane. The suspension was stirred at 50° C. for 4 h, cooled to RT, filtered and concentrated. Column chromatography on silica gel with CH2Cl2 yielded 8.8 g (60%) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester as colorless solid, MS: 370 (MH+, 1Br).
Reaction SMILES: [C:1]([C:4]1([C:29]([OH:31])=[O:30])[CH2:7][CH:6]([C:8]2([CH2:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:12]C(=O)N[C:9]2=[O:14])[CH2:5]1)([OH:3])=[O:2].[OH-:32].[Na+]>>[NH2:12][C:8]([CH:6]1[CH2:7][C:4]([C:1]([OH:3])=[O:2])([C:29]([OH:31])=[O:30])[CH2:5]1)([CH2:15][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:9]([OH:32])=[O:14]
Reactant: [OH-]
Reactant: O=C1NC(=O)C(CC(c2ccccc2)c2ccccc2)(C2CC(C(=O)O)(C(=O)O)C2)N1
Agent: [Na+]
Product: NC(CC(c1ccccc1)c1ccccc1)(C(=O)O)C1CC(C(=O)O)(C(=O)O)C1

Procedure:
A solution of 5-(3,3-dicarboxycyclobutyl)-5-(2,2-diphenylethyl)imidazolidine-2,4-dione (0.21 g, 0.5 mmol) in 2M sodium hydroxide (4 ml) was heated to 150° C. for 4 days in a PTFE lined stainless steel pressure vessel. After cooling, the mixture was filtered and the filtrate acidified with 5M hydrochloric acid (2 ml). The precipitate was cooled and filtered, washed with water and dried to give the title product (m.p. 182-185° C. with effervescence). 1H NMR (D2O/NaOH) δ 7.21-7.50 (10H, m)), 4.06 (1H, dd), 2.44-2.63 (2H, m), 2.11-2.38 (5H, m).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:26]=3)[CH2:23][C:22](=[O:38])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
The title compound was prepared from {2′-fluoro-3-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamic acid tert-butyl ester (Example M18) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (237 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:23])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.FC1C=C(B(O)O)C=CC=1.[NH2:34][C:35]1[S:36][CH:37]=[C:38]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[N:39]=1>>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][C:38]1[N:39]=[C:35]([NH:34][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([O:5][C@@H:4]([CH3:23])[CH2:3][O:2][CH3:1])[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:12]=2)[S:36][CH:37]=1)[CH3:45]
Reactant: COC[C@H](C)Oc1cc(Oc2cccc(F)c2)cc(C(=O)O)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: OB(O)c1cccc(F)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2cc(Oc3cccc(F)c3)cc(O[C@@H](C)COC)c2)n1

Procedure:
{2-[3-(3-fluoro-phenoxy)-5-((S)-2-methoxy-1-methyl-ethoxy)-benzoylamino]-thiazol-4-yl}-acetic acid ethyl ester was prepared from 3-{(1S)-2-methoxy-(methylethyl)oxy}-5-{[3-fluoro phenyl]oxy}benzoic acid (prepared in analogy to the method described in general synthetic descriptions F, using m-fluorophenylboronic acid in step D)) and ethyl 2-aminothiazol-4-ylacetate following synthetic description A
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[N:4]=1.B1C2CCCC1CCC2.[OH-:29].[Na+].OO>C1COCC1>[F:19][C:2]([F:1])([F:18])[C:3]1[N:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:29])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To the solution of 2-(trifluoromethyl)-6-(4-vinylphenoxy)pyridine (2.4 g, 9.05 mmol) in dry THF (25 mL), was added 9-BBN (30 ml, 15.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (12 mL, 36.0 mmol), and 30% H2O2 (12 mL). The reaction mixture was heated at 50° C. for 1 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (3.68 g, 8.44 mmol, 93% yield) as a white oil. LCMS: rt=3.00 min, [M+H+]=284
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][NH:6][C:7]1[CH2:8][C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1>C(O)(=O)C.O>[N:1]([CH2:5][NH:6][C:7]1[CH2:8][C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:3]
Reactant: O=N[O-]
Reactant: CNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=NCNC1=Nc2ccccc2N(c2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium nitrite, 5.9 g (0.086 moles), was added in 3 portions over a period of 30 minutes to a stirred solution of 18.9 g (0.071 m) of 3,5-dihydro-2-methylamino-5-phenyl-4H-1,5-benzodiazepin-4-one in 200 ml of acetic acid. After the addition was completed, the mixture was stirred for 20 minutes at room temperature and was then diluted with water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was crystallized from ether to yield product. Additional material was obtained from the concentrated mother liquors. For analysis, the material was recrystallized from ethyl acetate/hexane, mp 139°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:14])=[O:7]
Reactant: NCc1cccnc1
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2cccnc2)c1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (102 mg, 0.3 mmol), 3-aminomethyl pyridine (0.036 ml, 0.36 mmol) in DMF 3.0 mL was added EDC (86.3 mg, 0.45 mmol), HOBt (60.8 mg, 0.45 mmol) and DIPEA (0.078 ml, 0.45 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-pyridine-3-ylmethyl-benzamide as a white-solid (71.4 mg, 55% yield).
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[Cl:6][C:7]1[N:12]=[C:11](Cl)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1>C(#N)C.C(OC(=O)C)C>[Cl:6][C:7]1[N:12]=[C:11]([NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][N:8]=1
Reactant: C[C@@H](N)CO
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 315 mg (4.2 mmol) of (R)-2-Amino-propan-1-ol in 5 ml of acetonitrile is added slowly to a suspension of 388 mg (2.0 mmol) of 2,4-dichloro-5-nitro-pyrimidine in 20 ml acetonitrile at −30° C. to −20° C. The batch is stirred for 3 hours at −30° C. to −20° C. The batch is diluted with ethylacetate and ice water. The batch is extracted with ethyl acetate (3×). The combined organic phases are washed with NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. 350 mg (1.51 mmol, corresponding to 76% of theory) of the product is obtained.