Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[C:30]([CH:36]=O)=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:36][C:30]2[C:29]([CH3:28])=[CH:34][C:33]([CH3:35])=[CH:32][N:31]=2)[CH2:15][C:16]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ncccc2-c2ccccc2)CC1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2-c2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of the amine from above and 3,5-dimethyl-2-pyridinecarboxaldehyde in CH2Cl2 with NaBH(OAc)3 gave 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-(3-phenyl-pyridin-2-ylmethyl)amino]-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C)C=O.O>[CH3:19][C:17]([C:25]1[CH:26]=[CH:27][C:28]([O:31][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:29][CH:30]=1)([CH3:18])[CH2:20][C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (3.4 g, 0.024 mol), K2CO3 (6.6 g, 48 mmol) and 4-(tert-octyl)phenol (5.0 g, 0.024 mol) in dimethylformamide (50 mL) was heated at reflux for 24 hours. The mixture was allowed to cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (250 mL). The organic phase was washed with water (5×100 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the desired product as a yellow solid (7.8 g, 100%): 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (d, 9.2 Hz, 2 H), 7.48 (d, 8.8 Hz, 2 H), 7.09-7.05 (m, 4H), 1.72 (s, 2 H), 1.34 (s, 6 H), 0.69 (s, 9 H); MS (FAB) m/z 328 (MH+); Rf =0.92 (15:85 ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:17]3[O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:25][C:26]1[N:31]=[C:30]([NH:1][C:2]2[CH:3]=[C:4]([NH:9][C:10]([C:12]3[C:17]4[O:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:16]=4[CH:15]=[CH:14][CH:13]=3)=[O:11])[CH:5]=[CH:6][C:7]=2[CH3:8])[CH:29]=[CH:28][N:27]=1
Reactant: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1N
Reactant: Clc1ccnc(Cl)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc3c2oc2ccccc23)cc1Nc1ccnc(Cl)n1
Temperature: 120 °C
Yield: 40.8 %

Procedure:
A mixture of N-(3-amino-4-methylphenyl)dibenzofuran-4-carboxamide (1.5 g), 2,4-dichloropyrimidine (1.4 g), N,N-di-isopropylethylamine (2.9 ml) and n-butanol (70 ml) was stirred and heated to 120° C. for 76 hours. The mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of isohexane and ethyl acetate as eluent. The material so obtained was triturated under ethyl acetate. There was thus obtained the title compound (0.83 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 6.53 (d, 1H), 7.31 (d, 1H), 7.43-7.65 (m, 4H), 7.79 (m, 2H), 7.84 (d, 1H), 8.1 (d, 1H), 8.21 (d, 1H), 8.34 (d, 1H), 9.62 (s, 1H), 10.42 (s, 1H); Mass Spectrum: M+H+ 429 and 431.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[H-].[Na+].Br[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CN1CCCC1.C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: Brc1ncccn1
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CCN2c1ncccn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
300 mg 5-nitro-2,3-dihydro-1H-indole are dissolved in 4 ml N-methyl-pyrrolidine. 80 mg NaH (60% suspension in mineral oil) are added and the mixture is stirred for 15 minutes at ambient temperature. Then 380 mg of 2-bromopyrimidine are added and the mixture is then heated to 60° C. for 3 hours. It is then diluted with diethyl ether and washed with dilute citric acid solution and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:23]4[CH:29]=[CH:30][CH:31]=[CH:32][C:22]3=4)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[N:11]1([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[CH2:20][N:21]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:23]3[CH:29]=[CH:30][CH:31]=[CH:32][C:22]2=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(CN3C(=O)CCCc4ccccc43)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCc2ccccc2N1Cc1cccc(N2CCNCC2)c1

Procedure:
A solution of 0.6 g (1.38 mmole) 4-[3-(2-oxo-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester in 3 mL trifluoroacetic acid was concentrated under reduced pressure. The residue was partitioned between 10 mL saturated sodium carbonate containing 1 mL 5% sodium hydroxide and 35 mL ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure. The residue was converted to the maleate salt and recrystallized from methanol/ethyl acetate to provide 1-(3-Piperazin-1-yl-benzyl)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one as a maleate salt, 0.346 g, m.p. 149-150°.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[C:24]([CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:18].[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[Si:27]([O:26][CH2:25][C:24]1[C:19]([C:17]([C:3]2[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]3[C:10]([C:2]=2[NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=3)=[O:18])=[N:20][CH:21]=[CH:22][CH:23]=1)([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 employing 3-amino-2-[3-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-6-chloro-1-(ethoxycarbonyl)indole (step 3) and propionyl chloride. 1H-NMR (CDCl3) δ: 9.48 (1 H, br s), 8.45 (1 H, dd, J=1.5, 4.5 Hz), 8.25 (1 H, dd, J=1.5, 8.1 Hz), 8.16 (1 H, d, J=1.8 Hz), 8.08 (1 H, d, J=8.9 Hz), 7.44 (1 H, dd, J=4.6, 7.9 Hz), 7.25 (1 H, dd, J=1.8, 8.8 Hz), 5.20 (2 H, s), 3.86 (2 H, q, J=7.1 Hz), 2.50 (2 H, q, J=7.6 Hz), 1.26 (3 H, t, J=7.6 Hz), 1.00 (9 H, s), 1.00 (3 H, t, J=7.0 Hz), 0.18 (6 H, s).
Reaction SMILES: [CH3:1][Ge:2]([CH3:16])([CH3:15])[C:3]1[CH:4]=[C:5]([C:9]2([CH3:14])OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O>[CH3:15][Ge:2]([CH3:1])([CH3:16])[C:3]1[CH:4]=[C:5]([C:9](=[O:10])[CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(c2cccc([Ge](C)(C)C)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cccc([Ge](C)(C)C)c1

Procedure:
A mixture of 351 mg (1.25 mmol) of 2-(3-trimethylgermylphenyl)-2-methyl-1,3-dioxolane, 47 mg (0.187 mmol, 0.15eq) of pyridinium p-toluenesulfonate (PPTS), 1.1126 g (62.5 mmol, 50eq) of water and 10 ml of acetone was refluxed for 2.5hours. The reaction mixture was evaporated and extracted with petroleum ether. The extract was evaporated. The oily residue was purified by column chromatography to give 294 mg of colorless oily substance.
Reaction SMILES: [SH:1][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[C:18]1([C:24]2[N:25]=[C:26]([CH2:35]Br)[O:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]1([C:24]2[N:25]=[C:26]([CH2:35][S:1][CH:2]3[C:11]4[C:6](=[C:7]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:8]=[CH:9][CH:10]=4)[CH2:5][CH2:4][CH2:3]3)[O:27][C:28]=2[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: COC(=O)COc1cccc2c1CCCC2S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCCC2SCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Yield: 58.6 %

Procedure:
A solution of 1-hydroxy-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.42 g) and Lawesson's reagent (0.40 g) in toluene (4 ml) was refluxed under N2 atmosphere for 1 hour. The reaction mixture was purified by chromatography on silica gel to give 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.20 g). A solution of 1-mercapto-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.26 g), (4,5-diphenyloxazol-2-yl)methyl bromide (0.32 g) and potassium carbonate (0.14 g) in DMF (5 ml) was stirred for 6 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine. The dried solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give 1-[(4,5-diphenyloxazol-2-yl)methylthio]-1,2,3,4-tetrahydro-5-methoxycarbonylmethoxynaphthalene (0.29 g). MS (m/z): 486 (M+ +1) NMR (CDCl3, δ): 1.75-1.92 (1H, m), 2.00-2.22 (3H, m), 2.45-2.72 (1H, m), 2.80-3.02 (1H, m), 3.79 (3H, s), 3.91 (1H, s), 3.94 (1H, s), 4.36 (1H, m), 4.60 (2H, s), 6.50-6.55 (1H, m), 7.04-7.06 (2H, m), 7.33-7.40 (6H, m), 7.59-7.68 (4H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:19](#[N:21])[CH3:20]>>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:20][C:19]#[N:21])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cccc(Cl)c1/C=C/c1cccc(C=O)c1
Reactant: CC#N
Product: Cc1cccc(Cl)c1/C=C/c1cccc(C(O)CC#N)c1

Procedure:
(E)-3-(2-Chloro-6-methylstyryl)benzaldehyde was reacted with acetonitrile according to the procedure used in Example 50. Purification by flash chromatography (10 to 70% EtOAc-hexanes gradient) gave (E)-3-(3-(2-chloro-6-methylstyryl)phenyl)-3-hydroxypropanenitrile as an oil. Yield 0.0708 g, 77%): 1H NMR (400 MHz, CDCl3) δ 7.51-7.53 (m, 2H), 7.41 (t, J=8.0 Hz, 1H), 7.25-7.33 (m, 2H), 7.07-7.20 (m, 3H), 6.80 (d, J=16.8 Hz, 1H), 5.08 (t, J=6.4 Hz, 1H), 2.80 (dd, J=6.4, 0.8 Hz, 2H), 2.43 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:20][O:21][CH3:22])[NH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])([CH3:10])[CH3:9].[C:23]([N:42]1[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[C:53]2[CH:60]=[CH:59][C:56]([CH2:57]Br)=[CH:55][CH:54]=2)=[N:45][N:44]=[N:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>CN(C)C(=O)C>[OH:7][C:8]([C:11]1[N:12]=[C:13]([CH2:20][O:21][CH3:22])[N:14]([CH2:57][C:56]2[CH:55]=[CH:54][C:53]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[C:46]3[N:42]([C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:43]=[N:44][N:45]=3)=[CH:60][CH:59]=2)[C:15]=1[C:16]([O:18][CH3:19])=[O:17])([CH3:9])[CH3:10]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
194 mg of potassium t-butoxide were added, whilst ice-cooling, to a solution of 359 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethylimidazole-5-carboxylate [prepared as described in Preparation 2(v)] in 5 ml of N,N-dimethylacetamide, and the resulting mixture was stirred for 15 minutes. At the end of this time, a solution of 1.32 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide in 10 ml of N,N-dimethylacetamide was added. The mixture was first stirred at room temperature for 4 hours and then at 50° C. for a further 2 hours. The reaction mixture was then mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 848 mg of the title compound as crystals, melting at 120°-137° C. (with decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[C:42](B(O)O)=[CH:41][CH:40]=[CH:39][N:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:42]5[C:37]([O:36][CH3:35])=[N:38][CH:39]=[CH:40][CH:41]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: COc1ncccc1B(O)O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccnc5OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-methoxypyridine-3-boronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[NH:7][CH2:6][CH2:5]2.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:6][CH2:5]2
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2cc(Cl)c(Cl)cc21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2cc(Cl)c(Cl)cc2C1=O
Yield: 8.4 %

Procedure:
Using an analogous reaction conditions as described in example 1, 6,7-dichloro-3,4-dihydro-2H-isoquinolin-1-one (I-41d: 0.15 g, 0.6944 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.152 g, 0.6944 mmol), 1,4-dioxane (20 mL), copper iodide (0.013 g, 0.0494 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.032 mL, 0.2083 mmol) and potassium phosphate (0.368 g, 1.736 mmol) to afford the crude product. Purification by preparative HPLC afforded 18 mg of the product (8.4% yield).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][N:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[CH3:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=2)[CH:30]=O)[N:26]=1>>[CH3:20][O:19][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:25]3[N:26]=[C:22]([CH3:21])[S:23][CH:24]=3)[CH:28]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCCC(N)c1c(OC)cncc1OC
Reactant: Cc1nc(-c2cccc(C=O)c2)cs1
Product: COc1cncc(OC)c1C1CCCCC(=O)N1Cc1cccc(-c2csc(C)n2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(3,5-dimethoxypyridin-4-yl)hexanoate with commercially available 3-(2-methylthiazol-4-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.59 min.; [M+H]+: 438.09 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1.[CH3:26][C:27]([OH:31])([C:29]#[CH:30])[CH3:28]>>[OH:31][C:27]([CH3:28])([CH3:26])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH2:18][N:19]4[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:25]=1
Reactant: NC(=O)c1nc2n(c1CN1CCC(=O)C1)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(CN3CCC(=O)C3)n1CCO2
Yield: 31 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-3-((3-oxopyrrolidin-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a yellow solid (34.0 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](Br)=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:36]([NH2:40])(=[O:39])[CH:37]=[CH2:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[C:25](/[CH:38]=[CH:37]/[C:36](=[O:39])[NH2:40])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]4[C:28]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(/C=C/C(N)=O)c2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
50 mg (0.09 mmol) {1-[4-(8-Bromo-6-methyl-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 13.4 mg (0.19 mmol) acryl amide, 4.86 mg (0.016 mmol) tri-2-tolylphosphane, 2.1 mg (0.009 mmol) palladium(II) acetate and 0.02 mL (0.1 mmol) triethylamine in 0.7 mL degassed acetonitrile were heated in the microwave at 110° C. for 60′. Due to an incomplete reaction additional 13.3 mg acrylamide and 4.2 mg palladium(II) acetate were added, and heating in the microwave was continued for two hours. The reaction mixture was poured on water/saturated ammonium chloride/dichloromethane and vigorously stirred for 30 minutes. The organic phase was separated and the aqueous phase was once more extracted with dichloromethane. The combined organic extracts were washed twice with brine, dried, and the solvent was removed. The crude product (76 mg) was purified by chromatography on silicagel (eluents: hexane/ethyl acetate) yielding 24.2 mg (49.3%) of the desired compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I:13]I>C(O)(=O)C.OS(O)(=O)=O>[I:13][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1
Reactant: II
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 35 °C
Yield: 132.8 %

Procedure:
Into a solution of 40.15 gm (0.243 mol) of phenylalanine in a mixture of 220 mL of acetic acid and 29 mL of concentrated H2SO4 was added 24.65 gm (0.097 mol) of powered iodine and 10. 18 gm(0.051 mol) of powered NaIO3 while stirring. The reaction mixture was stirred at 70° C. for 21 h, during this time, two portions of 1 gm of NaIO3 were added. The mixture was cooled and the acetic acid was removed by using rotavapor while temperature was maintained at 35° C. and the residue oil was diluted by adding 400 mL of water. The aqueous solution was extracted once with 100 mL ether and once with 100 of dichloromethane. After decolorization with 5 gm of Norit, the aqueous solution was neutralized by adding solid NaOH to precipitate the crude product, which, after chilling, was filtered and rinsed with 800 mL of water and 300 mL of ethanol. The wet product was recrystallized from 200 mL of acetic acid to produce 37.5 gm of 4-iodo-L-phenylalanine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:20])[C:15]([F:19])([F:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)[CH2:27][CH2:28]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(Br)cc1
Product: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:6]=1[OH:29])(=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:8]1[C:9]([OH:11])=[CH:10][C:5]2[N:4]=[C:1]([CH3:2])[O:29][C:6]=2[CH:7]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1cc2oc(C)nc2cc1O

Procedure:
A mixture composed of 93.0 g of (1-c), 22.3 g of p-toluenesulfonic acid monohydrate and 1 l of toluene was refluxed with heating for 3 hours to distill away the water formed. After being allowed to cool, the crystals formed were washed with acetone and dried. Yield: 73 g.
Reaction SMILES: Br[CH:2]([C:4](=O)[CH2:5][CH3:6])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]=1>CCO>[CH2:5]([C:4]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]2[C:2]=1[CH3:3])[CH3:6]
Reactant: Nc1ccc(I)cn1
Reactant: CCC(=O)C(C)Br
Solvent: CCO
Product: CCc1nc2ccc(I)cn2c1C
Yield: 30.8 %

Procedure:
To a stirred mixture of 2-bromopentan-3-one (2.0 g), 2-amino-5-iodopyridine (1.0 g) and EtOH (50 ml) was heated at reflux for 16 h. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water (100 ml), and extracted with DCM. The DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (400 mg) as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[S:16])[NH2:15])=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[S:16]1[CH2:19][CH2:18][N:15]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: NC(=S)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc(C3=NCCS3)cc2)=NN1
Yield: 30.6 %

Procedure:
A solution of 3.5 g of 4-(1,6-dihydro-6-oxo-3-pyridazinyl)benzenecarbothioamide, 3.1 g of 1,2-dibromoethane in 75 ml of DMF containing 4.2 g of K2CO3 is heated on a steambath for three hours. The inorganic salts are filtered and the filtrate is evaporated under reduced pressure. The residue is crystallized from ethanol/tetrahydrofuran to yield 1.2 g of the product, 6-[4-(4,5-dihydro-2-thiazolyl)phenyl]-4,5-dihydro3(2H)-pyridazinone mp 236°-238° C.