Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C[O:13][C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:16]([CH:15]([CH3:21])[C:14]([OH:22])=[O:13])[C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C(=O)O)C(=Cc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
After careful addition of absolute methanol (0.1 mL) to a suspension of sodium hydride (60% in mineral oil, 16 g, 0.40 mol) in anhydrous toluene (200 mL), a solution of 4-chloro-benzaldehyde (28 g, 0.20 mol) and 2-methyl-succinic acid dimethyl ester (48 g, 0.30 mol) in anhydrous toluene (100 mL) was added dropwise at room temperature under a stream of nitrogen. After being stirred at room temperature for 2 hours, the resulting mixture was diluted by addition of 2 N sodium hydroxide (200 mL) dropwise. The mixture was heated to 80° C., and stirred at this temperature for 2 hours. After cooling to room temperature, the aqueous layer was separated, washed with ethyl acetate (100 mL×3), then acidified with 2 N hydrochloric acid to pH 2 and extracted with ethyl acetate (150 mL×3). The combined organic layers were dried over sodium sulfate, and concentrated in vacuo. The residue was precipitated from ethyl acetate/petroleum ether (10:1) to give 2-(4-chloro-benzylidene)-3-methyl-succinic acid (13.4 g, 26%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22]N3C4C=CC=CC=4N=N3)=O)([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][CH:44]([NH2:46])[CH3:45]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:17][CH2:16][C:15]([C:20]([NH:46][CH:44]([CH3:45])[CH3:43])=[O:22])([CH2:14][CH2:13]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CC(C)NC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 1-methylethylamine (10.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-1-methylethylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (33.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]1)[C:5]2=[O:33].[CH2:34](I)[CH3:35]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:34][CH3:35])[C:7](=[O:12])[N:6]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:17][CH2:18]1)[C:5]2=[O:33]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc(Cl)cc5c4=O)CC3)c2cc1OC
Reactant: CCI
Product: CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc(Cl)ccc21
Yield: 45 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.64 mmol) of Compound h was used in place of Compound 24 and ethyl iodide was used in place of methyl iodide. As a result, 145.9 mg (yield: 45%) of Compound 41 was obtained as white crystals.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCN(CC)CC>[CH2:18]([CH:23]1[CH2:24][CH:25]2[N:30]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:16])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(C)cc21
Yield: 69.3 %

Procedure:
Crude (S)-4-(3-Iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.15 g), Et3N (0.5 mL) and 3-pentyl-8-azabicyclo[3.2.1]octane (95 mg, 5.2 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/I-PrOH 92:8) gave the title compound (0.12 g, 68%). 1H NMR (CD3OD) δ 7.06 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (brd, J=8.0 Hz, 1H), 4.52 (ABq, J=14.8, 27.2 Hz, 2H), 4.06 (dd, J=5.6, 14.2 Hz, 1H), 4.96 (dd, J=8.8, 14.2 Hz, 1H), 3.16-3.02 (m, 2H), 2.34-2.07 (m, 7H), 2.31 (s, 3H), 2.04-1.81 (m, 3H), 1.70-1.55 (m, 3H), 1.46-1.21 (m, 10H), 0.92-0.85 (m, 6H); 13C NMR (CD3OD) δ 167.2, 145.1, 133.6, 129.4, 125.5, 117.7, 117.5, 68.7, 61.6, 60.2, 58.6, 46.1, 39.6, 37.2, 36.9, 33.1, 32.4, 29.6, 29.5, 28.5, 27.8, 23.7, 21.18, 17.0, 14.4.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4](=[O:10])[C:5]([O:7]CC)=O)#[N:2].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][CH:20]=1.[O-]CC.[Na+]>>[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([C:5](=[O:7])[C:4](=[O:10])[CH:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:1]#[N:2])[C:26]#[N:27])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Reactant: CSc1ccc(CC#N)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CSc1ccc(C(C#N)C(=O)C(=O)C(C#N)c2ccccc2)cc1

Procedure:
As described in Example 1, ethyl 3-cyano-3-phenylpyruvate is reacted with p-methylthiophenylacetonitrile in an alcoholic solution of sodium ethoxide to give 2-(p-methylthiophenyl)-5-phenyl-3,4-dioxoadiponitrile. The latter is refluxed in a mixture of water, glacial acetic acid and concentrated sulfuric acid to give a mixture of 4- and 4'-methylthiopulvinic acid which is then refluxed in acetic anhydride to result in the formation of 4-methylthiopulvinic acid lactone.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:8](=[O:20])[C:7]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])=[CH:6][C:5]=1[C:35](=[O:38])[CH2:36][CH3:37]>C1COCC1>[Br:1][CH:36]([CH3:37])[C:35]([C:5]1[CH:6]=[C:7]([C:21]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=2)=[O:22])[C:8](=[O:20])[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:4]=1[CH3:3])=[O:38]
Reactant: BrBr
Reactant: CCC(=O)c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Solvent: C1CCOC1
Product: Cc1c(C(=O)C(C)Br)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Bromine (84 μl, 1.61 mmol) in THF (5 ml) was added to a solution of 6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-5-propionyl-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (700 mg, 1.34 mmol) in TEF (10 ml). After 2 h, the yellow colour had disappeared. The reaction mixture was partitioned between water and ethyl acetate, the organic phase was separated, dried and evaporated under reduced pressure to give the title compound (800 mg, 99%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([F:35])=[C:25]([C:28]5[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([F:35])=[C:25]([C:28]5[O:32][C:31]([CH2:33][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:30][CH:29]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cc2F)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cc2F)o1

Procedure:
Prepared according to Procedure D from 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ 1H NMR (400 MHz, DMSO-d6) 10.16 (s, 1H), 8.91 (d, 1H), 8.46 (s, 1H), 8.11 (s, 2H), 7.65 (m, 3H), 7.26 (m, 5H), 6.93 (m, 1H), 6.54 (d, 2H), 5.65 (s, 2H), 3.89 (s, 2H), 3.28 (m, 2H), 2.99 (m, 5H). ESI-MS m/z 569 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[CH:3][C:4]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
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: CN(C)C=O
Solvent: O
Product: Cn1nccc1-c1cc(-c2ccc(F)cc2)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.4 mg (0.03 mmol) of (4-fluorophenyl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH2:12])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[H-].[Na+].C(N(CC)C(C)C)(C)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37](Cl)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:32][CH2:33][N:34]([C:37](=[O:38])[NH:12][C:10]2[S:9][C:5]3[N:6]=[CH:7][N:8]=[C:3]([O:2][CH3:1])[C:4]=3[N:11]=2)[CH2:35][CH2:36]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1ncnc2sc(N)nc12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ncnc2sc(NC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)nc12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of 7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylamine (3.5 g, 19.2 mmol) in tetrahydrofuran (100 mL) was treated with sodium hydride (60% in mineral oil, 2.3 g, 57 mmol) at 25° C. A slight evolution of gas was observed. The resulting purple slurry was warmed to 50° C. for 1 h. At this time, the reaction was cooled to 25° C. and was treated with N,N-diisopropylethylamine (10 mL, 57 mmol). The resulting mixture was stirred at 25° C. for 30 min. The mixture was then treated with a solution of 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester (4.73 g, 19 mmol) in tetrahydrofuran (20 mL) over a 10 min period. The reaction was stirred at 50° C. overnight. At this time, the reaction was concentrated in vacuo, diluted with methanol (100 mL) and absorbed onto silica gel (6 g). The silica gel was divided into two equal lots. ISCO chromatography (330 g, Silica, gradient elution 5/95 methanol/methylene chloride) afforded 4-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester (5.58 g, 74%) as an off-white solid; LRMS for C16H22N6O4S (M+H)+ at m/z=395. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C[N:40](C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=C(NC(OC(C)(C)C)=O)C=1)C>>[C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])[CH3:33])[C:11]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([NH2:40])[CH:31]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Reactant: CCOC(=O)CN(Cc1cccc(NC(=O)OC(C)(C)C)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1cccc(N)c1

Procedure:
Compound 737 was prepared by a method similar to the method used to prepare compound 706, except compound 703 was replaced with compound 736. ##STR116##
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[CH3:21][S:22]([C:25]1[S:29][C:28]([C:30](O)=[O:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:30]([C:28]2[S:29][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)=[O:31])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Product: CS(=O)(=O)c1ccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)s1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 5-(methylsulfonyl)thiophene-2-carboxylic acid (0.065 g). Title compound obtained as white solid (0.039 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]2[CH2:17][CH:16]3[CH:14]([CH2:15]3)[CH2:13][CH:12]2[C:18]([O-:20])=[O:19])=[CH:5][CH:4]=1.CO.[OH-].[Li+]>COCCOC>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH:11]2[CH2:17][CH:16]3[CH:14]([CH2:15]3)[CH2:13][CH:12]2[C:18]([OH:20])=[O:19])=[CH:5][CH:4]=1
Reactant: CSc1ccc(SCC2CC3CC3CC2C(=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: CSc1ccc(SCC2CC3CC3CC2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
Methyl(1S/R,3R/S,4R/S,6R/S)-4-({[4-(methylsulfanyl)phenyl]-sulfanyl}-methyl)bicyclo[4.1.0]heptane-3-carboxylate was dissolved in ethylene glycol dimethyl ether (3.0 mL) and methanol (1 mL) in a 25 mL round bottom flask. Aqueous solution of lithium hydroxide (3.0 mL, 6.0 mmol, 2 M) was added and the reaction mixture was stirred at ambient temperature for 36 h. After acidification with 2 M aqueous hydrochloric acid to pH 3, the product was extracted into ether. The combined ether extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to give (1S/R,3R/S,4R/S,6R/S)-4-({[4-(methylsulfanyl)phenyl]sulfanyl}-methyl)bicyclo[4.1.0]heptane-3-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH3:37][N:38]([CH3:45])[CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][C@@H:12]([NH:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:23][CH2:24]1)=[O:18])[C:13]([N:41]1[CH2:42][CH2:43][CH2:44][CH:39]([N:38]([CH3:45])[CH3:37])[CH2:40]1)=[O:14])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Reactant: CN(C)C1CCCNC1
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCCC(N(C)C)C2)cc1CC

Procedure:
Prepared analogously to Example 9i) from 400 mg (0.81 mmol) (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 130 mg (1.01 mmol) dimethyl-piperidin-3-yl-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([O:27][CH3:28])(=[O:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23].N1CCNCC1.C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:21]([C:20]([O:27][CH3:28])=[O:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:5][C:4]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CC(=O)OC
Reactant: COc1ccc(C=O)cc1OCCc1ccccc1
Agent: C1CNCCN1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccc(OC)c(OCCc2ccccc2)c1)C(=O)OC
Temperature: 25 °C
Yield: 90.6 %

Procedure:
4-Methoxy-3-(2-phenylethoxy)benzaldehyde (51.26 g), dimethyl malonate (26.43 g), piperazine (1.70 g) and acetic acid (1.20 g) were refluxed by heating in 300 ml of benzene under azeotropic dehydration conditions for 8 hours. After the reaction solution was cooled to room temperature, it was washed with water, 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of NaCl in consecutive order and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from isopropyl ether-dichloromethane to obtain 67.15 g of methyl 3-[4-methoxy-3-(2-phenylethoxy)phenyl]-2-methoxycarbonylacrylate.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[N:6]3[CH3:21].Cl.C(O)(=O)C>O>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH:5]([CH3:22])[N:6]3[CH3:21]
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CC(C)N2C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1Cc2c(F)c(F)cc3c(=O)c(C(=O)O)cn(c23)N1C
Yield: 88.1 %

Procedure:
To 830 mg (2.7 mmol) of the compound (156) obtained in Example 34, 4 ml of concentrated hydrochloric acid and 16 ml of acetic acid were added and the solution was heated at reflux for 3 hours. 10 ml of water was added to the solution. Solids were filtered off and washed with ethanol and ether in this order to obtain 700 mg of the subject compound (157) in a 88% yield.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(Br)n4n3)cc2)CC1
Reactant: COCc1ccccc1B(O)O
Product: COCc1ccccc1-c1ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nn12
Yield: 76.4 %

Procedure:
Analogous to Example 1499, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (85 mg, 0.22 mmol) and 2-(Methoxymethyl)phenyl-boronic acid (72.8 mg, 0.439 mmol) were reacted to afford 7-[2-(methoxymethyl)phenyl]-N-[4-(4-methylpiperazin-1-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-amine (72 mg, 76%). LCMS (HPLC): 0.88 min, m/z=429 (M+H); 1H-NMR (DMSO-d6): 9.18 (s, 1H), 8.94 (s, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.46-7.52 (m, 4H), 6.93 (d, 1H, J=4.6 Hz), 6.87 (d, 1H, J=4.6 Hz), 6.74 (d, 2H, J=9.0 Hz), 4.36 (s, 2H), 3.18 (s, 3H), 3.01 (m, 4H), 2.43 (m, 4H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([NH2:11])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15].CC(=O)CC>CCOC(C)=O>[CH3:1][CH:2]([N:11]=[C:13]([CH3:24])[C:14]([C:16]1[S:20][CH:19]=[C:18]([C:21]([NH2:23])=[O:22])[CH:17]=1)=[O:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(Br)C(=O)c1cc(C(N)=O)cs1
Reactant: CC(N)CCc1ccccc1
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CC(=NC(C)CCc1ccccc1)C(=O)c1cc(C(N)=O)cs1
Reaction time: 48 h

Procedure:
A solution of 1-methyl-3-phenylpropylamine (9.0 g) and 5-(2-bromo-1-oxopropyl)thiophene-3-carboxamide (7.6 g) was stirred for 2 h; butanone (75 ml) was added and stirring continued for 48 h. The resulting mixture was filtered and the filtrate evaporated to small volume (ca. 30 ml) and added to vigorously stirred light petroleum (b.p. 60°-80°: 500 ml) to precipitate a yellow gum (ca. 9 g) which was separated on a short path silica (7736H; 300 g) column eluted with ethyl acetate/2% isopropanol/20% triethylamine to give three products. TLC SiO2 (EtOAc/20% i-PrOH/2% Et3N) Rf 0.26, 0.39 and 0.5 respectively.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][N:4]=1.[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33].CCN(CC)CC>C(Cl)Cl>[CH3:1][N:2]([C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:11]1)[C:3]1[N:4]=[CH:5][C:6]([NH:9][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:7][CH:8]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN(c1ccc(N)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(N(C)[C@@H]2CCN(c3ncnc4c3ccn4COCC[Si](C)(C)C)C2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
To a solution of (R)—N2-methyl-N-{1-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrrolidin-3-yl}-pyridine-2,5-diamine (0.25 mmol) in DCM (5 mL) were subsequently added ethanesulfonyl chloride (0.3 mmol) and Et3N (0.3 mmol). The solution was stirred at the ambient temperature for 18 hours and then concentrated. The crude product was purified by preparative TLC to give the title compound in 42% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(Cl)c(Nc2c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3Cl)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 43.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-5-methylphenylamino)-6-(6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.140 g, 0.262 mmol) obtained in step 2 and ethanesulfonamide (0.142 g, 1.31 mmol), the title compound (0.071 g, 43%) was obtained.