Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1)#[N:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[C:1]([C:3]1[CH:4]=[N:5][N:6]([C:8](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1)#[N:2]
Reactant: CCOC(=O)Cn1cc(C#N)cn1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1cc(C#N)cn1
Yield: 88.5 %

Procedure:
Combined ethyl 2-(4-cyano-1H-pyrazol-1-yl)acetate (0.427 g, 2.383 mmol) with 1,1-diethoxy-N,N-dimethylmethanamine (1.403 g, 9.53 mmol) and heated in a closed vial at 100° C. for 2.5 h. The mixture was concentrated in vacuo and purified using flash column chromatography on NH silica gel (30 g SiO2, EtOAc in heptane, 10-50% gradient) to give the title compound (0.4942 g, 89% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, 3H) 1.91-2.43 (m, 3H) 2.70-3.29 (m, 3H) 4.03 (q, J=7.07 Hz, 2H) 7.59 (s, 1H) 8.14 (s, 1H) 8.56 (s, 1H). MS m/z [M+H]+ 235
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[CH2:28]([O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35](F)=[C:34]([F:39])[CH:33]=1)[CH3:29].C(OCC)(=O)C>CC(N(C)C)=O>[F:39][C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[O:7][C:8]1[CH:9]=[C:10]([C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=2)=[O:12])[CH:20]=[C:21]([O:23][C@@H:24]([CH3:27])[CH2:25][OH:26])[CH:22]=1)[C:31]([O:30][CH2:28][CH3:29])=[O:40]
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Reactant: C[C@@H](CO)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)c(F)c1
Temperature: 115 °C
Yield: 31 %

Procedure:
Cesium carbonate (8.3 g, 25.4 mmol) was added to a mixture of 3-hydroxy-5-{[(1S)-2-hydroxy-1-methylethyl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)benzamide (3.7 g, 12.7 mmol) and ethyl-3,4-difluorobenzoate (2.36 g, 12.7 mmol) in dimethylacetamide (60 mL) and the stirred mixture heated at 115° C. for 3 hours. The mixture was allowed to cool to RT and ethyl acetate (100 mL) added. The mixture was washed with water (5×40 mL), brine (40 mL), dried (MgSO4), filtered, and reduced in vacuo. The residue was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (1.8 g).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Pd].[Zn].O.CC(C)=O>[CH2:16]([O:15][C:9]1[CH:10]=[C:11]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[C:9]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH:12]=[CH:13][C:8]=1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOc1ccc(I)cc1OCCCCCC
Agent: [Pd]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCOc1ccc(-c2ccc(OCCCCCC)c(OCCCCCC)c2)cc1OCCCCCC
Temperature: 50 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A mixture of 1200 mL of distilled water/acetone (1/1), 194 g of Pd/C (Pd: 10%), 194 g of zinc powder, and 200 g (495 mmol) of 1,2-bishexyloxy-4-iodobenzene was stirred at 50° C. for 24 hours. The resulting reaction mixture was filtered with a glass filter and extracted with chloroform. The organic phase was washed with distilled water and dried over MgSO4. Then, the solvent was evaporated and 123 g of a yellow solid was obtained. The yellow solid was recrystallized from ethanol and 58.5 g of a white solid was obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Cl-].[C:20]1([PH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCC.CCOCC>[C:27]1([P:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: c1ccc(CN2CCCCC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: c1ccc(P(c2ccccc2)c2ccccc2CN2CCCCC2)cc1
Reaction time: 1 h

Procedure:
An 8.77 g portion of 1-(phenylmethyl)piperidine was mixed with 200 ml of ether under argon. A 27 ml portion of 2.6N butyl lithium in hexane was added, this mixture was allowed to stand one hour, then a solution of 12.6 ml of diphenylphosphine chloride in 50 ml of ether was added dropwise. This mixture was stirred 48 hours, then the ether layer was separated, washed with water, then extracted twice with 100 ml of water containing 8 ml of hydrochloric acid followed by water. The aqueous extracts were combined, basified with 12 ml of 10N sodium hydroxide and extracted twice with ether. The ether extracts were combined and concentrated, giving 15.5 g of diphenyl[2-(1-piperidinylmethyl)phenyl]phosphine as an oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])(C(C)(C)C)(C)C.[NH+]1C=CC=CC=1.O>C(O)C>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:37][CH:38]=1)[CH3:32]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 76.6 %

Procedure:
4-[9-(t-Butyldimethylsilyloxy)nonyl]-7-methoxymet hoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (1.34 g, 2.23 mmol) was dissolved in ethanol (70 ml), and pyridinium ptoluenesulfonate (426 mg, 1.70 mmol) was added thereto. The reaction mixture was stirred at room temperature for 10 hours, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=7:3 and 1:1) to give the title compound (831 mg, yield 77%) as a colorless oil. In this reaction, 247 mg (18%) of the unreacted starting compound was recovered.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[Si:16]([O:23][CH:24]1[CH2:28][C:27](=[O:29])[C:26]([S:30][CH2:31][CH2:32][CH2:33][CH:34]=O)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1C=CC=CC=1>[Si:16]([O:23][CH:24]1[CH2:28][C:27](=[O:29])[C:26]([S:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OC1C=C(SCCCC=O)C(=O)C1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)/C=C/CCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 0.17 h
Yield: 75 %

Procedure:
96 mg (2.0 mmoles) of 50% sodium hydride was suspended in 5 ml of dry benzene, and 841 mg (4.0 mmoles) of methyl diethylphosphonoacetate was added. The mixture was stirred for 10 minutes. 600 mg (1.91 mmoles) of 4(RS)-t-butyldimethylsilyloxy-2-(4-oxobutylthio)-2-cyclopentenone was dissolved in 10 ml of dry benzene. The solution was stirred under ice cooling. To the resulting solution was added the above reaction mixture. The mixture was stirred further for 15 minutes. The reaction mixture was washed with a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The extract was dried over anhydrous dodium sulfate, and concentrated. The resulting oily product was chromatographed on a silica gel column using hexane/ethyl acetate (8/1) as an eluent to give 531 mg (yield 75%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-trans-4-pentenylthio)-2-cyclopentenone.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:16][O:15][CH:14]3[CH:17]([OH:20])[CH2:18][O:19][CH:13]23)(=O)=O)=CC=1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[K].O>CS(C)=O>[OH:20][CH:17]1[CH:14]2[O:15][CH2:16][CH:12]([N:23]3[C:24](=[O:31])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]3=[O:21])[CH:13]2[O:19][CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1[K]
Reactant: Cc1ccc(S(=O)(=O)OC2COC3C(O)COC23)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1COC2C(O)COC21
Temperature: 130 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-methylbenzenesulfonate (10.24 g, 34.1 mmol) in DMSO (60 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (8.21 g, 44.3 mmol). The mixture was stirred under N2 atmosphere at 130° C. overnight then cooled down to room temperature, and poured into water. The resulting mixture was extracted with CH2C12 (300 mL×3), and the combined organic layers were washed with water (100 mL×3), dried over Na2SO4, and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/1) to afford the title compound as a white solid (2.35 g, 25.0%).
Reaction SMILES: Cl.Br[C:3]1[N:4]=[C:5]([C@H:13]2[CH2:18][CH2:17][C@H:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:14]2)[N:6]2[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=12.[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][C:41]=1[O:55][CH3:56])=[O:38])[N:31]2[CH3:36]>>[CH3:25][O:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH:29]=[C:30]([C:37]([NH:39][C:40]1[CH:45]=[CH:44][C:43]([C:3]3[N:4]=[C:5]([C@H:13]4[CH2:18][CH2:17][C@H:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)[CH2:15][CH2:14]4)[N:6]4[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[C:7]=34)=[CH:42][C:41]=1[O:55][CH3:56])=[O:38])[N:31]2[CH3:36]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCNCC2)CC1
Agent: Cl
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCNCC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C

Procedure:
Reaction of 1-bromo-8-methyl-3-((trans)-4-(piperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine hydrochloride (40 mg) and 4-methoxy-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (42 mg) according to the procedure described in example 4 step 4c and purification by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol) gave 4-methoxy-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(piperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (8 mg).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[Cl:10]/[CH:11]=[CH:12]/[CH2:13]Cl>>[Cl:10]/[CH:11]=[CH:12]/[CH2:13][N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: Cl/C=C/CCl
Reactant: O=[N+]([O-])C=C1NCCN1
Product: O=[N+]([O-])C=C1NCCN1C/C=C/Cl

Procedure:
Method B, reacting 2-(nitromethylene)imidazolidine with trans-1,3-dichloro-1-propene. Melting point: 134°-135°C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1F)#[N:2].C(O[CH2:24][CH3:25])(=O)C>CS(C)=O>[N:2]1([C:8]2[CH:7]=[CH:6][C:5]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=3)[C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[C:1]#[N:2])[CH2:25][CH2:24][CH2:7][CH2:8][CH2:3][CH2:1]1
Reactant: COC(=O)c1ccnc(-c2ccc(F)c(C#N)c2)c1
Reactant: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccnc(-c2ccc(N3CCCCCC3)c(C#N)c2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In 7 ml of DMSO was dissolved 2.22 g of methyl 2-(3-cyano-4-fluorophenyl)isonicotinate, and 2.44 ml of hexamethyleneimine was added thereto, followed by heating at 50° C. for 5 hours. After cooling, the reaction solution was diluted with ethyl acetate and was washed with 1M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and brine, successively. The organic layer was dried and then concentrated under reduced pressure and the resulting residue was dissolved in a mixed solvent of ethyl acetate and diisopropyl ether. Activated carbon was added thereto, followed by stirring for 1 hour. Then, the activated carbon was removed by filtration and washed with ethyl acetate. The resulting filtrate and washing liquid were combined and concentrated to obtain 2.58 g of methyl 2-(4-azepan-1-yl-3-cyanophenyl)isonicotinate. (2) Then, 2.49 g of the compound was dissolved in a mixed solvent of 15 ml of methanol and 30 ml of THF, and 11 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 80° C. for 1 hour.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[C:10]1([CH2:16][CH2:17][NH:18][C:19](=[O:51])[C@H:20]([CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[NH:21][C:22](=[O:43])[C@H:23]([CH2:39][C:40](=[O:42])[NH2:41])[NH:24][C:25](=[O:38])[C@H:26]([CH2:36][OH:37])[NH:27][C:28](=[O:35])[CH2:29][NH:30][C:31](=[O:34])[CH2:32][NH2:33])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N=C=N>>[C:10]1([CH2:16][CH2:17][NH:18][C:19](=[O:51])[C@H:20]([CH2:44][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:21][C:22](=[O:43])[C@H:23]([CH2:39][C:40](=[O:42])[NH2:41])[NH:24][C:25](=[O:38])[C@H:26]([CH2:36][OH:37])[NH:27][C:28](=[O:35])[CH2:29][NH:30][C:31](=[O:34])[CH2:32][NH:33][C:7](=[O:9])[C@@H:2]2[CH2:3][CH2:4][C:5](=[O:6])[NH:1]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1ccccc1
Agent: N=C=N
Product: NC(=O)C[C@H](NC(=O)[C@H](CO)NC(=O)CNC(=O)CNC(=O)[C@@H]1CCC(=O)N1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCCc1ccccc1
Yield: 82 %

Procedure:
Pyroglutamyl-glycyl-glycyl-seryl-asparaginyl-phenylalanine 2-phenylethylamide is prepared from pyroglutamic acid and glycyl-glycyl-seryl-asparaginyl-phenylalanine 2-phenylethylamide using the carbodiimide method similar to that described in the preceding example 5. Yield 82 %, m.p. 209°-211° C., Rf 0.25/S1, 0.67/S2.
Reaction SMILES: O.[N+:2]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([C@H:10]1[CH2:12][C@H:11]1[C:13](O)=[O:14])=O)([O-:4])=[O:3].O.[NH2:20][NH2:21]>C(O)C>[N+:2]([C:5]1[CH:6]=[C:7]([C:8]2[CH:10]3[CH:11]([C:13](=[O:14])[NH:20][N:21]=2)[CH2:12]3)[CH:16]=[CH:17][CH:18]=1)([O-:4])=[O:3]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)[C@H]1C[C@H]1C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1NN=C(c2cccc([N+](=O)[O-])c2)C2CC12
Yield: 69.6 %

Procedure:
4.4 g (17.4 millimoles) of cis-2-(m-nitrobenzoyl)-cyclopropanecarboxylic acid hydrate, 1.05 g (21.0 millimoles) of hydrazine hydrate and 100 ml of ethanol are refluxed for 7 hours. After filtering off the product at 10° C. and drying it under reduced pressure at 50° C., 2.8 g (70% of theory) of 2-(m-nitrophenyl)-3,4-diazabicyclo[4.1.0]hept-2-en-5-one are obtained as pale yellow crystals, of melting point 220°-221° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15]>>[CH:8]([C:7]1[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:11][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:9]
Reactant: COC(=O)CBr
Reactant: COc1ccc(O)c(C=O)c1
Product: COC(=O)COc1ccc(OC)cc1C=O
Yield: 86 %

Procedure:
In the same manner as in Reference Example 1, 5-methoxysalicylaldehyde was reacted with methyl bromoacetate to yield methyl 2-formyl-4-methoxyphenoxyacetate (yield 86%), which was then recrystallized from acetone-hexane to yield colorless prisms having a melting point of 74° to 75° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(N(CC)CC)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>CCCCCC>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([O:4][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CCOC(=O)C=C(C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A solution of 31.9 mL (0.25 mole) of ethyl acetoacetate is stirred in hexane (350 mL) at room temperature. Triethylamine (42 mL, 0.30 mole) is added, followed by dropwise addition of trimethylsilyl chloride (35 mL, 0.276 mole) keeping the internal temperature below 25° C. using a water bath (about 18° C.). The thick white slurry is stirred overnight at room temperature. 200 mL of hexane is then added and the mixture stirred in an ice bath for 1 hour. The mixture is filtered and the solids are washed with 50 mL of cold hexane. Evaporation of the combined filtrate and washings gives 46 g of 3-trimethylsilanyloxy-but-2-enoic acid ethyl ester as a colorless, slightly cloudy oil. This material is used without further purification in the following step.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[C:11]([O:15][C:16]([N:18]1[CH:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][N:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:35]=[O:36])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.O1CCOCC1>[C:11]([O:15][C:16]([N:18]1[CH:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][N:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:6])=[O:36])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CCC1C(F)(F)F
Reactant: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CCC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of sodium chlorite (214 mg; 2.36 mmol; 5.5 eq.) and sodium dihydrogenphosphate (186 mg; 1.55 mmol; 3.6 eq.) in water (2 mL) was added dropwise to a mixture of 4-(2-formyl-phenyl)-7-trifluoromethyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (160 mg; 0.43 mmol; 1 eq.) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water, the pH made acidic with 0.1M HCl and extracted with EA (2×). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (140 mg, 84%) as a yellow solid. UPLC/MS: (MS+) 389.2 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].[F:10][C:11]([F:18])([F:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]([F:18])([F:17])[F:10])[CH3:3]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(O)CCC(F)(F)F
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCC(F)(F)F
Yield: 40.7 %

Procedure:
Preparation 3A was prepared from (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.66 g, 36.1 mmol) and 4,4,4-trifluorobutanoic acid (5.02 g, 35.3 mmol) by the general methods shown for Preparation 1B. Preparation 3A was obtained as a colorless oil (3.64 g, 40%). 1H NMR (400 MHz, CDCl3) δ ppm 4.44 (1H, ddd, J=8.41, 3.51, 3.39 Hz), 4.31 (1H, t, J=8.66 Hz), 4.25 (1H, dd, J=9.03, 3.26 Hz), 3.13-3.32 (2H, m), 2.47-2.59 (2H, m), 2.38 (1H, dddd, J=13.96, 7.01, 3.89 Hz), 0.93 (3H, d, J=7.28 Hz), 0.88 (3H, d, J=6.78 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>ClCCl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])/[CH:16]=[CH:17]/[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:31]4[CH2:32][CH2:33][CH:28]([CH3:27])[CH2:29][CH2:30]4)=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1CCNCC1
Reactant: O=Cc1ccc(/C=C/C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC1CCN(Cc2ccc(/C=C/C(=O)Nc3ccc(-c4ccc(Cl)cc4)cc3)cc2)CC1

Procedure:
Prepared analogously to Example 4.30.c. from (E)-N-(4′-chlorobiphenyl-4-yl)-3-(4-formylphenyl)acrylamide and 4-methylpiperidine. Yield: 80 mg (21.7% of theory); melting point: 207° C.-208° C.; C28H29ClN2O (M=445.00); calc.: molecular ion peak (M+H)+: 445/447; found: molecular ion peak (M+H)+: 445/447; Rf value: 0.76 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)[O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([CH:4]([O:5][C:6]2[CH:7]=[C:8]([O:15][CH2:16][CH3:17])[CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=2)[C:3]([OH:25])=[O:2])=[CH:23][CH:22]=1
Reactant: CCOc1cc(OCC)cc(OC(C(=O)OC)c2ccc(Br)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOc1cc(OCC)cc(OC(C(=O)O)c2ccc(Br)cc2)c1

Procedure:
16.9 g (41.3 mmol) of methyl(4-bromophenyl)-(3,5-diethoxyphenoxy)acetate are dissolved in 80 ml of methanol and 8 ml of water under argon at RT, and 7.99 g (57.8 mmol) of potassium carbonate are added. The mixture is heated under RF for 4 h. After cooling, the precipitate is filtered off, the filtrate is concentrated, the residue is taken up in water and the solution is extracted four times with diethyl ether. The aqueous phase is adjusted to a pH of 2 by adding 10% strength hydrochloric acid and is extracted three times with ethyl acetate, and the combined ethyl acetate phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 16.1 g (99% of theory) of the product are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][CH2:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:23]=2)=[CH:15][C:14]=1[C:35]([F:38])([F:37])[F:36]>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([CH:29]3[CH2:34][CH2:33][N:32]([C:2]4[C:3]5[CH2:11][CH2:10][CH2:9][NH:8][C:4]=5[N:5]=[CH:6][N:7]=4)[CH2:31][CH2:30]3)[N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:23]=2)=[CH:15][C:14]=1[C:35]([F:36])([F:37])[F:38]
Reactant: Clc1ncnc2c1CCCN2
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Product: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc3c2CCCN3)CC1

Procedure:
The title compound was prepared according to the procedure described for the preparation of A5 by using 4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine coupling with 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine. LC-MS (M+H=518, obsd.=518);
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:46](=[O:47])[N:6]2[C:7]([C:33]([O:35]CC3C=CC([N+]([O-])=O)=CC=3)=[O:34])=[C:8]([C:11]3[S:15][C:14]4=[C:16]([C:19]([C:21]5[CH:22]=[N:23][CH:24]=[C:25]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH:26]=5)=[O:20])[N:17]=[CH:18][N:13]4[CH:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].I[CH2:49][C:50]([NH2:52])=[O:51]>>[C:50]([CH2:49][N+:23]1[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=[C:21]([C:19]([C:16]2[N:17]=[CH:18][N:13]3[CH:12]=[C:11]([C:8]4[C@H:9]([CH3:10])[C@@H:5]5[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:46](=[O:47])[N:6]5[C:7]=4[C:33]([O-:35])=[O:34])[S:15][C:14]=23)=[O:20])[CH:22]=1)(=[O:51])[NH2:52]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncc(-c6ccccc6)c5)c4s3)[C@H](C)[C@H]12
Reactant: NC(=O)CI
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5cc(-c6ccccc6)c[n+](CC(N)=O)c5)c4s3)[C@H](C)[C@H]12
Yield: 19.6 %

Procedure:
An N-quaternarized compound (91 mg) was prepared in substantially the same manner as in Example 24, except that 97 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(5-phenylpyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate and 185 mg of 2-iodoacetamide were used as the starting compounds. The title compound (16.7 mg) was prepared in substantially the same manner as in step c) of Example 1, except that this compound was used as the starting compound.