Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([NH2:14])[CH3:13].CN1C(=O)CCC1>O>[CH2:12]([NH:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1)[CH3:13]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCN
Solvent: O
Solvent: CN1CCCC1=O
Product: CCNc1ccc(C(F)(F)F)cn1
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (12 g), 70% of aqueous ethylamine solution (16 ml), and NMP (7 ml) was stirred with heating at 70° C. for 1 day. Into the reaction mixture cooled to room temperature, water was poured, and then the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 6.3 g of N-ethyl-(5-trifluoromethylpyridin-2-yl)-amine.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25]#[CH:26]>>[O:27]([CH2:24][C:25]1[N:3]=[N:2][N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:26]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCOc1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(COc3ccccc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and phenyl prop-2-yn-1-yl ether. MS (+ESI) m/z: 403.2.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:44]=[CH:43][C:14]([CH2:15][O:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[N:28]=[C:27]([N:29]5[C:33]([C:34]([F:37])([F:36])[F:35])=[C:32]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:31]=[N:30]5)[CH:26]=[CH:25][CH:24]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C.O>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:28]=[C:27]([N:29]4[C:33]([C:34]([F:36])([F:37])[F:35])=[C:32]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:31]=[N:30]4)[CH:26]=[CH:25][CH:24]=3)=[CH:43][CH:44]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC5(CC4)OCCO5)cc3)n2)c1C(F)(F)F
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC(=O)CC4)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the title compound from Example 10 Step D (300 mg, 0.49 mmol) in acetic acid (1.8 mL) and water (0.6 mL) was stirred at 80° C. After 2 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. The resulting oil was diluted with ether, then was washed successively with water, saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 564.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.96 (dd, J=8.0, 1.5 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.40-7.36 (m, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.12 (t, J=7.5 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H), 5.14 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.04 (dddd, J=12.0, 12.0, 3.5, 3.5 Hz, 1H), 2.54-2.50 (m, 4H), 2.25-2.21 (m, 2H), 1.99-1.91 (m, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26].[H-].[Na+].[Br-].[Na+]>COCCOC>[CH2:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CC(C)CCOCCCCOCCCCBr
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)CCOCCCCOCCCCOCc1ccc2c(c1)OCO2
Reaction time: 20 h

Procedure:
To a solution of 1.23 g (0.0081 mol) of piperonyl alcohol and 2.50 g (0.0085 mol) of 1-bromo-4-(4-isopentyloxy-butyloxy)-butane in 30 cc of absolute 1,2-dimethoxy-ethane, there is carefully added under nitrogen and while stirring, over the course of 20 minutes, 0.34 g (0.0077 mol) of 55% sodium hydride dispersion in oil. The mixture is stirred at 60° for 20 hours and the resulting sodium bromide is subsequently suction filtered, washed with ether and the filtrate is evaporated. After chromatography of the residue on silica gel with hexane/ethyl acetate (97:3) to (9:1), the [4-(4-Isopentyloxy-butyloxy)-butyl]-piperonyl ether is obtained as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O)[NH:7][C:8](=[O:21])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-])=O.[CH3:28][O:29][C:30]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH3:28][O:29][C:30]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:31]=1[C:32]1[NH:25][C:24]2[CH:23]=[CH:22][C:6]([NH:7][C:8](=[O:21])[C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)=[CH:5][C:4]=2[N:1]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(N2CCOCC2)ccc1C=O
Product: COc1cc(N2CCOCC2)ccc1-c1nc2cc(NC(=O)c3ccc(N4CCOCC4)cc3)ccc2[nH]1

Procedure:
Compound 424 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-morpholinobenzoyl)aniline and 2-methoxy-4-morpholinobenzaldehyde. [M+H]+ calcd for C29H31N5O4: 514.25; found: 514.05.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11](I)=[C:10]([F:15])[CH:9]=1.[F:16][C:17]1[C:22]([F:23])=[C:21]([Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=[CH:19][C:18]=1B1OCC(C)(C)CO1>O.O1CCOCC1.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>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([Si:24]([CH3:25])([CH3:27])[CH3:26])=[C:22]([F:23])[C:17]=2[F:16])=[C:10]([F:15])[CH:9]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CC1(C)COB(c2ccc([Si](C)(C)C)c(F)c2F)OC1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)c1ccc(-c2ccc(Br)cc2F)c(F)c1F
Yield: 88 %

Procedure:
A solution of 16.6 g (120 mmol) of K2CO3 in 50 ml of water is added to a solution of 15 g (50 mmol) of 4-bromo-2-fluoro-1-iodobenzene, 14.9 g (50 mmol) of 6 and 2.31 g (2 mmol) of [Pd(PPh3)4] in 100 ml of dioxane, and the mixture is refluxed overnight. The organic phase is washed with water and sat. NaCl, dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, petroleum ether is added to the oily residue, and the product is recrystallised at −25° C. (yield: 88%, m.p. 78.0° C.).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:32][CH2:33][CH:34]2[CH2:38][CH:37]=[CH:36][CH2:35]2)(=O)=O)=CC=CC=1>>[CH:34]1([CH2:33][CH2:32][N:8]2[C:9]([C:10](=[O:19])[C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]2=[O:20])[CH2:38][CH:37]=[CH:36][CH2:35]1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CC=CC1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CCC2CC=CC2)c1
Yield: 36.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-(cyclopent-3-en-1-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound (140 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:7][S:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:6])[CH3:2].C(N(CC)CC)C.[Br:36][CH2:37][C:38](Br)=[O:39]>C1COCC1>[CH2:1]([O:3][C:4](=[O:28])[C@H:5]([CH2:7][S:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:6][C:38](=[O:39])[CH2:37][Br:36])[CH3:2]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of S-triphenylmethyl-L-cysteine ethyl ester (18 g, 46 mmol.) and triethylamine (6.4 mL, 46 mmol.) in dry THF (250 mL) under nitrogen was cooled to 0° C. A solution of bromoacetyl bromide (9.28 g, 46 mmol.) in dry THF (60 mL) was added dropwise during which time the solution turned cloudy. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give an oil. The oil was partitioned between methylene chloride and water (60 mL each), the organic layer washed with 5% HCl, NaHCO3, dried (magnesium sulfate), filtered, and the volatiles removed to give the desired product (69%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21]>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CCC(N)CC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(CC)Nc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a 0° C. mixture of 2,6-dichloro-3-nitropyridine (12 g, 62 mmol) and potassium carbonate (17.1 g, 1.24 mmol) in acetonitrile (200 mL) was added 3-amino pentane by syringe over 30 minutes. After stirring overnight at room temperature, the reaction was concentrated in vacuo. The residue was dissolved in EtOAc and water and the organic layer was washed twice with water and once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (5%-35% EtOAc/Hexanes) provided the title compound as a yellow solid (7.3 g, 48%). m/z=244.1 (M+H)+
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]([CH:14]([CH3:16])[CH3:15])[C:12](=[O:17])[O:11][C:10]2=O)=[CH:5][CH:4]=1.[CH2:21]([C:28]1[CH:32]=[CH:31][NH:30][C:29]=1CO)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:13]([CH:14]([CH3:16])[CH3:15])[C:12]([O:11][CH2:10][C:29]2[NH:30][CH:31]=[CH:32][C:28]=2[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:17])=[CH:5][CH:4]=1
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1)C(=O)OCc1[nH]ccc1Cc1ccccc1

Procedure:
In the same way, 3-(4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione is reacted with 3-benzylpyrrolylmethyl alcohol to give 3-benzylpyrrolylmethyl 2-(4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].CO.[CH3:8][C:9]([CH2:11][CH3:12])=O>[Pd].O>[CH:9]([NH:1][CH2:2][C:3]([OH:5])=[O:4])([CH2:11][CH3:12])[CH3:8]
Reactant: NCC(=O)O
Reactant: CCC(C)=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCC(C)NCC(=O)O

Procedure:
338 g of glycine (4.5 mols), 1.5 liters of methanol, 15 g of 10% Pd on C, wet with water, and 500 g of methylethylketone (6.93 mols) are charged into the autoclave.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.CN1CCCC1=O>>[CH2:21]([N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(N(Cc2ccccc2)Cc2ccccc2)nc1Cl
Temperature: 120 °C
Yield: 86 %

Procedure:
A mixture of 2,6-dichloro-3-(trifluoromethyl)pyridine (1.0 g, 4.63 mmol), dibenzylamine (913 mg, 890 μL, 4.63 mmol), triethylamine (1.2 mL, 8.61 mmol) and 1-methyl-2-pyrrolidone (6 mL, 62.22 mmol) was heated at 120° C. for 9 h. The reaction mixture was cooled to the room temperature and poured into ice-water, extracted with EtOAc (20 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated and purified by silca gel column chromatography (2%-10% EtOAc in petroleum ether as eluant) to give N,N-dibenzyl-6-chloro-5-(trifluoromethyl)pyridin-2-amine (1.5 g, 86%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.7 Hz, 1H), 7.37-7.21 (m, 10H), 6.32 (d, J=8.7 Hz, 1H), 4.80 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:10])=[C:5]([Br:9])[C:6]=1[C:7]#[N:8].CC(C)([O-])C.[K+].Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].O>O1CCCC1>[Br:10][C:4]1[N:3]([C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:2]([Br:1])=[C:6]([C:7]#[N:8])[C:5]=1[Br:9]
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Reactant: O=C(Cl)Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(Br)c(Br)n(C(=O)Oc2ccccc2)c1Br

Procedure:
A mixture of 7.0 g of 2,4,5-tribromopyrrole-3-carbonitrile and 2.9 g of potassium t-butoxide in tetrahydrofuran is treated with 13.8 g of phenyl chloroformate, heated at reflux temperature for 12 hours, cooled, poured into water and filtered. The solid filter cake is washed with water and dried in vacuo to afford the title compound. A sample is recrystallized from a mixture of ethyl acetate and methylcyclohexane to give colorless crystals, mp 128°-129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:23])[C:8]([C:24]([O:26]CC)=[O:25])=[CH:7]1.[OH-].[Li+].Cl.O>C(O)C>[CH3:1][O:2][C:3]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:4]=1[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][CH2:18][C@@H:17]3[CH2:21][OH:22])[N:14]=2)[C:9](=[O:23])[C:8]([C:24]([OH:26])=[O:25])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccc(OC)cc2OC)c2nc(N3CCC[C@@H]3CO)ccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccc(N4CCC[C@@H]4CO)nc32)c(OC)c1

Procedure:
A mixture of EXAMPLE 2A (2 g) and 0.1M lithium hydroxide (80 mL) in ethanol (100 mL) at 25° C. was stirred for 24 hours, adjusted to pH 3 with 1M hydrochloric acid, treated with water, and filtered.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:28]=[CH:27][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]3[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=3)=[CH:28][CH:27]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: COc1cccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c1

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-methoxybenzyl)-1-piperidinecarboxamide (0.73 g, 2.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane according to Procedure G to give the title compound (0.53 g, 0.67 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl.Cl[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: Clc1ccncc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCN(c2ccncc2)CC1
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloropyridine hydrochloride (87 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL), sealed, and placed in a 120° C. bath. After 24 h, the mixture was cooled, concentrated, and the residue purified by column chromatography (SiO2: 5 to 10% 2 N ammonia in methanol:methylene chloride) affording 70 mg (57%) of the title compound.
Reaction SMILES: C(O[C:6](=[O:25])[CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[CH:9]=1)(C)(C)C.C(C1NC=CN=1)(C1[NH:29]C=CN=1)=O.N>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][N:21]1[CH2:20][CH2:19][N:18]([C:10]2[CH:9]=[C:8]([CH2:7][C:6]([NH2:29])=[O:25])[C:13]([C:14]([F:16])([F:15])[F:17])=[CH:12][N:11]=2)[CH2:23][CH2:22]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CN1CCN(c2cc(CC(=O)OC(C)(C)C)c(C(F)(F)F)cn2)CC1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2cc(CC(N)=O)c(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
[2-(4-Methyl-piperazin-1-yl)-5-trifluoromethyl-pyridin-4-yl]-acetic acid tert-butyl ester (475 mg, 1.32 mmol) is dissolved in a mixture of TFA and CH2Cl2 (10 ml/10 ml) and stirred at RT. After 1.5 h at RT, TLC analysis indicated complete conversion of starting material. The solvent is removed by rotary evaporation, and replaced by dry DMF (5 ml). Under an atmosphere of argon, carbonyl diimidazole (236 mg, 1.46 mmol) is added. After 3 h at RT, TLC analysis indicated complete conversion of the carboxylic acid. An aqueous solution of ammonia (25%, 20 ml) is added at RT. After 15 minutes at RT, solvents are removed under high vacuum. The residue is dissolved in CH2Cl2/MeOH (9:1) and purified by FCC (CH2Cl2/MeOH, slow gradient from 90:10 to 40:60) to yield the title compound. 1H NMR (d6-DMSO, 400 MHz): δ 2.69 (s, 3H), 2.93-3.18 (m, broad, 4H), 3.54 (s, 2H), 3.59-3.98 (m, broad, 4H), 6.95 (s, 1H), 7.02 (s, broad, 1H), 7.47 (s, broad, 1H), 8.45 (s, 1H). ES+−MS: 303.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]Cl)[CH2:2][CH2:3][CH3:4].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([F:16])=[CH:13][CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Yield: 96.3 %

Procedure:
A solution of 4-butoxy-7-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.95 g, 5.5 mmol) and potassium phthalimide (1.54 g, 8.3 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-{(4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (2.46 g, 96.5%) as crystals.
Reaction SMILES: [ClH:1].C([O:6][C:7]([CH2:9][O:10][N:11]=[C:12]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:20]([CH:23]=[CH2:24])[CH2:21][S:22][C@H:17]12)=[O:14])=[O:8])(C)(C)C.C(OC(C)C)(C)C>C(O)=O>[ClH:1].[C:7]([CH2:9][O:10][N:11]=[C:12]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([OH:27])=[O:26])=[C:20]([CH:23]=[CH2:24])[CH2:21][S:22][C@H:17]12)=[O:14])([OH:8])=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.6 %

Procedure:
Conc. hydrochloric acid (0.18 g) was added to a solution of benzhydryl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer)(3.0 g) in formic acid (12 ml) at 10° C. and stirred for 2.5 hours at ambient temperature. The reaction mixture was poured into diisopropyl ether (100 ml). The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid mono-hydrochloride (syn isomer)(1.6 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].O[CH:15]=[C:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([C:27]3[CH:28]=[C:29]([NH:33][C:34]([C:36]4[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=4)=[O:35])[CH:30]=[CH:31][CH:32]=3)=[O:26])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:43]>C1COCC1>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11]/[CH:15]=[C:16]2\[C:17](=[O:43])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:28]=[C:29]([NH:33][C:34]([C:36]4[N:40]([CH3:41])[N:39]=[C:38]([CH3:42])[CH:37]=4)=[O:35])[CH:30]=[CH:31][CH:32]=2)=[O:26])[CH:20]=3)=[CH:12][CH:13]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(N)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc(N/C=C2\C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cc(C)nn5C)c4)ccc32)cc1
Temperature: 70 °C
Yield: 55.5 %

Procedure:
A mixture of 4-((diethylamino)methyl)aniline (A-04; 100 mg, 0.25 mmol, 1 equivalent) and N-(3-(3-(hydroxymethylene)-2-oxoindoline-6-carbonyl)phenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (Scaffold S1; 50 mg, 0.25 mmol, 1 equivalent) was taken in anhydrous THF (2 mL, 0.125 M) and heated at 70° C. for 16 h. Solvent was evaporated under vacuum and the crude product was purified by preparative RP-HPLC. 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (3-{3-[1-(4-diethylaminomethyl-phenylamino)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-6-carbonyl}-phenyl)-amide (78 mg, 55%) was obtained as a brown powder.