Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:10]2[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1OCCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2OCCO3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
To a solution of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (351 mg, 1.95 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (400 mg, 1.95 mmol), HATU (1.11 g, 2.93 mmol) in anhydrous DMF (8 mL) is added DIPEA (484 μL, 2.93 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (59) as white solid (650 mg, 91%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26]C(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:32][C:33]([F:37])([F:36])[CH2:34][OH:35].F[C:39](F)(F)[CH:40](O)C>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:19][C@@H:20]4[N:21]([C:24]([O:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:26])[C@H:22]([CH2:39][CH2:40]4)[CH2:23]3)=[CH:13][C:12]2=[O:31])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccn(-c3ccc(S(C)(=O)=O)cc3)c(=O)c2)CC1
Reactant: CC(O)C(F)(F)F
Reactant: OCC(F)(F)F
Product: CS(=O)(=O)c1ccc(-n2ccc(OC3C[C@H]4CC[C@H](C3)N4C(=O)OCC(F)(F)F)cc2=O)cc1

Procedure:
Example 112 was prepared according to procedures described in Example 2 substituting (3-exo)-tert-butyl 3-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)-8-azabicyclo[3.2.1]octane-8-carboxylate (Example 25) for tert-butyl 4-(1-(4-(methylsulfonyl)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate at Step A and 2,2,2-trifluoroethanol for 1,1,1-trifluoro-2-propanol at Step B. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=8.80 Hz, 2 H), 7.61 (d, J=8.80 Hz, 2 H), 7.20-7.32 (m, 1 H), 6.24 (d, J=2.75 Hz, 1 H), 6.09 (dd, J=7.70, 2.75 Hz, 1 H), 4.73-4.87 (m, 1 H), 4.54-4.67 (m, 1 H), 4.39-4.55 (m, 3 H), 3.10 (s, 3 H), 2.17-2.30 (m, 2 H), 2.04-2.19 (m, 2H), 1.68-1.94 (m, 4 H). MS (ESI) 501 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:51][C@@H:52]([CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=1)[CH2:53][N:54]1[C:62](=[O:63])[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]1=[O:64]>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:51][C@@H:52]([CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:53][N:54]2[C:62](=[O:63])[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:55]2=[O:64])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=1[Cl:17]
Reactant: N[C@@H](Cc1cccc(F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: CCn1ncc(Cl)c1-c1cc(C(=O)O)sc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2cccc(F)c2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Reaction time: 0.17 h
Yield: 80.7 %

Procedure:
To a solution of 5-chloro-4-(4-chloro-1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (180 mg, 0.618 mmol) [from Example 235(c)] in DCM (5 mL) at 25° C. was added PyBrOP in one portion, followed by addition of DIPEA (0.54 mL, 3.09 mmol). After stirring for 10 min, 2-[(2S)-2-amino-3-(3-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (203 mg, 0.68 mmol) was added to above solution in one portion. After stirring for 2 h, the solution was concentrated and purified via column chromatography (silica, 20-50% EtOAc/Hexane) affording the title compound (285 mg, 77%) as a white solid: LC-MS (ES) m/z=571 (M+H)+.
Reaction SMILES: NN.[CH:3]1[C:8](N=C=S)=[CH:7][C:6]2[C:12]([O:14][C:15]3([C:25]4[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=4[O:23][C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]3=4)[C:5]=2[CH:4]=1)=[O:13].C(N(C(C)C)CC)(C)C.C1C=CC([C:62]([OH:64])=[O:63])=C(C2C3C=CC(O)=CC=3OC3C=2C=CC(C=3)=O)C=1>CN(C=O)C>[CH:3]1[C:8]([C:62]([OH:64])=[O:63])=[CH:7][C:6]2[C:12]([O:14][C:15]3([C:25]4[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=4[O:23][C:17]4[CH:18]=[C:19]([OH:22])[CH:20]=[CH:21][C:16]3=4)[C:5]=2[CH:4]=1)=[O:13]
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: NN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc2c(c1)C(=O)OC21c2ccc(O)cc2Oc2cc(O)ccc21
Reaction time: 12 h

Procedure:
Peptide-resin obtained via Method 5 containing an ivDde protecting group on the epsilon nitrogen of lysine, was mixed with a solution of hydrazine in DMF (10% hydrazine/DMF, 2×10 mL, 10 min) to remove the ivDde group. The epsilon nitrogen of the lysine was labeled with fluorescein-5-isothiocyanate (0.12 mmol) and diisopropylethylamine (0.12 mmol) in DMF . The mixture was agitated for 12 h (fluorescein-containing compounds were protected from light). The resin was then washed with DMF (3×10 ml) and twice with CH2Cl2 (10 mL) and dried under nitrogen for 1 h. The peptide was cleaved from the resin using reagent B for 4 h and the solution collected by filtration. The volatiles were removed under reduced pressure, and the residue was dried under vacuum. The peptide was precipitated with ether, collected and the precipitate was dried under a stream of nitrogen. The precipitate was added to water (1 mg/mL) and the pH of the mixture was adjusted to 8 with 10% aqueous meglumine. Cyclization of the peptide was carried out for 48 h and the solution was freeze-dried. The crude cyclic peptide was dissolved in water and purified by RP-HPLC on a C18 column with a linear gradient of acetonitrile into water (both phases contained 0.1% TFA). Fractions containing the pure product were collected and freeze-dried. The peptides were characterized by ES-MS and the purity was determined by RP-HPLC (linear gradient of acetonitrile into water/0.1% TEA).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[NH:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1.CC1CCCO1.O.C([O-])([O-])=O.[Na+].[Na+].Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].Cl>>[CH3:2][C:3]1[CH:14]=[C:13]([CH3:15])[C:6]2[N:7]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(C)c2c(c1)C(=O)CCCN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: Cc1cc(C)c2c(c1)C(=O)CCCN2C(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 50 h
Yield: 91.9 %

Procedure:
Charge a 22 L flask with an overhead stirrer, thermocouple, 3 L addition funnel, baffle, cooling bath and N2 purge and 7,9-dimethyl-3,4-dihydro-1H-benzo[b]azepin-5(2H)-one hydrochloride (1,000 g, 4.43 moles). Add 2-methyltetrahydrofuran (6.44 kg, 7.5 L, 74.5 moles) and agitate the off-white slurry. Cool to 5-15° C. Add water 2.5 L, 138.8 moles and Na2CO3 (1.12 kg, 3 moles) to the addition funnel then slowly add to the reaction mixture at a fast drip over about 25 m. Charge a 2 L addition funnel with benzyl chloroformate (91.59 kg, 8.86 moles) add dropwise to the reaction, while maintaining the reaction mixture below about 15° C. Transfer the resulting mixture to a flask equipped with a condenser and heat to 25-25° C. and stir for about 50 h. Cool to about 15° C., add HCl (5 M, until the pH is about 5). Separate the layers. Extract the aqueous layer with methyltetrahydrofuran (4 L); combine the organic layers and wash with water (4 l). Concentrate the organic layer at about 40° C. Add IPA (4 L) and then concentrate to 2 L. Transfer to a 12 L flask equipped with an overhead stirrer, thermocouple, heating mantle condenser, 2 L addition funnel and N2 purge. Heat the flask contents to about 70-80° C. and add heptane (5 L). Slowly cool to RT overnight; seed the mixture if necessary to induce crystallization of the titled compound. Cool and collect the solid; rinse the solid with cold heptane and dry in a vacuum at 50° C. to provide 1,316 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]3)=[C:13]([O:23][CH3:24])[CH:12]=2)[N:3]=1.[CH3:25][C@H:26]1[O:31][C@@H:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>>[CH3:32][C@@H:30]1[O:31][C@H:26]([CH3:25])[CH2:27][N:28]([C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]4)=[C:13]([O:23][CH3:24])[CH:12]=3)[N:3]=2)[CH2:29]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(N2C[C@@H](C)O[C@@H](C)C2)n1

Procedure:
The title compound was prepared from (4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and cis-2,6-dimethylmorpholine in analogy to example 1c. It was purified by column chromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent to give the title compound as a yellowish solid in 58% yield.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27].[CH:28]([NH2:31])([CH3:30])[CH3:29]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:31][CH:28]([CH3:30])[CH3:29])=[C:14]([O:23][CH3:24])[CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[CH:7][CH:8]=2)[C:3]1=[O:27]
Reactant: COc1ccc2cc(-c3ccc(OCC4CO4)c(OC)c3)n(C)c(=O)c2c1
Reactant: CC(C)N
Product: COc1ccc2cc(-c3ccc(OCC(O)CNC(C)C)c(OC)c3)n(C)c(=O)c2c1
Yield: 77 %

Procedure:
2-Methyl-3-[3-methoxy-4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[3-methoxy-4-(2,3-epoxypropoxy)-phenyl]-7-methoxy-isoquinolin-1(2H)-one and isopropylamine.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:7]([O:17][CH3:18])=[C:8]([C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:9]([OH:11])=O.C1(C)C=CC=CC=1.[NH2:26][CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[CH2:33][CH3:34]>C(C(C)=O)C.CCOCC>[ClH:3].[CH2:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[CH2:27][NH:26][C:9](=[O:11])[C:8]1[C:12]([O:15][CH3:16])=[CH:13][CH:14]=[C:6]([Cl:5])[C:7]=1[O:17][CH3:18])[CH3:34]
Reactant: O=S(Cl)Cl
Reactant: CCN1CCCC1CN
Reactant: COc1ccc(Cl)c(OC)c1C(=O)O
Solvent: CCC(C)=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN1CCCC1CNC(=O)c1c(OC)ccc(Cl)c1OC
Product: Cl

Procedure:
30 ml of thionyl chloride is added to 17.0 g (0.078 mol) of 3-chloro-2,6-dimethoxybenzoic acid. The mixture is heated on a steam bath for 30 minutes. To the solution is added 50 ml of toluene. The solvent and excess thionyl chloride is evaporated at reduced pressure. The residue is dissolved in 50 ml of dry methyl ethyl ketone. The solution is added dropwise while stirring to 10.0 g (0.078 mol) of 2-(aminomethyl)-1-ethylpyrrolidine in 50 ml of methyl ethyl ketone. After stirring for 30 minutes at room temperature 150 ml of ether is added. The obtained precipitate is filtered off, washed with ether and recrystallized twice from ethanol - isopropyl ether. Yield: 21.3 g, m.p. 175°-77° C. (first recrystallization). m.p. 179°-80° C. (second recrystallization).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C([Sn]([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH:15]1([N:7]2[C:8]3[C:3](=[C:2]([C:37]#[C:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:11]([F:12])=[C:10]([F:13])[C:9]=3[F:14])[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C#C[Si](C)(C)C)c2c1=O
Yield: 78.6 %

Procedure:
1.95 g of ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 2.7 g of tributylstannyl-trimethylsilyl-acetylene and 0.29 g of tetrakis-(triphenylphosphine)palladium(0) are refluxed for 4 hours in 20 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is filtered at room temperature; the solid is washed with a small amount of toluene and dried. 1.6 g of the title compound are obtained (78% of theory).
Reaction SMILES: O1CCCCC1O[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:15].O1CCN(C2CCCC=2)CC1.[C:27]1(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(OCC)C>C1C=CC=CC=1>[OH:32][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:8][CH2:9][C:10]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]=1
Reactant: O=CCCCCCCOC1CCCCO1
Reactant: O=C1CCCC1
Agent: C1=C(N2CCOCC2)CCC1
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1CCC=C1CCCCCCCO
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 7-(2-tetrahydropyranyloxy)heptanal (22 g.) and 1-morpholinocyclopentene, i.e. the morpholine enamine of cyclopentanone, (21.4 g.) in benzene (25 ml.) was heated under reflux for 12 hours under nitrogen, and the water liberated was continuously removed with a Dean and Stark head. Benzene (10 ml.) and then, dropwise, 18% hydrochloric acid (28 ml.) were added and the mixture was stirred for 2 hours. The organic layer was separated and evaporated. Concentrated hydrochloric acid (72 ml.) and butanol (300 ml.) were added to the residue. The mixture was heated at 100° C. for 1 hour, and then the solution was concentrated to give an oil. Diethyl ether was added, and the ether solution was washed with aqueous sodium bicarbonate and then water, and dried over sodium sulphate. The solvent was evaporated and the residue was distilled under reduced pressure to give 2-(7-hydroxyheptyl)cyclopent-2-en-1-one (11.7 g.), b.p. 125°-170° C./0.15 mm.Hg, nD25 1.490, λmax 228 mμ (ethanol).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([NH:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:13])=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:33]>>[ClH:33].[NH2:17][CH2:16][CH2:15][NH:14][C:12]([C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][NH:10][N:9]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1n[nH]cc1-c1ccccc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCNC(=O)c1n[nH]cc1-c1ccccc1
Yield: 76.8 %

Procedure:
5.0 g (15.1 mmol) of t-butyl [2-(4-phenyl-3-pyrazolecarboxamido)ethyl]carbamate were stirred at room temperature for 16 hours with 6 ml (78.4 mmol) of trifluoroacetic acid and 10 ml of methylene chloride and thereafter evaporated under reduced pressure. The residue was treated with 7 ml of ethanolic hydrochloric acid (17.5% w/v) and evaporated. Recrystallization of the residue from methanol yielded 3.1 g (76.8%) of N-(2-aminoethyl)-4-phenyl-3-pyrazolecarboxamide hydrochloride as white crystals, melting point 285°-286°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-].C(N(CC)CC)C.[Cl:17]C1C=CC=CC=1>>[Cl:17][C:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: Clc1ccccc1
Reactant: Cc1ccc(Cl)[n+]([O-])c1
Solvent: CCN(CC)CC
Product: Cc1ccc(Cl)nc1Cl

Procedure:
101.5 g (0.50 mol) of o-phthaloyl chloride in 50 ml of chlorobenzene are added dropwise under nitrogen to a solution of 35.9 g (0.25 mol) of 2-chloro-5-methylpyridine-1-oxide and 50.6 g (0.50 mol) of triethylamine in 200 ml of chlorobenzene in the course of 30 min. The mixture is subsequently heated under reflux for a further 12 hours, then the precipitate is filtered off with suction, the filter cake is washed with 50 ml of methylene chloride and the solvent is removed by distillation. The bottom is subjected to steam distillation, the pH of 6 being maintained by continuously adding 45 per cent sodium hydroxide solution. The distillate is extracted three times using 100 ml of methylene chloride each time, the solvent is removed by distillation and the residue is recrystallized from hexane.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C1(C)C=CC=CC=1.C([O-])(=[O:26])C.[K+].[OH-].[Na+]>O>[OH:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]#[N:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1ccc(CO)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A 750 ml flask is charged with 54.4 g (0.2 mol) of 4′-bromomethyl-biphenyl-2-carbonitrile and 250 ml of toluene. To this suspension is added a solution of 30 g (0.3 mol) of potassium acetate in 15 ml of water. The heterogeneous mixture is heated up to an internal temperature of 90° C. to become a clear biphasic solution. After 12 hours at an internal temperature of 90° C. the conversion to the OAc derivative is complete. The biphasic mixture is cooled down to internal temperature of about 50° C. followed by addition of 150 ml NaOH (2N). The mixture is heated up to an internal temperature of ca. 70° C. (extern. temp. 80° C.). After 5 hours at this temperature the PTC saponification is complete (100% conversion, HPLC). Additional 150 ml toluene is added and the warm reaction solution (ca. 50° C.) is washed three times with 50 ml of hot water until the pH is around 7. The toluene phase is evaporated under reduced pressure and the resulting crystalline residue is dried at 50° C. over 24 hours in vacuum to give the white crystalline product with 98% purity (HPLC) and a water content of 0.23%.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2ccc(Cl)cc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(4-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 9, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[C:25]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[CH:24]2.[CH3:38][CH2:39][C:40](Cl)=[O:41].O>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[C:25]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[C:24]2[CH2:38][CH2:39][C:40]([N:9]1[CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5][C:4]1=[O:3])=[O:41]
Reactant: Cn1c(-c2ccc(Cl)cc2)cc2cc(Cl)ccc21
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)N2CCN(C(=O)OCc3ccccc3)CC2=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5 %

Procedure:
Oxalyl chloride (0.08 mL, 114 mg, 0.9 mmol) was added dropwise to a stirred, cooled (0° C.) solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoic acid (Description 12, 330 mg, 0.95 mmol) and DMF (1 drop) in toluene (15 mL) and the mixture was stirred at room temperature for 2 h. to give a solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoyl chloride. Sodium hydride (60% dispersion in mineral oil, 19 mg, 0.48 mmol) was added to a solution of phenylmethyl 3-oxo-1-piperazinecarboxylate (Eur.J.Med.Chem. 1981, 16, 229-232) (111 mg, 0.48 mmol) in DMF (3 mL) and the mixture was stirred at room temperature for 30 min. A portion of the solution of 5-chloro-2-(4-chlorophenyl)-1-methyl-1H-indole-3-propanoyl chloride (7.5 mL) was added dropwise and the mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with ether. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (80:20). The fractions containing product were combined, washed with aqueous sodium hydroxide (4M) and water, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with aqueous hydrochloric acid (2M), saturated aqueous sodium carbonate and water, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as a colorless oil (14 mg, 5%). δ7.58 (1H, s), 7.47 (2H, d, J 8.4 Hz), 7.39-7.16 (9H, m), 5.15 (2H, s), 4.22 (2H, s), 3.81 (2H, m), 3.61 (2H, m), 3.53 (3H, s), 3.15 (2H, m), and 3.00 (2H, m). m/z (ES+) 564, 566 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][NH:5][C:6]([C:8]1[O:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=[O:7].[ClH:17].[N:18]([O:20]CCC(C)C)=O>>[Cl:17][C:2]([CH3:16])([CH3:1])[CH:3]([N:18]=[O:20])[CH2:4][NH:5][C:6]([C:8]1[O:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=[O:7]
Reactant: Cl
Reactant: CC(C)CCON=O
Reactant: CC(C)=CCNC(=O)c1ccc([N+](=O)[O-])o1
Product: CC(C)(Cl)C(CNC(=O)c1ccc([N+](=O)[O-])o1)N=O
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
N-(3-Methyl-2-butenyl)-5-nitro-2-furancarboxamide (2.2 g, 0.01 mol) was suspended in isoamyl nitrite (60 mL) and cooled to -5° C. concentrated HCl (1 mL, 37%, 0.01 mol) was added through a syringe. The reaction mixture was stirred at -5° C. for 30 min and at room temperature for 30 min. The solid was filtered and washed with chilled (-10° C.) ethanol-ether (100 mL). A light green powder was obtained. Yield: 1.5 g (52%). mp 110°-112° C. MS m/z 254 [(M+H)-HCl]+. 1H NMR (DMSO-d6) ε 1.82 [s, 6H, (CH3)2C=], 4.28 (d, 2H, CH2C=N), 7.49 and 7.75 (d, 2H, furanyl-H), 8.66 (t, 1H, NHCO), 11.72 (s, 1H, C=NOH).