Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:12](OCC)(=[O:16])[CH:13]([CH3:15])[CH3:14]>C1COCC1>[CH3:14][CH:13]([CH3:15])[C:12](=[O:16])[CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(=O)C(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.2 %

Procedure:
Benzylcyanide (1500 mg, 12.8 mmol) was dissolved in 150 ml dry THF and cooled down to 0° C. The solution was stirred at that temperature while NaH (60% in mineral oil, 663 mg) was added slowly. After the addition was completed, the mixture was stirred at 0° C. for 30 min and then the ice bath was removed and stirring continued at RT for 120 min. Ethyl isobutyrate (1785 mg, 15.4 mmol) was added at once and the reaction mixture heated at 60° C. for 2 h. The THF was removed in vacuo and the residue was then poured into ice-water. HCl 6M was added with stirring until neutral pH was reached. The mixture was extracted with EtOAc, dried over MgSO4 and concentrated in vacuo. The compound was purified by flash chromatography [silica; n-heptane-EtOAc (9:1)] to afford 4-methyl-3-oxo-2-phenyl-pentanenitrile (460 mg, 19%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[ClH:21].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][Cl:26]>CN(C=O)C>[ClH:26].[ClH:21].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[CH:11]1
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ncccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(S(=O)(=O)c2ccccc2)c2cccnc21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.55 mmol) in dry DMF is chilled to 0° C., treated with sodium hydride (60% in oil, 97 mg, 2.43 mmol), stirred for 3 h at 20° C., cooled to −20° C., treated with 2-(dimethylamino)-ethyl chloride hydrochloride (336 mg, 2.33 mmol), stirred at 60° C. for 16 h, cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the free amine of the title compound as a yellowish gum. The gum is dissolved in ethanol, treated with 1 N aqueous HCl and concentrated in vacuo. Crystallization of the resultant residue from ethanol/ether affords the title compound as a light tan solid, 111 mg, mp 214-217° C., characterized by mass spectral and HNMR analyses.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1.Br[CH:32]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)[CH3:33]>C1COCC1>[Br:11][C:12]1[CH:13]=[C:14]([CH:18]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)=[O:20])[CH:32]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)[CH3:33])[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Reactant: COc1ccc(COC(=O)Cc2cccc(Br)c2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C(C(=O)OCc2ccc(OC)cc2)c2cccc(Br)c2)cc1
Temperature: 25 °C

Procedure:
LHMDS (1.0M THF, 2.6 mL) was added dropwise to a −78° C. THF (4 mL) solution containing the intermediate from Step A (0.827 g, 2.47 mmol). After stirring 10 minutes a THF (4 mL) solution containing methyl 4-(1-bromoethyl)benzoate (0.6 g, 2.47 mmol) was added dropwise. The solution was allowed to warm to room temperature. After 1.5 hours the solution was partitioned between ethyl acetate and aqueous 1N HCl. The organic phase was washed with water, brine and dried over magnesium sulfate. The solution was filtered and the residue purified by silica gel chromatography using a hexanes/ethyl acetate gradient to give the title compounds as a 1.67/1 mixture of diastereomers. 1H NMR (400 MHz, CDCl3): selected data δ 5.16 (d, J=12.0 Hz); 5.01 (d, J=12.0 Hz); 4.82 (d, J=12.0 Hz); 4.64 (d, J=11.9 Hz); 1.34 (d, J=6.8 Hz); 1.02 (d, J=7.0 Hz). Minor diastereomer: LCMS1 4.08 min (N+Na)=519. Major diastereomer: LCMS1 4.19 min (M+Na)=519.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]2[CH2:13][CH2:12]2)=[CH:4][C:3]=1[F:17].[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][N:27]=1)[C:22](O)=[O:23]>>[CH:11]1([N:8]2[C:9]3[C:5](=[CH:4][C:3]([F:17])=[C:2]([NH:1][C:22](=[O:23])[C:21]4[CH:25]=[CH:26][N:27]=[C:19]([CH3:18])[CH:20]=4)[CH:10]=3)[C:6]([CH3:15])([CH3:16])[C:7]2=[O:14])[CH2:13][CH2:12]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)c(F)cc21
Reactant: Cc1cc(C(=O)O)ccn1
Product: Cc1cc(C(=O)Nc2cc3c(cc2F)C(C)(C)C(=O)N3C2CC2)ccn1

Procedure:
Prepared in analogy to example 26 from 6-amino-1-cyclopropyl-5-fluoro-3,3-dimethyl-1,3-dihydro-indol-2-one and 2-methylisonicotinic acid. The title compound was obtained as light yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([O:23]CC4C=CC=CC=4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:6]=1>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[N:18]=[CH:19][C:20]([OH:23])=[CH:21][N:22]=3)[CH2:15][CH2:16]2)[CH:6]=1
Reactant: Clc1cnn(CCCCN2CCN(c3ncc(OCc4ccccc4)cn3)CC2)c1
Agent: [Pd]
Solvent: CCO
Product: Oc1cnc(N2CCN(CCCCn3cc(Cl)cn3)CC2)nc1
Temperature: 24 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
A mixture of 6.87 g (16.07 mmol) of 2-{4-[4-(4-chloropyrazol-1-yl)butyl ]-1-piperazinyl}-5-benzyloxypyrimidine and 0.63 g of 10% palladium on carbon in 160 ml of ethanol is stirred for 12 hours under a hydrogen atmosphere at room temperature (24° C.) and at a pressure of 2 atmospheres. After filtration, washing with ethanol and evaporation to dryness, the product is chromatographed on silica gel, yielding 2.65 g (49%) of 2-{4-[4-(4-chloropyrazol-1-yl ) butyl]-1-piperazinyl}-5-hydroxypyrimidine with a melting point of 131°-2° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:16][CH2:17][C:18](Cl)=[O:19].O>CC(C)CC(=O)C>[Cl:16][CH2:17][C:18]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8])=[O:19]
Reactant: CCOC(=O)C(C)c1ccc(O)c(N)c1
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)c1ccc(O)c(NC(=O)CCl)c1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Ethyl 2-(3-amino-4-hydroxyphenyl)propanoate (104 mg, 0.497 mmol) in 4-methyl-2-pentanone (4 mL) was added chloroacetylchloride (56 mg, 0.496 mmol) at room temperature and stirred for 20 hours at 80° C. The reaction mixture was cooled to room temperature and added water (30 mL). The mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and filtered. EtOAc was removed by evaporation. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=2/1.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=O.[OH-].[Na+].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>O>[CH2:11]([N:15]1[C:3](=[O:5])[CH:2]2[CH2:6][CH2:7][CH2:8][N:1]2[C:16]1=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN=C=O
Reactant: O=C(O)C1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN1C(=O)C2CCCN2C1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
DL-Proline (2.5 g 0.0217 mole) was dissolved in water (20 ml) containing 2 N NaOH (10.9 ml, 0.0219 equiv) cooled to 0° C. and n-butyl isocyanate (3.27 g 0.33 mole) added dropwise to the stirred solution during 2 hours. The mixture was left at room-temperature overnight, filtered and washed with ether. The aqueous solution was acidified with concentrated hydrochloric acid (30 ml) and heated on the steam-bath for 30 minutes, cooled and continuously extracted with ether for 2 hours. Removal of the solvent gave a clear oil which was distilled under reduced pressure in a Kugelrohr apparatus to yield the product as a colourless oil, b.p. 90° C. at 0.02 mm. Yield 3.5 g=83%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[C:12]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([CH2:15][CH3:16])([CH3:14])[CH3:13].CS(C)=O>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]([CH2:15][CH3:16])([CH3:13])[CH3:14])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCC(C)(C)c1ccc(O)cc1
Solvent: CS(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.4 %

Procedure:
Following procedure A, 3,4-difluoronitrobenzene (502 mg, 3.16 mmol, 1.00 eq) and 4-tert-pentylphenol (693 mg, 4.22 mmol, 1.34 eq) were dissolved in DMSO (6 mL) Anhydrous K2CO3 (656 mg, 4.75 mmol, 1.50 eq) was added and the reaction mixture was stirred at room temperature for 22 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:50) to afford the title compound as pale yellow oil (943 mg, 3.11 mmol, 99% yield). Rf=0.61 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C17H19NO3+ [M+H]+ 304.1343. found: 304.1332. 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J=10.3, 2.7 Hz, 1H, aromatic H), 7.96 (ddd, J=9.1, 2.7, 1.5 Hz, 1H, aromatic H), 7.42-7.35 (m, 2H, aromatic H), 7.07-6.99 (m, 2H, aromatic H), 6.95 (dd, J=9.1, 8.0 Hz, 1H, aromatic H), 1.66 (q, J=7.4 Hz, 2H, Ar—C(CH3)2CH2CH3), 1.31 (s, 6H, Ar—C(CH3)2CH2CH3), 0.71 (t, J=7.4 Hz, 3H, Ar—C(CH3)2CH2CH3). 13C NMR (101 MHz, CDCl3) δ 153.40, 152.19, 151.98, 151.87, 150.88, 147.11, 127.97, 120.71, 120.68, 119.34, 117.73, 117.71, 113.11, 37.92, 37.08, 28.64.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[C:21]([C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][CH:57]=2)[N:54]([CH2:58][CH2:59][OH:60])[CH:53]=[CH:52]3)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([O:36]C)=[O:35])[N:25](COCC[Si](C)(C)C)[C:24]=2[CH:48]=1>C1COCC1>[Cl:19][C:20]1[C:21]([C:49]2[CH:50]=[C:51]3[C:55](=[CH:56][CH:57]=2)[N:54]([CH2:58][CH2:59][OH:60])[CH:53]=[CH:52]3)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[CH:48]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc5c(ccn5CCO)c4)c(Cl)cc3n2COCC[Si](C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2nc3cc(-c4ccc5c(ccn5CCO)c4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
TBAF (1 M in THF) (0.9 mL, 0.9 mmol) was added to a solution of methyl 5-[(6-chloro-5-[1-(2-hydroxyethyl)-1H-indol-5-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate (105 mg, 0.173 mmol) in THF (2 mL). The reaction was heated at 80° C. for 1 h. TBAF (1 M in THF) (0.2 mL, 0.2 mmol) was added and heating continuted for an additional 1 h. Volatiles were removed and the residue was dissolved in MeOH (3 mL) and treated with 2.5 N aqueous NaOH (1 mL). The mixture was stirred at 45° C. for 1.5 h, then at ambient temperature overnight. The reaction was diluted with EtOAc and the layers were separated. The organic layer was washed with 1 M aqueous HCl, water and brine, dried (Na2SO4), filtered, and concentrated. Chromatography over silica eluting with 8% MeOH/DCM containing AcOH (60 drops in 200 mL) afforded the title compound as an off-white solid. LC-MS: calculated for C25H20ClN3O4 461.90, observed m/e 462.3 (M+H)+ (Rt 1.77 min). 1H NMR (500 MHz, CD3OD): δ 7.86 (d, 1H), 7.55 (s, 1H), 7.47 (s, 1H), 7.46-7.36 (m, 3H), 7.34, (s, 1H), 7.27 (d, 1H), 7.19 (dd, 1H), 6.47 (d, 1H), 4.29 (t, 2H), 3.89 (t, 2 H), 2.61 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][C:10]=1[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=1)[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:23]=[C:24]([CH:29]=[CH:30][N:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[CH:11][C:10]=1[C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(OB(O)O)ccc1OCc1ccccc1
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: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(OCc3ccccc3)c(C#N)c2)c1
Temperature: 10 °C

Procedure:
[4-(Benzyloxy)-3-cyanophenyl]boric acid and methyl 2-chloroisonicotinate were dissolved in a mixture liquid of toluene and an aqueous 2 M sodium carbonate solution, and in the presence of tetrakis(triphenylphosphine)palladium, the mixture was stirred under heating in an argon atmosphere at 10° C. to obtain methyl 2-[4-(benzyloxy)-3-cyanophenyl]isonicotinate. F: 345.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:24])[C:5]([C:7]1([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]=[C:8]1[O:17][CH3:18])=[O:6].C[O:26][C:27]1[C@](C(N2CCC[C@@H]2CO)=O)(CCC(C)C)C2C(C[CH:36]=1)=CC=CC=2>>[C:27]([O:1][CH2:2][CH2:3][N:4]([C:5]([C:7]1([CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]=[C:8]1[O:17][CH3:18])=[O:6])[CH3:24])(=[O:26])[CH3:36]
Reactant: COC1=CCc2ccccc2C1(CCC(C)C)C(=O)N(C)CCO
Reactant: COC1=CCc2ccccc2[C@]1(CCC(C)C)C(=O)N1CCC[C@@H]1CO
Product: COC1=CCc2ccccc2C1(CCC(C)C)C(=O)N(C)CCOC(C)=O

Procedure:
The title compound was prepared using the procedure described for Example 171C, substituting the product from Example 176B for the product from Example 171B. The title compound was purified by column chromatography on silica gel using a solvent gradient of 35-65% ethyl acetate in hexane, and was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[C:12]([N+:13]([O-])=O)=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[Sn](Cl)Cl>Cl>[CH2:1]([C:3]1[C:12]([NH2:13])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2cccnc2c1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Product: CCc1ccc2cccnc2c1N
Yield: 99.5 %

Procedure:
In a similar fashion using route 1 general procedure 4, 7-ethyl-8-nitroquinoline (Intermediate 60) (170 mg, 0.84 mmol), tin (II) chloride (500 mg, 2.52 mmol) and 6 N HCl (2 drops) gave the title compound (144 mg, 100%) which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].Cl.[CH3:21][O:22][C:23](=[O:31])[C@H:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[NH2:25].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH:24]([NH:25][C:13](=[O:15])[CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:16]([F:19])([F:18])[F:17])[CH:4]=1)[C:23]([O:22][CH3:21])=[O:31]
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)CS(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1)C(=O)OC

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.836 g (10 mmol) of L-aspartic acid dimethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:27])[CH2:10][CH2:11][C:12]2([CH2:23][CH2:24][CH2:25][CH3:26])[C:20]=1[C:19]1[C:14](=[CH:15][C:16]([O:21]C)=[CH:17][CH:18]=1)[CH2:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:8]1[C:9](=[O:27])[CH2:10][CH2:11][C:12]2([CH2:23][CH2:24][CH2:25][CH3:26])[C:20]=1[C:19]1[C:14](=[CH:15][C:16]([OH:21])=[CH:17][CH:18]=1)[CH2:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC12CCC(=O)C(Cc3ccccc3)=C1c1ccc(OC)cc1C2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC12CCC(=O)C(Cc3ccccc3)=C1c1ccc(O)cc1C2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 4-benzyl-9a-butyl-7-methoxy-1,2,9,9a-tetrahydrofluoren-3-one (25.9 mg, 0.718 mmol) in anhydrous CH2Cl2 (1.2 mL) was cooled in a dry ice-acetone bath and stirred under a nitrogen atmosphere while 1M BBr3 in CH2Cl2 (0.215 mL, 0.215 mmol) was added dropwise by syringe. The cooling bath was removed and the mixture was stirred at room temperature for 3.5 hours, after which it was diluted with EtOAc (8 mL), water (3 mL) and 2N HCl (1 mL) and shaken vigorously. The organic phase was separated, washed with water (3 mL), 1M pH 3 phosphate (3 mL) and brine (3 mL), dried over MgSO4, filtered and evaporated under vacuum to a solid (25 mg). The crude product was purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate, using 5% MeOH in CH2Cl2 as developing solvent. The major UV visible band at Rf 0.40-0.53 gave 4-benzyl-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=1.C[O-].[Na+].[C:28](=O)(O)[O-:29].[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:24])[CH:8]=2)[N:3]=[C:2]([O:29][CH3:28])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)cc1
Reactant: O=C([O-])O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 92 °C
Reaction time: 13 h

Procedure:
A heterogeneous mixture of 2,4-dichloro-6-iodo-3-(4-(trifluoromethyl)benzyl)quinoline (515 g, 1.068 mol, Intermediate 62: step b) and sodium methoxide (577.1 g, 10.68 mol) in toluene (5.34 L) was heated to 92° C. for 18 h and then 100° C. for 13 h. After cooling to room temperature the slurry was poured over an aqueous solution of sodium bicarbonate (11.54 kg, 7 wt %, 9.615 mol). The biphasic system was mixed and then the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Br.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21]
Reactant: COc1cccc(CBr)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(CC(C#N)(C#N)CCC(F)(F)F)c1
Yield: 32.1 %

Procedure:
Using 0.20 g of 3-methoxybenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.09 g of 2-(3-methoxybenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (32)).
Reaction SMILES: C([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:6][C:5]1=[O:22])(O)=O.C1(C)C(C)=CC=CC=1.C(=O)=O>CCCCCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[CH:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:6][C:5](=[O:22])[CH2:4]2)=[CH:10][CH:11]=1
Reactant: O=C(O)C1C(=O)NC(c2ccccc2)C1c1ccc(Cl)cc1
Agent: O=C=O
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C1CC(c2ccc(Cl)cc2)C(c2ccccc2)N1

Procedure:
12 g. of 3-carboxy-4-p-chlorophenyl-5-phenyl-2-pyrrolidinone in 200 ml. of xylene are refluxed until evolution of CO2 ceased (about 20 minutes). The solution is cooled, 200 ml. of hexane are added and the reaction product crystallizes out. 8 g. of 4-p-chlorophenyl-5-phenyl-2-pyrrolidinone are obtained. M.P. : 159°-160°C.
Reaction SMILES: [CH2:1]([NH+:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2].[F:9][C:10]([F:16])([F:15])[S:11]([OH:14])(=[O:13])=[O:12]>>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[CH2:1]([NH+:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: CC[NH+]1CCCCC1
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
Equimolar amounts of ethylpiperidinium and trifluoromethanesulfonic acid were weighed in a glove box under argon atmosphere. The weighed ethylpiperidinium and trifluoromethanesulfonic acid were mixed and stirred while being cooled by liquid nitrogen, thus obtaining a target ionic conductor.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.O.[NH2:27][NH2:28]>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:27][NH2:28])=[S:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(O)=S)cc1
Reactant: NN
Agent: CC(C)COC(=O)Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(=S)NN)cc1
Yield: 27.1 %

Procedure:
To p-methylthiobenzoic acid (1.68 g, 10 mmol) in THF (20 ml) were added triethylamine (1.39 ml, 10 mmol) and isobutylchloroformate (1.31 ml, 10 m). After 20 min at 20° C. ether (20 ml) was added, the mixture filtered, and hydrazine hydrate (0.49 ml, 10 mmol) added to the filtrate. After 1 h at 20° C. the solution was evaporated in vacuo and the residue recrystallised from water to give p-methylthiobenzohydrazide as short colourless needles (0.45 g, 25%); m.p. 140°-142° C.; δH (dmso-d6) 9.6 (1H, bs, NH), 7.2, 7.7 (4H, ABq, aryl), 3.8 (2H, bs, NH2), 2.5 (3H, s, sMe).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:15]=[C:14]([OH:16])[C:13]([NH:17][C:18](=[O:32])[CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][N:11]=1)C1C=CC=CC=1>CO.[Pd]>[OH:16][C:14]1[C:13]([NH:17][C:18](=[O:32])[CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][N:11]=[C:10]([CH2:9][OH:8])[N:15]=1
Reactant: O=C(Nc1cnc(COCc2ccccc2)nc1O)C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1cnc(CO)nc1O)C(c1ccccc1)c1ccccc1
Yield: 62.8 %

Procedure:
To a solution of step D product, 3-f, (1.2 g, 2.8 mmol) in MeOH (100 mL) was added Pd/C (200 mg, 10%) and HCO2NH4 (0.36 g, 5.6 mmol). The mixture was stirred and refluxed for 5 h. The reaction mixture was filtered. The liquids were concentrated and purified by column chromatography to afford the product, 3-g (590 mg, 64%). 1H NMR (300 MHz, DMSO) δ 4.30 (d, J=4.2 Hz, 2H), 5.66 (s, 1H), 7.21-7.35 (m, 11H), 8.66 (s, 1H), 9.64 (s, 1H). LC-MS (M+H)+ 326.1.