Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:7][NH:8][C:9]1[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH2:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[N:10]=1.O.[Na]>O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH2:7][NH:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([N:20]2[CH2:28][C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[N:10]=1
Reactant: CCOC(=O)c1cnc(N2Cc3cccnc3C2)nc1NCc1ccc(OC)c(Cl)c1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2nc(N3Cc4cccnc4C3)ncc2C(=O)O)cc1Cl
Reaction time: 8 h
Yield: 36 %

Procedure:
Methanol (30 mL) was added in ethyl 4-((3-chloro-4-methoxybenzyl)amino)-2-(5H-pyrrolo[3,4-b]pyridin-6 (7H)yl)-5-pyrimidine carboxylate (3.0 g, 6.82 mmol). Sodium hydrate (0.55 g, 13.6 mmol) was dissolved in water (10 mL) and added into the solution. The reaction was conducted in an oil bath of 50 to 60° C. overnight. LC-MS was used to monitor the reaction. The organic solvent was removed by rotary evaporation. The residual aqueous phase was adjusted to a pH of 3 to 4. Solid was precipitated, filtrated, and dried (1.0 g, 36.0% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-])=O.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Nitrophenol (25.0 g, 180 mmol) and ethyl bromoacetate (20.0 ml, 180 mmol) were dissolved in N,N-dimethylformamide (40 ml), and potassium carbonate (27.4 g, 198 mmol) was added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction mixture was poured into water (100 ml) and extracted with an equivalent mixture of n-hexane and ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure to quantitatively give 40.5 g of ethyl 4-aminophenoxyacetate as a colorless solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:15]=[O:16])=[CH:8][N:9]2[C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1)[CH3:2].CC(=CC)C.O.[O-:23]Cl=O.[Na+]>C1COCC1.C(O)(C)(C)C>[C:12]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([CH2:1][CH3:2])[CH:11]=2)[C:7]([C:15]([OH:23])=[O:16])=[CH:8]1)(=[O:13])[NH2:14]
Reactant: CCc1ccc2c(C=O)cn(C(N)=O)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1ccc2c(C(=O)O)cn(C(N)=O)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Ethyl-3-formyl-indole-1-carboxylic acid amide (720 mg, 3.33 mmol) was dissolved in a mixture of THF (60 mL) and t-butanol (18 mL). 2-methyl-2-butene (2 M solution in THF, 66.6 mL, 133 mmol) was added, followed by a water (16 mL) solution of NaClO2 (80%, 3.76 g, 33.3 mmol) and NaH2PO4 (3.20 g, 26.6 mmol). The resulting solution was stirred at RT for 4 h and THF was concentrated. EtOAc was added and the layers separated. The aqueous layer was acidified by addition of HCl 1N and extracted twice with EtOAc. The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to EtOAc to CH2Cl2/MeOH 8:2) to give the desired compound. tR (HPLC conditions a): 2.17 min. 1H-NMR (400 MHz, CDCl3): δ (ppm): 12.9 (m, 1H), 8.81 (s, 1H), 8.66 (bs, 1H), 8.23 (d, 1H),), 8.09 (m, 2H), 7.70 (dd, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]=[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH3:16])=[O:14].Br[CH2:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH3:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:9]1([C:13]([O:15][CH3:16])=[O:14])[CH2:10][CH2:11][CH2:12][C:8]1=[O:7]
Reactant: COC(=O)C1CCCC1=O
Reactant: CC(C)(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C1(CCC(C)(C)C)CCCC1=O
Temperature: 25 °C

Procedure:
117.0 g (846.0 mmol) of potassium carbonate are added to a solution consisting of 40.0 g (281.7 mmol) of methyl 2-oxocyclopentanecarboxylate in 160 ml of dry toluene. 93 g (563.4 mmol) of 1-bromo-3,3-dimethylbutane are then added dropwise, and the mixture is stirred at reflux for 14 hours. After the reaction has ended the mixture is cooled to room temperature and filtered off through Celite. The product is concentrated under reduced pressure and purified by column chromatography (silica gel 100-200 mesh, mobile phase: ethyl acetate 5%/petroleum ether). This gives 48 g (75% of theory) of methyl 1-(3,3-dimethylbutyl)-2-oxocyclopentanecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]([NH:24][CH3:25])[CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[CH2:29][CH2:30][CH2:31][OH:32]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([NH:24][CH2:25][CH2:29][CH2:30][CH2:31][OH:32])[CH3:23])=[CH:20][CH:21]=3)[CH2:14][CH2:15]2)[CH3:9])=[O:7])=[CH:26][CH:27]=1
Reactant: CNC(C)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Reactant: OCCCBr
Product: CC(NCCCCO)c1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-methyl-4-[4-(1-methylaminoethyl)phenyl]cyclohexylamine and 3-bromo-1-propanol. Melting point: 88°-90° C.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.[CH:27]1([C:33]2[CH:38]=[CH:37][C:36]([C:39]([NH:41][C:42]3[CH:51]=[CH:50][C:49]([C:52]#[C:53][Si](C)(C)C)=[CH:48][C:43]=3[C:44]([O:46][CH3:47])=[O:45])=[O:40])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(OCC)(=O)C>[CH:27]1([C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][C:42]3[CH:51]=[CH:50][C:49]([C:52]#[CH:53])=[CH:48][C:43]=3[C:44]([O:46][CH3:47])=[O:45])=[O:40])=[CH:37][CH:38]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1NC(=O)c1ccc(C2CCCCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc(NC(=O)c2ccc(C3CCCCC3)cc2)c(C(=O)OC)c1
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
351 mg (1.1 mmol) of tetrabutyl ammonium fluoride trihydrate was added to a THF (9 mL) solution comprising 322 mg (0.74 mmol) of methyl 2-{[(4-cyclohexylphenyl)carbonyl]amino}-5-[(trimethylsilyl)ethynyl]benzoate at 0° C., and the mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was diluted with ethyl acetate, and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 208 mg of methyl 2-{[(4-cyclohexylphenyl)carbonyl]amino}-5-ethynylbenzoate (yield: 78%).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[C:6]1([CH:16]=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].Cl>C(O)C.O>[C:6]1([CH2:16][CH:2]([C:1]#[N:5])[C:3]#[N:4])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: N#CCC#N
Reactant: O=Cc1cccc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CC(C#N)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 168 h
Yield: 80 %

Procedure:
To a mixture of malononitrile (1.32 g, 20 mmol) in Ethanol (50 mL) and Water (2.50 mL) was added 1-naphthalenecarbaldehyde (3.12 g, 20 mmol). The reaction was stirred at rt for 7 days. The mixture was cooled to 0° C. in an ice bath. Sodium borohydride (0.204 g, 5.40 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (20 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave (1-naphthalenylmethyl)propanedinitrile (3.3 g, 80%). To a solution of (1-naphthalenylmethyl)propanedinitrile (3.3 g, 16 mmol) in Ethanol (80 mL) was added hydrazine hydrate (0.785 mL, 16.00 mmol). The mixture was heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (MeOH/DCM: 0˜10%) to give the product (2.18 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.96 (s, 2H) 7.26 (d, J=7.07 Hz, 1H) 7.31-7.44 (m, 1H) 7.45-7.58 (m, 2H) 7.74 (d, J=8.08 Hz, 1H) 7.85-7.97 (m, 1H) 8.12-8.26 (m, 1H) 10.05 (bs, 1H). LC/MS: MS (ES+) m/e 239.0 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH2:23][CH3:24])(OCC)OCC>C(O)C>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:1]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]3[CH:23]=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:10][CH:9]=2)=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Nc2ccccc2)cc1
Solvent: CCO
Product: C(=Nc1ccc(Nc2ccccc2)cc1)Nc1ccc(Nc2ccccc2)cc1
Yield: 72.4 %

Procedure:
The procedure of Example 1 is repeated using 10.0 g (0.054 mol) of N-phenyl-1,4-phenylenediamine and 3.3 g (0.22 mol) of triethyl orthoformate. The residue is slurried with ethanol to give 7.4 g (83%) of a brown solid, mp. 173°-175° C.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH3:24][NH:25][NH2:26].C(O)(=O)C.[OH-].[Na+]>O.C(O)C>[CH3:24][N:25]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([CH2:5][C:4]([OH:3])=[O:23])[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:26]1
Reactant: CNN
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(-c2ccccc2)c(CC(=O)O)c1-c1ccccc1
Yield: 66.8 %

Procedure:
6.2 grams 3,3-dibenzoyl-propionic acid-ethyl ester, 1.0 gram methyl hydrazine and 4 grams glacial acetic acid were mixed and the mixture heated to the boiling temperature under reflux for 4 hours. The reaction mixture was then evaporated, the residue taken upon benzene and extracted with water. The benzene was then distilled from the benzene phase and the residue, constituting the crude ester reaction product, was heated with 2.0 grams sodium hydroxide, 20 milliliters ethanol and 20 milliliters water to the boiling temperature under reflux for 2 hours. The reaction mixture was then worked up and the reaction product was recovered by the general procedure set out in Example (2a). The recovered free acid was recrystallized from a mixture of benzene and petroleum ether boiling in a range from 50°-70° C. 3.9 grams 1-methyl-3,5-diphenyl-pyrazol-4-acetic acid, melting at 170°-172° C., were obtained, representing a yield of 67%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[C:50]([OH:61])=[C:51]([CH2:55][CH2:56][NH:57][C:58](=[O:60])[CH3:59])[CH:52]=[CH:53][CH:54]=1>>[C:58]([NH:57][CH2:56][CH2:55][C:51]1[CH:52]=[CH:53][CH:54]=[C:49]([F:48])[C:50]=1[O:61][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:60])[CH3:59]
Reactant: CC(=O)NCCc1cccc(F)c1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2c(F)cccc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of N-[2-(3-fluoro-2-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.42 (EtOAc); Rt=5.65.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:14]([C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1)#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COC(=O)C=Cc1ccc(Br)cc1
Reactant: C#CCCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccc(C=CC(=O)OC)cc1
Yield: 46 %

Procedure:
To a deaerated solution of methyl 4-bromocinnamate (9.64 g, 40 mmole) in dry triethylamine (120 ml) was added triphenylphosphine (308 mg) followed by 1-tridecyne (8.00 g, 45 mmole) and palladium (II) acetate (92 mg) under nitrogen. The mixture was heated to reflux for 24 hours, the reaction being followed by hplc. After this time the mixture was cooled and the precipitated triethylamine hydrobromide was filtered off and washed with a little triethylamine. The filtrate was evaporated to a red solid which was chromatographed on 220 g of silica eluting with petroleum ether [bp 60-80]-dichloromethane (3:2) to give 6.26 g (47%) of title compound as a pale yellow solid of mp (MeOH) 57°-59° C., υmax (mull) 1710, 1630, 1600, 1315, 1170, 1000, 830 cm-1, δ(CDCl3). 0.85 (3H, distorted t, terminal CH3), 1.28 (18H, m, alkylene chain), 2.38 (2 H, t, J 6.5 Hz, C≡C--CH2), 3.78 (3H, s, ester CH3), 6.37 (1H, d, J 16 Hz, =CHCO2), 7.42 (4H, near s, arom), 7.63 (1H, d, J 16 Hz, ArCH=)
Reaction SMILES: CC(OC)(C)C.[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C@@H:13]([C@@H:18]1[CH2:20][O:19]1)[CH2:12][CH2:11]2>>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C@@H:13]([C@H:18]1[CH2:20][O:19]1)[CH2:12][CH2:11]2
Reactant: Fc1ccc2c(c1)CC[C@H]([C@@H]1CO1)O2
Solvent: COC(C)(C)C
Product: Fc1ccc2c(c1)CC[C@H]([C@H]1CO1)O2
Yield: 100 %

Procedure:
The resulting catalyst residue was dissolved in (2R)-6-fluoro-2-[(2S)-oxiran-2-yl]-3,4-dihydro-2H-chromene (0.97 g), (2R)-6-fluoro-2-[(2R)-oxiran-2-yl]-3,4-dihydro-2H-chromene (0.97 g) [(R,R)-,(R,S)-epoxide diastereoisomeric mixture)] and MTBE (2.36 ml) and the mixture obtained was treated with H2O (0.099 g).
Reaction SMILES: [C:1]([N:4]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH:24]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:36])[CH2:6]1)(=[O:3])[CH3:2].[OH-].[K+]>O1CCCC1.CO>[C:1]([N:4]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:35]=[CH:34][C:20]([O:21][CH2:22][CH2:23][CH:24]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:36])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)C(CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C(CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)C(=O)O
Temperature: 50 °C
Yield: 55 %

Procedure:
Methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydro-quinolin-1(2H)-yl]carbonyl}phenoxy)-2-(diethylamino)butanoate was hydrolyzed to the acid by dissolving in 6 ml tetrahydrofuran/methanol (1/1) and potassium hydroxide (0.04 g in 2 ml water) was added. The mixture was heated to 50° C. for 18 hours. The mixture was cooled to room temperature and concentrated. Then neutralized with 1M HCl and extracted with dichloromethane. The dichloromethane solution was dried and concentrated. The residue was purified by silica gel chromatography (87% CH2Cl2/13% methanol) to afford 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}phenoxy)-2-(diethylamino)butanoic acid (0.04 g, 55%).
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:24]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:25]([NH:27][N:28]([S:35]([CH3:38])(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:10].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.ClCCl>[OH:7][NH:8][C:9]([C@H:11]([C@@H:24]([CH2:39][CH:40]([CH3:42])[CH3:41])[C:25]([NH:27][N:28]([S:35]([CH3:38])(=[O:37])=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](C/C=C/c1ccc([N+](=O)[O-])cc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](C/C=C/c1ccc([N+](=O)[O-])cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A solution of 0.080 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-(4-nitrophenyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in a mixture of 3 ml of methanol and 1.5 ml of dichloromethane was treated with 0.020 g of 4-toluenesulphonic acid. The mixture was stirred for 5 hours at room temperature and the solution was evaporated. The resulting gum was triturated with diethyl ether to give 0.063 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-(4-nitrophenyl)-3-butenyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in the form of a light-brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:27])[CH3:26])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:35])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:27])[CH3:26])=[C:8]2[C:16]([Cl:35])=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccc(F)cc2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccc(F)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 124(b) from 4-acetoxy-7-cyano-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NCS in MeCN. The title compound, ESI MS (m/z): 402 (M+H)+.
Reaction SMILES: C([O:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][CH:29]([CH3:31])[CH3:30])[CH:23]=3)=[CH:15][CH:14]=2)[O:10][N:9]=1)(=O)C(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.[OH-].[Na+]>[CH:29]([NH:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]3[O:10][N:9]=[C:8]([OH:7])[CH:12]=3)=[CH:14][CH:15]=2)[CH:27]=[CH:26][CH:25]=1)([CH3:31])[CH3:30]
Reactant: CC(C)Nc1cccc(CCOc2ccc(-c3cc(OC(=O)C(C)(C)C)no3)cc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Nc1cccc(CCOc2ccc(-c3cc(O)no3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(4-(2-(3-(isopropylamino)phenyl)ethoxy)phenyl)-3-isoxazolyl pivalate (24.9 mg) in methanol (1 ml), 0.05 ml of 4N aqueous sodium hydroxide was added, and the reaction solution was stirred at room temperature for 1 hour. To the reaction solution was added 10% aqueous citric acid, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by preparative thin layer chromatography (Kieselgel™ 60 F254, Art5744, made by Merck & Co., chloroform/methanol (90:10)) to afford the title compound as a colorless amorphous matter.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[NH:15]C(=O)C.[N:20](OC(C)(C)C)=O.O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]2[C:6](=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=2)[NH:15][N:20]=1)=[O:19]
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)Cc1ccc(C(F)(F)F)cc1NC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1n[nH]c2cc(C(F)(F)F)ccc12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-acetylamino-4-trifluoromethylphenyl)-acetic acid methyl ester (16 g, 0.058 mol) in acetic acid (50 mL) was added dropwise t-butyl nitrite (90%) (7.35 g, 0.063 mol) over a period of 20 min. at 90-95° C. The mixture was then stirred for 0.5 h at 95° C., poured into cold water and stirred for 1 h. The precipitates were collected by filtration and washed with water. The crude material was dissolved in ethyl acetate and dried over sodium sulfate. The solvent was removed in vacuo. This material (13.4 g, 95%) was used without further purification in the next step. A small sample was crystallized from ethyl acetate to yield a white solid, mp 240-242° C. 1H NMR (DMSO-d-6) 8.25 (d, J=8.5 Hz, 1H), 8.04 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 3.95 (s, 3H). MS (FAB) m/z: 245.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B1C2CCCC1CCC2.Br[C:25]1[CH:34]=[N:33][C:32]2[N:31]3[CH2:35][CH2:36][CH2:37][C@H:30]3[C:29](=[O:38])[NH:28][C:27]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:25]3[CH:34]=[N:33][C:32]4[N:31]5[CH2:35][CH2:36][CH2:37][C@H:30]5[C:29](=[O:38])[NH:28][C:27]=4[CH:26]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C=C1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=C1Nc2cc(Br)cnc2N2CCC[C@@H]12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C1Nc2cc(CC3CCN(c4ccc(Cl)cc4)CC3)cnc2N2CCC[C@@H]12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
1-(4-chlorophenyl)-4-methylenepiperidine (70 mg, 0.337 mmol) was diluted with 0.5M THF solution of 9-BBN (0.674 mL, 0.337 mmol) under nitrogen and stirred at 75° C. for 1 h. The reaction mixture was then added to a suspension of (S)-3-bromo-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (90 mg, 0.337 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.26 mg, 10.11 μmol) and potassium carbonate (93 mg, 0.674 mmol) in DMF (1.0 mL) and water (0.1 mL) and stirred at 60° C. for 4 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])[CH:6]=[CH:7][CH:8]=O.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:31]2[O:27][C:28](=[O:33])[NH:29][C:30]2=[O:32])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20]
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 3-methoxy-4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.161-162° C.