Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[OH-].[NH4+:22]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:22]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a one liter, stirred flask equipped with a reflux condenser was placed 89.7 gms. of ##STR8## 61.6 gms. of 2-chloroacetamido-5-chlorobenzophenone, 22.4 mls. of 26% ammonium hydroxide and 425 mls. of ethanol. Ammonia was bubbled into the reaction mixture while it was stirred and heated to reflux. Refluxing was continued for 5 hrs. thereafter with stirring. The reaction mixture was distilled to dryness in a Swissco evaporator. The residue was then heated at reflux for one hour in a mixture of 100 mls. of toluene and 100 mls. of water and cooled to room temperature yielding 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one. The product was filtered, washed with 20 mls. of water and 20 mls. of toluene and dried. It weighed 92.5 gms. or 85.4%. The crude product melted at 210°-213° C.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([CH3:26])([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH:28]1([C:34]2[O:35][C:36]([CH3:52])=[C:37]([CH2:39][CH2:40]OS(C3C=CC(C)=CC=3)(=O)=O)[N:38]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][C:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:40][CH2:39][C:37]2[N:38]=[C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:35][C:36]=2[CH3:52])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(OC(F)(F)F)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc(OC(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The representative procedure (B) was utilized to prepare the title compound from 3-(4-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethoxy-phenoxy)-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 7.79-7.94 (m, 2H), 7.43-7.41 (m, 3H), 7.18 (d, 2H, J=8.8 Hz), 7.07 (d, 2H, J=8.4 Hz), 6.89 (d, 2H, J=8.8 Hz), 6.82 (d, 2H, J=8.4 Hz), 4.19 (t, 2H, J=6.4 Hz), 3.24 and 3.14 (d of Abq, 2H, J=14.0 Hz), 3.01 (t, 2H, J=6.4 Hz), 3.00 (bs, 1H), 2.39 (s, 3H), 1.42 (s, 3H). IR (KBr) 3600, 2980, 1725, 1611, 1504, 1265 cm−1. HRMS (ES+) m/z exact mass calcd for C29H27NO6F3 542.1790, found 542.1802.
Reaction SMILES: II.Br[CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][O:7]1.[CH3:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=[O:15]>C1COCC1>[O:7]1[CH2:8][CH2:9][O:10][CH:6]1[CH2:5][CH2:4][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[CH3:11])[OH:15]
Reactant: BrCCC1OCCO1
Reactant: Cc1ccccc1C=O
Agent: II
Solvent: C1CCOC1
Product: Cc1ccccc1C(O)CCC1OCCO1
Temperature: 63 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Mg turnings (134.0 mg, 5.6 mg-at.) and catalytic amount of iodine in 20 mL THF was added dropwise 2-(2-bromoethyl)-[1,3]dioxolane (500.0 mg, 2.8 mmol) with heating over a period of 30 min. After stirring the mixture for 30 min at 63° C. the reaction was cooled to −30° C. and 2-methyl-benzaldehyde (275.0 mg, 2.5 mmol) was slowly added as a solution in 5 mL THF. The temperature was maintained at −30° C. for 1 h and then slowly raised to room temperature over a period of 3 h. The excess Grignard reagent was destroyed by the careful addition of saturated aqueous NH4Cl (40 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL) and the combined organic layers washed with brine (2×20 mL). After evaporation of the solvent, the product was isolated by flash column chromatography eluting with 0 to 50% EtOAc/hexanes affording 290 mg of the title compound as a light yellow oil.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:43])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18](C3CCCCO3)[N:17]=[C:16]4[C:28]3[NH:42][C:31]4[CH:32]=[N:33][CH:34]=[C:35]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[C:30]=4[N:29]=3)[CH:10]=[N:9][CH:8]=2)[CH2:3][CH2:2]1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6](=[O:43])[C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][N:17]=[C:16]4[C:28]3[NH:42][C:31]4[CH:32]=[N:33][CH:34]=[C:35]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[C:30]=4[N:29]=3)[CH:10]=[N:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(NCC1CC1)c1cncc(-c2ccc3c(c2)c(-c2nc4c(-c5cccnc5)cncc4[nH]2)nn3C2CCCCO2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CC1)c1cncc(-c2ccc3[nH]nc(-c4nc5c(-c6cccnc6)cncc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
A solution of N-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)nicotinamide (XXXII) (125 mg, 0.22 mmol) and Et3SiH (87 μL, 0.55 mmol) in DCM (5 mL) was slowly added TFA (2.5 mL). The reaction was stirred at r.t. for 3 h. The reaction was evaporated under vacuum and the residue was treated with water, basified with aq. ammonia. The solids were filtered, washed with cold water and dried. The crude product was heated in MeOH and filtered hot to remove impurities. The hot MeOH solution was allowed to slowly cool to r.t. to produce N-(cyclopropylmethyl)-5-(3-(7-(pyridin-3-yl)-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-5-yl)nicotinamide (3) as a off-white solid (48 mg, 0.10 mmol, 44% yield). 1H NMR (DMSO-d6) δ ppm 0.28 (d, J=4.28 Hz, 2H), 0.42-0.58 (m, 2H), 1.09 (br s, 1H), 3.25 (t, J=6.06 Hz, 2H), 7.50-7.70 (m, 1H), 7.79-8.11 (m, 2H), 8.48-8.68 (m, 1H), 8.69-8.82 (m, 1H), 8.81-8.97 (m, 3H), 9.00-9.18 (m, 2H), 9.46 (br s, 1H); ESIMS found C28H22N8O m/z 487 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:35]5[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]5)=[O:21])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)N1CCNCC1
Product: CS(=O)(=O)N1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 1-methanesulfonylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 19.2 mg of 262. MS (Q1) 527.7 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[C:26]([O:28]CC)=O)[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:32][NH2:33]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:24][C:25](=[O:31])[C:26]([NH:32][NH2:33])=[O:28])[CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)CC(C)C(=O)OCC
Solvent: CO
Product: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(=O)NN
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
To a solution of (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-methylpentanoate (637 mg, 1.43 mmol) in MeOH (40 mL) is added a solution of 50% wt hydrazine (0.09 mL, 1.43 mmol) in MeOH (10 mL) at −20° C. After stirring for 18 hour at room temperature, the reaction mixture is concentrated under reduced pressure to give (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-hydrazinyl-2-oxoacetamido)-2-methylpentanoate (542 mg). HPLC retention time=1.54 minutes (condition A); MS 432.3 (M+1).
Reaction SMILES: C([O:8][C:9](=[O:21])[C:10]1[C:15]([F:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[F:20])C1C=CC=CC=1.[OH-].[Na+].Cl>O1CCCC1.O>[F:20][C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[C:9]([OH:21])=[O:8]
Reactant: O=C(OCc1ccccc1)c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To 2,6-difluoro-3-nitro-benzoic acid benzyl ester (47, 750 mg, 2.6 mmol) in 4 mL of tetrahydrofuran and 2 mL of water, sodium hydroxide (0.2 g, 5.0 mmol) is added and the reaction is stirred for 2 hours. The reaction is acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated under vacuum to provide the desired compound (48, 300 mg).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:9]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C#N)cc1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 1.8 %

Procedure:
A mixture of 4-acetylbenzonitrile (2.00 g, 14 mmol), methyl thiosalicylate (4.63 g, 28 mmol), triethylamine (2.79 g, 28 mmol) and toluene (10 ml) was heated and refluxed for 72 hours under a nitrogen flow. The reaction solution was concentrated under reduced pressure and the residue was applied to column chromatography using silica gel (100 g). Fractions eluted with hexane-ethyl acetate (3:1, v/v) were concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40]>CCO>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: NCCOCCO
Solvent: CCO
Product: O=C(NCCOCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
A mixture of ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.066 mmol) and 2-[(2-aminoethyl)oxy]ethanol (100 μL) was heated in EtOH (3 mL) at 175° C. for 45 min. in a microwave. The reaction mixture was evaporated in vacuo and partitioned between 1N NaHSO4 and CH2Cl2. The aqueous phase was back-extracted with CH2Cl2 and the combined organic layers were dried over MgSO4, filtered, evaporated in vacuo and triturated with Et2O to provide the product as a white solid: 1H NMR (d6-DMSO) δ 10.35 (1H, t, J=5 Hz), 8.54 (1H, s), 8.09 (1H, s), 7.39 (2H, dd, J=5, 9 Hz), 7.11 (2H, t, J=9 Hz), 4.59 (1H, t, J=5 Hz), 4.36 (2H, t, J=6 Hz), 4.14 (2H, s), 3.33-3.56 (12H, m), 1.93 (2H, t, J=8 Hz), 1.74 (2H, t, J=7 Hz); ES+ MS: 513 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[NH:17][C:16](=[O:21])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][CH2:36][OH:37].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([O:21][CH2:35][CH2:36][OH:37])[C:15]=3[N+:22]([O-:24])=[O:23])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(c3ccc(F)cc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(OCCO)c([N+](=O)[O-])c(N2CCN(c3ccc(F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.5 %

Procedure:
0.180 g (0.540 mmol) of the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-3H-pyrimidin-4-one (example 1) and 0.142 g (1.1 mmol) of N-ethyldiisopropylamine, dissolved in 5.0 ml of N,N-dimethylformamide, were slowly added between −5° C. and 0° C. to a suspension of 0.923 g (7.0 mmol) of 2-bromo-ethanol and 0.897 g (6.5 mmol) of potassium carbonate in 5.0 ml of N,N-dimethylformamide. The reaction mixture was then stirred at room temperature for 48 hours. It was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 1:1 v/v gradient of hexane and ethylacetate as the eluent giving 0.039 g (0.10 mmol, 19.1% of theory) of the 2-{6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-2-methyl-5-nitro-pyrimidin-4-yloxy}-ethanol as a light yellow amorphous solid; MS: [M+H]+=378; and 0.091 g (0.241 mmol, 44.7% of theory) of the 6-[4-(4-fluoro-phenyl)-piperazin-1-yl]-3-(2-hydroxy-ethyl)-2-methyl-5-nitro-3H-pyrimidin-4-one as yellowish amorphous solid; MS: [M+H]+378.
Reaction SMILES: [C:1](C1N(CC[C@H](NS(C2C=CC=CC=2)(=O)=O)C)CCS1)([OH:3])=[O:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:33]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[Cl:54])[C@H:34]([CH3:46])[CH2:35][CH2:36][N:37]2[CH2:41][CH:40](CC(O)=O)[S:39][CH2:38]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[OH-].[K+].[K+].[Br-]>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[Cl:54])[C@H:34]([CH3:46])[CH2:35][CH2:36][N:37]2[CH2:41][CH:40]([C:1]([OH:3])=[O:2])[S:39][CH2:38]2)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: C[C@H](CCN1CSC(CC(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C[C@H](CCN1CCSC1C(=O)O)NS(=O)(=O)c1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Product: C[C@H](CCN1CSC(C(=O)O)C1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-(3-(5-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide was prepared analogous to 4-chloro-N-2,5-dichlorophenyl)-N-(3-(2-carboxy-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide by reacting 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(5-carboxymethyl-3-thiazolidinyl)-1(R)-methylpropyl)benzenesulfonamide with 50% aqueous KOH. Yield=70%; White foam: IR (KBr) 1467, 1350, 1167, 1094, 753, 622 cm−1; MS (ESI+), 525 (M+H)+.
Reaction SMILES: CO.[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][C@H:11]2[C:22]([O:24]C)=[O:23])=[N:8][CH:9]=1.[OH-].[Na+]>O>[C:18]([O:17][C:15]([N:13]1[CH2:14][C@@H:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][N:8]=2)[C@H:11]([C:22]([OH:24])=[O:23])[CH2:12]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a methanol solution of the compound (2.8 g) obtained in step 7 was added a solution of sodium hydroxide (0.7 g) in water (30 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure, diluted with water, and washed with ethyl acetate. The aqueous layer was acidified (pH 5) with acetic acid, extracted with dichloromethane, dried and concentrated under reduced pressure to give (3S,4S)-1-(tert-butoxycarbonyl)-4-(5-fluoropyridin-2-yl)pyrrolidine-3-carboxylic acid (2.3 g, 85%) as a white oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].C(N(CC)CC)C.C([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])(=O)C>C(#N)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:24](=[O:23])[C:25]([F:28])([F:27])[F:26])=[CH:11][CH:12]=1)([O-:4])=[O:3]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OCC(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reaction time: 24 h

Procedure:
To a suspension of 4-nitrobenzylamine hydrochloride (10.0 g) and triethylamine (22.2 ml) in acetonitrile (100 ml) was added trifluoroethyl acetate (12.6 ml) at room temperature and the mixture was stirred for 24 hours. The solvent was removed under reduced pressure, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration. The crystals were washed with hexane, to give N-(4-nitrobenzyl)trifluoroacetoamide (12.79 g) as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:20]([Mg]Br)[CH3:21].C(OCC)C>C1COCC1>[OH:2][CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:20][CH3:21]
Reactant: CCOC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(-c2ccc(C(O)CC)nc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 44.8 %

Procedure:
Ethyl 4-(6-formylpyridin-3-yl)benzoate (500 mg, 1.9 mmol) in THF (15 mL) was cooled to 0° C., 3M Ethyl magnesium bromide in diethyl ether (1.3 mL, 3.9 mmol) was slowly added at 0° C., and the reaction mixture was stirred for 2 h at 0° C., while monitoring reaction progress by TLC. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with brine solution (10 mL), the organic layer was dried over Na2SO4 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60-120 microns) using 15% ethyl acetate in hexane eluent to afford ethyl 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzoate as a brown liquid (250 mg, 44.8% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.84 (s, 1H), 8.13-8.11 (d, 1H), 8.04 (d, 2H), 7.87 (d, 2H), 7.57 (d, 1H), 5.33 (d, 1H), 4.57-4.53 (m, 1H), 4.35-4.30 (m, 2H), 1.89-1.76 (m, 1H), 1.68-1.34 (m, 1H), 1.24 (t, 3H), 0.86 (t, 3H), LC-MS m/z calcd for [M+H]+ 286.14. found 286.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1.[CH3:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([CH3:21])[N:5]([C:26](=[O:27])[CH2:25][CH2:24][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]#[N:20])=[CH:9][CH:8]=1
Reactant: CCCC(=O)Cl
Reactant: COC(=O)[C@H](C)NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CCN(CC)CC
Product: CCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@@H](C)C(=O)OC

Procedure:
Reaction of 2.0 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester, 1.23 ml of triethylamine and 0.92 ml of n-butyryl chloride yields N-butyryl-N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-alanine methyl ester. (TLC: N2) Rf : 0.5.
Reaction SMILES: [CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([O:22]C)=[CH:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1.Cl.[OH-].[NH4+].C>CO.ClCCl>[CH3:1][N:2]1[C@@H:7]2[CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]4[O:17][C@H:18]5[C:19]([CH2:20][CH2:21][C@@H:6]2[C@:5]5([C:10]=34)[CH2:4][CH2:3]1)=[O:22]
Reactant: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Yield: 84.9 %

Procedure:
In this Example, 8,14-dihydro-thebaine (6.00 g, 19.14 mmol) was mixed with 24 ml of approx. 6 N Hydrochloric acid (144 mmol, prepared by mixing concentrated hydrochloric acid (12 ml) with DI water (12 ml)) at room temperature with stirring. The homogeneous light yellow colored solution was stirred for 4 hours. Thin Layer chromatography on silica gel plates 90:10:1 (dichloromethane:methanol: concentrated ammonium hydroxide) indicated that the reaction was complete. Decolorizing charcoal (Darco, 0.3 g) was added to the mixture and the reaction stirred for 20 minutes and then filtered. The charcoal was washed with DI water (2×5 ml). The combined acidic phases were cooled to <5° C. and the pH was adjusted to 9.64 with concentrated (28.0-30.0%) ammonium hydroxide solution (approx. 20 ml). The solid was filtered and washed with 2×10 ml of DI water. The product was dried at 60° C. under 22″ Hg vacuum until constant weight to give hydrocodone as a white amorphous said (4.87 g, 84.9% yield, 96.2 wt % by assay).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)N(C(C)=O)CC2
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A stirred solution of 1-acetyl-6-bromoindolin-5-ol (Tetrahedron 1973, 29(8), 1115; 40 g, 0.15 mole) in DMF (500 ml) was treated with K2CO3 (61 g, 0.45 mole) and iodomethane (11.7 ml, 0.19 mole) and maintained at room temperature for 20 h, then concentrated under vacuum to 200 ml. The residue was treated with water (200 ml) and the precipitate filtered off, dried and recrystallised from EtOAc to afford the title compound as a white solid (35.7 g, 85%). MH+ 270/272.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=1[C:5](Cl)=[O:6].[NH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([C:36]([F:39])([F:38])[F:37])[CH:29]=1.C(N(CC)CC)C>ClCCl>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([NH:27][C:5](=[O:6])[C:4]2[C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])=[CH:29][C:30]=1[C:36]([F:37])([F:38])[F:39])#[N:33]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Methoxy-6-pentadecyl-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-methoxy-6-pentadecyl-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.