Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:19][CH3:20])(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[CH2:19]([C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:20]
Reactant: CCc1cc2ccccc2n1S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc2ccccc2[nH]1

Procedure:
1.2 g (4.2 mmol) 1-benzenesulphonyl-2-ethyl-1H-indole in 10 mL EtOH were mixed with 5 mL of a (20 mmol) 4 N aqueous sodium hydroxide solution and refluxed for 8 h. Then the solvent was eliminated using the rotary evaporator and the residue was diluted with ice water. After acidifying with semi-concentrated aqueous hydrochloric acid the grease precipitated was extracted with ethyl acetate. The organic phase was dried on sodium sulphate, filtered off, evaporated down and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:38])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](I)=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[C:44](=O)([O-:46])[O-:45].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:44]([OH:46])=[O:45])=[CH:33][N:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:38])=[C:16]([F:22])[CH:17]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(I)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
In a 50 ml pressure tube, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-(5-iodopyridin-2-yl)-5-neopentylpyrrolidine-2-carboxamide (87 mg, 130 μmol, Eq: 1.00) was combined with DMF (3.48 ml) and water (174 μl). Potassium carbonate (35.9 mg, 260 μmol, Eq: 2) was added. The mixture was bubbled with nitrogen and then palladium (II) acetate (3.48 mg, 15.5 μmol, Eq: 0.119) was added. The tube was subjected to CO atmosphere at 40 PSI and stirred for 3 hours at 70° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[NH2:8].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=S.[CH3:24]O>>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[O:1][C:2]2[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: S=C=Nc1ccccc1Br
Reactant: CO
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Product: CCOC(=O)Cc1ccc2nc(Nc3ccccc3Br)oc2c1
Temperature: 25 °C
Yield: 66 %

Procedure:
Methyl 3-hydroxy-4-aminophenylacetate (2.97 g, 16.4 mmol) was dissolved in methanol (30 ml). Under stirring at room temperature, 2-bromophenyl isothiocyanate (2.65 ml, 19.7 mmol) was added to the resulting solution. The reaction mixture was then stirred at room temperature for 1.5 hours. Mercuric oxide (yellow) (3.55 g, 16.4 mmol) was added to the reaction mixture, followed by heating and refluxing for 50 minutes. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off through Celite under reduced pressure. The filtrate was distilled under reduced pressure to remove the solvent. The residue was then purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, ethyl 2-(2-bromophenylamino)-6-benzoxazolylacetate (3.87 g, 66%) was obtained as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=C(C#N)[CH:9]=[CH:8][N:7]2[CH:14]=1)([CH3:3])[CH3:2].[OH-:15].[Li+].Cl.[CH2:18]([OH:20])[CH3:19]>>[CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[C:19]([C:18]([OH:15])=[O:20])[CH:9]=[CH:8][N:7]2[CH:14]=1)([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)c1cn2ccc(C#N)cc2n1
Reactant: CCO
Agent: Cl
Agent: [Li+]
Product: CC(C)c1cn2ccc(C(=O)O)cc2n1
Yield: 83 %

Procedure:
2-Isopropylimidazo[1,2-a]pyridine-7-carbonitrile (15.9 g, 85.8 mmol) obtained in step 1 was dissolved in a 50% ethanol aqueous solution (80 mL). Under water-cooled condition, lithium hydroxide.1 hydrate (7.20 g, 172 mmol) was added, and the mixture was stirred under heat and reflux for 3 hours. Under ice-cooled condition, 3 mol/L hydrochloric acid (62 mL) was added to the reaction mixture. The precipitated crystals were collected by filteration, washed with water, and dried to give 2 isopropylimidazo[1,2-a]pyridine-7-carboxylic acid (14.6 g, yield 83%).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([O:9]C)=[O:8]>C1COCC1.O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(N2CCCCC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)ccc1N1CCCCC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
Lithium hydroxide (2.5 g; 103 mmol; 5 eq.) was added to a solution of methyl 3-methyl-4-piperidin-1-ylbenzoate (4.8 g; 20.6 mmol; 1 eq.) in THF (100 mL) and water (5 mL) and the reaction mixture was stirred at 50° C. for 12 hours. The solvent was removed in vacuo, the residue diluted with water and the aqueous layer washed with DCM (2×50 mL). The aqueous layer was acidified to pH 4 with conc. HCl and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound (4.0 g, 89%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23](Cl)[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:30][CH2:31][CH3:32].[Na+]>C(O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Cl:29])=[CH:21][N:22]=[C:23]([O:30][CH2:31][CH3:32])[C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:16])=[O:17])[CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(S(=O)(=O)c2cccc3c(Cl)ncc(Cl)c23)C1
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(Cl)c2c(S(=O)(=O)N3CC[C@H](N(C)C(=O)OC(C)(C)C)C3)cccc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
A solution of Intermediate 25 (230 mg) obtained in Example 36-1 in ethanol (10 ml) was added with sodium ethoxide (204 mg, Aldrich), and the mixture was stirred at 50° C. for 12 hours. The reaction mixture was added with saturated brine (10 ml), and extracted three times with ethyl acetate (10 ml for each time), and the combined organic layer was washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (223 mg).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:38][CH:37]=2)=[CH2:35])[N:28]=3)=[C:21]([F:50])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:32]([N:33]=2)=[CH:31][CH:30]=[C:29]([C:34]2([C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)=[CH:38][CH:37]=4)[CH2:1][CH2:35]2)[N:28]=3)=[C:21]([F:50])[CH:20]=1
Reactant: CC(C)(C)[O-]
Reactant: C=C(c1ccc(OCc2ccccc2)cc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2n1
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(c4ccc(OCc5ccccc5)cc4)CC3)nc2s1
Reaction time: 4 h

Procedure:
A solution of potassium tert-butoxide (0.206 g, 1.83 mmol) and trimethylsulfoxonium iodide (0.404 g, 1.83 mmol) in 5 mL DMSO under nitrogen was added 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)vinyl)-thiazolo[5,4-b]pyridine (0.385 g, 0.734 mmol) as a solution in 6 mL THF (min volume to dissolve) slowly dropwise via addition funnel over 1 h. The cloudy reaction mixture was allowed to stir for 4 h and was quenched with ice. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with water, brine, dried, and concentrated in vacuo to give an oil/solid which was purified by silica gel chromatography 0-100% EA/hexanes to give 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)cyclopropyl)thiazolo[5,4-b]pyridine as a yellow solid. The aqueous suspension from the extraction was further extracted with DCM, the combined org extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give additional 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(4-(benzyloxy)phenyl)-cyclopropyl)thiazolo[5,4-b]pyridine. MS (ESI) m/z: calculated: 538.2; Observed: 539.1 (M++1).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9](=O)[CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].[BH4-].[Na+].C(N(CC)CC)C.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CO.C(OCC)(=O)C.Cl>[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([S:42]([N:6]2[CH2:7][CH:8]3[CH2:9][CH2:10][CH:5]2[C:3](=[O:2])[O:4]3)(=[O:44])=[O:43])=[CH:38][CH:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C1OC2CCC1N(S(=O)(=O)c1ccc(OCc3ccccc3)cc1)C2
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.5 %

Procedure:
To a solution of 4-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.1 g, 3.9 mmol) in 20 mL of methanol was added sodium borohydride (0.14 9, 3.9 mmol) at 0° C. After stirring for 2 h at 0° C., the mixture was diluted with ethyl acetate, washed with 1M HCl, 1M NaOH, and brine, dried over Na2SO4, filtered and concentrated. The residue was taken up in 10 mL of 6M aqueous HCl and was refluxed for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the residue was dissolved in 5.5 mL of anhydrous DMF. The solution was cooled to 0° C. and was treated with triethylamine (4.8 mL, 34 mmol) and 4-benzyloxy-benzenesulfonyl chloride (2.5 g, 8.8 mmol). After stirring for 2 h, the mixture was diluted with 1M HCl, extracted 3× with ethyl acetate, and the organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was filtered through a small pad of silica gel eluting with 1:1 ethyl acetate-hexane, affording 0.43 g of 5-(4-benzyloxy-benzenesulfonyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3one as a colorless solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:27][C:28](=[O:49])[C@@H:29]([NH:37][C:38](=[O:48])[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])=[CH:13][CH:12]=2)[S:6]1(=[O:51])=[O:50])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CO.ClCCl.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:27][C:28](=[O:49])[C@@H:29]([NH:37][C:38](=[O:48])[CH2:39][C:40]3[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=3)[CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])=[CH:13][CH:12]=2)[S:6]1(=[O:51])=[O:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCNC(=O)[C@H](Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)Cc1ccc(OC)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Solvent: ClCCl
Solvent: CCO
Product: CCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)Cc1ccc(OC)cc1
Yield: 95.4 %

Procedure:
A solution of 401-A (50 mg, 0.07 mmol) and 5% Pd/BaSO4 (5 mg, 10 wt %) in ethanol (1.5 mL), methanol (1.0 mL) and dichloromethane (2 drops) was stirred under an atmosphere of hydrogen for 5 h. The reaction mixture was filtered and concentrated to yield the 401-B (48 mg, 96%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.30–7.26 (m, 4H), 7.22–7.16 (m, 4H), 7.00–6.94 (m, 4H), 6.85–6.81 (m, 2H), 6.43 (dd, J=8.3, 4.9 Hz, 1H), 5.90–5.84 (m, 1H), 5.79 (dd, J=8.8, 6.8 Hz, 1H), 4.75 (ddd, J=10.7, 9.3, 2.0 Hz, 1H), 4.61–4.57 (m, 1H), 4.50 (dd, J=12.2, 6.3 Hz, 1H), 3.82 (s, 3H), 3.43–3.35 (m, 2H), 3.22–3.09 (m, 4H), 3.05–3.03 (m, 1H), 3.00–2.90 (m, 1H), 2.90–2.80 (m, 1H), 1.66 (s, 9H), 1.40–1.35 (m, 2H), 1.35–1.23 (m, 2H), 1.23–1.17 (m, 2H), 0.88 (t, J=7.1 Hz, 3H); LCMS found for C39H51N4O7S (M+H)+: m/z=719.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.C(N1CC(OC2C=CC=C(C(F)(F)F)C=2)C1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([CH3:51])[C:46]=1[N:52]=[C:53]=[S:54]>C(Cl)Cl>[CH3:51][C:47]1[CH:48]=[CH:49][CH:50]=[C:45]([CH3:44])[C:46]=1[NH:52][C:53]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[S:54]
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: Cc1cccc(C)c1N=C=S
Agent: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=S)N1CC(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
Crude 3-[3-(trifluoromethyl)phenoxy]azetidine from catalytic debenzylation of 30.0 g (0.078 mole) of 1-benzhydryl-3-[3-(trifluoromethyl)phenoxy]azetidine was dissolved in 100 ml of methylene chloride and treated dropwise under a nitrogen atmosphere with a solution of 12.7 g (0.078 mole) of 2,6-dimethylphenylisothiocyanate in 25 ml of methylene chloride. The product began to precipitate during the addition and an additional 50 ml of methylene chloride was added to facilitate stirring. After stirring overnight at ambient temperature, the product was collected by filtration (13.5 g, m.p. 196°-199° C.). A 6.0 g sample was recrystallized from isopropanol to give 5.3 g of product, m.p. 197°-199° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=1.S(=O)(=O)(O)O.[CH2:28](O)[CH3:29]>>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([CH:15]=[C:16]([CH3:18])[N:17]=2)[CH:9]=[C:10]([C:12]([O:14][CH2:28][CH3:29])=[O:13])[CH:11]=1
Reactant: CCO
Reactant: Cc1cn2cc(C(=O)O)cc(OCc3ccccc3F)c2n1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(OCc2ccccc2F)c2nc(C)cn2c1

Procedure:
To 350 mg of 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylic acid were added 18 ml of ethanol and 200 μl of sulfuric acid, followed by heating to reflux overnight. Under reduced pressure, the solvent was removed by filtration to around one third of the amount thereof, and a saturated aqueous sodium hydrogen carbonate solution and chloroform were then added thereto to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 330 mg of ethyl 8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:5])[CH3:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.ClCCl>[C:18]([O:17][C:13]([CH2:14][CH2:15][C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CCOC(=O)C1(CCC(=O)OC(C)(C)C)CCCCC1=O
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 2-ethoxycarbonylcyclohexanone (5.0 g, 0.029 mol) and tert-butyl acrylate (4.83 g, 0.037 mol) in tert-butanol (30 ml) was added, in one portion, potassium carbonate (4.0 g, 0.029 mol). The suspension was stirred at room temperature for 22 hours, diluted with dichloromethane (100 ml) and distilled water (100 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (2×100 ml) and the combined dichloromethane extracts dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica by eluting with hexane/ethyl acetate (4:1) to give, after combination and evaporation of appropriate fractions, the title compound as a colorless oil, (7.99 g, 92.3%; 98.92% by GC normalization) (MH+ 299.03, 8.53%). Rf. 0.15 (silica, hexane/ethyl acetate 4:1). 1H-NMR (300 MHz, CDCl3):=1.20 (t, 3H), 1.37 (s, 9H), 1.52-2.46 (m, 12H), 4.08-4.21 (m, 2H) ppm. 13C-NMR (62 MHz, CDCl3):=13.97, 22.38, 27.36, 27.91, 29.52, 30.49, 36.06, 40.85, 59.87, 61.19, 80.10, 171.61, 172.22, 207.39 ppm. Analysis %: Found: C, 64.19; H, 8.80; C16H26O5 requires: C, 64.41; H, 8.78.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH2:15][C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]=3)[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2].N1C=CC=CC=1.[C:36](OC=O)(=[O:41])C(C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:28])=[C:12]([CH:15]=[C:16]3[C:25]4[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=4)[CH2:19][CH2:18][N:17]3[CH:36]=[O:41])[CH:13]=2)[NH:8][C:7]=1[CH3:29])=[O:5])[CH3:2]
Reactant: CC(C)(C)C(=O)OC=O
Reactant: CCOC(=O)c1c(C)[nH]c2cc(Br)c(CC3=NCCc4cc(OC)ccc43)cc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1c(C)[nH]c2cc(Br)c(C=C3c4ccc(OC)cc4CCN3C=O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of 6-bromo-5-(6-methoxy-3,4-dihydro-isoquinoline-1-ylmethyl)-2-methyl-1H-indole-3-carboxylic acid ethyl ester (2.03 g, 4.5 mmol) in CH2Cl2 (50 mL) is added pyridine (2.3 g, 30 mmol) and 3N formic pivalic anhydride (5 mL; 14.5 mmol) at 0° C., and the reaction is stirred at room temperature for 3 hours. CH2Cl2 (50 mL) is then added to the reaction mixture and the organic layer is washed with water (2×50 mL), IN HCl (50 mL), 1N NaOH (50 mL), and brine (50 mL). The solution is dried (Na2SO4), filtered, and concentrated in vacuo to give the desired product (1.3 g, 60%). MS: 483, 485 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@@H:13]2[CH3:22])[C:9]2[C:4](=[C:5]([O:23][CH3:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1>CN(C)C=O>[ClH:1].[CH3:24][O:23][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([F:25])=[CH:27][C:28]=1[CH3:33])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@@H:13]1[CH3:22]
Reactant: COc1cccc2c(N3CCc4ccccc4[C@@H]3C)nc(Cl)nc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: COc1cccc2c(N3CCc4ccccc4[C@@H]3C)nc(Nc3ccc(F)cc3C)nc12
Product: Cl
Yield: 44 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 2.64 g of the compound (7.77 mM) prepared in Example 7 and 15 ml of dimethyl-formamide, 1.33 ml of 4-fluoro-2-methylaniline(16.3 mM) was added, 1.60 g of the title compound was prepared.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][CH3:19])[C:10]=1[CH3:20].[N:21]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:22]=[O:23]>C(#N)C.C(Cl)Cl>[CH2:28]([O:27][C:25]([CH2:24][NH:21][C:22]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH2:17][O:18][CH3:19])[C:10]=1[CH3:20])=[O:23])=[O:26])[CH3:29]
Reactant: COCCn1ccc(=O)c(O)c1C
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Oc1c(C)n(CCOC)ccc1=O
Reaction time: 0.17 h

Procedure:
5.60 ml of triethylamine are added to a mixture of 5.49 g of 3-hydroxy-1-(2-methoxyethyl)-2-methyl-4(1H)-pyridinone in 150 ml of acetonitrile and 150 ml of methylene chloride, followed by the addition of 6.83 ml of ethyl isocyanatoacetate at room temperature. The slightly exothermic reaction, in the course of which a solution forms within 10 minutes, is complete after 3 hours. The solvent is removed under reduced pressure and the residue is dried under a high vacuum and crystallised from ethyl acetate. The mother liquor is discarded. 1 g of the pale beige product is partitioned between methylene chloride and water. The bulk of the product is present in the aqueous phase, which is concentrated by evaporation. The residue is dissolved in methanol and the solution is treated with activated carbon and concentrated by evaporation. The residue is crystallised from ethyl acetate, to give white crystalline 3-(ethoxycarbonylmethylaminocarbonyloxy)-1-(2-methoxyethyl)-2-methyl-4(1H)-pyridinone with a melting point of 134°-135° C.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CO>[CH2:8]([S:15][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: C=C(CBr)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=C(CSCc1ccccc1)C(=O)O
Reaction time: 23 h
Yield: 89 %

Procedure:
2-Bromomethylacrylic acid (3.00 g, 18.1 mmol) was dissolved in methanol (100 mL), cooled on an ice bath and treated with benzyl mercaptan. Aqueous sodium hydroxide (1N, 39.8 mL) was added dropwise and the reaction mixture was allowed to adjust to room temperature with stirring for 23 hours. Methanol was removed by rotary evaporation at reduced pressure and water (100 ml) was added to the residue, which was then washed with ether. The aqueous layer was cooled on ice and acidified to pH 2.5. The precipitated solid was isolated by filtration and dried to give 2-benzylsulfanylmethyl-acrylic acid (3.346 g, 89%).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH:7]([F:11])[C:8]([OH:10])=[O:9].[CH3:12]O>>[ClH:3].[CH3:12][O:9][C:8](=[O:10])[CH:7]([F:11])[CH2:6][NH2:5]
Reactant: O=S(Cl)Cl
Reactant: NCC(F)C(=O)O
Reactant: CO
Product: COC(=O)C(F)CN
Product: Cl
Reaction time: 17 h
Yield: 33 %

Procedure:
Dry methanol (5.3 mL) was cooled to −15° C. on an ice bath and thionyl chloride (2.5 mL) was added dropwise maintaining the temperature below 5° C. To this cold solution was added (RS)-3-amino-2-fluoropropionic acid (0.27 g, 2.52 mmol) and stirring was continued until a homogeneous solution was obtained. The ice bath was removed and stirring was continued for 17 hours at room temperature. The solution was concentrated in vacuo and further co-evaporated three times with dry methanol. The residue was filtered off, washed with DCM and dried to afford 0.13 g (33%) of 3-amino-2-fluoropropionic acid methyl ester hydrochloride as a solid.