Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:6]=2[N:7]=1>Cl.CCO>[ClH:1].[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][NH:9][CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCO
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2

Procedure:
A solution of (S)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 1) (200 mg, 0.56 mmol) in 1M HCl in EtOH (5 mL) was stirred at room temperature (20° C.) overnight. The material was concentrated in vacuo to give a white solid.
Reaction SMILES: N1(CCOC2C=CC(NC3C4N(C=CN=4)C(C4C=NNC=4)=CN=3)=CC=2)CCOCC1.[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=2)[CH2:34][CH2:33]1>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:31][N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][O:39][C:40]2[CH:41]=[CH:42][C:43]([NH2:46])=[CH:44][CH:45]=2)[CH2:34][CH2:33]1
Reactant: CN1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Agent: c1cn2c(-c3cn[nH]c3)cnc(Nc3ccc(OCCN4CCOCC4)cc3)c2n1
Solvent: CCO
Product: CN1CCC(COc2ccc(N)cc2)CC1

Procedure:
In the same way as described for Compound 150, step 1, using 1-methyl-4-(4-nitro-phenoxymethyl)-piperidine (0.65 g, 2.6 mmol) in ethanol (40 mL) and palladium hydroxide (0.182 g, 0.26 mmol). Filtration over Celite 521 and evaporation gave a red oil that was purified by silica gel column chromatography eluting with DCM and a 80:20 mixture DCM:MeOH. The title compound was obtained as a white solid (0.402 g, 70%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.30-1.51 (2H, m), 1.65-1.88 (3H, m), 1.89-2.09 (2H, t), 2.29 (3H, s), 2.90 (2H, d), 3.45 (2H, br s), 3.73 (2H, d), 6.67 (2H, d), 6.75 (2H, d).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[N+:17]([CH3:19])[CH3:18].CC1C=CC=CC=1C=O.CNC>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:16]([N:17]([CH3:18])[CH3:19])[C:15]1[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=1[CH3:13])[CH3:2]
Reactant: CCc1cccc2cc[nH]c12
Reactant: Cc1ccccc1C=[N+](C)C
Agent: CNC
Agent: Cc1ccccc1C=O
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3C)N(C)C)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and (2-methyl-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 2-methyl-benzaldehyde and dimethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:19]=1[C:20]#[N:21]>CN(C)C=O>[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[C:22]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:19]=1[C:20]#[N:21]
Reactant: COc1ccc(CO)cc1
Reactant: N#Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc(F)c2C#N)cc1
Reaction time: 15 h
Yield: 70.9 %

Procedure:
4-Methoxybenzyl alcohol (5.0 g) and cesium carbonate (8.3 g) were added to an N,N-dimethylformamide (0.5 L) solution of 2,6-difluorobenzonitrile (7.0 g), and stirred for 15 hours. The reaction solution was evaporated under reduced pressure, water (50 mL) was added to the residue, extracted with ethyl acetate, dried with sodium sulfate, and concentrated under reduced pressure. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a white solid (6.6 g).
Reaction SMILES: [CH3:1][C:2]12[CH2:13][CH2:12][CH:5]([C:6](=[N:10][OH:11])[C:7]1=[N:8][NH2:9])[C:4]([CH3:15])([CH3:14])[O:3]2.CO[C:18](OC)(OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:18]2[N:9]=[N:8][C:7]3[C:2]4([CH3:1])[CH2:13][CH2:12][CH:5]([C:4]([CH3:15])([CH3:14])[O:3]4)[C:6]=3[N+:10]=2[O-:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC12CCC(C(=NO)C1=NN)C(C)(C)O2
Reactant: COC(OC)(OC)c1ccccc1
Product: CC12CCC(c3c1nnc(-c1ccccc1)[n+]3[O-])C(C)(C)O2

Procedure:
A solution of 2.11 g. (0.01 mole) 1,3,3-trimethyl-2-oxabicyclo[2,2,2]octan-5,6-dione-5-oxime-6-hydrazone in 10 ml. trimethylorthobenzoate is refluxed under nitrogen for 18 hours at a bath temperature of 140° C. during which time all distillate is removed. The resulting mixture is cooled and evaporated to dryness in vacuo. After filtering the residue dissolved in 2% methanol-chloroform through silica gel, and evaporation of the filtrate the resulting solid is triturated with ether, giving 3-phenyl-5,8-dihydro-6,6,8-trimethyl-5,8-ethano-6H-pyrano [4,3-e]-as-triazine-4-oxide; m.p. 186.5° to 189° C.
Reaction SMILES: Br.[N:2]1([C:7]([CH2:9][C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][N:4]=[CH:3]1.[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][NH:20][C:21]([C@H:23]([C@@H:33]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:34]([NH:36][NH:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22].C(N1CCOCC1)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][NH:20][C:21]([C@H:23]([C@@H:33]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:34]([NH:36][N:37]([C:10](=[O:12])[CH2:9][C:7]([N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1)=[O:8])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:22]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Reactant: O=C(O)CC(=O)n1ccnc1
Agent: Br
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A solution of 0.415 g of 2-(1-imidazoyl)acetic acid hydrogen bromide and 0.461 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dimethylformamide was treated with 0.230 g of N-ethylmorpholine and 0.422 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the mixture stirred overnight at room temperature. Evaporation gave a residue which was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride solution. Drying over anhydrous magnesium sulphate, evaporation and trituration with diethyl ether followed by filtration and evaporation gave 0.340 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-2′-[2-(1-imidazoyl)acetyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH:1]1([C:4](=[O:17])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C[Si]([I:22])(C)C.S(=O)(O)[O-].[Na+]>C(Cl)Cl>[I:22][CH2:3][CH2:2][CH2:1][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[O:17]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)C2CC2)cc1
Reactant: C[Si](C)(C)I
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCI)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 10.5 g of 4-(cyclopropyl-oxo-methyl)-α,α-dimethylphenylacetic acid, prepared in accordance with Example 2, in 250 mL of CH2Cl2 was cooled in an ice-MeOH bath and 25 g of trimethylsilyliodide was then added rapidly via pipette. The mixture was stirred in the ice bath for one hour, warmed to ambient temperature, and stirred for one hour. A solution of aqueous sodium bisulfite was then added and the mixture was stirred well. The phases were partitioned and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated in vacuo to afford 12.6 g (77%) of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(F)cc3)n2)c1

Procedure:
Intermediate 4 was coupled with 2-(4-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 458. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 3H) 7.7 (m, 1H) 7.5 (m, 2H) 7.2 (m, 2H) 6.9 (m, 2H) 4.5 (s, 2H) 3.8 (m, 2H) 3.7 (m, 1H) 3.4 (m, 2H) 2.9 (m, 7H) 1.9 (s, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32](O)[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38].C(O)C(C)(C)C.[CH:46]12[CH2:51][CH:50]1[C:49](=[O:52])[NH:48][C:47]2=[O:53]>O1CCCC1>[CH2:32]([N:48]1[C:49](=[O:52])[CH:50]2[CH:46]([CH2:51]2)[C:47]1=[O:53])[CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=[CH2:38]
Reactant: C=CCCCCCO
Reactant: O=C1NC(=O)C2CC12
Agent: CC(C)(C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCCN1C(=O)C2CC2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Diethyl azodicarboxylate (0.5 g) was added dropwise over 1 minute to a stirred solution of triphenylphosphine (0.75 g) in tetrahydrofuran (20 ml) at -78° C. under a nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and then 6-hepten-1-ol (0.36 g) was added dropwise over 1 minute, followed by stirring at -78° C. for a further 5 minutes. Neopentanol (0.12 g) was added to the reaction mixture, followed by 3-azabicyclo[3.1.0]hexane-2,4dione (0.32 g) and stirring was continued for a further 5 minutes at -78° C. The reaction mixture was warmed to room temperature and stirred overnight. The volatiles were removed by evaporation in vacuo and the residue was triturated with hexane/dichloromethane and then filtered. The filtrate was evaporated in vacuo and then purified by chromatography on silica gel using 20% ethyl acetate/hexane as eluant. The title compound was obtained as a colourless oil (boiling point 150-160° C. @ 1 mmHg).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][CH2:15][C:16]1[N:17]=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)(C)(C)C.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[C:40]2[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=2[CH:38]=[C:37]([C:46](Cl)=[O:47])[CH:36]=1.FC(F)(F)C(O)=O>ClCCl>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[C:16]([CH2:15][N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[C:46]([C:37]2[CH:36]=[C:35]([O:34][CH3:33])[C:40]3[O:41][C:42]([CH3:45])([CH3:44])[O:43][C:39]=3[CH:38]=2)=[O:47])[N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2cn1
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cc3ccccc3cn2)C[C@@H]2CCCN2)cc2c1OC(C)(C)O2
Yield: 43.5 %

Procedure:
Experimental conditions analogous to Example 60, from 0.17 g (0.38 mmol) of (S)-2-{[(isoquinolin-3-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (double trifluoroacetic acid salt), 6 mL dichloromethane, 159 μL (1.14 mmol) of triethylamine, 0.10 g (0.42 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride and 0.6 mL trifluoroacetic acid. Purification using reverse phase HPLC, mobile phase with a gradient 10-70% acetonitrile in 40 min, gave 74 mg of the product as the free base as a colorless solid. LC-MSD, m/z for C26H29N3O4 [M+H]+: 448.6.
Reaction SMILES: [Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:22])[F:21])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3]([OH:5])=O.C(Cl)(=O)C([Cl:29])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2](=[CH:6][C:7]1[CH:12]=[C:11]([C:13]2[C:17]([Cl:18])=[C:16]([O:19][CH:20]([F:21])[F:22])[N:15]([CH3:23])[N:14]=2)[C:10]([F:24])=[CH:9][C:8]=1[Cl:25])[C:3]([Cl:29])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 90 °C

Procedure:
A solution of 27 g of 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acrylic acid (64 mmol) in 200 ml of toluene was treated with 3 drops of dimethylformamide and 33 g (0.26 mol) of oxalyl chloride. The mixture was subsequently stirred at 90° C. until the vigorous evolution of gas had ceased (after approximately 2.5 hours). The reaction mixture was then concentrated. Yield: 26 g of crude product which was further reacted without purification.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]([NH2:13])[C:10]([NH2:12])=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@@H:3]1[OH:16].[CH:17]([CH:19]=O)=O.Cl>C(O)C>[NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]3[C:10]([N:12]=[CH:17][CH:19]=[N:13]3)=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]1[OH:16]
Reactant: O=CC=O
Reactant: CC1(C)Oc2cc(N)c(N)cc2[C@H](N)[C@H]1O
Agent: Cl
Solvent: CCO
Product: CC1(C)Oc2cc3nccnc3cc2[C@H](N)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of (3R*,4S*)-4,6,7-triamino-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-3-ol (280 mg, 1.25 mmol) in ethanol (5.6 mL), 40% aqueous glyoxal solution (226 mg, 1.56 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, 1 mol/L hydrochloric acid was added thereto, the resulting solution was washed with ethyl acetate, the resulting aqueous phase was adjusted to pH 14 with 1 mol/L aqueous sodium hydroxide solution. Then, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (ethyl acetate/methanol=10/1) to obtain the aimed product (yield: 35%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[CH:13]=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:12]=1[CH:13]=[N:9][NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: COc1ccc(F)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(C=NNc2ccc(F)cc2)c1

Procedure:
(4-fluorophenyl)hydrazine (6.5 g, 40 mmol), 2-fluoro-5-methoxybenzaldehyde (6.2 g, 40 mmol) and cesium carbonate (13 g, 40 mmol) were stirred in DMF (40 mL) at r.t. under argon atmosphere for 1.5 h and was then poured with stirring into water and extracted with ethyl acetate. The organic phase was washed trice with water, then brine and evaporated. The residue crystallized slowly to afford the subtitle compound as a beige-light brown crystal mass (10.21 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([S:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]2[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[S:9][CH:10]=1)=[O:5])C.CO.[OH-].[Na+].Cl>O1CCCC1>[Si:22]([O:21][CH2:20][C@H:15]1[CH2:16][CH2:17][C:18](=[O:19])[N:14]1[CH2:13][CH2:12][S:11][C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)([C:25]([CH3:28])([CH3:26])[CH3:27])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1csc(SCCN2C(=O)CC[C@@H]2CO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CCSc1nc(C(=O)O)cs1
Reaction time: 1 h

Procedure:
To a solution of 2-(2-((2R)-2-(t-butyldimethylsilyloxymethyl)-5-oxopyrrolidin-1-yl)ethylthio)-1,3-thiazole-4-carboxylic acid ethyl ester (240 mg; the compound described in Reference Example 17 of WO03/74483) in tetrahydrofuran (4 mL)-methanol (2 mL) was added 2N aqueous sodium hydroxide solution (2 mL) at room temperature and the solution was stirred for 1 hour. The reaction solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (240 mg) having the following physical data.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[N:26]([C:32]3[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=3)[C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:21]=12)(=[O:17])[CH3:16].CC(C)([O-])C.[K+].[Cl-].[Cl-].[Ca+2]>CC(N(C)C)=O>[C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[N:26]([C:32]3[CH:33]=[CH:34][C:35]([O:38][C:3]4[N:2]([CH3:1])[C:6]5=[N:7][CH:8]=[CH:9][CH:10]=[C:5]5[N:4]=4)=[CH:36][CH:37]=3)[C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:21]=12)(=[O:17])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(COC(C)=O)c21
Agent: CC(C)(C)[O-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(COC(C)=O)c21
Yield: 4.2 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (110 mg) was added to a solution of [1-ethyl-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]methyl acetate (170 mg) and potassium tert-butoxide (69.9 mg) in DMA (1 mL) at room temperature. The mixture was stirred at 100° C. under a dry atmosphere (CaCl2 tube) for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-100% EtOAc in hexane) to give (1-ethyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)methyl acetate (10 mg) as colorless crystals.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[CH2:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:20]([O:22][CH3:23])=[O:21])[CH2:24][O:9]2)=[CH:17][CH:18]=1
Reactant: C=C(C(=O)OC)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(c2ccc(Cl)cc2)CO1
Temperature: 25 °C

Procedure:
MCPBA (35 g, 77%, 156 mmol) was added to a solution of methyl 2-(4-chlorophenyl)-acrylate (20 g, 102 mmol) in CHCl3 (200 mL). The mixture was refluxed for 24 hours. The reaction was cooled to room temperature, diluted with chloroform (200 mL) and washed with 10% Na2S2O3, 10% NaHCO3 and water. The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (9:1) to give methyl 2-(4-chlorophenyl)oxirane-2-carboxylate. Methyl 2-(4-chlorophenyl)oxirane-2-carboxylate (2 g, 9.4 mmol) and ethanol (10 mL) and isopropylamine (1 mL, 11.7 mmol) were added to a 50 mL high pressure bomb. The mixture was heated to 90° C. for 12 hours in the bomb. After cooling, the solvent was removed, and the residue was dissolved in DCM (20 mL) and TEA (2 mL). (Boc)2O (4 g, 23.0 mmol) was added to the mixture. The mixture was stirred at room temperature for 48 hours. The solvent was removed, and the residue was dissolved in THF (20 mL). LiOH (3M, 14 ml) was added to the mixture. The mixture was stirred at room temperature for 16 hours and refluxed for 2 hours. After cooling, the mixture was quenched with 2N HCl (21 mL). The solvent was removed, and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (1:1) to give 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)-2-hydroxypropanoic acid. LCMS (APCI+) [M-Boc+H]+ 258.1; Rf: 3.66 min.
Reaction SMILES: [NH2:1][OH:2].O.[CH3:4][C:5]1[O:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:6]=1.CCCCCC>C1COCC1.C(OCC)(=O)C>[OH:2][NH:1][S:10]([C:8]1[O:9][C:5]([CH3:4])=[CH:6][CH:7]=1)(=[O:12])=[O:11]
Reactant: NO
Reactant: Cc1ccc(S(=O)(=O)Cl)o1
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NO)o1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a solution of hydroxylamine (0.92 mL of a 50% aqueous solution; 13.8 mmol) in THF (6 mL) and water (2 mL) cooled to 0° C. was added 5-methylfuran-2-sulfonyl chloride (1 g, 5.5 mmol) as a solution in THF (6 mL) dropwise so as to maintain the temperature below 10° C. The reaction was stirred for 5 minutes, after which time TLC (1:1 hexane:ethyl acetate (H:EA)) showed substantially complete consumption of the sulfonyl chloride. The reaction was diluted twice with 50 mL dichloromethane (DCM) and the organic portion was separated and washed with water (10 mL). The organic portion was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was chromatographed by silica gel chromatography eluting with heptanes:EtOAc followed by trituration with heptane to provide the title compound as a yellow solid (0.59 g, yield 61%). LC-MS tR=0.91 min; 1H NMR (DMSO, 500 MHz) δ ppm 9.82 (1H, d, J=3.1 Hz), 9.64 (1H, d, J=3.2 Hz), 7.10 (1H, d, J=3.4 Hz), 6.36 (1H, d, J=3.4 Hz), 2.36 (3H, s).
Reaction SMILES: CC([Si](C)(C)[O:6][C:7]1[C:8]([F:17])=[C:9]([CH2:14][C:15]#[N:16])[CH:10]=[C:11]([F:13])[CH:12]=1)(C)C.[CH3:20][O:21][CH2:22][CH2:23]Br.[F-].[K+]>CN(C=O)C>[F:17][C:8]1[C:7]([O:6][CH2:23][CH2:22][O:21][CH3:20])=[CH:12][C:11]([F:13])=[CH:10][C:9]=1[CH2:14][C:15]#[N:16]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(CC#N)c1F
Reactant: COCCBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(F)cc(CC#N)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.7 %

Procedure:
To a solution of (3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,5-difluorophenyl)acetonitrile (1.22 g, 4.30 mmol) in DMF (10 mL) was added 2-bromoethyl methyl ether (485 μl, 5.16 mmol) and potassium fluoride (0.5 g, 8.6 mmol). The mixture was stirred at room temperature for 15 hrs. The reaction mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford an orange oil, which was purified by column chromatography. Eluting with 30% ethyl acetate in hexanes gave 690 mg, 3.04 mmol (71%) of (2,5-difluoro-3-{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile as a colorless oil. 1H NMR (CDCl3): 6.75-6.69 (m, 2H), 4.17-4.15 (m, 2H), 3.78-3.74 (m, 4H), 3.44 (s, 3H); MS (EI) for C11H11NO2F2: 228 (MH+).