Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:22][NH:23][CH3:24].[CH2:25]=O>C(O)(=O)C>[CH3:22][N:23]([CH2:25][C:16]1[S:15][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:13][C:12]=1/[CH:11]=[CH:10]\[C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:24]
Reactant: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)cs1
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)c(CN(C)C)s1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of N-{4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide (500 mg) in acetic acid (3 ml) were added dimethylamine hydrochloride (169 mg) and paraformaldehyde (62.2 mg), and the mixture was stirred at 100° C. (bath temp.) for 2 hrs. The solvent was removed in vacuo, and the mixture was adjusted to pH=9 with saturated sodium hydrogen carbonate aqueous solution, extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The crude compound was purified by flash column chromatography over silica gel with dichloromethane/methanol (100:1)→(20:1) as an eluent to give N-{5-[(dimethylamino)methyl]-4-[(Z)-2-(4-nitrophenyl)vinyl]-1,3-thiazol-2-yl}acetamide as a yellow amorphous substance.
Reaction SMILES: CC1(C)[N:6](C(OC(C)(C)C)=O)[C@@:5]([CH3:42])([C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[C:21]([C:38]([F:41])([F:40])[F:39])[CH:20]=3)=[CH:17][N:18]=2)[CH2:4][O:3]1>C(#N)C.O>[NH2:6][C@@:5]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:21]([C:38]([F:40])([F:41])[F:39])[CH:20]=2)=[CH:17][N:18]=1)([CH3:42])[CH2:4][OH:3]
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1ncc(-c2ccc(OCCCCCCc3ccccc3)c(C(F)(F)F)c2)s1
Solvent: CC#N
Solvent: O
Product: C[C@](N)(CO)c1ncc(-c2ccc(OCCCCCCc3ccccc3)c(C(F)(F)F)c2)s1

Procedure:
The title compound was prepared from (R)-tert-butyl 2,2,4-trimethyl-4-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate. HPLC retention time on a C18 column (30×4.6 mm, 3.5μ) was 2.41 min with gradient 10-95% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=479.4; 1H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.65 (d, 1H, J=2.0 Hz), 7.55 (dd, 1H, J=8.8 Hz, J=2.0 Hz), 7.28-7.23 (m, 2H), 7.18-7.15 (m, 3H), 6.96 (d, 1H, J=9.2 Hz), 4.06-3.99 (m, 4H), 2.62 (t, 2H, J=7.6 Hz), 1.85-1.78 (m, 5H), 1.69-1.62 (m, 2H), 1.56-1.50 (m, 2H), 1.44-1.38 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12](N3CCN(CC)CC3)[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.C(N(CC)CC)C.CC([OH:62])(C#C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:62])[C:11]3[CH:22]=[CH:23][S:24][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCN1CCN(c2nc(-c3ccc(Br)cc3)cc3sccc23)CC1
Reactant: C#CC(C)(C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Yield: 109.5 %

Procedure:
6-(4-Bromophenyl)-4-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.96 g) was heated under reflux in the presence of bistriphenylphosphine dichloride (48 mg), triphenylphosphine (174 mg) and cuprous iodide (46 mg), in 2-methyl-3-butyn-2-ol (0.26 g), pyridine (15 ml) and triethylamine (30 ml) for 1.5 hr. The reaction solution was evaporated, and the resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.80 g of the title compound as a pale yellow oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][S:14][CH2:15][CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1>C(OCC)(=O)C>[CH3:13][S:14][CH2:15][CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCSC)CC2)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCCSC)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogen carbonate (0.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(4-{trans-4-[2-(methylsulfanyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.2 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.072 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.061 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.13 g, 59%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].C(OP([CH:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(OCC)=O)C.C=O>O>[CH2:1]=[C:15]([CH2:21][CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Solvent: O
Product: C=C(CC)C(=O)OCC
Temperature: 85 °C
Reaction time: 0.75 h

Procedure:
Potassium carbonate (5.5 g) was dissolved in water (15 mL). To the solution, ethyl 2-(diethoxyphosphoryl)butyrate (5.0 g) and a 37% aqueous formaldehyde (6.2 g) were added at room temperature, and the mixture was stirred at 85° C. for 45 minutes. Organic matter was extracted with diethyl ether, dried over anhydrous sodium sulfate, and filtered, and the solvent in the filtrate was distilled off under reduced pressure to obtain a crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(N(CC)CC)C.C[O-].[Na+].Cl>C1COCC1.ClCCl>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: Nc1ccccn1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.1 %

Procedure:
To a stirring solution of 2-aminopyridine 9 (2.00 g, 21.3 mmol) in THF (45 mL) were successively added dichloromethane (88 mL), 4-nitrobenzenesulfonyl chloride (9.89 g, 44.6 mmol), and triethylamine (6.51 mL, 46.75 mmol). The solution was heated to reflux for 2 h and the resultant light yellow solid was collected by filtration. This material was suspended in 200 mL of methanol and a large excess (>10 eq) of sodium methoxide was added. The mixture was stirred at r.t. for 6 h, treated with HCl 1N (2 mL) and concentrated in vacuo at 80° C. to 50 mL volume. This solution was transferred into an Erlenmeyer flask and further neutralized with 1N HCl. A precipitate was formed which was collected by filtration, washed with water and dried, to afford the title compound 10 (2.8 g, 47% yield). 1H NMR (DMSO-d6) δ (ppm): 8.32 (d, J=6.8 Hz, 2H), 8.07 (d, J=7.0 Hz, 2H), 7.92 (bs, 1H), 7.80 (bs, 1H), 7.26 (bs, 1H), 6.85 (bs, 1H). LRMS (ESI): (calc) 279.03 (found) 280.0 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1>>[N:15]1[CH:20]=[CH:19][C:18]([CH:21]([N:28]2[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][N:4]3[C:8](=[O:9])[C:7]4=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]4[C:5]3=[O:14])[CH2:30][CH2:29]2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: c1ccc(C(c2ccncc2)N2CCNCC2)cc1
Product: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccccc2)c2ccncc2)CC1
Yield: 77 %

Procedure:
The title compound was prepared in a yield of 77% in a similar manner to that described in Preparation 1' by reacting N-(2-bromoethyl)phthalimide and 4-[α-(4-pyridyl)benzyl]piperazine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[C:11]([NH2:17])[CH:10]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[C:12]([Cl:16])=[CH:13][C:14]=1[Cl:15]
Reactant: Nc1cc(N)c(Cl)cc1Cl
Reactant: O=C(Cl)CCCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Nc1cc(NC(=O)CCCCl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
14.1 g (0.10 mol) of γ-chlorobutyryl chloride in 50 ml of chloroform are added dropwise in the course of 1 hour, at 10°-15° C., to a solution of 17.7 g (0.10 mol) of 1,3-diamino-4,6-dichlorobenzene and 8.7 g (0.11 mol) of pyridine in 500 ml of chloroform. The mixture is then stirred for 2 hours at room temperature, the solution is washed with water and filtered through 40 g of silica gel and the filtrate is concentrated. The resulting product is recrystallised from hexane/toluene. Yield: 13.5 g; melting point 125°-128° C.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[C:17]([CH2:24][CH3:25])[CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:12])[CH3:11])=[C:17]([CH2:24][CH3:25])[CH:16]=1
Reactant: CCc1cc(Br)ccc1CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CCO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
Imidazole (2.1 g, 30.6 mmol) followed by tert-butylchlorodimethylsilane (2.5 g, 16.8 mmol) were added to a solution of 36B (3.5 g, 15.3 mmol) in CH2Cl2 (100 mL). The reaction mixture was stirred for 2 h then washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (0% to 30% EtOAc in hexanes) to yield 46A (4.3 g, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm −0.02 (s, 6 H) 0.86 (s, 9 H) 1.20 (t, J=7.42 Hz, 3 H) 2.63 (q, J=7.51 Hz, 2 H) 2.79 (t, J=7.15 Hz, 2 H) 3.74 (t, J=7.15 Hz, 2 H) 7.22 (dd, J=7.97, 1.92 Hz, 1 H) 7.29 (d, J=2.20 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[C:14]=2[CH3:28])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]2[N:5]([C:34](=[O:35])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([B:19]4[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]4)[C:14]=3[CH3:28])[C:10](=[O:11])[CH:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1CC(=O)Nc1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: COc1cccn2c(=O)n(-c3cccc(B4OC(C)(C)C(C)(C)O4)c3C)c(=O)cc12
Temperature: 110 °C
Yield: 37 %

Procedure:
A mixture of 2-(3-methoxypyridin-2-yl)-N-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (1.45 g, 3.78 mmol) and CDI (2.45 g, 15.1 mmol) in toluene (19 mL) was heated at 110° C. for 3 h. The cooled mixture was partitioned between EtOAc and water. The organic layer was washed sequentially with water and brine, dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes, to give 5-methoxy-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione as a yellow solid (0.571 g, 37% yield). Mass spectrum m/z 409 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.96 (d, J=7.0 Hz, 1H), 7.91 (dd, J=7.4, 1.2 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.22 (dd, J=7.8, 1.2 Hz, 1H), 6.39-6.30 (m, 2H), 6.24 (s, 1H), 3.93 (s, 3H), 2.34 (s, 3H), 1.34 (s, 12H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[C:14](=[O:32])[CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C([O-])(=[O:35])C.[K+]>CN(C=O)C>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][N:15]2[CH2:16][CH2:17][N:12]([S:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:35])=[CH:8][CH:7]=3)(=[O:11])=[O:10])[CH2:13][C:14]2=[O:32])[CH2:20][CH2:21]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CBr)cc3)CC2=O)CC1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(CO)cc3)CC2=O)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
To absolution of 4-[4-(bromomethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-2-piperazinone (2.85 g) in DMF (30 ml) was added potassium acetate (1.58 g), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried and concentrated, and the residue was dissolved in methanol (50 ml). To the solution was added sodium methoxide (28% methanol solution, 290 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, dried (MgSO4) and concentrated. The residual crystals were washed with ether to give colorless crystals of 1-[1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-[4-(hydroxymethyl)benzenesulfonyl]-2-piperazinone (2.02 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][NH2:15]>C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]([NH:15][CH3:14])[CH:10]([OH:11])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Product: CNC1CN(C(=O)OC(C)(C)C)CC1O
Temperature: 50 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Dissolve 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.50 g, 8.10 mmol) in methylamine (15 mL, 40% solution in water). Warm to 50° C. and stir in a sealed vessel overnight. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Dry the organics over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-10% methanol (2N NH3)/CH2Cl2 to give 1.87 g (97%) of 3-hydroxy-4-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13]([S-])(=[S:17])OCC.[K+]>N1C=CC=CC=1>[S:17]=[C:13]1[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[O:12]1
Reactant: CCOC(=S)[S-]
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)c1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C

Procedure:
Methyl 4-amino-3-hydroxybenzoate (16.7 g, 100 mmol, Chemical Abstracts number 63435-16-5, available from Alfa Chemicals, 26 Parkridge Rd, Ward Hill, Mass. 01835-8099) and potassium O-ethyl carbonodithioate (20.8 g, 130 mmol) were combined in pyridine (100 mL) and refluxed for two hours. The reaction mixture was cooled to ambient temperature and the product was filtered, washed with water, and dried in a vacuum oven overnight at 45° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.87 (d, 3 H) 7.34 (d, J=8.33 Hz, 1 H) 7.92 (d, J=1.59 Hz, 1 H) 7.97 (dd, J=12.69, 1.59 Hz, 1 H); MS (ESI−) m/z 207.9 (M−H)−.
Reaction SMILES: CI.[Br:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([OH:11])=[C:6]([F:12])[CH:5]=1.[C:13]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:13][O:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([Br:3])=[CH:5][C:6]=1[F:12]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(F)cc(Br)cc1F
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Methyl iodide (17.11 g, 0.12 mol) was added at 0° C. to a well stirred suspension of 4-bromo-2,6-difluorophenol (21 g, 0.1 mol; see step (i) above) and K2CO3 (27.78 g, 0.2 mol) in dry acetone (150 mL). Stirring was continued at 60° C. overnight under a nitrogen atmosphere. The reaction mixture was filtered, the solvent was evaporated and the residue was purified by column chromatography over silica gel, using petroleum ether as eluent, to give 11.5 g of the sub-title compound as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: N
Product: NS(=O)(=O)c1ccccc1Cl
Temperature: 70 °C

Procedure:
2-Chlorobenzenesulphonyl chloride (58 g) in either (60 ml) was added dropwise with stirring to concentrated ammonia solution (575 ml). When addition was complete, the mixture was stirred and heated at 70° C. for 1 hour. The mixture was then cooled and the solid filtered off, washed with water, and dried to give the required 2-chlorobenzenesulphonamide (39 g) with a melting point of 186° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:26]=[C:27]([Cl:41])[C:28](=[O:40])[N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:30]=1.C(OC(C1C=CN(C(C)C)C=1C(C1C=CC(Cl)=CC=1)O)=O)C.NC1C(=O)N(C)C=C(Cl)C=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:24][C:25]1[CH:26]=[C:27]([Cl:41])[C:28](=[O:40])[N:29]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH:30]=1)[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(Cn2cc(N)cc(Cl)c2=O)cc1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(C#N)cc1
Agent: CCOC(=O)c1ccn(C(C)C)c1C(O)c1ccc(Cl)cc1
Agent: Cn1cc(Cl)cc(N)c1=O
Product: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(Cc2ccc(OC)cc2)c1)c1ccc(C#N)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step L3, but 2-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step H4) and 5-amino-3-chloro-1-(4-methoxy-benzyl)-1H-pyridin-2-one (Step O4) were used instead of 2-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester and 3-amino-5-chloro-1-methyl-1H-pyridin-2-one respectively. The title compound was obtained as a white solid. ESI-MS: tR=1.20 min, [M+H]+ 559/561 (LC-MS 1).
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:6](=[O:15])[NH:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CCCCCC.C(=O)([O-])[O-].[Ag+2]>[Br:4][C:5]1[C:6]([O:15][CH2:2][CH3:3])=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:12])[F:13])[CH:10]=1
Reactant: CCI
Reactant: O=c1[nH]cc(C(F)(F)F)cc1Br
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Product: CCOc1ncc(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 64 h
Yield: 59.8 %

Procedure:
Iodoethane (1.33 ml, 16.6 mmol) was added to a suspension of 3-bromo-5-trifluoromethyl-2(1H)-pyridone (2.0 g, 8.3 mmol) and silver carbonate (1.16 g, 4.2 mmol) in hexane (50 ml) and the mixture stirred for 64 h at room temperature. The resulting suspension was filtered, the filtrate evaporated and the residue purified by chromatography on silica gel to give the product as a colourless oil (1.34 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH2:9]([N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]#[N:18])[CH:10]=[CH2:11].[CH3:19][O:20]C(Cl)Cl>C(Cl)Cl>[CH2:9]([N:12]1[CH:16]=[C:15]([CH:19]=[O:20])[CH:14]=[C:13]1[C:17]#[N:18])[CH:10]=[CH2:11]
Reactant: C=CCn1cccc1C#N
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: C=CCn1cc(C=O)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a 100 mL flask charged with AlCl3 (3.3 g, 25 mmol, 2.5 equiv.) and 35 mL of dry CH2Cl2 was added 2 mL of nitromethane. The mixture was cooled to 0° C. and a solution of 1-allyl-1H-pyrrole-2-carbonitrile (1.3 g, 10 mmol, 1 equiv.) in 5 mL of CH2Cl2 was added followed by a solution of dichloromethyl methyl ether in 10 mL of CH2Cl2 dropwise. After 30 minutes, the reaction was warmed to room temperature, stirred for 1.5 hours, poured over 100 mL of ice water, and the organic layer was separated. The organic layers were washed with 30 mL of 3M HCl, 30 mL of water, 18% aqueous sodium sulfite, filtered through CELITE® filter aid and concentrated in vacuo. The residue was purified by flash chromatography eluting with EtOAc-hexanes (5-40% gradient) to provide 1.25 g (78%) of 1-allyl-4-formyl-1H-pyrrole-2-carbonitrile as a yellow oil.
Reaction SMILES: [O:1]([C:8]1[N:9]=[C:10]2[C:16]([C:17](O)=[O:18])=[CH:15][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCCN=C=NCC.[NH2:39][C@H:40]([CH:48]([CH3:50])[CH3:49])[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:42]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:49][CH:48]([CH3:50])[C@@H:40]([NH:39][C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=2)[N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:27])[CH3:25])[CH:15]=1)=[O:18])[C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:42]
Reactant: CC(C)[C@@H](N)C(=O)N1CCCC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Oc3ccccc3)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Oc3ccccc3)nc12)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.10 g, 0.26 mmol), 4-dimethylaminopyridine (0.048 g, 0.39 mmol) and (3-dimethylamino-propyl)-ethyl-carbodiimide (0.075 g, 0.39 mmol) in CH2Cl2 (2 mL) was added (R)-2-amino-3-methyl-1-pyrrolidin-1-yl-butan-1-one (0.066 g, 0.39 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred at room temperature overnight, then quenched with water and extracted with ethyl acetate (3×). The organic layer was washed with water and saturated aqueous NaCl solution and dried over MgSO4, filtered and concentrated. The residue was purified by SiO2 column chromatography (0-100% EtOAc/hexanes) to afford 2-phenoxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-methyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a yellow oil.