Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C@H:16]2[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[H][H]>CO.C1COCC1.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:2][CH2:3]2)(=[O:6])=[O:5])=[C:8]([C@H:16]2[C@H:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:18][N:17]2[C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH:9]=1
Reactant: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc([N+](=O)[O-])ccc1S(=O)(=O)C1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1cc(N)ccc1S(=O)(=O)C1CC1
Yield: 102.8 %

Procedure:
To 76F (1.6 g) in methanol (40 mL) and THF (20 mL) was added 10% Pd/C (500 mg). The mixture was hydrogenated with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration and the filtrate was concentrated to afford 76H (1.54 g, 95% yield). 1H NMR (400 MHz, DMSO-d6, 100° C.) δ ppm 0.86-0.97 (m, 2H) 0.98-1.06 (m, 3H) 1.13-1.24 (m, 4H) 1.30 (s, 9H) 1.98 (dd, J=12.09, 8.24 Hz, 1H) 2.16 (d, J=11.54 Hz, 1H) 2.68 (s, 1H) 2.83 (d, J=7.15 Hz, 1H) 3.42 (d, J=7.15 Hz, 1H) 3.61-3.71 (m, 1H) 4.11 (q, J=7.15 Hz, 2H) 5.74 (s, 1H) 6.50-6.57 (m, 2H) 7.47 (d, J=9.34 Hz, 1H), LC-MS 439 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:25])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12.[OH-].[Na+].C(O)=O>CS(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:25])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(OC)c3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(-c2c(Br)sc3nc(C)c(C(=O)O)c(N)c23)c1
Temperature: 150 °C
Yield: 78.5 %

Procedure:
A mixture of ethyl 4-amino-2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylate (700 mg, 1.661 mmol) (Description 15) in DMSO (7 mL) and aqueous NaOH (2M) (4.15 mL, 8.31 mmol) was heated at 150° C. for 1 h. The mixture was cooled to RT, diluted with water (20 mL) and acidified with formic acid to pH 6. The mixture was then extracted with ethyl acetate (5×30 mL) and the combined organics washed with brine (2×30 mL), dried and concentrated, to give the title compound (513 mg). LCMS (A) m/z: 393/395 [M+1]+, Rt 1.04 min (acidic).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24]CCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCC1CC[N:67]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:66][CH2:65]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH:18]1[CH2:19][CH2:24][N:67]([C:70]([O:72][CH2:73][C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:71])[CH2:66][CH2:65]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCBr)CC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(2-bromoethyl)-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:17](=[O:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(N)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(NC(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To an ice-cold solution of p-anisidine (25 g, 203.0 mmol) in DCM (300.0 mL) was added triethyl amine (90.0 mL, 609.0 mmol) dropwise and the reaction mixture was stirred at the same temperature for 15 min. Acetyl chloride (23.0 mL, 304.50 mmol) was then added and the reaction mixture was continued to stir at room temperature for 1 h. After the completion of the reaction (TLC monitoring), water (500 mL) was added and extracted with DCM (2×300 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (30.0 g, 90%). 1H NMR (400 MHz, DMSO-d6): δ 1.99 (s, 3H), 3.70 (s, 3H), 6.86 (d, J=8.80 Hz, 2H), 7.48 (d, J=8.80 Hz, 2H) and 9.77 (br s, 1H).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[F:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]>>[F:18][C:19]1[CH:26]=[C:25]([C:2]2[N:6]=[CH:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)[N:3]=2)[CH:24]=[CH:23][C:20]=1[CH:21]=[O:22]
Reactant: CC1(C)OB(c2ccc(C=O)c(F)c2)OC1(C)C
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Product: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1F

Procedure:
The title compound was prepared as described in Example 86 using 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (C1) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (CB5) and isolated as a white solid (0.569 g, 47%): 1H NMR (400 MHz, CDCl3) δ 10.42 (d, J=0.7 Hz, 1H), 8.61 (s, 1H), 8.12 (ddd, J=8.1, 1.5, 0.8 Hz, 1H), 8.05-7.95 (m, 1H), 7.81 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 1H), 7.45-7.39 (m, 2H); ESIMS m/z 352 ([M+H]+).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:13](=[O:16])([O-])[O-].[K+].[K+].[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C=O)C>O>[CH2:19]([O:12][C:7]1[C:6]2[C:11](=[C:2]([O:16][CH2:13][CH2:4][CH2:3][CH2:2][CH2:11][CH3:10])[CH:3]=[CH:4][CH:5]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc2c(O)cccc12
Reactant: CCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCOc1cccc2c(OCCCCCC)cccc12
Temperature: 90 °C
Yield: 163.2 %

Procedure:
To a 500 mL round-bottomed flask were added 1,5-dihydroxynaphthalene (15.0 g, 0.094 mol), potassium carbonate (27.2 g, 0.2 mol), n-hexylbromide (32.5 g, 0.2 mol), and 200 mL of DMF. The reaction was heated to 90° C. overnight, cooled to room temperature, and poured into 700 mL of water. The dark brown precipitate was filtered and washed with methanol. The crude product was refluxed in methanol and then filtered to give light green solid 25.2 g (80% yield). 1H NMR (CDCl3) δ (ppm): 0.92 (t, J=6.5 Hz, 6H), 1.35-1.41 (m, 8H), 1.52-1.57 (m, 4H), 1.85-1.92 (m, 4H), 4.10 (t, J=6.4 Hz, 4H), 6.81 (d, J=7.6 Hz, 2H), 7.30-7.36 (m, 2H), 7.84 (d, J=8.3 Hz); M.p. 92-93° C.
Reaction SMILES: [CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32]O)[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2].[CH3:36][S:37](Cl)(=O)=O.CCN(C(C)C)C(C)C.C([S-])C.[Na+]>CN(C=O)C>[CH:1]([O:3][C:4]([N:6]1[CH2:30][C@:29]2([C:31](=[O:34])[CH2:32][S:37][CH3:36])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:35])[CH2:7]1)=[O:5])=[CH2:2]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CO)C1
Reactant: CS(=O)(=O)Cl
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(=O)CSC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
A mixture of compound 164 (203 mg, 0.413 mmol), methansulfonyl chloride (38.6 μl, 0.496 mmol) and DIPEA (108 μl, 0.620 mmol) in dry DMF (3 ml) is stirred at RT under nitrogen for 1 hour. Further methansulfonyl chloride (16.09 μl, 0.207 mmol) and DIPEA (54.1 μl, 0.310 mmol) are added and the mixture is stirred at RT for 2 hours. Sodiumethanethiolate (87 mg, 1.239 mmol) is added and the mixture is stirred at RT for 16 hours. The reaction the mixture is partitioned between AcOEt and brine, then the aqueous phase is extracted with AcOEt and the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a oil which is purified by silica gel chromatography (eluent: AcOEt/petroleum ether 2/3) to afford the title compound (118 mg, 0.226 mmol, 54.8% yield).
Reaction SMILES: [C@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@H:3]([CH2:4][CH2:5][CH2:6]1)[CH2:2]2.[CH:12]([OH:15])([CH3:14])[CH3:13].[C:16]1(C)[CH:21]=CC(S(O)(=O)=O)=C[CH:17]=1.O>C1(C)C=CC=CC=1>[C@H:3]1([C:7]([O:9][CH:16]([CH3:21])[CH3:17])=[O:8])[CH2:4][CH2:5][CH2:6][C@@H:1]([C:10]([O:15][CH:12]([CH3:14])[CH3:13])=[O:11])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)O
Reactant: O=C1OC(=O)[C@H]2CCC[C@@H]1C2
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)OC(=O)[C@@H]1CCC[C@H](C(=O)OC(C)C)C1

Procedure:
Anhydride 1 (1.21 g; 7.8 mmol) was dissolved in isopropanol (6.0 mL; 78 mmol; 10 equiv) and toluene (6 mL). p-Toluenesulfonic acid (74 mg; 0.39 mmol; 0.05 equiv) was added and the reaction mixture was heated to reflux under conditions where water could be continuously distilled using a Dean-Stark trap. After 7 hr at reflux, GC analysis indicated >96% conversion to 2d. The reaction mixture was washed with saturated aqueous sodium bicarbonate (2×10 mL). The organic solution was dried over MgSO4 and concentrated to afford cis-2d which was a single peak by GC analysis.
Reaction SMILES: [C:1]1([CH2:7][S:8][CH:9]([C:13]([OH:15])=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][C:19]=1[CH3:27].[K+].[Br-]>CCOCC>[OH:15][C:13]1[CH:25]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[C:19]([CH3:27])[CH:20]=2)[O:12][C:10](=[O:11])[C:9]=1[S:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(C(C)=O)cc1C
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc1C
Yield: 68 %

Procedure:
This compound is prepared by the condensation of diethyl ester of [(phenylmethyl)thio]propanedioic acid (1 g, mmol) with the corresponding trimethylsilylenol ether of 4'-methoxy-3'-methylacetophenone as described in general procedure A. Isolated Yield: 68%. m.p. 159-106° C. 1H NMR (400 MHz, CDCl3) δ7.67 (dd, 1 H), 7.61 (s, 1 H), 7.2 (m, 5 H), 6.8 (d, 1 H), 6.38 (s, 1 H), 3.96 (s, 2 H), 3.89 (s, 3 H), 2.25 (s, 3 H); IR (KBr) 3432, 2945, 1613, 1507, 1402, 1262, 1142, 1030, 812, 704 cm-1; MS (CI) m/e 355 (78.3), 263 (19.6), 235 (11.8), 149 (12.7), 91 (100); Analysis calc'd for: C, 67.78; H, 5.12; found: C, 67.35; H, 5.17.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[C:13]([O:21][CH3:22])=[CH:12][C:11]2=[O:23])[CH2:4][CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.[Cl:36]CCl.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:36].[ClH:36].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=5)[C:13]([O:21][CH3:22])=[CH:12][C:11]4=[O:23])[CH2:6][CH2:7]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: ClCCl
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1cc(=O)n(CCN2CCC(N)CC2)c2cc(F)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(=O)n(CCN2CCC(NCc3cc4c(cn3)OCCO4)CC2)c2cc(F)ccc12
Product: Cl
Reaction time: 8 h

Procedure:
A solution of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-4-(methyloxy)-2(1H)-quinolinone (0.057 g, 0.18 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (0.027 g, 0.16 mmol) in 1:1 dichloromethane/methanol (4 ml) was stirred with 3A sieves for 2 h then sodium triacetoxyborohydride (0.115 g, 0.54 mmol) added and the mixture stirred overnight. The solution was diluted with dichloromethane and washed with sodium carbonate solution. The aqueous was extracted with dichloromethane/methanol (10%) and the combined organics dried and concentrated. Chromatography over silica (20 g SPE gradient elution dichloromethane/methanol 0-20%) provided the free base of the title compound (0.022 g) which was converted to the title dihydrochloride salt by dissolving in dichloromethane and adding 4N HCl in 1,4-dioxane. Ether was added to the solution and the precipitate collected (0.022 g, 23%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:19])=O.N>>[Cl:19][C:6]1[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ncc(CCc2ccccc2)c(O)n1
Agent: N
Product: Nc1ncc(CCc2ccccc2)c(Cl)n1
Temperature: 90 °C
Yield: 40.7 %

Procedure:
A mixture of 2-amino-5-phenethylpyrimidine-4-ol (600 mg, 2.79 mmol) and phosphorous oxychloride (5 ml) was kept to warm at 90° C. for 6 hours. The reaction mixture was condensed in vacuo. Ice-water was added to the residue and an aqueous ammonia was cautiously added thereto. The solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=8:2) to give the object compound (265 mg, 40.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:31]=1[CH2:32][Zn+]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:32][C:31]5[C:30]([F:29])=[CH:37][CH:36]=[CH:35][C:34]=5[F:38])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: Fc1cccc(F)c1C[Zn+]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3c(F)cccc3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,6-difluoro-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 4): tR=1.22 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](SC)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.O[O:17][S:18]([O-:20])=O.[K+].[C:22]([O-])(O)=O.[Na+]>CO>[CH3:22][S:18]([C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[CH:13]=[CH:12][N:11]=1)(=[O:20])=[O:17]
Reactant: O=C([O-])O
Reactant: CSc1nccc(-c2cccc(C)n2)n1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2ccnc(S(C)(=O)=O)n2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 4-(6-methyl-pyridin-2-yl)-2-methylsulfanyl-pyrimidine (785 mg, 3.61 mmol) in MeOH (25 ml) was cooled at 0° C. and then an aqueous solution of oxone (6.67 g, 10.85 mmol in 25 ml of water) was slowly added. After stirring 3 hours at room temperature, the mixture was basified with 5% NaHCO3 and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 625 mg of the title compound that was used in the next step without further purification (70% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-:30])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(c1ccccn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCCl
Product: CC(c1cccc[n+]1[O-])C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 54.8 %

Procedure:
A solution of 2-(2,4-difluorophenyl)-3-(pyridin-2-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (diastereoisomeric pair B from Example 1) (1.60 g) and 85% w/w 3-chloroperoxybenzoic acid (1.60 g) in dichloromethane (10 ml) was stirred at room temperature for 36 hours and then worked up as described in Example 15(i) to give the title compound, (0.92 g), m.p. 159°-160°.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].S(Cl)([Cl:17])=O.[CH3:19]O>>[ClH:17].[NH2:1][C@@H:2]([C@@H:6]([C:8]1[CH:9]=[CH:10][C:11]([I:14])=[CH:12][CH:13]=1)[CH3:7])[C:3]([O:5][CH3:19])=[O:4]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: C[C@H](c1ccc(I)cc1)[C@H](N)C(=O)O
Product: COC(=O)[C@@H](N)[C@H](C)c1ccc(I)cc1
Product: Cl
Temperature: 0 °C
Yield: 82 %

Procedure:
To an ice cooled solution of 2(S)-amino-3(R)-(4-iodophenyl)-butyric acid (124 mg, 0.42 mmol) in methanol (0.5 mL) was added dropwise thionyl chloride (150 μL, 2.0 mmol). Methanol (1 mL) was added and the reaction mixture was heated to reflux for 2 hr. After cooling, the mixture was filtered and the filtrate concentrated by rotoevaporation to yield 2(S)-amino-3(R)-(4-iodophenyl)-butyric acid, methyl ester hydrochloride (116 mg, 82% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:10]([CH2:28][F:29])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:32].Cl[C:34](OC1C=CC([N+]([O-])=O)=CC=1)=[O:35].[CH:46]1([CH2:49][NH2:50])[CH2:48][CH2:47]1>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:30]=[CH:31][C:2]([NH:1][C:34]([NH:50][CH2:49][CH:46]4[CH2:48][CH2:47]4)=[O:35])=[C:3]([F:32])[CH:4]=3)[CH2:9][CH:10]2[CH2:28][F:29])[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2CF)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCC1CC1
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)c(F)c3)CC2CF)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-((4-(4-amino-3-fluorobenzoyl)-2-(fluoromethyl)piperazin-1-yl)-methyl)-N-tert-butylbenzamide (150 mg, 0.34 mmol) in dichloromethane (4 mL) at room temperature was added 4-nitrophenyl chloroformate (71.4 mg, 0.354 mmol). The reaction mixture was stirred at room temperature for 1 hour before the addition of cyclopropane-methylamine (150 μL). The mixture was stirred at room temperature overnight before being applied to a silica carbonate column. The eluant was concentrated under reduced pressure and redissolved in methanol. Purification by basic reverse phase HPLC gave the title compound (2 mg), MS (ESI) m/z 542.5 [M+H]+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([C@H:12]3[CH2:15][CH2:14][C@H:13]3[C:16](O)=[O:17])=O)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19].O.[NH2:21][NH2:22]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[CH:12]4[CH:13]([C:16](=[O:17])[NH:21][N:22]=3)[CH2:14][CH2:15]4)=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:19]
Reactant: O=C1Cc2cc(C(=O)[C@H]3CC[C@H]3C(=O)O)ccc2N1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc(C3=NNC(=O)C4CCC34)ccc2N1
Yield: 92.1 %

Procedure:
5.22 g (0.02 mole) of cis-2-(indolin-2-on-5-oyl)cyclobutanecarboxylic acid are refluxed with 1.1 g (0.022 mole) of hydrazine hydrate and 50 ml of ethanol for 11 hours. The solid is filtered off with suction at room temperature and recrystallized from dimethylformamide/water to give 4.7 g (92%) of 2-(indolin-2-on-5-yl)-3,4-diazabicyclo[4.2.0]oct-2-en-5-one of melting point 309°-312° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[OH:13])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[O:13][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CCC[C@H]1c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1CCC[C@H]1c1ccc(Cl)nc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
trans-2-(6-Chloropyridin-3-yl)cyclopentanol (0.225 g, 1.14 mmol) was dissolved in CH2Cl2 (10 mL) in a 50 mL round bottom flask, the solution cooled in an ice bath under nitrogen and treated with Et3N (0.172 g, 1.71 mmol, 0.24 mL) and methanesulfonyl chloride (0.163 g, 1.42 mmol, 0.11 ml) via syringe with stirring. After 1 h, TLC (hexanes:EtOAc/2:1) indicated a complete conversion. The reaction mixture was concentrated in vacuo then partitioned between EtOAc and 1 N HCl, the layers separated, the organics dried (Na2SO4) filtered and concentrated to give trans-methanesulfonic acid 2-(6-chloropyridin-3-yl)cyclopentyl ester (0.303 g, 97%) as an oil: LC/MS (ESI) m/z 275, 1H NMR (300 MHz, CDCl3) δ 8.28 (d, 1H, J=2.7 Hz), 7.56 (dd, 1H, J=8.1, 2.7 Hz), 7.3 (d, 1H, J=8.1 Hz), 4.93 (apparent q, 1H, J=5.7 Hz), 3.28 (apparent q, 1H, J=8.7 Hz), 2.86 (s, 3H), 2.26 (m, 2H), 2.10-1.80 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](=[N:9][OH:10])[NH2:8].Br[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=O)=[CH:16][C:15]=1[CH2:24]OC.[CH2:27](Cl)[CH2:28]Cl>CC#N.N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:7]2[N:8]=[C:24]([C:15]3[CH:14]=[CH:23][C:22]([C:5]4[CH:6]=[CH:11][CH:2]=[CH:3][C:27]=4[CH3:28])=[C:17]([CH2:18][O:20][CH3:21])[CH:16]=3)[O:10][N:9]=2)[CH:11]=1
Reactant: ClCCCl
Reactant: NC(=NO)c1cnc(O)c(Cl)c1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Solvent: c1ccncc1
Solvent: CC#N
Product: COCc1cc(-c2nc(-c3cnc(O)c(Cl)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-N′,6-dihydroxynicotinimidamide (Bionet, 1.46 g; 7.78 mmol) and Intermediate A1 (1.66 g; 6.48 mmol) in MeCN (50 mL) was added EDC (1.61 g; 8.42 mmol). The reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with pyridine (20 mL) and heated at 115° C. for 24 hours. The solvent was removed in vacuo and the residue dissolved in DCM. The mixture was washed with water and the organic phase passed through a hydrophobic frit. The solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica, eluting with iso-hexane/EtOAc (100% iso-hexane to 100% EtOAc) to afford the title product as an off-white solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.84 (1 H, s), 8.32 (1 H, s), 8.26 (1 H, d, J=2.3 Hz), 8.21 (1 H, d, J=2.4 Hz), 8.17 (1 H, dd, J=7.9, 1.9 Hz), 7.45 (1 H, d, J=7.9 Hz), 7.41-7.37 (2 H, m), 7.34-7.29 (1 H, m), 7.17 (1 H, d, J=7.4 Hz), 4.22 (2 H, q, J=9.4 Hz), 3.27 (3 H, s), 2.06 (3 H, s). LC/MS: 408 (M+H)+. HPLC (Method C) Rt 3.79 min (Purity: 99.4%).