Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(S([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:24][C:23]3[C:22]4=[N:32][N:33]=[CH:34][N:21]4[CH:20]=[CH:19][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)[CH3:9])=O)(C)C.Cl.O>CO>[C:26]1([C:25]2[C:16]([C:13]3[CH:12]=[CH:11][C:10]([CH:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=3)=[N:17][C:18]3[CH:19]=[CH:20][N:21]4[CH:34]=[N:33][N:32]=[C:22]4[C:23]=3[CH:24]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(NS(=O)C(C)(C)C)c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(N)c1ccc(-c2nc3ccn4cnnc4c3cc2-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-methyl-N-{1-[4-(9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]ethyl}propane-2-sulfinamide (7-3, 180 mg, 0.38 mmol) in methanol (6 mL) was added conc. HCl (1.5 mL). After 1 h, water was added and the mixture was washed with methylene chloride. The aqueous portion was basified with saturated sodium carbonate solution and extracted with methylene chloride. 2N HCl (5 mL) was added to the organic layer and the mixture was concentrated to a minimum volume. The crude product was purified using reverse phase preparative HPLC to give the title compound as a pale yellow solid. LRMS m/z (M+1) Calcd: 366.2. Found 366.3.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=O)(C)(C)C.[ClH:28]>C(OCC)C>[ClH:28].[CH2:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[N:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccccc2)cn1
Agent: Cl
Solvent: CCOCC
Product: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)nc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To the product from step 3 (25 mg, 0.068 mmol) was added 2N HCl (3 mL) in diethyl ether. The resulting mixture was stirred at rt for 2 h. The solvent was removed to give the title compound (20 mg, 97%). MS; m/z 269 (M+H)>90%1H NMR (DMSO-d6, 400 MHz) δ 1.59-2.12 (4H, m), 3.19 (2H, m), 3.88 (2H, s), 4.34 (1H, d, J=8.0 Hz), 4.48 (1H, dd, J1=4.0 Hz, J2=11.6 Hz), 6.80 (1H, d, J=8.4 Hz), 7.17-7.30 (5H, m), 7.58 (1H, dd, J1=2.4 Hz, J2=8.4 Hz), 8.09 (1H, d, J=2.4 Hz), 8.93 (1NH, s), 9.49 (1NH, s).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=O)[N:3]=1.[CH2:11]([C@@H:18]1[NH:23][CH2:22][CH2:21][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:19][N:20]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH:33]([F:35])[F:34])[CH:25]=2)[CH2:21][CH2:22][N:23]1[C:8](=[O:10])[CH2:7][C:4]1[N:3]=[C:2]([CH3:1])[NH:6][N:5]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC(F)F
Reactant: Cc1nc(CC(=O)O)n[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3n[nH]c(C)n3)[C@@H](Cc3ccccc3)C2)cc1OC(F)F

Procedure:
Prepared by the method outlined for Example 189 using (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid and (S)-3-benzyl-1-(3-difluoromethoxy-4-methoxy-phenyl)-piperazine (Example 69, Compound 157) as starting materials. Product as an oil. LC/MS (Method B) 2.57 min, [M+1]+ 472. Potency class A.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:21][CH3:22])[S:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)(Cl)Cl>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[N:17]=[C:18]([S:21]([CH3:22])=[O:31])[S:19][CH:20]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CSc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cs1
Yield: 55.2 %

Procedure:
In 5 ml of chloroform was dissolved 0.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylthiothiazole and then 0.4 g of m-chloroperbenzoic acid (80%) was added portionwise to the solution with stirring. After 30 minutes since then, the reaction mixture was washed with an aqueous 5% sodium hydrogencarbonate solution and the chloroform layer was concentrated. The crystals thus obtained were recrystallized from hexane to provide 0.45 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-methylsulfinylthiazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>O1CCOCC1.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[N:17][S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[S@](=O)N=Cc1cccc(C#N)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In a flame dried flask under N2, 3-cyanobenzaldehyde (7.050 g, 53.76 mmol) was dissolved in anhydrous dioxane (100 mL). Ti(IV) ethoxide (28.183 mL, 134.40 mmol) was added followed by (S)-(−)-2-methyl-2-propanesulfinamide (7.167 g, 59.14 mmol). The r×n was heated to 110° C. After 2.5 hr the reaction was cooled to RT and brine (150 mL) was added. A precipitate formed and the reaction was rapidly stirred for 1 hr. The suspension was filtered through celite and the filter cake was washed with brine and ethyl acetate. The layers of the filtrate were separated. The aqueous layer was extracted with ethyl acetate (1×). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to afford (S)—N-[(3-cyanophenyl)methylidene]-2-methylpropane-2-sulfinamide as a light orange solid. 1H NMR (CD3OD) (8.61 (s, 1H), 8.26 (s, 1H), 8.22-8.20 (m, 1H), 7.94-7.92 (m, 1H), 7.72 (t, 1H, J=7.81 Hz), 1.28 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1.[N+](C1C=C(S(O[CH2:26][C@@H:27]2[CH2:29][O:28]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[C:6]([NH:8][C:9]([NH2:11])=[O:10])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: NC(=O)Nc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)Nc1cc(Cl)ccc1OC[C@@H]1CO1
Temperature: 25 °C

Procedure:
A solution of N-(5-chloro-2-hydroxyphenyl)urea (0.9 g, 4.9 mmol) and (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (1.0 g, 3.8 mmol) in dimethylformamide were stirred under nitrogen. Cesium carbonate (1.9 g, 5.7 mmol) was added to the mixture and the reaction was stirred under nitrogen at room temperature over night. The mixture was partitioned between water and dichloromethane, and the organic phase was washed with water. After drying, filtration and evaporation of the solvent 0.48 g, (52%) of subtitle compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]([NH2:23])=[NH:22])[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:27].[C:28]([OH:34])([C:30](F)(F)F)=O>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[NH:23][C:26]5[C:28](=[O:34])[CH:30]=[CH:6][CH:5]=[CH:4][C:3]=5[N:22]=4)[C:16]3=[O:24])[CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[CH3:27]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCN(CC(=N)N)C3=O)CC2)cc1C
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(Cc4nc5ccccc(=O)c5[nH]4)C3=O)CC2)cc1C

Procedure:
The title compound (18 mg) was prepared following the general procedures of Example 28 starting with 2-{(R)-3-[4-(4-methoxy-3-methyl-benzoyl)-piperidin-1-yl]-2-oxo-pyrrolidin-1-yl}-acetamidine (405 mg, 0.85 mmol). HRMS calculated for C27H30N4O4 474.5646. found (ESI, [M+H]+). found 475.2345. 1H NMR (400 MHz, CDCl3-d) 8 ppm 1.74-2.11 (m, 4H) 2.22-2.44 (m, 5H) 2.57 (d, J=8.03 Hz, 1H) 3.09 (d, J=6.53 Hz, 3H) 3.28-3.40 (m, 1H) 3.50 (t, J=8.28 Hz, 2H) 3.62-3.83 (m, 1H) 3.89-3.97 (m, 3H) 4.82 (br. s, 2H) 6.87 (d, J=8.53 Hz, 1H) 7.00-7.11 (m, 1H) 7.26-7.36 (m, 5H) 7.38-7.47 (m, 1H) 7.72-7.86 (m, 3H) HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.874 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]([O:31][Si](C)(C)C)=[CH:28][CH2:29][CH3:30]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:28]([CH2:29][CH3:30])[C:27]([O:26][CH3:25])=[O:31])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reactant: CCC=C(OC)O[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC(C(=O)OC)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 62.9 %

Procedure:
To a solution of (1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methanol (250 mg, 0.79 mmol) and (1-methoxybut-1-enyloxy)trimethylsilane (32 mmol) which was prepared using General Silyl Ketene Acetal Method A in 10 mL of dry DCM was added TiCl4 (0.8 mL of 1.0 M DCM solution, 0.8 mmol) and then stirred 1 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2× EtOAc. The organic layers were dried over MgSO4, filtered, concentrated and purified on SiO2 by MPLC using a EtOAc/hexane gradient to give 200 mg (63% yield) of methyl 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butanoate. MS found: (M+H)+=403.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH:7]=[C:6]1[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(O)cc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(-c2ccccc2)ccc1-c1ccc(OCCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
A solution [2-(4-Hydroxy-phenyl)-5-phenyl-pyrrol-1-yl]-acetic acid methyl ester (0.1 mmol) in DMF (1 mL) is added phenethyl bromide (0.2 mmol) followed by K2CO3 (80 mg, 578 μmol). The mixture is heated without agitation overnight at 60° C. and monitored by TLC. The mixtures are cooled, water (2 mL) and CH2Cl2 (2 mL) are added, vortexed, centrifuged and the organics separated. The process is repeated with solely CH2Cl2 (1 mL). The organics are combined and concentrated in vacuo.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:15][C:14]=2[O:25][CH3:26])[N:10]=1.[CH:28](I)([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:27])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH:28]([CH3:30])[CH3:29])=[O:23])=[CH:15][C:14]=2[O:25][CH3:26])[N:10]=1
Reactant: CC(C)I
Reactant: COc1cc(CCCC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CCCC(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 0 °C
Reaction time: 4 h
Yield: 90.7 %

Procedure:
A mixture of 4-[4-[2-(2-furyl)-5-methyl-4-oxazolyl methoxy]-3-methoxyphenyl]butanoic acid (106 g), isopropyl iodide (58.2 g), potassium carbonate (47.3 g) and N,N-dimethylformamide (DMF) (100 ml) was stirred for 4 hours at temperatures ranging from 65 to 70° C. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:2), was obtained isopropyl 4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]butanoate (107 g, 91%), which was recrystallized from acetone-hexane to give colorless needles, m.p.45-46° C.
Reaction SMILES: C([O:5][C:6](=O)[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(OCC)=O>C(Cl)Cl.C1COCC1>[CH:6]([N:7]([CH3:8])[CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])=[O:5]
Reactant: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Solvent: CCOC=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C=O)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (65 mg, 0.14 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added THF (5 mL), triethylamine (0.1 mL, 0.72 mmol), and ethyl formate (5 mL), and the resulting mixture was refluxed for 4 days. Mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 35 mg of the title compound as a light yellow solid. MS: (+) m/z 381.34 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[CH:19]=[C:18]5[O:23][CH2:24][O:25][C:17]5=[CH:16][C:15]=4[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:26])=[N:4][CH:3]=1.CN(C)C=O>>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[CH:19]=[C:18]5[O:23][CH2:24][O:25][C:17]5=[CH:16][C:15]=4[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:26])=[N:4][CH:3]=1
Reactant: Cc1ncc(C)n2nc(/C=C/c3ccc4cc5c(cc4n3)OCO5)nc12
Solvent: CN(C)C=O
Product: Cc1ncc(C)n2nc(CCc3ccc4cc5c(cc4n3)OCO5)nc12
Temperature: 130 °C

Procedure:
6-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-1,3-dioxolo[4,5-g]quinoline (0.183 g, 0.530 mmol) was dissolved in N,N-Dimethylformamide (11 mL, 140 mmol). [B] p-Toluenesulfonylhydrazide (0.296 g, 1.59 mmol; Supplier=Avocado) was added and the reaction was stirred at 130° C. under an atmosphere of Argon ON. LCMS was done and showed almost complete conversion. 0.100 g [B] was added to the mixture was stirred 2 days at 130 C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-:17].[K+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([OH:17])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: Cc1cc(-n2c(C)ccc2C)nc(C)c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-n2c(C)ccc2C)nc(C)c1O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 2.37 g (8.49 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-bromo-4,6-dimethylpyridine (14) in 30 mL of dioxane-degassed water 1:1 were added 311 mg (0.34 mmol) of Pd2dba3 followed by 288 mg (0.68 mmol) of 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbyphenyl (L1) and 1.42 g (25.46 mmol) of potassium hydroxide. The reaction mixture was stirred at 100° C. under argon atmosphere during 3 h. The reaction mixture was poured into 150 mL of water and extracted with two portions of 150 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and the concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 3:1 gave the expected product as a white solid: yield 1.19 g (65%). 1H-NMR (CDCl3) δ 6.89 (s, 1H), 5.75 (s, 2H), 2.45 (s, 3H), 2.22 (s, 3H), 2.05 (s, 6H); 13C-NMR (CDCl3) δ 148.80, 145.03, 143.12, 135.51, 128.43, 122.32, 106.01, 18.48, 15.95, 12.80.
Reaction SMILES: [OH:1][CH:2]([CH:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][O:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[N:23]1([CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:2]([O:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:3][O:4][C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: O=C(OCC(O)C(c1ccccc1)n1ccc2ccccc21)c1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(COC(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)n1ccc2ccccc21

Procedure:
To a solution of (2RS, 3RS)-4-nitro-benzoic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester and triethylamine (1.4 mL, 10.5 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.59 mL, 7.6 mmol) dropwise at 0-5° C. with stirring. After stirring for 30 minutes, the mixture was washed with a 1N aqueous solution of hydrochloric acid, 5% aqueous sodium bicarbonate, and water, dried over anhydrous sodium sulfate, filtered, and concentrated to give a light yellow fluffy solid. The crude product was recrystallized from dichloromethane with a minimum amount of diethyl ether to give (2RS,3RS)-4-nitro-benzoic acid-3-indol-1-yl-2-methanesulfonyloxy-3-phenyl-propyl ester as a yellow solid. MS (ESI) m/z 495 ([M+H]+).
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][N:27]=1)[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:2]1([C:1](=[N:14][C:16]2[CH:17]=[C:18]([CH:25]=[CH:26][N:27]=2)[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccnc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Benzophenone imine (2.17 g, 12.0 mmol) was added to 2-bromo-N-methoxy-N-methylisonicotinamide (2.45 g, 10.0 mmol), tris(dibenzylideneacetone)dipalladium (458 mg, 0.50 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (552 mg, 1.30 mmol) and sodium t-butoxide (2.40 g, 25.0 mmol) in toluene (40 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and filtered through Arbocel™. The filtrate was washed with water (100 mL) then the organic phase was dried over sodium sulphate and evaporated in vacua. The crude material was purified by silica gel column chromatography eluting with heptane:EtOAc 100:0 to 30:70 to afford the title compound as an orange gum (71%, 2.44 g).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.CC(C)=O>CC(C)=O>[C:1]1([CH:7]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(O)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1c[nH]c2cc(OCC(=O)OC(C)(C)C)ccc12

Procedure:
The compound ethyl 3-phenyl-3-(6-hydroxyindol-3-yl)propionate 4 prepared analogously to Example 1.1-1.3 (3.23 mmol) is stirred overnight at 60° C. with 0.94 ml (6.4 mmol) of tert-butyl bromoacetate and 1.8 g (13 mmol) of potassium carbonate in 20 ml of acetone. When the reaction is complete (TLC check toluene/acetone 4:1), the residue is filtered off, the solution is evaporated, and the crude product is purified by chromatography on silica gel (eluent toluene/acetone 9:1), giving ethyl 3-phenyl-3-[6-(tert-butoxycarbonylmethoxy)indol-3-yl]propionate.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.FC(F)(F)S(O[C:22]1[C:23]([N+:28]([O-:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1)(=O)=O.O>CC(N(C)C)=O>[F:2][CH:3]1[CH2:8][CH2:7][N:6]([C:22]2[C:23]([N+:28]([O-:30])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1ncccc1OS(=O)(=O)C(F)(F)F
Reactant: FC1CCNCC1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ncccc1N1CCC(F)CC1
Temperature: 110 °C

Procedure:
To a solution of 4-fluoropiperidine hydrochloride (1.54 g, 11 mmol) and triethylamine (4.5 mL, 33 mmol) in dimethylacetamide (30 mL) was added 2-nitropyridin-3-yl trifluoro-methanesulfonate (3.00 g, 11 mmol) and the mixture heated to 110° C. for 1 hour. Water was added and the mixture extracted with ethyl acetate. The organic phase was washed with brine and dried with sodium sulfate. The solvent was evaporated in vacuo and the product used without further purification. The title compound was obtained as a yellow oil (2.22 g, 89%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13](Cl)=[O:14])[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[CH2:24][NH:25][C:19]=2[CH:18]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[O:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[CH2:24][N:25]([C:13](=[O:14])[CH2:12][N:9]3[C:7](=[O:8])[C:5]4[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=4)[C:10]3=[O:11])[C:19]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetyl chloride (4.00 grams), 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine (4.16 grams) and triethylamine (2.8 mi) were refluxed in toluene (100 mi) under nitrogen for 3 hours. The resulting mixture was poured into 1N HCl at 0° C., and the biphasic mixture was shaken vigorously. The insoluble product was collected by filtration, washed with toluene and ethyl ether, and dried in vacuo at 56° C. The yield of the title compound was 6.36 grams (85%). Mp: 184°-185° C.