Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[OH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:22]=[CH:21][C:6]([CH2:7][O:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH2:26][CH2:25]1
Reactant: OC1CCNCC1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccc(CN3CCC(O)CC3)cc2)cc1
Temperature: 60 °C
Reaction time: 21 h
Yield: 99.9 %

Procedure:
A mixture of methyl 3-(4-{[4-(chloromethyl)benzyl]oxy}phenyl)propanoate (0.6 g, 1.88 mmol), 4-hydroxypiperidine (0.29 g, 2.82 mmol), potassium carbonate (0.39 g, 2.82 mmol) and N,N-dimethylformamide (12 mL) was stirred at 60° C. for 21 hr. The reaction mixture was diluted with ethyl acetate, and the mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.72 g, yield 99%) as a beige powder. MS (ESI+): 384 (M+H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]1([CH3:27])[CH:18]=[CH:17][C:16]([S:19]([O:22][CH2:23][CH:24]([OH:26])[CH3:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:47][C:48]1[CH:53]=[C:52]([O:54][C:55]([F:58])([F:57])[F:56])[CH:51]=[CH:50][C:49]=1O>>[I:47][C:48]1[CH:53]=[C:52]([O:54][C:55]([F:56])([F:57])[F:58])[CH:51]=[CH:50][C:49]=1[O:26][CH:24]([CH3:25])[CH2:23][O:22][S:19]([C:16]1[CH:15]=[CH:14][C:13]([CH3:27])=[CH:18][CH:17]=1)(=[O:20])=[O:21]
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Reactant: Cc1ccc(S(=O)(=O)OCC(C)O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(S(=O)(=O)OCC(C)Oc2ccc(OC(F)(F)F)cc2I)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.8 %

Procedure:
Diethyl azodicarboxylate (5 ml, 31.8 mmol) was added dropwise to a stirred solution of (p-toluenesulphonyloxy)propan-2-ol (Description 19; 7.6 g, 33 mmol), triphenylphosphine (9.0 g, 34 mmol) and 2-iodo-4-trifluoromethoxyphenol (10 ml, 33 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (18.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:7])=[CH:4][C:3]=1[CH2:10][CH3:11].II.[Cl:14]Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][CH3:11])=[CH:4][C:5]([CH2:6][Cl:7])=[CH:8][C:9]=1[Cl:14]
Reactant: ClCl
Reactant: CCc1cc(CCl)ccc1Br
Agent: II
Solvent: ClC(Cl)Cl
Product: CCc1cc(CCl)cc(Cl)c1Br

Procedure:
To a solution of 46 parts of 4-bromo-3-ethylbenzyl chloride and 3 parts of iodine in 300 parts of chloroform is added 16 parts of chlorine. The solution is refluxed in the absence of light for 6 hours, then cooled and extracted with water and dilute sodium bisulfite solution. The organic phase is separated, dried and concentrated. The residue is chromatographed on Florisil or alumina and 4-bromo-2-chloro-5-ethylbenzyl chloride, 4-bromo-2-chloro-3-ethylbenzyl chloride, and a small amount of 4-bromo-3-chloro-5-ethylbenzyl chloride are isolated as three of the fractions.
Reaction SMILES: [CH:1]1([N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=2)[CH3:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]1([N:4]([CH3:5])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: CN(Cc1cccc(I)c1)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CN(Cc1cccc(C#C[Si](C)(C)C)c1)C1CC1
Yield: 79.4 %

Procedure:
Following General Procedure D and using cyclopropyl-(3-iodo-benzyl)-methyl-amine (Intermediate 89, 0.97 g, 3.4 mmol), triethyl amine (10 mL), copper(I)iodide (0.051 g, 0.27 mmol), trimethylsilyl acetylene (2 mL, 14 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.19 g, 0.27 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane-5% ethyl acetate in hexane as the eluent, the title compound (0.695 g, 80%) was obtained.
Reaction SMILES: Cl.[CH3:2][CH:3]([C:8]#[N:9])[C:4](=[NH:7])[O:5][CH3:6].[N:10]#[C:11]N>C1C=CC=CC=1>[C:11]([N:7]=[C:4]([O:5][CH3:6])[CH:3]([C:8]#[N:9])[CH3:2])#[N:10]
Reactant: N#CN
Reactant: COC(=N)C(C)C#N
Agent: Cl
Solvent: c1ccccc1
Product: COC(=NC#N)C(C)C#N
Yield: 86.8 %

Procedure:
2.97 g of methyl α-methylcyanoacetimidate hydrochloride and 1.26 g of cyanamide were suspended in 30 ml of benzene and made to react for 5 hours at 25°C. Then, ammonium chlordie precipitate was filtered off and then the filtrate was concentrated to dryness in vacuo and 2.38 g of methyl N-cyano-α-methycyanoacetimidate was obtained (yield 86.8%) mp 68.5°C. Analysis calculated for C6H7N3O (%) C 52.54, H 5.15, N 30.64, found C 52.57, H 5.14, N 30.62.
Reaction SMILES: [CH:1]12B[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3]C2.[OH-].[Na+].[CH2:12]([OH:14])C.OO>O1CCCC1>[CH:7]1([CH:6]([CH:5]2[CH2:4][CH2:3]2)[CH2:12][OH:14])[CH2:8][CH2:1]1
Reactant: B1C2CCCC1CCC2
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCC(C1CC1)C1CC1
Temperature: 5 °C
Reaction time: 18 h

Procedure:
To a solution of the compound of Preparation 155 (1 g, 9.24 mmol) in tetrahydrofuran (15 ml) under nitrogen was added 9-borabicyclo[3.3.1]nonane (18.5 ml of a 0.5M solution in tetrahydrofuran, 1 mol. equiv.) and the solution stirred for 18 hours. Sodium hydroxide (3.08 ml of a 3M aqueous solution, 1 mol. equiv.) was added followed by ethanol (5 ml). The reaction was cooled to 5° C. and hydrogen peroxide (3.14 ml of a 30% w/w aqueous solution, 3 mol. equiv.) added. The reaction was stirred at room temperature for 1 hour.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[C:19]1([CH2:25][C:26](O)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:26](=[O:27])[CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
To a 4 mL vial was added the product from Example 1B (20 mg in dimethyl acetamide), phenylacetic acid [1.5 equivalents in dimethyl acetamide], O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2 equivalents in dimethyl acetamide) and triethylamine (3 equivalents, neat). The vial was capped and microwaved at 150° C. for 30 minutes. The reaction was checked by LC/MS and concentrated to dryness upon completion. The residue was dissolved in 1:1 MeOH:DMSO and purified by reverse phase HPLC (conditions from Example 10C): 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.33-8.28 (m, 1H), 8.03 (d, J=7.5, 1H), 8.01-7.96 (m, 1H), 7.94-7.87 (m, 1H), 7.40-7.33 (m, 4H), 7.33-7.25 (m, 1H), 3.86-3.78 (m, 4H), 3.67 (s, 2H), 3.11-3.06 (m, 4H); MS (ESI+) M/Z 365 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:32](OCC)=[O:33].[O-]CC.[Na+].Cl>C(O)C>[OH:33][CH:32]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[N:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])=[CH:15][CH:14]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4)cc2)n(C(C)(C)C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Temperature: 78 °C
Yield: 81 %

Procedure:
2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.634 g, 1.63 mmol) and ethyl formate (0.391 mL, 4.89 mmol) were dissolved in anhydrous ethanol (3.50 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (3.05 mL, 8.16 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.548 g, 1.32 mmol, 81%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH3:18])=[C:12]([CH:15]=1)[CH:13]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH3:18])=[C:12]([CH:15]=1)[CH:13]=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: CCOc1ccc(Br)cc1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1cc(Br)ccc1OCC
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Methyltriphenylphosphonium bromide (1.09 g, 3.05 mmol) was added to a solution of potassium t-butoxide (0.5 g, 2.29 mmol) in THF (8 mL). The resulting reaction mixture turned bright yellow and was stirred for 40 min after which, it was cooled to −78° C. 5-bromo-2-ethoxybenzaldehyde was dissolved in THF (2 mL) and added to the reaction which was stirred for 2 h. The reaction was warmed to rt, diluted with ether and filtered through celite. The filtrate was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 15% EtOAc/hexanes yielded 320 mg of the desired product: 1H NMR (500 MHZ, CDCl3) δ 7.58 (d, J=2.5 Hz, 1H), 7.31 (dd, J=6.4, 2.4 Hz, 1H), 6.96-7.04 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.77 (d, 1H), 5.32 (d, 1H), 4.03-4.07 (m, 2H), 1.45 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.I[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([CH2:24][NH:25][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Ic1cccnc1
Reactant: NCC1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Product: c1cncc(NCC2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)c1
Yield: 18 %

Procedure:
The title compound (28 mg, 18%) was prepared from 1-(4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-yl)methanamine and 3-iodopyridine similarly to the procedure used for example 153. 1H NMR (400 MHz, CDCl3) δ 1.66-1.94 (m, 8H), 2.01-2.06 (m, 4H), 2.17-2.20 (m, 4H), 2.60-2.68 (m, 2H), 2.76 (m, 1H), 3.22-3.27 (m, 3H), 3.57 (t, 2H), 3.77-3.81 (m, 2H), 4.32 (m, 1H), 6.73 (d, 1H), 6.92 (d, 2H), 6.99 (m, 1H), 7.23 (d, 2H), 7.88 (m, 2H). HRMS ESI+ m/z 422.2789 [MH]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:23]=[CH:22][C:21]([C:24]2NN=[N:26][N:25]=2)=[CH:20][CH:19]=1.N1C=CC=CC=1>O>[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:19]=[CH:20][C:21]([C:24]2[O:7][C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])=[N:26][N:25]=2)=[CH:22][CH:23]=1
Reactant: c1cc(C2OCCO2)ccc1-c1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: O
Product: O=[N+]([O-])c1ccccc1-c1nnc(-c2ccc(C3OCCO3)cc2)o1
Yield: 77.2 %

Procedure:
A mixture of 2-nitrobenzoyl chloride (0.190 g), 5-[4-(1,3-dioxolan-2-yl)phenyl]-1H-tetrazole (0.200 g) and pyridine (5 ml) was heated under reflux for 1 hr. After cooling, water was added to the reaction mixture, and the crystals were collected by filtration, and dissolved in ethyl acetate. This solution was washed with 1 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with hexane to give 2-[4-(1,3-dioxolan-2-yl)phenyl]-5-(2-nitrophenyl)-1,3,4-oxadiazole (0.240 g, yield 77%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 88–89° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:24])[C@@H:13]([NH:16]C(OC(C)(C)C)=O)[CH2:14][F:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:24])[C@@H:13]([NH2:16])[CH2:14][F:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 160 mg 4-((R)-2-tert-Butoxycarbonylamino-3-fluoro-propionyl)-piperazine-1-carboxylic acid ethyl ester in 5 ml dichloromethane was added 1.0 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 216 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[NH:20][CH:19]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([Sn](CCCC)(CCCC)C=C)[CH2:29]CC.C(OCC)(=O)C>CN(C=O)C>[CH:28]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[C:16]([C@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17])=[CH2:29]
Reactant: O=C(c1c[nH]c2ccc(Br)cc12)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1ccc2[nH]cc(C(=O)[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
A solution (R)-3-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl )-5-bromo-1H-indole (Example 5a, 252 mg, 0.59 mmol), tributyl(vinyl)tin (0.20 mL, 0.68 mmol) and tetrakistriphenyphosphine palladium (0) (84 mg, 0.073 mmol) in anhydrous DMF (3 mL) was stirred at 95-100° C. for 1 day. After cooling to room temperature, the product was taken into ethyl acetate, filtered through celite, washed with water (2×) and brine (1×), dried over sodium sulfate and the solvent was removed in vacuo. Flash chromatography on silica gel (60-100% ethyl acetate in hexanes) yielded (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl)carbonyl]-1H-indole (115 mg, 52%). A solution of LAH (0.77 mL, 1M in THF, 0.77 mmol) was added slowly to a cooled (0° C.) solution of (R)-5-vinyl-3-[(N-carbobenzyloxypyrrolidin-2-yl) carbonyl]-1H-indole (115 mg, 0.31 mmol) in THF (5 mL). Once the addition was completed, the reaction mixture was stirred at reflux for 2 h prior to quenching with sodium sulfate decahydrate. The product was taken into ethyl acetate, filtered to remove the solid residue, and the solvent was removed in vacuo. Flash chromatography on silica gel (5% 2M methanolic ammonia in dichloromethane) yielded (R)-5-vinyl-3-[(N-methylpyrrolidin-2-yl) methyl]-1H-indole (52 mg, 71%). HRMS-FAB+ for C16H20N2 : calculated MH+ :241.17047; found MH+ :241.17036.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[O:9][C:10](=[O:11])[C:5]=2[CH:4]=1.[H-].[Na+].I[CH3:20].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[N:7]([CH3:20])[C:8](=[O:12])[O:9][C:10](=[O:11])[C:5]=2[CH:4]=1
Reactant: CI
Reactant: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
9.00 g (40.3 mmol) 6,7-Dimethoxy-1H-benzo(d)(1,3)oxazine-2,4-dione were dissolved in 60 ml dried dimethylformamide and cooled to 0° C. 1.32 g (52.3 mmol) sodium hydride was added and the solution was stirred for 30 min at room temperature (Argon). After cooling to 0° C. again 7.42 g (3.27 ml, 52.3 mmol) iodomethane was added and stirred at room temperature for 1 h. 300 ml water was added and the residue is filtrated, rinsed with water and ethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH3:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: Cc1ccccc1B(O)O
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3C)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-methyl-phenylboronic acid (44 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[CH:12][C:11]2[C:14](=[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[O:15][CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[C:9]=1[Cl:33]>C(O)(C)C>[Cl:33][C:9]1[C:10]2[CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:15][C:14](=[C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[C:11]=2[CH:12]=[N:13][C:8]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: O=C1Nc2ccccc2C1=C1OC(c2ccccc2)c2c1cnc(Cl)c2Cl
Solvent: CC(C)O
Product: O=C1Nc2ccccc2C1=C1OC(c2ccccc2)c2c1cnc(N1CCOCC1)c2Cl
Temperature: 25 °C
Yield: 44.9 %

Procedure:
A solution of morpholine (155 mg, 1.78 mmol) in 4 mL of isopropanol is treated with 3-(6,7-Dichloro-1-phenyl-1H-furo[3,4-c]pyridin-3-ylidene)-1,3-dihydro-indol-2-one (100 mg, 0.25 mmol) in one portion and the reaction mixture is heated to reflux overnight. The reaction mixture is cooled to room temperature, absorbed to silica gel and purified by chromatography (silica gel, MeOH, chloroform). The product containing fractions are concentrated to give the title compound as a yellow solid (50 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.C1(C2[N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH:18]([CH2:24][OH:25])[O:17]2)C=CC=CC=1.[H-].[Na+]>>[Cl:1][C:2]1[C:7]([O:25][CH2:24][CH:18]([OH:17])[CH2:19][NH:20][CH:21]([CH3:23])[CH3:22])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(Cl)n1
Reactant: CC(C)N1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1cnc(Cl)c(OCC(O)CNC(C)C)n1

Procedure:
Analogously to the description in Example 11, 8.2 g (0.05 mol) of 2,3-dichloro-5-methyl-pyrazine, 11 g (0.05 mol) of 2-phenyl-3-isopropyl-5-hydroxymethyl-oxazolidine and 3.4 g of a 50% strength suspension of sodium hydride in paraffin oil give 2-chloro-3-(3'-isopropylamino-2'-hydroxy-propoxy)-5-methyl-pyrazine, melting point 109°-110° C. when crystallised from benzene. The fumarate prepared therefrom by means of fumaric acid crystallises from methanol-ether, melting point 164°-165° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH:27]=[O:28])=[C:25]([Cl:29])[N:24]=[C:23]2[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:10]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(S(=O)(=O)NC(=O)CN)cc1

Procedure:
Intermediate (2d) (5.6 g) was dissolved into 20 mL 30% TFA:DCM and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to yield the title compound as an oil in a quantitative yield. MS m/z: [M+H+] calcd for C17H21ClN4O4S 413.1; found 413.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([CH:26]([CH3:28])[CH3:25])[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1ccc(OC2CCNCC2)cc1Cl
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(Oc2ccc(C#N)c(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
2-Chloro-4-(4-piperidinyloxy)benzonitrile hydrochloride (D30) (1.5 g) was dissolved in DCM (40 ml) and triethylamine (2.29 ml) was added followed by acetone (0.64 g). The mixture was stirred for 5 min and then sodium triacetoxyborohydride (1.94 g) was added and the reaction stirred at rt under argon overnight. The reaction mixture was then washed with saturated potassium carbonate solution (2×40 ml) and brine (40 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D31) as a white solid (1.51 g). MS electrospray (+ion) 279 (MH+).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)([O-])=O.[CH2:11]([O-:13])[CH3:12].[Na+]>C1COCC1>[CH2:11]([O:13][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][CH:5]=1)[CH3:12]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a mixture of 4-nitropyridine 1-oxide (50 g, 357 mmol) in THF (500 mL) was added sodium ethanolate (48.6 g, 714 mmol). The mixture was stirred at 25° C. for 16 h. The reaction residue was concentrated. The crude material was purified by silica column chromatography (DCM/MeOH=25:1). All fractions found to contain product by TLC (DCM/MeOH=25:1, Rf=0.6) were combined and concentrated to yield a dark red solid of 4-ethoxypyridine 1-oxide (25 g, 162 mmol, 45.3% yield): 1H NMR (400 MHz, CD3OD) δ 8.20-8.18 (m, 2H), 7.11-7.10 (m, 2H), 4.21-4.15 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); ES-LCMS m/z 140.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:18]=[CH:17][C:16](OC)=[CH:15][CH:14]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=O.[O:26]1CCOC[CH2:27]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[O:26][CH3:27])=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C1COCCO1
Reactant: COC=C(c1ccc(OC)cc1)c1cc(Br)cnc1N
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Temperature: 100 °C
Yield: 82 %

Procedure:
A 50 ml round bottomed flask was charged with 403 mg of 5-bromo-3-[2-methoxy-1-(4-methoxy-phenyl)-vinyl]-pyridin-2-ylamine (1.2 mmol; combined E- and Z-isomers), 1,4-dioxane (5 ml), and 70% aqueous perchloric acid (250 μl). The flask was fitted with a reflux condenser and nitrogen inlet adapter and heated in an oil bath to 100° C. for 8 hours. The reaction mixture was concentrated, then treated with 15 ml of a saturated aqueous solution of sodium bicarbonate followed by ethyl acetate (20 ml). The layers were separated, and the aqueous fraction was extracted twice with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was triturated with ether to afford 300 mg (82%) of 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a tan powder. 1H-NMR (d6-DMSO) δ=12.16 (br. s, 1H), 8.36 (d, 1H), 8.18 (d, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 7.36 (t, 1H), 7.19 (d, 1H), 7.10 (t, 1H), 3.88 (s, 3H); MS m/z: 303 [MH]+.