Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH2:18][N:19]3[C@@H:23]([CH3:24])[C@@H:22]([C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([F:35])[CH:26]=4)[O:21][C:20]3=[O:36])=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:61]1[C:70]([CH3:71])=[CH:69][C:64]([C:65]([O:67][CH3:68])=[O:66])=[CH:63][C:62]=1[CH3:72].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.[Pd](Cl)Cl.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:35][C:27]1[CH:26]=[C:25]([C@H:22]2[O:21][C:20](=[O:36])[N:19]([CH2:18][C:11]3[C:10]([C:4]4[CH:3]=[C:2]([C:61]5[C:70]([CH3:71])=[CH:69][C:64]([C:65]([O:67][CH3:68])=[O:66])=[CH:63][C:62]=5[CH3:72])[CH:7]=[N:6][C:5]=4[O:8][CH3:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=3)[C@H:23]2[CH3:24])[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=1
Reactant: COC(=O)c1cc(C)c(Br)c(C)c1
Reactant: COc1ncc(Cl)cc1-c1cnc(SC)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Temperature: 130 °C
Yield: 60.7 %

Procedure:
A mixture of (4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 18, 211 mg, 0.389 mmol), bis(pinacolato)diboron (296 mg, 1.17 mmol), and potassium acetate (114 mg, 1.17 mmol) in N,N-dimethylacetamide (2.0 mL) was degassed three times with nitrogen gas before the addition of (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (XPHOS Biphenyl Precatalyst) (15.5 mg, 0.019 mmol). The system was degassed three times and was then heated to 130° C. for 24 hours. LC/MS analysis indicated complete conversion to the product, but almost exclusively as the boronic acid. For this reason the crude reaction mixture was taken directly into the next step. Accordingly, methyl 4-bromo-3,5-dimethylbenzoate (142 mg, 0.584 mmol), (1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (24.5 mg, 0.039 mmol), and aqueous potassium carbonate (0.389 mL, 2.0 M) were added. The mixture was degassed, flushed with nitrogen and heated to 100° C. for 45 minutes. The reaction was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography to afford methyl 4-{5-[4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfanyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (158 mg, 0.236 mmol). LCMS (M+H)+: 671.1
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[NH:21][C:22]1[N:23]=[CH:24][C:25]2[CH2:31][N:30]([C:32](=[O:35])[CH:33]=[CH2:34])[CH2:29][CH2:28][C:26]=2[N:27]=1.[CH2:36]([OH:39])[C:37]#[CH:38]>>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[NH:21][C:22]1[N:23]=[CH:24][C:25]2[CH2:31][N:30]([C:32](=[O:35])[CH2:33][CH2:34][O:39][CH2:36][C:37]#[CH:38])[CH2:29][CH2:28][C:26]=2[N:27]=1
Reactant: C#CCO
Reactant: C=CC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCOCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 50 °C
Yield: 47.7 %

Procedure:
Add 1,8-diazabicyclo [5.4.0]undec-7-ene (0.035 mL; 0.15 equiv; 0.23 mmoles) to a solution of 1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]prop-2-en-1-one (0.5 g; 1.0 equiv; 1.56 mmoles) and 2-propyn-1-ol (5.0 mL; 55 equiv; 85.86 mmoles). Stir the reaction at ambient temperature for 16 hours, then heat to 50° C. for 36 hours. Concentrate the solution to a brown oil, then purify the crude product by column chromatography (20 to 100% ethyl acetate in dichloromethane) to afford the desired 1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-(prop-2-yn-1-yloxy)propan-1-one (0.28 g; 48%): MS (m/z): 377 (M+1).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC(COC(=O)CCCCCCCCCCCCCCC)CSCCC(NCC1C=CC(C(N[C@H](C(O)=O)CCC(O)=O)=O)=CC=1)=O)(=O)CCCCCCCCCCCCCCC.[C:110]([O:114][C:115](=[O:123])[C:116]1[CH:121]=[CH:120][C:119]([NH2:122])=[CH:118][CH:117]=1)([CH3:113])([CH3:112])[CH3:111].P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:110]([O:114][C:115](=[O:123])[C:116]1[CH:117]=[CH:118][C:119]([NH:122][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:120][CH:121]=1)([CH3:113])([CH3:111])[CH3:112]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Agent: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (2.0 g), 4-aminobenzoic acid t-butyl ester (600 mg) and phosphorus trichloride (207 mg) in pyridine (40 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform) to yield the title compound (2.157 g, yield 99%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([OH:15])([CH3:14])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].CO[C:18](OC)([CH3:20])[CH3:19].CC1C=CC(S(O)(=O)=O)=CC=1.CC(=O)OCC>CC(C)=O>[CH3:19][C:18]1([CH3:20])[O:15][C:2]([CH3:1])([CH3:14])[CH:3]([C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)[O:4]1
Reactant: CC(C)(O)C(O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(c2ccc([N+](=O)[O-])cc2)C(C)(C)O1
Yield: 84.1 %

Procedure:
A solution of 2-methyl-1-(4-nitrophenyl)propane-1,2-diol (1.5 g, 7.1 mmol), 2,2-dimethoxypropane (1.45 g, 14.2 mmol) and TsOH (cat., 260 mg, 1.5 mmol) in acetone (40 mL) was stirred at 30° C. for 16 h. The reaction mixture was concentrated. The residue was purified by silica gel chromatography, eluting with PE:EA (8:1), to obtain the desired product (1.5 g, 85% yield) as a white solid. 1H-NMR (500 MHz, CDCl3) δ ppm 8.23 (d, 2H, J=9.0 Hz), 7.57 (d, 2H, J=9.0 Hz), 4.93 (s, 1H), 1.59 (s, 3H), 1.48 (s, 3H), 1.46 (s, 3H), 0.78 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=2)[O:6][C:5](=[O:7])[NH:4][CH2:3]1.[OH-].[K+].[CH3:21]I>O1CCCC1>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]([C:2]2([CH3:1])[O:6][C:5](=[O:7])[N:4]([CH3:21])[CH2:3]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH3:18]
Reactant: CI
Reactant: CCOc1cc(C2(C)CNC(=O)O2)ccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C2(C)CN(C)C(=O)O2)ccc1OC
Yield: 37.9 %

Procedure:
500 mg (2.0 mmol) of 5-methyl-5-(3-ethoxy-4-methoxyphenyl)-2-oxazolidinone, 125 mg (2.22 mmol) of potassium hydroxide, and 0.167 ml (2.38 mmol) of methyl iodide were stirred in 4 ml of tetrahydrofuran for 4 hours at room temperature. The process was continued analogously to Example 8, thus obtaining 201 mg of 5-(3-ethoxy-4-methoxyphenyl)-3,5-dimethyl-2-oxazolidinone as an oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[Cl:33])[CH:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:42])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[S:32][C:31]5[C:26](=[N:27][CH:28]=[CH:29][C:30]=5[Cl:33])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:6]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cc4nccc(Cl)c4s3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CN(C(=O)[C@H](NC(=O)c2c[nH]c3ncc(-c4cc5nccc(Cl)c5s4)nc23)C2CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (30 mg, 0.048 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.37 mL, 4.82 mmol). The reaction mixture was stirred for 3 h at room temperature then concentrated and dried under high vacuum for 1 h. The residue was dissolved in 3 mL of CH2Cl2:MeOH:NH4OH (80:19:1) and stirred at room temperature for 18 h then evaporated to dryness under vacuum. The crude residue was washed with MeOH (3×3 mL) to give 17 mg (72%) of 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide. MS: (M+H)+=492.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.I[C:21]1[CH:25]=[CH:24][S:23][CH:22]=1.CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Ic1ccsc1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2ccsc2)c(=O)c1N1CCc2nc(N)ncc2C1
Temperature: 70 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
A degassed solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one (26 mg, 0.097 mmol), 3-iodothiophene (23 mg, 0.102 mmol), N1,N2-dimethylethane-1,2-diamine (5 mg, 0.049 mmol), copper iodide (4 mg, 0.020 mmol), and potassium phosphate (41 mg, 0.194 mmol) in 2 mL of N-methylpyrrolidone was heated to 70° C. After allowing the reaction to stir overnight (16 h) at 70° C., the reaction was complete and therefore allowed to cool to room temperature. The reaction was extracted with with EtOAc (3×5 mL) and with NaHCO3 (2×10 mL). The crude organic layers were combined, dried over anhydrous Na2SO4 (s), filtered and then concentrated in vacuo. The crude mixture was then purified over silica using a 0-100% EtOAc gradient/100-0% Hexane gradient mixture after which, the appropriate fractions were concentrated to afford a solid. This solid was further purified by recrystallization using an Et2O/Hexane solvent mixture to give the title compound (11 mg, 35%). 1H NMR (DMSO) δ: 7.98 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=6.2, 1H), 7.22 (d, J=6.2, 1H), 6.28 (m, 1H), 6.17 (d, J=7.0 Hz, 2H), 3.98 (br. S, 2H), 3.33 (s, 2H), 2.56(t, j=5.3 Hz, 2H), 2.17 (s, 3H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:14]([O-])=O)[C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].CO>[Pd].O1CCCC1>[NH2:14][C:5]1[C:6]([OH:13])=[C:7]([CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C#N)cc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C#N)cc(N)c1O
Temperature: 50 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
To a mixture of 2.71 g of methyl 5-cyano-2-hydroxy-3-nitrobenzoate in a 60 ml of methanol and 40 ml of tetrahydrofuran was added palladium on carbon (500 mg, 10% wet). This suspension was purged with, and stirred under, an atmosphere of hydrogen (via balloon) for 4 h at 50° C. The mixture was then filtered through a plug of Celite, eluting with ethyl acetate (75 ml). The eluent was concentrated in vacuo and the residue was taken up in ethyl acetate (50 ml) and methanol (as needed to dissolve) and was then filtered through a plug of silica gel. The eluent was concentrated in vacuo again and purified via column chromatography using a Biotage Horizon, 65i column, eluting with 1 column volume of 100% hexanes followed by a gradient of 0 to 100% ethyl acetate in hexanes over 10 column volumes, followed by 2 column volumes of 100% ethyl acetate to provide the title compound (1.83 g, 78%). Mass spectrum (ESI) 190.9 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](Cl)=[S:14])[CH3:11].[H-].[Na+]>CN1CCCC1=O>[CH2:10]([N:12]([CH2:16][CH3:17])[C:13](=[S:14])[O:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=1)[CH3:11]
Reactant: CCN(CC)C(=S)Cl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCN(CC)C(=S)Oc1cc(Br)cc(Br)c1
Temperature: 20 °C
Yield: 91.3 %

Procedure:
A solution of 3,5-dibromophenol (prepared according to Recl. Trav. Chim. Pays-Bas. 1908, 27, 30) (10.08 g, 40 mmol) and diethylthiocarbamyl chloride (7.9 g, 52 mmol) in 1-methyl-2-pyrrolidinone (80 ml) was cooled to 0° C. under an atmosphere of nitrogen. Sodium hydride (60% dispersion in mineral oil, 1.92 g, 48 mmol) was added portionwise with stirring. The mixture was allowed to warm to 20° C. and stirred under nitrogen for two hours. The mixture was partitioned between diethyl ether (250 ml) and water (350 ml) and the aqueous layer was further extracted with diethyl ether (250 ml then 100 ml). The organic layers were combined, washed with water (150 ml) and brine (150 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow solid. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:pentane (1:1, by volume) to provide the title compound (13.4 g) as a white solid, m.p. 72–74° C.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:21]/[NH:20][C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)OC(C)(C)C)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and tert-Butyl carbazate according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 4H), 1.54 9s, 9H), 1.69-1.75 (m, 2H), 3.70 (t, 2H), 3.86 (s, 3H), 6.41 (d, 1H), 6.60 (dd, 1H), 7.66 (d, 1H), 12.201 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.O.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.[Fe]>[NH2:17][C:15]1[CH:14]=[C:11]([CH:10]=[C:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=1)[C:12]#[N:13]
Reactant: Cc1ccc(Oc2cc(C#N)cc([N+](=O)[O-])c2)cn1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Oc2cc(N)cc(C#N)c2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
A mixture of 3-(6-methylpyridin-3-yloxy)-5-nitrobenzonitrile (3 g, 0.012 mol) and iron powder in acetic acid (200 mL) was stirred at RT for 6 h. H2O was added and the mixture was adjusted to pH 7 with saturated Na2CO3 solution. The aqueous layer was extracted with EtOAc, and the combined organics were washed with brine, dried (MgSO4), concentrated in vacuo and purified by silica gel chromatography to afford 3-amino-5-(6-methylpyridin-3-yloxy)benzonitrile (2 g, 76% yield). 1H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.42 (d, J=10 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 6.62 (s, 1H), 6.51 (s, 1H), 6.38 (s, 1H), 5.78 (s, 2H), 2.49 (s, 3H); MS (ESI) m/z: 226.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[N:26]1([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[S:7][C:6]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[NH:17][S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])=[N:5][CH:4]=2)[CH2:28][CH2:27]1)[CH3:37]
Reactant: O=S(=O)(Nc1cccc2cc(-c3ncc(CCl)s3)[nH]c12)c1cccs1
Reactant: CCOC(=O)CN1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.460 g) in N,N-dimethylformamide (12 ml) were added ethyl piperazin-1-ylacetate (0.385 g) and triethylamine (0.31 ml), and the mixture was stirred at room temperature for 15 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-hexane to give the title compound (0.507 g, yield 83%) as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])[C:3](O)=[O:4].B.C1COCC1.[OH-].[Na+]>>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])[CH2:3][OH:4]
Reactant: NC(C(=O)O)c1cccc(Cl)c1Cl
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(CO)c1cccc(Cl)c1Cl

Procedure:
Quantities of 1.0 g (4.54 mmol) of amino-(2,3-dichlorophenyl)acetic acid and 18.18 ml (18.18 mmol) of borane-THF complex (1M solution in THF) were stirred together at RT until the reaction was complete. For work-up, pieces of ice were added. After the end of the evolution of gas, the mixture was adjusted to a pH of 9-10 using 1M aqueous sodium hydroxide solution, and extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 880 mg (91% of theory) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH:4]([CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14])[CH:3]1[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH2:6][C:5]([CH3:7])([CH3:8])[C:4]([CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14])=[C:3]1[CH3:16]
Reactant: CC(C=CC1C(C)C(=O)CC1(C)C)=CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CC(C=CC1=C(C)C(=O)CC1(C)C)=CC=O
Reaction time: 5 h

Procedure:
2 g. of the 5-(3-oxo-2,5,5-trimethyl-cyclopent-1-yl)-3-methyl-penta-2,4-dien-1-al, 50 mg. of p-toluenesulfonic acid, 2.5 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 40 ml. of toluene was heated to boiling for 5 hours under reflux conditions. After cooling, the mixture is filtered. After evaporation of the filtrate, there is obtained 5-(3-oxo-2,5,5-trimethyl-cyclopent-1-en-1-yl)-3-methyl-penta-2,4-dien-1-al which, after purification by adsorption on silica gel, has a melting point of 91°-93°C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C[Mg+].[Br-].[CH3:41]CN(CC)CC.CS(Cl)(=O)=O>C1COCC1.C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:12]([C:14]2[N:15]=[CH:16][N:17]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=2)=[CH2:41])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1c(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccc2cccnc12
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: C[Mg+]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2cccnc2c1C
Yield: 59.8 %

Procedure:
A solution of (8-methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone (Intermediate M4) (3.59 g, 7.49 mmol) in THF (100 mL) at 0° C. was treated with MeMgBr (5.0 mL, 3M in ether) for 16 h. The reaction mixture was quenched with NH4Cl (aq) and extracted with EtOAc. The layers were separated and dried over MgSO4, filtered, evaporated and purified by column chromatography on silica gel with 3 to 4% NH3-MeOH. The alcohol in CH2Cl2 (100 mL) was treated with Et3N (8.4 mL, 60.3 mmol) and methane sulfonyl chloride (1.75 mL, 22.6 mmol) at 0° C. for 3 h. The mixture was quenched with water and extracted with CH2Cl2. The organic layers were pooled and evaporated to give 8-methyl-7-[1-(1-trityl-1H-imidazol-4-yl)vinyl]quinoline (Intermediate M5) 2.14 g (60% over two steps). This material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]1[NH:21][C:20](=[O:22])[C:19]([CH3:24])([CH3:23])[O:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.O>CN(C=O)C.CCCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[CH:17]1[N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)[C:20](=[O:22])[C:19]([CH3:24])([CH3:23])[O:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Oc2ccccc2)cc1
Reactant: COc1cccc(OCc2ccccc2)c1C1NC(=O)C(C)(C)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCCC
Solvent: CN(C)C=O
Product: COc1cccc(OCc2ccccc2)c1C1OC(C)(C)C(=O)N1Cc1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
To a cold (0° C.) solution of 2-(2-benzyloxy-6-methoxy-phenyl)-5,5-dimethyl-oxazolidin-4-one (410 mg) in dry DMF (5 mL) is added portionwise NaH 90% (45 mg, 1.5 eq). The reaction mixture is stirred for 15 min at 0° C. and then commercially available 1-(bromomethyl)-4-phenoxybenzene (395 mg, 1.2 eq) is added and the reaction mixture is stirred at RT for 1 h. The reaction mixture is poured into water, extracted with DCM. The combined organic extracts are dried (MgSO4), filtered and concentrated to yield a crude oil. FC (EN n-heptane: 0/1 to 4/6) gives 2-(2-benzyloxy-6-methoxy-phenyl)-5,5-dimethyl-3-(4-phenoxy-benzyl)-oxazolidin-4-one as a colorless oil (0.495 g, 77%); LC-MS: tR=0.88 min; [M+H]+=510.33.
Reaction SMILES: C([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20](=[O:22])[NH2:21])[CH:12]=1)=[O:10])C1C=CC=CC=1>CN(C=O)C.C1COCC1.CCOCC.[Pd]>[C:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([C:9]([OH:10])=[O:8])=[CH:12]1)(=[O:22])[NH2:21]
Reactant: NC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)n1cc(C(=O)O)c2ccccc21
Reaction time: 8 h

Procedure:
1-Carbamoyl-1H-indole-3-carboxylic acid benzyl ester (1.33 g, 4.52 mmol) was dissolved in a mixture of DMF/THF 1:1 (28 mL), Pd/C (10%, 250 mg) was added and the solution was degassed 3 times replacing air with nitrogen then nitrogen with hydrogen. The reaction mixture was further stirred under hydrogen atmosphere overnight and the catalyst was removed through a pad of Celite and washed with THF. The solvents were concentrated under high vacuum to give a yellow solid which was taken up in Et2O and filtered-off to afford the title compound. 1H-NMR (400 MHz, DMSO): δ (ppm) 12.6 (m, 1H), 8.54 (bs, 1H), 8.28 (d, 1H), 8.05 (d, 1H), 7.85 (m, 2H), 7.34-7.27 (m, 2H).