Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH:34]([CH3:36])[CH3:35])[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH:34]([CH3:36])[CH3:35])[C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:23][CH:22]=1
Reactant: C=CC[C@H](NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Reactant: CC(C)N(c1ccc(I)cc1)c1ncccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](C/C=C/c1ccc(N(c2ncccn2)C(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 7 h
Yield: 63.3 %

Procedure:
Under an argon atmosphere, palladium acetate (19.9 mg) and tris(2-methylphenyl)phosphine (25.9 mg) were added to a suspension of (S)-2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (514.4 mg), N-(4-iodophenyl)-N-isopropylpyrimidin-2-amine (577.4 mg) and potassium carbonate (352.9 mg) in DMF (6 ml), and the resulting mixture was stirred at 80° C. for 7 hours. After cooling the reaction solution to room temperature, ethyl acetate was added thereto, and the resulting mixture was washed twice with water and once with saturated brine, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→1/1→1/3). The obtained crudely purified product was purified again by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=6/1→4/1→2/1) to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (553.6 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].O>C(N(CC)CC)C.CN(C)C=O.[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>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1OCC
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#C[Si](C)(C)C)cc1OCC
Temperature: 50 °C
Yield: 90.3 %

Procedure:
Ethyl 2-ethoxy-4-iodobenzoate (0.763 g, 2.38 mmol, example 14), copper(I) iodide (0.0227 g, 0.119 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.167 g, 0.238 mmol) and (trimethylsilyl)acetylene (0.404 mL, 2.86 mmol) were dissolved under nitrogen in a flame-dried flask in a mixture of triethylamine (3.5 mL) and dimethylformamide (3.5 mL). The reaction mixture was heated at 50° C. for 2 h and then allowed to cool. Water (100 mL) was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over Sodium sulfate and evaporated. Purification of the crude residue by flash column chromatography (silica gel, eluting with 10% ethyl acetate in hexanes) gave ethyl 2-ethoxy-4-trimethylsilanylethynyl-benzoate as a yellow oil (0.624 g, 90%).
Reaction SMILES: C(OC[CH2:12][N:13](C)[CH3:14])(=O)CCCCCCC.[C:16]([O:33][CH2:34][CH2:35][CH2:36]Br)(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].CNC.C(Cl)(Cl)Cl.CO>C(#N)C>[C:16]([O:33][CH2:34][CH2:35][CH2:36][N:13]([CH3:14])[CH3:12])(=[O:32])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCC(=O)OCCCBr
Reactant: CCCCCCCC(=O)OCCN(C)C
Agent: CNC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)OCCCN(C)C
Yield: 72 %

Procedure:
This intermediate was prepared in a manner analogous to that of 2-(dimethylamino)ethyl octanoate from 3-bromopropyl hexadecanoate (3 g, 7.95 mmol) and 40% aqueous dimethylamine (15 mL, 119 mmol) in acetonitrile (20 mL). The resulting material was applied to a silica gel column (discontinuous gradient of chloroform/methanol 95:5, 8:2 as eluent) affording 1.3 g pure product. Yield 72%; mp 49°-50° C.; 1H NMR (CDCl3) 0.85-0.95 (t, CH3 (CH2)12), 1.20-1.40 (m, CH3 (CH2)12), 1.55-1.70 (m, CH2 CH2 CO), 1.88-2.00 (m, O CH2 CH2 CH2 N), 2.27-2.35 (t, CH2 CH2 CO), 2.37-2.45 (s, (CH3)2 N) 2.50-2.62 (t, O CH2 CH2 CH2 N), 4.10-4.18 (t, O CH2 CH2 CH2 N).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[SH:10][CH:11]([CH3:15])[C:12]([OH:14])=O.S(=O)(=O)(O)O>O.C1(C)C=CC=CC=1>[SH:10][CH:11]([CH3:15])[C:12]([O:1][CH2:2][C:3]([CH2:8][O:9][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])([CH2:6][O:7][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])[CH2:4][O:5][C:12](=[O:14])[CH:11]([SH:10])[CH3:15])=[O:14]
Reactant: OCC(CO)(CO)CO
Reactant: CC(S)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(S)C(=O)OCC(COC(=O)C(C)S)(COC(=O)C(C)S)COC(=O)C(C)S
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
To a 500-milliliter round-bottom flask equipped with a magnetic stirring bar, a water separator, and a condenser were added 27.23 grams (0.200 mol) of pentaerythritol, 90.22 grams (0.850 mol) of 2-mercaptopropionic acid, 100 milliliters of toluene, and 0.5 milliliter of concentrated sulfuric acid. The mixture was heated under reflux with stirring. After about 2 days, the solid material had disappeared, and about 17 milliliters (0.94 mol) of water had been collected by the water separator. Upon cooling to room temperature, the mixture was extracted with 30 milliliters of saturated NaHCO3 solution and washed with two 50-milliliter portions of water. The organic layer was dried over anhydrous MgSO4, and most of the toluene and residual 2-mercaptopropionic acid were removed by distillation under vacuum. Recrystallization of the residue from ethanol gave 86.0 grams (88.4%, calcd. 97.3 grams) of pentaerythritol tetrakis(2-mercaptopropionate) as a white solid, mp 93-96° C.; 1H NMR (in CDCl3 w/TMS, ppm): 4.17-4.30 (AB m, 8H, CH2O), 3.50 (pentuplet, 4H, CHSH), 2.17 (d of d, 4H, SH), 1.51 (d, 12H, CH3); {1H}13C NMR (in CDCl3 w/TMS, ppm): 172.79 (C═O), 62.47 (CH2O), 43.05 [C(CH2)4], 35.43 (CHSH), 20.94 (CH3).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[NH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([OH:39])=O.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:39]
Reactant: Nc1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(C(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
HATU (230 mg, 0.605 mmol) and aniline (0.063 mL, 0.691 mmol) was added to a solution of 3-aminobenzoic acid hydrochloride (100 mg, 0.576 mmol) and N,N-diisopropylethylamine (0.217 mL, 1.267 mmol) in 1.5 mL of DMF. The reaction solution was stirred at RT for 3 h. The crude material was purified by reverse-phase preparative HPLC using 0.1% TFA in CH3CN/H2O, gradient 20% to 45%. Desired fractions were collected and the solvents were removed under reduced pressure. The residue was passed through 2 g SCX column and washed by 2M NH3 in MeOH to provide 3-amino-N-phenylbenzamide (42 mg, 0.198 mmol, 34.4% yield) as a light-yellow solid.
Reaction SMILES: [K].[S:2]([NH2:6])([NH2:5])(=[O:4])=[O:3].[C:7](OCC)(=[O:13])[C:8](OCC)=[O:9]>C(O)(C)C.CO>[OH:9][C:8]1[C:7]([OH:13])=[N:6][S:2](=[O:4])(=[O:3])[N:5]=1
Reactant: NS(N)(=O)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [K]
Solvent: CC(C)O
Solvent: CO
Product: O=S1(=O)N=C(O)C(O)=N1
Yield: 145 %

Procedure:
The compound was prepared according to Carmack et al. (J. Org. Chem. 1975, 40, 2743) as follows. Potassium metal (10.0 g, 0.26 mol) was dissolved in cool isopropanol (50 mL) which was then diluted with methanol (50 mL). A methanolic solution (100 mL) of sulfamide (12.32 g, 0.13 mol) was added dropwise with vigorous stirring, followed by dropwise diethyl oxalate (17.4 mL, 0.13 mol). The resulting mixture was heated at reflux for 18 hours. The mixture was cooled, filtered, and the solid was washed with methanol and dried to give 28.3 g of 3,4-dihydroxy-[1,2,5]thiadiazole-1,1-dioxide as the di-potassium salt. This was stirred with PCl5 (90.0 g, 0.43 mol) at 150° C. for 10 minutes. When enough POCl3 was generated to maintain stirring, the mixture was cooled to 60° C. and stirred for 18 hours. The reaction was cooled, diluted with diethyl ether, filtered, and washed with additional diethyl ether. The ether filtrate was added dropwise to ethanol (500 mL) at 0° C. The resulting solution was heated to reflux for 1.5 hours, cooled, and concentrated to 1/4 volume. The diethoxy derivative was collected as a white solid (4.80 g). The mother liquor afforded an additional 1.80 g. (Total yield: 26%): mp 171°-172° C. (Th. 178°-179° C.); 1H NMR (CDCl3): δ 4.59 (q, 4H), 1.50 (t, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:24])=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)[N:34]=1.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:18])([OH:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:24][CH2:32][C:33]3[O:37][N:36]=[C:35]([C:38]4[S:39][CH:40]=[CH:41][CH:42]=4)[N:34]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: ClCc1nc(-c2cccs2)no1
Reactant: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(OCc4nc(-c5cccs5)no4)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
4-Amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-ol (100 mg, 0.3 mmol), cesium carbonate (195 mg, 0.6 mmol), 5-(chloromethyl)-3-(2-thienyl)-1,2,4-oxadiazole (71 mg, 0.33 mmol), tetrabutylammonium bromide (10 mg, 0.03 mmol), triethylamine (0.5 ml), and acetonitrile (10 mL) were combined and stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure and dichloromethane was added to the residue. Undissolved solids were removed by filtration. The filtrate was concentrated under reduced pressure and subsequently purified by flash column chromatography on silica gel, eluting with a gradient of 0-5% methanol in dichloromethane. The clean fractions were combined and concentrated under reduced pressure. The solid was recrystallized from acetonitrile to yield 71 mg of 1-[4-amino-2-ethoxymethyl-7-[3-(thiophen-2-yl)-[1,2,4]oxadiazol-5-ylmethoxy]-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white solid, mp 173.0-175.0° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.C(O)(=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(Br)c3c(N)ncnn23)C1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 192.9 %

Procedure:
To a cooled (−20° C.) solution tert-butyl 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (891 mg, 2.81 mmol) in DMF (8.7 mL) and acetic acid (7.0 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (401 mg, 1.40 mmol) in 3 portions over 10 min. The mixture was allowed to stir at −20° C. for 90 min. The reaction was quenched with the addition 5% aqueous K2CO3 (20 mL) and was allowed to warm to rt. The mixture was extracted with ethyl acetate (3×20 mL). The combined organics were washed with brine, dried (Na2SO4) and evaporated to provide 1.07 g (96%) of the desired product. ES-MS m/z 396.06 [M+H]+, HPLC RT (min) 3.05.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH2:3]1.Br[C:18]1[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]=1[CH3:28].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:16][C:2]1([CH3:1])[CH2:6][C:5]([C:18]2[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]=2[CH3:28])=[CH:4][CH2:3]1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1noc(C2=CCC(C)(C)C2)c1C
Temperature: 90 °C

Procedure:
To a 2-5 mL microwave vial containing a solution of 2-(4,4-dimethylcyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (214 mg, 0.966 mmol) in acetonitrile (2 mL), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (226 mg, 0.966 mmol) was added followed by K2CO3 (400 mg, 2.90 mmol), PdCl2(dppf).CH2Cl2 adduct (Alfa Aesar) (79 mg, 0.097 mmol) and water (1 mL). The vial was flushed with nitrogen, sealed and heated in the microwave (Biotage Smith Initiator) at 90° C. for 1 hour. The resulting mixture was filtered through Celite®, washing with EtOAc (50 mL). The filtrate was washed with water (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give a brown oil. The crude material was adsorbed onto silica and purification by chromatography eluting with 100% iso-hexane afforded the title compound;
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].O>CO>[NH2:24][CH:4]1[CH2:3][C:2]([CH3:17])([CH3:1])[CH2:11][C:10]2[C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]1=2
Reactant: COC(=O)c1cccc2c1CC(C)(C)CC2=O
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc2c1CC(C)(C)CC2N
Temperature: 60 °C
Yield: 95.6 %

Procedure:
A solution of 3.0 g (13 mmol) of methyl 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylate (J. Org. Chem. 17 (1976), 2918) in 45 ml of methanol was treated with 10 g (130 mmol) of ammonium acetate and 5.7 g (90 mmol) of sodium cyanoborohydride and heated at 60° C. for 20 hrs. After addition of 10 ml of water, the mixture was completely concentrated in vacuo and the residue was taken up in EA and aqueous ammonia. The organic phase was washed with water, dried over magnesium sulfate and concentrated in a rotary evaporator, and 2.9 g of methyl 5-amino-7,7-dimethyl-5,6,7,8-tetrahydro-1-naphthalenecarboxylate were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]2[C:14]([CH2:19][OH:20])=[N:15][C:16]([Cl:18])=[CH:17][C:12]=2[N:11]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:49](Cl)([CH3:51])=[O:50]>C(Cl)Cl>[C:49]([O:20][CH2:19][C:14]1[C:13]2[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][N:11]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:12]=2[CH:17]=[C:16]([Cl:18])[N:15]=1)(=[O:50])[CH3:51]
Reactant: OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCc1nc(Cl)cc2c1c(OCc1ccccc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methanol (2.443 g, 4.59 mmol) and DIPEA (3.0 ml, 17.18 mmol) in DCM (25 ml) was charged with AcCl (0.70 ml, 9.84 mmol). Stirred at RT for 45 min. Diluted with DCM, washed organics with 2N HCl, dried over MgSO4, filtered, concentrated in vacuo and obtained (3-(benzyloxy)-6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl. MS: [M+H]+ m/z 574.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[H-].[Na+].I[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:22])[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2n1C
Reaction time: 0.17 h

Procedure:
To a solution of the title compound of Example 1 Step B (98.0 mg, 0.37 mmol) in DMF was added NaH (15.0 mg, 60% suspension in mineral oil, 0.37 mmol). After 10 min, iodomethane (0.023 mL, 0.37 mmol) was added, and the mixture was stirred for 2 h, whereupon it was quenched by addition of sat. aq. NaHCO3. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10%, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS C, tr=2.78 min, m/z 278.3 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.65 (app t, J=1.0 Hz, 1H), 7.31 (d, J=1.0 Hz, 2H), 7.20 (s, 1H), 4.05 (s, 3H), 2.95 (t, J=7.0 Hz, 2H), 1.79-1.72 (m, 2H), 1.43-1.26 (m, 6H), 0.90 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18].ClCCl.CO>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17](=[NH:18])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C#N)c1
Reactant: Nc1ccccc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc(C(=N)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a 500 mL 3-neck round bottom flask was added aniline (5.38 g, 57.8 mmol) and 150 mL toluene. The solution was cooled in an ice bath under nitrogen. Next trimethylaluminum solution in toluene was added dropwise via dropping funnel (2.0 M, 40.4 mL, 81 mmol) and the reaction mixture was stirred at room temperature for 2 h. Next 3-methoxybenzonitrile (10 g, 75 mmol) in 50 mL toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and then poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol. The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid which was triturated with hexane, filtered, and washed with more hexane and dried to give desired product (7.81 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3([CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([N+:19]([O-])=O)[CH:16]=4)[CH2:11]3)[C:9](=[O:22])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[H][H]>CCOC(C)=O.[Pd]>[NH2:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[NH:8][C:9]1=[O:22])[CH2:18]2
Reactant: [H][H]
Reactant: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 2 h

Procedure:
To a solution of (±)-4′-chloro-5-nitro-1,3-dihydrospiro[indene-2,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′H)-one (40 mg, 0.126 mmol, described in Intermediate 4) in EtOAc (10 mL) was added triethylamine (0.026 mL, 0.189 mmol). The mixture was hydrogenated at 30 psi hydrogen over 10% Pd/C (10 mg). After 2 h, the reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=287 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(CC)CC.[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]1[CH2:29][CH2:28][N:27]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)c(Cl)c1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
According to Scheme 4 Step 1: Isobutyryl chloride (1.24 mmol, 0.13 mL) and Et3N (2.48 mmol, 0.35 mL) were added to a solution of 1-(2-chloro-4-nitrophenyl)piperazine (0.83 mmol, 200 mg) in DCM (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over Na2SO4, was filtered and was concentrated under reduced pressure to afford 1-(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.83 mmol, 261 mg, 100%). The product was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH2:48][CH2:49][CH3:50])[CH:45]=3)[CH:40]([C:51]3[CH:56]=[CH:55][C:54]4[O:57][CH2:58][O:59][C:53]=4[CH:52]=3)[CH:39]2[C:60]([O-:62])=[O:61])=[C:34](OS(C(F)(F)F)(=O)=O)[CH:33]=1.[C:71]([O:75]C)(=[O:74])[CH:72]=[CH2:73]>C(N(CC)CC)C.C(#N)C.CN(C=O)C.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([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:71](/[CH:72]=[CH:73]/[C:34]1[CH:33]=[C:32]([O:31][CH3:30])[CH:37]=[CH:36][C:35]=1[CH:38]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH2:48][CH2:49][CH3:50])[CH:45]=2)[CH:40]([C:51]2[CH:56]=[CH:55][C:54]3[O:57][CH2:58][O:59][C:53]=3[CH:52]=2)[CH:39]1[C:60]([OH:62])=[O:61])([OH:75])=[O:74]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)[O-])C2c1ccc2c(c1)OCO2
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1/C=C/C(=O)O)C(C(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1,3-bis(diphenylphosphino)propane (0.066 mmol), tris(dibenzylideneacetone)-dipalladium(0) (24 mg, 0.026) and bis(triphenylphosphine)palladium(II) choride (18 mg, 0.026 mmol), were dissolved in a 4:1 mixture of triethylamine/acetonitrile (5 mL) under argon. After 10 min at room temperature, a solution of methyl (1RS, 2SR, 3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (160 mg, 0.26 mmol) and methyl acrylate (679 mg, 7.89 mmol) was added in the above solvent mixture (3 mL). The reaction mixture was heated to reflux under argon for 20 h, cooled to room temperature and a small aliquot analyzed by 1H NMR, which showed no reaction had taken place. Palladium(II) acetate (6 mg, 0.025 mmol) and methyl acrylate (679 mg, 7.89 mmol) in dry DMF (5 mL) were then added. The reaction mixture was heated to reflux overnight. On cooling the solution was filtered through a short column of silica gel and concentrated to yield an oil. The crude product was purified by flash column chromatography ( silica gel, gradient elution: 10 % to 20% ethyl acetate/hexanes to afford the title compound as a tan solid. (87 mg, 62%).