Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH2:9][NH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.[O:16]=[C:17]1[CH2:22][O:21][C:20]2[CH:23]=[C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=O)[CH:25]=[N:26][C:19]=2[NH:18]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:12][CH2:13][CH2:14][CH3:15])=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][N:10]([CH3:11])[C:29](=[O:31])/[CH:28]=[CH:27]/[C:24]1[CH:25]=[N:26][C:19]2[NH:18][C:17](=[O:16])[CH2:22][O:21][C:20]=2[CH:23]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)OCC(=O)N2
Reactant: CCCOc1c(CNC)cccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)cccc1OC
Reaction time: 0.13 h
Yield: 35.5 %

Procedure:
To a solution of (3-methoxy-2-propoxyphenyl)-N-methylmethanamine (75 mg, 0.36 mmol) in DMF (5 mL) were added in sequential order (E)-3-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)acrylic acid (75 mg, 0.26 mmol), 1-hydroxybenzotriazole (50 mg, 0.36 mmol), diisopropylethylamine (150 uL, 0.67 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (72 mg, 0.36 mmol). The mixture was placed in a microwave at a temperature of 140° C. for 8 minutes. The product precipitated with the addition of water and was filtered, triturated with ether and dried to yield title compound as a white solid (38 mg, 36%): 1H NMR (400 MHz, CDCl3) δ 8.03-8.12 (rotamers, 2s, 1H), 7.63-7.69 (dd, J=15.2 Hz, J=11.2 Hz, 1H), 7.44-7.35 (rotamers, 2s, 1H), 7.02-7.04 (m, 1H), 6.80-6.91 (m, 2H), 6.72 (d, J=7.2 Hz, 1H), 4.67-4.81 (rotamers, 4s, 4H), 3.91-4.01 (m, 2H), 3.90 (2s, rotomers, 3H), 3.10 (s, 3H), 1.76-1.89 (m, 2H), 1.05 (t, J=7.2 Hz, 3H); MS (ESI) m/e 412 (C22H25N3O5+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][CH:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:3]1([CH2:13][C:14]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A suspension of 2.96 g (0.062 mol) of NaH. oil (50%) was washed with THF to remove the oil, then suspended in 300 mL THF, and then treated with 20.0 g (0.056 mol) of di-t-butyl (1-naphthylmethyl)malonate. The solution was refluxed for 40 minutes, then cooled to room temperature. A solution of 6.8 mL (0.057 mol) of benzyl bromide in 40 mL THF was then added and the mixture heated at reflux for 15 minutes, then left stirring at room temperature overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed with 1N citric acid, saturated NaCl, saturated NaHCO3, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 25 g of a yellow oil. Chromatography on silica gel, eluting with hexane:EtOAc (90:10) gave 20.0 g (80% yield) of the product as a clear oil. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O-:5])=[O:4].[Na+].[CH2:9]([CH:11]1[O:13][CH2:12]1)Cl>[Cl-].C[N+](C)(C)C.O>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:9][CH:11]1[O:13][CH2:12]1)=[O:4]
Reactant: CC(C)(O)C(=O)[O-]
Reactant: ClCC1CO1
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(O)C(=O)OCC1CO1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
Into a 200 mL three-necked flask equipped with a stirrer and reflux tube was charged 37.83 g (0.3 mol) of sodium 2-hydroxyisobutyrate, 138.7 g (1.5 mol) of epichlorohydrin, 0.25 g of tetramethylammonium chloride and pure water at room temperature under normal pressure, and heated at temperatures from room temperature to an inner temperature of 120° C. over a period of 10 minutes, then, reacted while keeping this temperature for 1.5 hours, then, cooled to room temperature. To this was added water and allowed to stand for 1.5 hours, then, an organic solvent phase was removed. After epichlorohydrin was distilled off in a distillation apparatus equipped with a Vigreux distilling column, the obtained residual liquid was distilled under reduced pressure to obtain glycidyl 2-hydroxyisobutyrate. The charging molar ratio, reaction conditions and reaction yield, and the amount of by-products after distillation under reduced pressure are shown in Tables 1 and 2. The addition ratio of catalysts and water in the tables were calculated based on the total weight of a raw material compound of the formula (1), epichlorohydrin, catalyst and water.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].[CH2:21]([N:23](CC)CC)C.O>CCOCC>[CH3:16][S:17]([O:12][CH:11]([C:21]#[N:23])[C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)(=[O:19])=[O:18]
Reactant: CCN(CC)CC
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: O
Product: CS(=O)(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
The cyanohydrin of m-phenoxybenzaldehyde (8.5 g, 0.038 mol) is dissolved in 150 ml ether and cooled to 0° in an ice bath. To this is slowly added methanesulfonyl chloride in 20 ml ether. The mixture is stirred for 10 min, then triethylamine in 20 ml ether is added dropwise. The solution turns white, and a precipitate appears. The reaction mixture is kept at 0° overnight and is then worked up with water and extracted with ether. The ether phase is washed with 30% sodium bisulfite solution (2X), ether and water (2X), and dried over sodium sulfate. The mixture is filtered and the filtrate concentrated to give α-cyano-m-phenoxybenzyl methanesulfonate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10][CH2:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>ClCCCC>[C:12]([NH:1][C:2]1[C:11]2[S:10][CH2:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1cccc2c1SCC=C2
Reactant: CC(=O)OC(C)=O
Solvent: CCCCCl
Product: CC(=O)Nc1cccc2c1SCC=C2

Procedure:
To a solution of 21.1 g of 8-amino-2H-1-benzothiopyran in 200 ml of 1-chlorobutane was added a solution of 13.3 ml of acetic anhydride in 50 ml of 1-chlorobutane. The temperature of the mixture rose during the addition and the mixture was refluxed for an additional 30 minutes. The solution was cooled in ice and filtered to give 18.0 g of the desired acetamide as colorless needles, m.p. 133°-135° C. The mother liquor was concentrated to ~1/5 volume to give a second crop of 4.1 g, m.p. 133°-135° C.
Reaction SMILES: C=C.[CH2:3]=[CH:4][CH3:5].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH2:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:4]([CH3:5])[CH3:3]
Reactant: Cc1ccccc1
Reactant: C=CC
Agent: C=C
Product: CC(C)Cc1ccccc1
Product: CCCc1ccccc1

Procedure:
Particularly preferred reactions are those of toluene with ethene or propene to give propylbenzene or isobutylbenzene, that of cumene with ethene to give tert-amylbenzene and those xylenes with butadiene to give 5-tolylpentenes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=[CH:6][CH:7]=1.[C-:23]#[N:24].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2cccc(Br)c2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCCCCc1cccc(Br)c1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
A mixture of toluene-4-sulfonic acid 4-(3-bromophenyl)butyl ester (2.3 g, 6 mmol) and powdered sodium cyanide (0.65 g, 13 mmol) in DMSO was heated up to 80° C., stirred for 1.5 hours and monitored by NMR. When the reaction was complete, the reaction mixture was cooled to room temperature, diluted with H2O and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of this residue on silica gel (ISCO) using (hexanes/EtOAC 9.5/0.5) as the eluting solvent gave 5-(3-bromo-phenyl)pentanenitrile as a colorless oil (1.12 g, 78% yield). m/e (M)+ 237; 1H NMR (400 MHZ, DMSO-d6) δ ppm, 2.63-2.65 (m, 2H), 2.75-2.78 (m, 2H), 2.35-2.38 (m, 2H), 2.60-2.63 (m, 2H), 7.05-7.10 (m, 2H), 7.25-7.28 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])(C)(C)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:24]([CH:25]=[O:26])=[CH:23][N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:19]2=[N:20][CH:21]=1>O1CCCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:24]([CH:25]([OH:26])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH2:8][OH:9])=[CH:23][N:22]([CH2:27][O:28][C:29](=[O:34])[C:30]([CH3:32])([CH3:31])[CH3:33])[C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)C(=O)OCn1cc(C=O)c2cc(Br)cnc21
Reactant: OCc1ccccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1cc(C(O)c2ccccc2CO)c2cc(Br)cnc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a −78° C. solution of (2-bromo-phenyl)-methanol (2.27 g, 12.14 mmol) in tetrahydrofuran (100 ml) was added tert-butyllithium (1.7 M in hexanes, 15.7 ml, 26.69 mmol). The reaction mixture was stirred for 10 minutes at −78° C. A solution of 2,2-dimethyl-propionic acid 5-bromo-3-formyl-pyrrolo[2,3-b]pyridin-1-ylmethyl ester (2.06 g, 6.07 mmol) in tetrahydrofuran (30 ml) was added to the stirring reaction mixture. After the reaction mixture was allowed stirred for an additional 20 minutes at −78° C., the reaction was quenched with saturated, aqueous sodium bicarbonate solution. The quenched solution was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the mixture was concentrated in vacuo. The crude material was purified by flash chromatography (0-100% ethyl acetate in hexanes) to give 1.60 g (59%) of 2,2-dimethyl-propionic acid 5-bromo-3-[hydroxy-(2-hydroxymethyl-phenyl)-methyl]-pyrrolo[2,3-b]pyridin-1-ylmethyl ester. MS: m/z 446.0, 448.0 (M+H+).
Reaction SMILES: [N+:1]([CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>C(O)(C)(C)C>[N+:1]([C:4]1([CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])C1C2C=CC(CC2)C1c1ccccc1
Reactant: C=CC(=O)OC
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COC(=O)CCC1([N+](=O)[O-])C2C=CC(CC2)C1c1ccccc1

Procedure:
Variant B: 0.18 mole of 2-nitro-3-phenyl-bicyclo[2.2.2]-oct-5-ene, 0.18 mole of methyl acrylate and 3.8 ml of Triton B in 50 ml of tert.-butanol and stirred for 24 hours, a further 0.18 mole of methyl acrylate and 70 mlof dioxan are then added and the mixture is heated to the reflux temperature for 24 hours. After cooling, the reaction mixture crystallizes. A little ethanol is added, the mixture is neutralized with 2N hydrochloric acid and the crystal sludge is filtered. Recrystallization of the crystals from isopropanol with the addition of animal charcoal gives crystals of melting point 127°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C:9]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:45])([F:44])[F:43])[CH:36]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:13][CH:12]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:51])([F:50])[F:49].[Li+].[OH-].CO>C1COCC1>[F:1][C:2]1[CH:47]=[CH:46][C:5]([C:6]([NH:8][C:9]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][C:42]([F:43])([F:44])[F:45])[CH:36]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:16]=2)=[O:7])=[CH:4][C:3]=1[C:48]([F:49])([F:50])[F:51]
Reactant: CCOC(=O)CCc1ccc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1ccc(CC(NC(=O)c2ccc(F)c(C(F)(F)F)c2)(c2cccc(OC(F)(F)F)c2)c2cccc(OC(F)(F)F)c2)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoate (11 mg, 0.015 mmol) in THF (0.75 mL) was added 1 N LiOH (0.15 mL) and methanol (0.30 mL). The reaction mixture was heated at 50° C. for 0.5 h. The solvents were removed under a stream of nitrogen then 1 N HCl (2 mL) was added to the residue and the mixture was extracted with CH2Cl2 (2×5 mL). The combined organics were dried over Na2SO4, filtered and the volatiles removed. The resulting residue was purified on ISCO silica gel eluting with 0 to 10% MeOH/CH2Cl2 to give 3-(4-(2-(4-fluoro-3-(trifluoromethyl)benzamido)-2,2-bis(3-(trifluoromethoxy)phenyl)ethyl)phenyl)propanoic acid (Example 277) as a clear, colorless oil (9 mg, 85% yield). LCMS: RT=2.18 min [M+H] 704.1 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); NMR: 400 MHz 1H (CDCl3) δ ppm 2.55 (t, J=7.69 Hz, 2H), 2.82 (t, J=7.69 Hz, 2H), 3.83 (s, 2H), 6.54 (d, J=8.35 Hz, 2H), 6.60 (s, 1H), 6.93 (d, J=7.91 Hz, 2H), 6.97 (s, 2H), 7.08-7.14 (m, 4H), 7.17-7.23 (m, 1H), 7.28-7.33 (m, 2H), 7.73-7.77 (m, 1H), 7.83-7.86 (m, 1H).
Reaction SMILES: C(O)C.[NH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:7][CH2:6]1.[ClH:17]>C(OCC)(=O)C>[ClH:17].[NH2:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH2:9][CH2:10]1
Reactant: NC1CCC(N2CCNC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N[C@H]1CC[C@@H](N2CCNC2=O)CC1

Procedure:
A mixture of 9500 ml of anhydrous ethyl alcohol and 2323 g of 1-(4-aminocyclohexyl)-2-imidazolidinone is heated with mixing to effect solution. The solution is cooled to room temperaure and 3200 ml of a saturated solution of anhydrous hydrogen chloride gas in ethyl acetate is added to pH 1. The temperature of the mixture rises to 60° and the product crystallizes. The mixture is cooled to 10°. The crude product is filtered off, washed with 3500 ml of anhydrous ethyl alcohol and dried at 50°-60° in vacuo for 2 days. The crude hydrochloride salt is recrystallized twice from anhydrous methanol-ethyl ether (ca 1:1) to give cis 1-(4-aminocyclohexyl)-2-imidazolidinone monohydrochloride, m.p. 327°-8°.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:7]O[CH2:5][CH2:4]1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.[CH2:24](Br)[CH:25]=[CH2:26]>O.CCOC(C)=O>[CH2:26]([N:10]1[C:11]2[CH:5]=[CH:4][CH:3]=[CH:7][C:12]=2[S:13][CH2:14][CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:9]1=[O:8])[CH:25]=[CH2:24]
Reactant: C1CCOC1
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCN1C(=O)C(NC(=O)OC(C)(C)C)CSc2ccccc21
Yield: 81 %

Procedure:
54 mg of sodium hydride as a 60% suspension (2.24 mmol) are introduced at room temperature into a 100 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 25 ml of THF and 660 mg of 52 (2.24 mmol). The medium is stirred for 1 hour and 452 mg (2.24 mmol) of allyl bromide are then added. The medium is stirred overnight, 25 ml of EtOAc and 25 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed with 20 ml of water. The organic phase is dried, filtered and then evaporated to dryness. 0.7 g of crude product is recovered, which product is chromatographed on a silica cartridge (20 g) with a 75/25 heptane/EtOAc mixture. 610 mg of product 56 are recovered (yield=81%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][C:32]([C@@H:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([C@@H:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH:7]=1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3cc(Cl)nc(N4CCCC4)n3)CC2)cc1
Temperature: 25 °C

Procedure:
To 22 mg (0.1 mmol) 4,6-dichloro-2-pyrrolidin-1-yl-pyrimidine in 1 mL THF are added 17 μL (0.1 mol) DIPEA and 25 mg (0.1 mmol) (S)—N-[1-(4-piperidin-4-yl-phenyl)ethyl]-acetamide (V.1). The mixture is stirred at rt over night. The solvent is removed in vacuo and the residue is purified using reversed phase HPLC (eluent A: water+0.1% TFA, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:5]
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Product: Cc1ccc(C#N)c(NC(=O)NC(=O)c2ccccc2)c1

Procedure:
Prepared as in Example 1a from 2-amino-4-methylbenzonitrile and benzoyl isocyanate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.10-7.13 (m, 1H), 7.54 (t, J=7.8 Hz, 2H), 7.66 (t, J=7.8 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 8.02-8.04 (m, 2H), 8.07 (s, 1H), 11.32 (s, 1H), 11.44 (s, 1H). MS 280 (MH+).
Reaction SMILES: OCC1C(CO)CC1N1C=NC2C(=O)NC(N)=NC1=2.[OH:20][CH2:21][CH:22]1[CH:25]([CH2:26]O)[CH2:24][CH:23]1[N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][CH:31]=[N:32][C:33]=2[NH2:37]>>[OH:20][CH2:21][CH:22]1[CH:25]([CH3:26])[CH2:24][CH:23]1[N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][CH:31]=[N:32][C:33]=2[NH2:37]
Reactant: Nc1ncnc2c1ncn2C1CC(CO)C1CO
Agent: Nc1nc2c(ncn2C2CC(CO)C2CO)c(=O)[nH]1
Product: CC1CC(n2cnc3c(N)ncnc32)C1CO

Procedure:
Following the procedures described in Example 40, replacing 9-(2',3'-bis(hydroxymethyl)-cyclobutyl)guanine, the product of Example 1, with 9-(2',3'-bis(hydroxymethyl)cyclobutyl)adenine, the product of Example 4, the title compound is prepared.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([OH:43])=[C:38](B(O)O)[CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:36]3[CH:35]=[C:34]([Cl:33])[CH:39]=[CH:38][C:37]=3[OH:43])[CH:16]=2)[N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn(C(=O)OC(C)(C)C)c2ccc(-c3cc(Cl)ccc3O)cc12
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of tert-butyl 3-[bis(tert-butoxycarbonyl)amino]-5-bromo-1H-indazole-1-carboxylate (2.97 g, 5.81 mmol) in dimethoxyethane (25 mL) was added (5-chloro-2-hydroxyphenyl)boronic acid (1.00 g, 5.81 mmol), tetrakis(triphenylphosphine)palladium (0.67 g, 0.58 mmol) and 2 M aqueous sodium carbonate (5.8 mL, 11.6 mmol). The mixture was heated at refluxed for 5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL), washed with water (2×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 30-60% gradient of ethyl acetate in hexanes to afford tert-butyl 3-[bis(tert-butoxycarbonyl)amino]-5-(5-chloro-2-hydroxyphenyl)-1H-indazole-1-carboxylate as a colorless solid in 84% yield (2.57 g): 1H NMR (300 MHz, DMSO-d6) δ8.21 (d, J=7.8 Hz, 1H), 7.62-7.59 (m, 2H), 7.46 (s, 1H), 6.90-6.86 (m, 2H), 5.33 (br s, 1H), 1.72 (s, 9H), 1.42 (s, 18H); MS (ES+) m/z 560.0 (M+1), 562.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([CH:35]5[CH2:37][CH2:36]5)=[O:34])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1)C1CC1

Procedure:
Example 112 was prepared from 1-(4-chlorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.03–7.87 (br, 1H), 7.56–7.02 (m, 8H), 6.91–6.65 (br, 1H), 3.30–3.05 (m, 4H), 2.62–2.38 (m, 3H), 2.38–2.21 (m, 2H), 1.98–1.51 (m, 15H), 1.14–1.01 (m, 2H), 0.93–0.70 (m, 2H) ESMS m/e: 508.2 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N+:23]([CH3:26])([O-:25])=[O:24].C(N)CN>C(#N)C>[CH2:15]([S:22][C:2]1([CH2:26][N+:23]([O-:25])=[O:24])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: SCc1ccccc1
Solvent: CC#N
Solvent: NCCN
Product: CC(C)(C)OC(=O)N1CCC(C[N+](=O)[O-])(SCc2ccccc2)CC1
Yield: 70.7 %

Procedure:
A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (1.00 g), benzyl mercaptan (2.48 g), nitromethane (3.05 g), ethylenediamine (0.3 g) and acetonitrile (15 mL) was heated under reflux for 8 hr. The reaction solution was concentrated under, reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-3:1) to give the title compound (1.3 g, yield 71%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([OH:13])=[O:12].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:13][C:11](=[O:12])[C:3]=12)=[O:7])(=[O:16])[CH3:15]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1C(=O)OC2=O
Temperature: 2.5 °C
Yield: 61 %

Procedure:
A 1 L 3-necked round bottom flask was equipped with a mechanical stirrer, thermometer, and condenser and charged with 3-aminophthalic acid (108 g, 596 mmol) and acetic anhydride (550 mL). The reaction mixture was heated to reflux for 3 hours and cooled to ambient temperature and further to 0-5° C. for another 1 hour. The crystalline solid was collected by vacuum filtration and washed with ether. The solid product was dried in vacuo at ambient temperature to a constant weight, giving 75 g (61% yield) of 3-acetamidopthalic anhydride as a white product. 1H-NMR (CDCl3) δ: 2.21 (s, 3H), 7.76 (d, 1H), 7.94 (t, 1H), 8.42 (d, 1H), 9.84 (s, 1H).