Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1O[CH2:3]1.[NH2:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH2:27][CH3:28])[C:18](=[O:26])[N:19]([CH2:24][CH3:25])[C:20](=[O:23])[C:21]=1[CH3:22].CN(C)C=O.[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38]>C(OCC)(=O)C.O>[C:34]([OH:41])(=[O:40])/[CH:35]=[CH:36]/[C:37]([O:39][CH:2]([CH2:3][NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]([CH2:27][CH3:28])[C:18](=[O:26])[N:19]([CH2:24][CH3:25])[C:20](=[O:23])[C:21]=1[CH3:22])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:38]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCn1c(NCCN)c(C)c(=O)n(CC)c1=O
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCn1c(NCCNCC(COc2ccccc2)OC(=O)/C=C/C(=O)O)c(C)c(=O)n(CC)c1=O
Reaction time: 24 h

Procedure:
3.8 g. Phenyl glycidyl ether and 9.8 g. 4-(2-aminoethylamino)-5-methyl-1,3-diethylpyrimidine-2,6(1H,3H)-dione are dissolved in 10 ml. dimethylformamide and left to stand for 24 hours at ambient temperature. The reaction mixture is then poured into water, extracted with methylene chloride, dried and chromatographed on silica gel using, as elution agent, methylene chloridemethanol (9:1 v/v). The yellowish oil (6.8 g.) obtained by evaporation of the pure fractions is dissolved in ethyl acetate, whereafter a solution of 2.1 g. fumaric acid in ethyl acetate is added thereto. The crystalline precipitate obtained is filtered off with suction and washed with ethyl acetate. There are obtained 5.4 g. (42% of theory) of the desired product in the form of colorless crystals which melt at 141°-142° C., with bubble formation.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH:17]([C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[CH:5]=[CH:17]/[C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Reactant: CCOC(=O)CCCCCOc1c(C=O)oc(COC(=O)C(C)(C)C)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCC(=O)/C=C/c1oc(COC(=O)C(C)(C)C)cc(=O)c1OCCCCCC(=O)OCC
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution, under nitrogen, of 0.206 g (4.3 mmole) of sodium hydride (50% dispersion in mineral oil) in 15 ml of dry THF was added dropwise 1.04 g (4.69 mmole) of dimethyl (2-oxoheptyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.55 g (3.9 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.425 g (22%) of pure 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone as an oil. NMR (CDCl3): δ0.88 (3H, t, J=5 Hz); 1.25 (9H, s), 2.27 (2H, t, J=6.5 Hz); 2.60 (2H, t, J=6.5 Hz); 4.91 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]F)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:1][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][C:9]([N:15]([CH3:18])[CH:16]=[O:17])=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Reactant: CN(C=O)c1ccc2c(c1)[nH]c1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOc2ccc3c(c2)[nH]c2cc(N(C)C=O)ccc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
To N-(7-hydroxy-9H-carbazol-2-yl)-N-methylformamide (45 mg, 0.187 mmol) and 2-(2-(2-fluoroethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (172 mg, 0.38 mmol) in 0.5 mL NMP was added Cs2CO3 (65 mg, 0.2 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with EtOAc (50 mL). It was washed with water (2×50 mL), 0.5 M HCl (50 mL) and brine (50 mL), and dried over MgSO4. Solvent was removed under reduced pressure and the crude product was purified with silica chromatography (hexane/EtOAc) to afford 2-(2-(2-(7-(N-methylformamido)-9H-carbazol-2-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (AD-CB-004 Pa-WZ01179) as a light-brown oil (48 mg, 48%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1 H), 8.45 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.80-7.77 (m, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.17 (d, J=2.4 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.89 (dd, J=8.8, 2.4 Hz, 1H), 4.23 (m, 1H), 4.17 (m, 2H), 3.88 (m, 2H), 3.72-3.68 (m, 4H), 3.66-3.61 (m, 2H), 3.39 (s, 3H), 2.41 (s, 3H); MS (ESI) m/z 527 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH2:12][NH:13][CH3:14].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:31].[NH2:32][C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=O)=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:31].[NH2:32][C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([N:13]([CH2:12][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][C:9]=3[CH3:11])[CH3:14])=[O:43])=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Reactant: CNCc1cc2cccc(C)c2n1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1cccc2cc(CN(C)C(=O)/C=C/c3cnc(N)c(CN4CCOCC4)c3)n(C)c12
Yield: 80 %

Procedure:
According to the procedure of Example 1, except substituting (1,7-dimethyl-1H-indol-2-ylmethyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.31 g, 80%) was prepared as pale yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.38-8.35 (m, 1H), 7.54-7.49 (m, 1H), 7.31-7.14 (m, 2H), 6.85-6.81 (m, 2H), 6.37-6.08 (m, 1H), 5.03-4.81 (m, 2H), 4.31 (br s, 2H), 3.96-3.72 (m, 7H), 3.42-2.99 (m, 10H), 2.72 (s, 3H);
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH:11]=[C:10](I)[CH:9]=[C:8]2[C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Ba+2].[OH-].COCCOC>CCOC(C)=O.O>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:9]=[C:8]2[C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(=O)c1cc(I)cn1Cc1ccc(F)cc1
Reactant: OB(O)c1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(-c2ccccc2)cn1Cc1ccc(F)cc1
Temperature: 20 °C

Procedure:
To a 100 mL round bottomed flask with a stirring bar, reflux condenser and an argon inlet was added 1-[1-(4-fluorobenzyl)-4-iodo-1H-pyrrol-2-yl]ethanone AIII-1-1 (1.00 g, 2.91 mmol), phenylboronic acid (0.431 g, 3.54 mmol), tetrakis(triphenylphosphine)palladiumo (0.20 g, 0.17 mmol), barium hydroxide (1.37 g, 4.37 mmol), DME (40 mL), and H2O (5 mL). This well stirred mixture was heated at reflux 4 h. The reaction mixture was cooled to 20° C. and diluted with EtOAc. This solution was washed with H2O, 1N HCl, H2O, and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an amorphous material. The crude product was chromatographed on silica gel using 15% EtOAc in hexanes as eluant to give 1-[1-(4-fluorobenzyl)-4-phenyl-1H-pyrrol-2-yl]ethanone AIX-1-1 as an oil. 1H NMR (CDCl3) δ 2.47 (3H, s), 5.57 (2H, s), 6.98 (2H, m), 7.13 to 7.28 (5H, complex multiplet), 7.36 (2H, m), 7.51 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:32][C:33]([N:35]([CH3:46])[C:36]1[CH:45]=[CH:44][C:39]2[N:40]=[C:41]([CH3:43])[O:42][C:38]=2[CH:37]=1)=[O:34]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]([CH2:32][C:33]([N:35]([CH3:46])[C:36]3[CH:45]=[CH:44][C:39]4[N:40]=[C:41]([CH3:43])[O:42][C:38]=4[CH:37]=3)=[O:34])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccc(N(C)C(=O)CBr)cc2o1
Reactant: COc1ccc2c(-c3cccc(F)c3)n[nH]c(=O)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(-c3cccc(F)c3)nn(CC(=O)N(C)c3ccc4nc(C)oc4c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A 0° C. solution of 4-(3-fluorophenyl)-7-methoxyphthalazin-1(2H)-one (7.0 g, 25.9 mmol) in THF (160 mL) was treated with LiHMDS (1M in THF) (38 mL, 38 mmol) and stirred for 30 min. 2-Bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (7.33 g, 25.9 mmol) in THF (40 mL) was added dropwise and stirring was maintained at rt for 16 h. The reaction mixture was diluted with water (200 mL) and the product extracted with EtOAc (3×150 mL). The organics were washed with brine (100 mL), dried over Na2SO4, and concentrated. The crude was triturated with MeOH (250 mL) to yield 2-(4-(3-fluorophenyl)-7-methoxy-1-oxophthalazin-2(1H)-yl)-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (9.1 g, 74%). (472.87 [M+H]) 1H NMR: (400 MHz, DMSO) δ: 2.62 (s, 3H), 3.33 (s, 3H), 4.95 (s, 3H), 4.73 (s, 2H), 7.37-7.43 (m, 4H), 7.48-7.51 (d, J=2.4, 8.8, 1H), 7.58-7.73 (m, 4H), 7.90 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[S:16][C:14]=3[N:15]=2)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[S:16][C:14]=3[N:15]=2)=[O:31])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(CSc2nc3sc4ccccc4c3[nH]2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3sc4ccccc4c3[nH]2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 1 g of 2-(4-methoxy-2-picolylmercapto)-1H-benzothieno[2,3-d]imidazole in 75 ml of dichloromethane at room temperature was added 0.6 g of m-chloroperbenzoic acid and, after stirring for 20 minutes, saturated aqueous sodium bicarbonate solution was added, and the organic phase was separated off. After the solvent had been evaporated off under reduced pressure, crystallization was induced by treatment with a little ethyl acetate and diisopropyl ether. Colorless solid, decomposition above 90° C.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1.CS(C)=[O:15].C(=O)([O-])O.[Na+].[OH2:22]>>[OH:22][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[O:11])=[N:8][CH:9]=1)[C:2]([OH:15])([CH3:12])[CH3:1]
Reactant: O
Reactant: CS(C)=O
Reactant: CC(C)=Cc1ccc(C=O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(O)C(O)c1ccc(C=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 5-(2-methylprop-1-en-1-yl)pyridine-2-carbaldehyde (9.40 g) in a mixed solvent of dimethyl sulfoxide (230 ml) and water (1.89 mL) was added N-bromosuccinic imide (18.7 g) at 0° C. The reaction solution was allowed to warm to room temperature, and stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in tetrahydrofuran (200 ml) was added 4.5M aqueous sulfuric acid solution, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80 to 100:0, volume ratio) to give the title compound (9.00 g, yield 79%) as a pale-yellow oil. MS: 196 (MH+).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH:14](C1NC=C(C(OCC)=O)N=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C1C=CC=C2C=1CC(Br)C2=O)=O)C1C=CC=CC=1.[CH2:52]([O:54][C:55]([C:57]1[NH:58][CH:59]=[CH:60][N:61]=1)=[O:56])[CH3:53]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH:14]([C:59]1[N:58]=[C:57]([C:55]([O:54][CH2:52][CH3:53])=[O:56])[NH:61][CH:60]=1)[C:15]2=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: CCOC(=O)c1c[nH]c(C2Cc3c(C(=O)NCc4ccccc4)cccc3C2=O)n1
Agent: O=C(NCc1ccccc1)c1cccc2c1CC(Br)C2=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(C2Cc3c(C(=O)NCc4ccccc4)cccc3C2=O)c[nH]1

Procedure:
4-Benzylcarbamoyl-2-(ethoxycarbonylimidazolyl)-1-indanone can be prepared in the following way: a mixture of 0.5 g of 4-benzylcarbamoyl-2-bromo-1-indanone, 0.37 g of 2-ethoxycarbonylimidazole and 10 ml of toluene is heated at reflux for 12 hours. The reaction mixture is concentrated on a rotary evaporator. Dichloromethane is added to the evaporation residue, filtration is carried out and the filtrate is washed with distilled water, dried over sodium sulphate and evaporated on a rotary evaporator. The brown oil obtained (0.26 g) is purified by chromatography on a silica column (diameter: 1.5 cm, height: 30 cm), elution being carried out with a dichloromethane/methanol (95/5 by volume) mixture. The foamy product obtained is triturated with 5 ml of ethyl acetate, filtered and the solid is washed-with ethyl acetate (2 x 5 ml) and dried at 50° C. under vacuum (1 mm Hg; 0.13 kPa). 0.07 g of 4-benzylcarbamoyl-2-(2-ethoxycarbonylimidazolyl)-1-indanone is obtained in the form of an orange solid melting at 218° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2([C:21]([O-:23])=[O:22])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH3:25]N(C)P(=O)(N(C)C)N(C)C.IC>CC1C=CC=CC=1>[C:1]1([NH:7][C:8]2([C:21]([O:23][CH3:25])=[O:22])[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: O=C([O-])C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Solvent: CI
Solvent: Cc1ccccc1
Product: COC(=O)C1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 21 h

Procedure:
A mixture of 66.4 parts of sodium 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate in 375 parts of hexamethylphosphoric triamide is heated to 70° C. After cooling to 10° C, 31.2 parts of iodomethane are added (slightly exothermic reaction). The whole is stirred for 21 hours at room temperature. The reaction mixture is diluted with 360 parts of methylbenzene. The whole is washed with water and the layers are separated. The aqueous phase is washed with methylbenzene. The combined organic layers are washed successively once with 300 parts of a 10% sodium hydroxide solution and twice with 300 parts of water, dried, filtered and evaporated, yielding methyl 4-(phenylamino)-1 (phenylmethyl)-4-piperidinecarboxylate as a residue.
Reaction SMILES: Br[C:2]1([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.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>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[N:3]=[C:2]([C:8]([OH:10])=[O:9])[CH:7]=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)C1(Br)C=CC=CN1
Reactant: CC1(C)COB(c2ccc(F)cc2)OC1
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: CCO
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 2-bromo-picolinic acid (2.02 g, 10 mmol, Aldrich) in DME containing 4 mL of 10% aq. Na2CO3 was purged with Ar gas, treated with Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2.40 g, 11.5 mmol, Aldrich) and EtOH (20 mL). This mixture was then also purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromo-picolinic acid (900 mg) and Pd(PPh3)4 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacetic acid (20 mL) was added to the reaction and the mixture was concentrated in vacuo. MeOH (150 mL) was added to the residue and the insoluble material was filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by flash column chromatography on silica gel eluting with EtOAc/MeOH (9:1) followed by EtOAc/MeOH/HOAc (14:30:1) to afford the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94–7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, J=8.8 Hz); MS(ESI+) m/z 234 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]([C@@H:9]3[O:14][C@H:13]([CH3:15])[C@@:11]([C:16](=[O:18])[CH3:17])([OH:12])[C@H:10]3[F:19])[CH:7]=[N:8][C:4]=2[CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>C1(C)C=CC=CC=1>[Br:30][C:7]1[N:6]([C@@H:9]2[O:14][C@H:13]([CH3:15])[C@@:11]([C:16](=[O:18])[CH3:17])([OH:12])[C@H:10]2[F:19])[C:5]2[CH:20]=[C:21]([Cl:22])[C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H]1F
Solvent: Cc1ccccc1
Product: CC(=O)[C@@]1(O)[C@@H](C)O[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H]1F
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
5,6-Dichloro-1-(3-acetyl-2,5-dideoxy-2-fluoro-beta-D-ribofuranosyl)-1H-benzimidazole (0.45 g, 1.3 mmoles) was boiled in toluene to remove water. Excess toluene was removed in vacuo. THF (Aldrich, Sure Seal, 20 mL) was added and the solution heated to reflux in an 85° C. oil bath. NBS (Aldrich, 0.46 g, 2.6 mmoles, 2 eq.) was added and the reaction refluxed 7 mins. A second portion (0.23 g, 1.3 mmoles, 1 eq.) was added and reflux continued 10 mins. The reaction was removed from the heat, diluted with chloroform (40 mL) and cooled to room temperature. The solution was washed with sat. sodium bicarbonate (2×), dried with MgSO4 and filtered. The solvents were removed in vacuo and the residue purified by chromatography on 75 g of silica gel eluted with ethyl acetate/hexane (1:4, v/v). The product containing fractions were combined and the solvents removed in vacuo. The yield was 0.42 g, 75%. MS (FAB+): m/z, 425; 1H NMR (DMSO-d6) δ7.99 (s,1H, Ar—H), 7.97 (s, 1H, Ar—H), 6.27 (d, 1H, H-1′, J=19 Hz), 5.69 (d, 1H, H-2′, J=53 Hz), 5.1 (m, 1H), 4.25 (m, 1H), 2.13 (s, 3H, acetyl), 1.45 (d, 3H, H-5′, J=6 Hz).
Reaction SMILES: Cl[O:2][N:3]=[CH:4][C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH2:12]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1.C(N(CC)CC)C>CCOCC>[CH3:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[CH2:12][C:13]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[O:14]2)[O:2][N:3]=1
Reactant: Cc1ccccc1C=NOCl
Reactant: C=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccccc1C1=NOC2(C1)OC(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 40 h
Yield: 58.7 %

Procedure:
To a solution of o-tolualdehyde chlorooxime (26.8 g, 0.158 mole), 3-methylenephthalide (14.6 g, 0.1 mole) and ether (400 ml.) was added dropwise a solution of triethylamine (16 g, 0.158 mole) in 30 ml. of ether at 5°-10° C. in 45 minutes. The mixture was stirred at room temperature for 40 hours and filtered. The solid material collected was dissolved in 1 liter of chloroform and 200 ml. of water. The chloroform solution was then washed two times with water, dried over CaSO4 and concentrated under vacuum to give 16.4 g of white solid, m.p. 146°-149° C. The original ether solution was washed two times with water, dried over CaSO4 and concentrated to 100 ml. Another 1.64 g of the spiro compound precipitated out. The ether solution was then further concentrated to 10.8 g of yellow-brown oil which did not contain a significant amount of the desired product. Recrystallization of 12 g of the crude spiro compound from tetrahydrofuran-ether gave 9.87 g of a pure white solid, m.p. 159°-164° C. with decomposition.
Reaction SMILES: [CH:1]1N=C[N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.NCC1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1.NC1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1>[OH-].[Na+]>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6](=[O:7])[NH:3][CH2:2][C:1]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: NCc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCc1ccc(C(=O)O)cc1)NCc1ccc2ccccc2c1
Yield: 93.3 %

Procedure:
N,N-carbonyldiimidazole (1.62 g, 10 mmol), 2-aminomethylnaphthalene (1.57 g, 10 mmol), p-aminobenzoic acid (1.52 g, 10 mmol), and 10 ml of 1 mol/L sodium hydroxide solution are used according to the method for the production of compound III in Method two to obtain 3.12 g of 4-[3-(2-naphthylmethyl)ureidomethyl]benzoic acid (intermediate M-40) as a white solid, with a yield of 93.3%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][C:25]([CH3:31])([CH2:29][CH3:30])[C:26](O)=[O:27]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:26](=[O:27])[C:25]([CH3:31])([CH3:24])[CH2:29][CH3:30])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCC(C)(C)C(=O)O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)C(C)(C)CC)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2,2-dimethyl-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2,2-dimethylbutyric acid (110 μl, 0.89 mmol). The title compound was obtained as yellow powder (186 mg, 56%).