Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:43]=[CH:42][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[C@H:26]([CH2:27][O:28]C(=O)C5C=CC=CC=5)[CH2:25][O:24][C:23]4=[O:37])=[CH:18][C:17]=3[S:38]([CH3:41])(=[O:40])=[O:39])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:44]B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[OH:28][CH2:27][C@@H:26]1[CH2:25][O:24][C:23](=[O:37])[N:22]1[C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:11]2[CH2:10][CH2:9][CH:8]([C:6](=[O:7])[C:5]3[CH:42]=[CH:43][C:2]([CH3:44])=[CH:3][CH:4]=3)[CH2:13][CH2:12]2)=[O:15])=[C:17]([S:38]([CH3:41])(=[O:39])=[O:40])[CH:18]=1
Reactant: CS(=O)(=O)c1cc(N2C(=O)OC[C@H]2COC(=O)c2ccccc2)ccc1C(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a mixture of benzoic acid (R)-3-{4-[4-(4-chlorobenzoyl)piperidine-1-carbonyl]-3-methanesulfonylphenyl}-2-oxooxazolidin-4-ylmethyl ester (938 mg) described in Preparation Example 24, methylboronic acid (359 mg), palladium (II) acetate (34 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (123 mg) and potassium fluoride (697 mg) was added tetrahydrofuran (9 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in methanol (3 mL) and 1,4-dioxane (3 mL) and 1N aqueous sodium hydroxide solution (6 mL) were added, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (113 mg).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:40])C(=O)C1>CN(C=O)C>[Br:40][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCCCCC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: BrCCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
To a solution of 6-cyclohexyl-hexan-1-ol (0.98 g, 5.3 mmol) in DMF (15 mL) was added triphenylphosphine (1.56 g, 5.9 mmol). The solution was cooled to 0° C. and NBS (1.02 g, 5.7 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (0.6 mL). The solution was diluted with ether (80 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford (6-bromo-hexyl)-cyclohexane (1.16 g, 89%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 3.41 (2H, t, J=7.2 Hz), 1.85 (2H, m), 1.66 (5H, m), 1.42 (2H, m), 1.08–1.36 (10H, m), 0.88 (2H, m); 13C NMR (75 MHz, CDCl3) δ 37.91, 37.68, 34.37, 33.72, 33.14, 29.39, 28.51, 27.04, 26.96, 26.73.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]2[CH2:21][OH:22])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O:22][CH2:21][C@@H:12]2[CH2:13][C@@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:15][N:11]2[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=2)=[O:10])(=[O:40])=[O:39])=[CH:34][CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CO)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol (8.7 g: 24.2 mmole) in dichloromethane(80 ml) are added triethylamine (4.05 ml), p-toluenesulfonyl chloride (5.08 g) and 4-dimethylaminopyridine (148 mg). The mixture is stirred at room temperature overnight. The reaction mixture is washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=1:1) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (11.75 g). Yield: 95%.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]=1[F:1])=[O:18]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-3-(trifluromethyl)aniline (0.515 g, 0.37 mL, 2.88 mmol) was added to a solution of 3-bromo-4-fluorobenzoyl chloride (0.650 g, 2.74 mmol) in dichloromethane (5 ml), and the mixture stirred at room temperature for 30 min. Triethylamine (0.360 g, 0.50 ml, 3.56 mmol) was added and the solution stirred at room temperature for 1 h. The reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a light yellow solid. Trituration with dichloromethane and filtering afforded 3-bromo-4-fluoro-N-(2-fluoro-3-(trifluoromethyl)phenyl)benzamide as a white solid. MS (M−H+) 377.9; Calculated for C14H7BrF5NO: 379.
Reaction SMILES: O[CH:2]([C:6]1[S:14][C:13]2[C:12](=[O:15])[N:11]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[CH:10]=[N:9][C:8]=2[CH:7]=1)[CH:3]([CH3:5])[CH3:4].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][N:22]([C:19]2[CH:18]=[CH:17][C:16]([N:11]3[C:12](=[O:15])[C:13]4[S:14][C:6]([CH:2]=[C:3]([CH3:5])[CH3:4])=[CH:7][C:8]=4[N:9]=[CH:10]3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1
Reactant: CC(C)C(O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)=Cc1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1

Procedure:
6-(1-Hydroxy-2-methylpropyl)-3-[4-(4-methyl[1,4]diazepan-1-yl)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one and p-toluenesulfonic acid were reacted by method AA. The crude product was purified by preparative HPLC. The product with the molecular weight of 394.54 (C22H26N4OS) was obtained in this way; MS (ESI): 395 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19]C(=O)C2C=CC=CC=2)[C@@H:3]1[OH:28].N>CO>[NH2:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH2:1])[C@H:3]1[OH:28]
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Agent: N
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](N)[C@H]1O
Yield: 76 %

Procedure:
A mixture of 1-(6-benzoylamino-9H-purin-9-yl)-3-amino-1,3-dideoxy-β-D-ribofuranuronic acid (1.0 g) prepared in Example 1, concentrated aqueous ammonia (16 ml) and methanol (8 ml) was refluxed for 1.75 hours. The reaction mixture was evaporated to dryness and the residue was triturated in methanol (20 ml) to give 1-(6-amino-9H-purin-9-yl)-3-amino-1,3-dideoxy-β-D-ribofuranuronic acid (554 mg), mp. 245°-249° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[NH:10][CH:11]=2)[CH:2]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C=O)C.C1COCC1>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([S:32]([N:10]2[CH:11]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]=[C:9]2[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)(=[O:34])=[O:33])=[CH:30][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(-c2cc(-c3cccnc3)c[nH]2)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2cc(-c3cccnc3)cc2-c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 4-(3-pyridyl)-2-(3,4,5-trimethoxyphenyl)-pyrrole (155 mg, 0.5 mmol, Example 76a) in dry DMF or THF (1.5 ml) NaH dispersion (48 mg, 2 equiv.) and p-methoxyphenylsulfonyl chloride (103 mg, 0.5 mmol) is added under a stream of nitrogen at 4° C. The reaction mixture is subsequently stirred for 12-18 h at room temperature and extracted with saturated aqueous NaHCO3 solution and ethyl acetate. The organic layer is dried and purified by flash chromatography and preparative HPLC. RT (program 1) 3.79. MS: 480.7.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1.[CH:15]1(Br)[CH2:19][CH2:18][CH2:17][CH2:16]1.[H-].[Na+]>>[CH:15]1([O:14][C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Oc1cccc2c1oc1ccccc12
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Product: c1ccc2c(c1)oc1c(OC3CCCC3)cccc12
Yield: 91.2 %

Procedure:
Reaction of dibenzo[b,d]furan-4-ol (1 g, 5.43 mmol) with cyclopentyl bromide (1.60 g, 10.86 mmol) in the presence of 60% sodium hydride (326 mg, 8.12 mmol), gave 1.25 g (92%) of the product as viscous liquid, IR (neat) 2957, 2870, 1449, 1269, 1193 cm−1. 1H NMR (300 MHz, CDCl3) δ 1.57-1.72 (m, 2H), 1.84-1.89 (m, 2H), 1.93-2.04 (m, 4H), 5.01 (quint., 1H), 6.97 (d, J=8.1 Hz, 1H), 7.22 (t, J=7.9 Hz, 1H), 7.30 (t, J=8.1 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:46])[NH:20]2>C(Cl)Cl>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:39][CH:40]4[CH2:45][CH2:44][N:43]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:42][CH2:41]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:46])[NH:20]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
Diisopropylethylamine (72 μl, 0.41 mmol) and methanesulphonyl chloride (32 μl, 0.41 mmol) were added to a suspension of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the starting material in Example 11), in methylene chloride (4 ml). After a few minutes all the material had gone into solution. The mixture was stirred for 3 hours at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. The solid was suspended in methanol and filtered to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}quinazoline (83 mg, 47%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:10][CH:11]=1
Reactant: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccn2cc(-c3ccc(CCCCO)cc3)nc2c1
Yield: 92.6 %

Procedure:
The product of Step B, Example 33 (0.3 g) in ethanol (15 mL) was hydrogenated over 5% palladium on barium sulfate (0.06 g) for 4.5 hours. The reaction mixture was filtered and evaporated to afford the title compound (0.282 g).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[NH:3][C:2]1=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.[H-].[Na+].Br[CH2:18][CH3:19]>>[CH2:18]([N:3]1[C:4]2[CH:13]=[CH:12][C:11]3[C:6]([C:5]=2[NH:1][C:2]1=[O:14])=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH3:19]
Reactant: O=c1[nH]c2ccc3ccccc3c2[nH]1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Product: CCn1c(=O)[nH]c2c3ccccc3ccc21

Procedure:
3-Ethyl-naphto[1,2-d]imidazolinone (1d) was prepared analogously by treatment of naphto[1,2-d]imidazolinone with sodium hydride (1.1 eq.) and bromoethane (1.1 eq.), successively. Yield after column-chromatographic workup: 2%. Mp. 240-242° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]([C:17]([OH:19])=O)[F:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]([C:17](=[O:19])[NH2:26])[F:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(F)C(=O)O)cc2s1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccc(C(F)C(N)=O)cc2s1
Reaction time: 0.33 h

Procedure:
To a slurry of 6-(carboxy-fluoro-methyl)-benzo[b]thiophene-2-carboxylic acid ethyl ester (400 mg, 1.42 mmol) in DCM (10 mL) was added oxalyl chloride (0.148 mL, 1.70 mmol) and 2 drops of DMF. After 20 min, the resultant solution was added to a solution of NH4OH (0.9 mL, 7.08 mmol) in DCM (5 mL) dropwise. After 1 h, the solvent was removed in vacuo and the solid was triturated with MeOH and H2O. The white solid was filtered and used without further purification. 1H NMR (DMSO-d6) δ 8.20 (s, 1H), 8.11 (s, 1H), 8.04 (d, J=8.2 Hz, 1H), 7.91 (br s, 1H), 7.62 (br d, J=2.4 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 5.94 (d, J=45.7 Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H). cal'd 282 (MH+), exp 282 (MH+).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.[CH3:16][Mg]Br>C1COCC1>[OH:1][C:2]1([CH3:16])[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:3]1
Reactant: C[Mg]Br
Reactant: O=C1CC(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: CC1(O)CC(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Treat a −78° C. solution of benzyl 3-oxocyclobutanecarboxylate (11.05 g, 54.1 mmol) in THF (155 mL) drop-wise with methyl magnesium bromide (3M in diethyl ether, 27.1 mL, 81 mmol) and stir at −78° C. for 0.5 h. Add satd. NH4Cl, extract with EtOAc (2×), dry the combined organics, evaporate and purify via silica gel chromatography (acetone/hexanes) to afford the title compound (5.589 g, 47%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.36-7.29 (m, 5H); 5.08 (m, 3H); 2.75-2.66 (m, 1H); 2.13-2.12 (m, 4H); 1.21 (s, 3H); MS (ESI) m/z: 243.1 (M+Na+).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][C@@H:7]([C@@H:9]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:10][C@@H:11]([CH:30]([CH3:32])[CH3:31])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:15]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:14]=2)[O:6][C:5]1=[O:41])([CH3:3])[CH3:2].[NH2:42][CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>C(O)(=O)C>[O:48]1[CH2:49][CH2:50][N:45]([CH2:44][CH2:43][NH:42][C:5](=[O:41])[C@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][C@H:7]([OH:6])[C@@H:9]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])=[O:35])[CH2:10][C@@H:11]([CH:30]([CH3:31])[CH3:32])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][OH:23])=[C:15]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:14]=2)[CH2:46][CH2:47]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1OCCCO
Reactant: NCCN1CCOCC1
Solvent: CC(=O)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@H](C(=O)NCCN2CCOCC2)C(C)C)C(C)C)ccc1OCCCO
Temperature: 45 °C
Reaction time: 6 h

Procedure:
A mixture of 84 mg of 3(S)-isopropyl-5(S)-{1(S)-tert-butoxycarbonylamino-3(S)-isopropyl-4-[4-(3-hydroxypropyloxy)-3-(3-methoxypropyloxy)-phenyl]-butyl}-tetrahydrofuran-2-one, 0.6 ml of 4-(2-aminoethyl)-morpholine and 0.025 ml of glacial acetic acid is stirred for 16 hours at room temperature and for 6 hours at 45° C. and is then partitioned between diethyl ether (2×) and saturated NaHCO3 solution (1×) and water (2×). The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (5 g of silica gel, dichloromethane/methanol=98:2), yielding the title compound: Rf (dichloromethane/methanol=95:5)=0.16; HPLC Rt =14.49 minutes; FAB-MS (M+H)+ =710.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=O)[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[S:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:26]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[CH3:23][N:21]1[CH:22]=[C:17]([CH:16]2[C:11]3[N:12]=[C:13]([CH3:15])[S:14][C:10]=3[CH:9]=[CH:8][C:7]3[CH:26]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]2=3)[C:18](=[S:36])[NH:19][C:20]1=[O:24]
Reactant: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CCc1ccc2c(c1)C=Cc1sc(C)nc1C2c1cn(C)c(=O)[nH]c1=S

Procedure:
A mixture of the product of step (xii) (0.070 g) and Lawesson's reagent (0.077 g) in 1,4-dioxane (5 ml) was heated at reflux for 16 hours. The solvent was evaporated under reduced pressure. Purification was by chromatography eluting with 2% ethanol in dichloromethane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]1C=CC=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:5]2[OH:23].[Cl:24]C1C=C([Mg]Br)C=CC=1>C1COCC1>[Cl:24][C:2]1[CH:3]=[C:4]([C:5]([C:6]2[CH:7]=[N:8][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[O:23])[CH:9]=[CH:10][CH:11]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1cccc(C(F)(F)F)c1
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (1.23 g, 5.25 mmol, Intermediate 2: step b) in THF (12 mL) at 4° C. was added 0.5 M (3-chlorophenyl)magnesium bromide in THF (12.7 mL, 6.35 mmol). The mixture was stirred at 4° C. to room temperature overnight, and quenched with NH4Cl (aqueous). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (40 g silica gel column, 0-70% EtOAc in heptanes) to provide the title compound as an oil, which solidified upon standing.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=O)[CH:10]=[CH:9][C:7](=O)[C:5]=2[CH:6]=1.C(O)(=O)C1C(=CC=CC=1)C(O)=O>O>[CH:6]1[C:5]2[C:4](=[CH:11][CH:10]=[CH:9][CH:7]=2)[CH:3]=[CH:2][CH:1]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: O=C(O)c1ccccc1C(=O)O
Solvent: O
Product: c1ccc2ccccc2c1

Procedure:
A scale deposition from an aqueous slurry of naphthoquinone and phthalic acid can be prevented by adding fine crystals of phthalic acid to the aqueous slurry of naphthoquinone and phthalic acid collected, which slurry is obtained by contacting a gas resulting from a catalytic gas phase oxidation of naphthalene with water or a mother liquor recycled. The fine crystals of phthalic acid have diameters of less than 100μ, preferably 10 to 40μ, and can be in an aqueous slurry of phthalic acid pulverized by a pulverizer.
Reaction SMILES: [C:1]([C:4]1[N:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[S:3])[NH2:2].CN(C=O)C.[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25](=O)[CH2:26]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]2[N:2]=[C:1]([C:4]3[N:14]=[CH:13][CH:12]=[CH:11][C:5]=3[C:6]([O:8][CH2:9][CH3:10])=[O:7])[S:3][CH:26]=2)=[CH:23][CH:22]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCOC(=O)c1cccnc1C(N)=S
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1-c1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
To a suspension of ethyl 2-carbamothioylnicotinate (1.9 g, 9.04 mmol) in 20 ml of DMF 4-fluorophenacylbromide (2.0 g, 9.22 mmol) was added, and the resulting mixture stirred for 2 hours at room temperature. The mixture was filtered under suction, the mother liquor evaporated to dryness, and the remaining oil purified by chromatography on silica gel (eluent: CH2Cl2+0-5% methanol) to give 434 mg of the title compound as amorphous solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][N:11]1[C:19](=[O:20])[C:18]2[C@@H:17]3[C:21]([CH3:23])([CH3:22])[C@@:14]([CH3:24])([CH2:15][CH2:16]3)[C:13]=2[N:12]1[CH3:25].[OH-].[Na+]>O1CCCC1.CO>[CH3:25][N:12]1[C:13]2[C@@:14]3([CH3:24])[C:21]([CH3:22])([CH3:23])[C@H:17]([CH2:16][CH2:15]3)[C:18]=2[C:19](=[O:20])[N:11]1[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1ccccc1Cn1c(=O)c2c(n1C)[C@]1(C)CC[C@H]2C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c2c(c(=O)n1Cc1ccccc1C(=O)O)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A mixture of 2-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid methyl ester (304 mg, 0.86 mmol) and 1 M NaOH (1.5 mL, 1.5 mmol) in tetrahydrofuran (2.4 mL) and methanol (1.2 mL) was stirred overnight at room temperature. The reaction mixture was partitioned between water (100 mL) and ether (100 mL). The aqueous layer was acidified to pH<3 with 1 M HCl and the resulting mixture was extracted with chloroform (100 mL) and then chloroform containing a small amount of methanol (100 mL). The combined organic extracts were dried (magnesium sulfate), filtered, evaporated, and dried under vacuum to give 2-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid (188 mg, 64%) as an off-white solid).
Reaction SMILES: [Se](=O)=O.[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[CH3:15].[OH-:16].[Na+]>O1CCOCC1.O>[Br:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[C:10]2[CH:15]=[O:16]
Reactant: Cc1ccnc2c(Br)cccc12
Reactant: [OH-]
Agent: O=[Se]=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccnc2c(Br)cccc12
Temperature: 77 °C

Procedure:
As shown in step 9-iii of Scheme 9, selenium dioxide (764.7 g, 6.754 mol) was taken up in 3.25 L of dioxane and 500 mL of water. The stirred solution was heated to 77° C. and 8-bromo-4-methylquinoline (compound 2030, 500 g, 2.251 mol) was added in one portion. The reaction mixture was stirred at reflux for 30 minutes and then cooled with a water bath to about 45° C., at which temperature a precipitate was observed. The suspension was filtered through diatomaceous earth which was subsequently washed with the hot THF to dissolve any residual solids. The filtrate was concentrated to a minimum volume under reduced pressure and 2M NaOH (2.81 L, 5.63 mol) was added to achieve a pH of 8 to 9. The reaction mixture was stirred at this pH for 30 minutes. A precipitate resulted which was collected by filtration and air-dried overnight to produce 8-bromoquinoline-4-carbaldehyde (compound 2031) as an yellowish solid: MS=236.16 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.52 (s, 1H), 9.34 (d, J=4.2 Hz, 1H), 9.05 (dd, J=8.5, 1.2 Hz, 1H), 8.18 (dd, J=7.5, 1.3 Hz, 1H), 7.88 (d, J=4.2 Hz, 1H), 7.60 (dd, J=8.5, 7.5 Hz, 1H). This material was used as is in subsequent reactions.