Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:27][C:28]1[C:36]([OH:37])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[C:31]([CH3:38])[NH:32]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:37][C:36]4[C:28]([F:27])=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][C:31]([CH3:38])=[CH:30]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A mixture of 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (20.0 g, 52.3 mmol), 4-fluoro-5-hydroxy-2-methylindole (10.5 g, 63.3 mmol), (prepared as described for the starting material in Example 1), and cesium carbonate (34.4 g, 106 mmol) in acetone (500 ml) was heated at reflux for 4 hours. The mixture was cooled and allowed to stand overnight. The mixture was filtered and the solid suspended in water and re-filtered and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (95/5) to give 7-[3-(4-acetylpiperazin-1-yl)propoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (20.4 g, 77%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:8]=[C:9]([OH:16])[CH:10]=[CH:11][C:12]=1[CH:13]([CH3:15])[CH3:14]>>[Cl:1][CH2:2][C:3]([O:16][C:9]1[CH:10]=[CH:11][C:12]([CH:13]([CH3:14])[CH3:15])=[C:7]([CH3:6])[CH:8]=1)=[O:4]
Reactant: Cc1cc(O)ccc1C(C)C
Reactant: O=C(Cl)CCl
Product: Cc1cc(OC(=O)CCl)ccc1C(C)C

Procedure:
By the same method of Synthesis Example 6, chloroacetyl chloride was allowed to react with 3-methyl-4-isopropylphenol, the reaction mixture was washed with water and then the solvent was evaporated under a reduced pressure to obtain the title compound as a transparent oil. The title compound was used in the subsequent reaction without distillation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:15])=[CH:13][CH:12]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(OS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl-4-hydroxyphenylcarbamate (1.0 g, 4.78 mmol) and triethylamine (0.80 mL, 5.73 mmol) were combined in dichloromethane (50 mL), cooled in an ice bath and treated with methanesulfonyl chloride (0.41 mL, 5.26 mmol). The solution was stirred at ambient temperature for 2 h, then was washed with 1M HCl, dried over sodium sulfate, filtered, and concentrated to give 1.2 g (87%).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][CH2:7][C:8]1[NH:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH:9]=1.O>C(O)(=O)C>[Cl:4][C:9]1[C:10](=[O:15])[NH:11][C:12](=[O:14])[NH:13][C:8]=1[CH2:7][Cl:6]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
Sulfuryl chloride (120 ml) was added dropwise to a suspension of 6-chloromethyluracil (163 g) in acetic acid (500 ml) over 20 minutes at room temperature, and the mixture was stirred for an additional 3 hours at room temperature. The resultant solution was poured into iced water (500 ml), and then precipitated crystals were collected through filtration, to there by obtain 182.3 g of 5-chloro-6-chloromethyluracil (92% yield).
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:7]=1[OH:14].N1C2C(=CC=CC=2)C=CC=1>ClCCl>[Cl:3][C:1]([O:14][C:7]1[CH:8]=[C:9]([Cl:13])[C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])=[O:2]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccc2ncccc2c1
Product: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
About 7 g of phosgene are passed into a solution of 10.0 g of 2,4,5-trichlorophenol in 50 ml of dichloromethane at 0° C., and the mixture is stirred at 0° C. for 15 min. 7.2 ml of quinoline in 20 ml of dichloromethane are added dropwise over the course of 30 min, and the orange-colored suspension is then stirred in an ice bath for 1 h. Subsequently nitrogen is passed through the suspension for 1 h in order to blow out excess phosgene (absorber tower). The mixture is subsequently filtered, and the filtrate is washed twice with water, dried, again filtered and evaporated to dryness in vacuo. The 4.45 g of oily brownish residue are relatively pure 2,4,5-trichlorophenyl chloroformate, which crystallizes in the refrigerator and can be employed without further purification.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:9]2[C:10](=[O:16])[C:11]([S:14][CH3:15])=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].ClC1C=CC=C(C(OO)=[O:34])C=1>>[CH3:15][S:14]([C:11]1[C:10](=[O:16])[C:9]2[CH:17]=[C:18]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[O:13][CH:12]=1)=[O:34]
Reactant: CSc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)c1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
7-Methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one was reacted with m-chloroperbenzoic acid in equimolar amounts to obtain 3-methylsulfinyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one [Compound No. 5].
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]1[O:9][CH2:8]1.[Na]>>[CH:1]1([O:6][CH2:7][CH2:8][OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CO1
Reactant: OC1CCCC1
Agent: [Na]
Product: OCCOC1CCCC1
Temperature: 75 °C

Procedure:
200 g (2.32 mols) of cyclopentanol, 38.5 cc (0.77 mol) of ethylene oxide and 2.3 g (0.1 g atom) of sodium metal are introduced at 0° C. into a 500 ml autoclave. The mixture is then heated for 4 hours at 75° C. The autoclave is left to cool and the reaction mixture is then distilled. This gives the title compound, which boils at 90°-92° C. under a pressure of 15 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:12]2[CH2:13][CH2:14][CH:10]([OH:9])[CH2:11]2)[N:3]=1
Reactant: OC1CCNC1
Reactant: Brc1cccc(Br)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: OC1CCN(c2cccc(Br)n2)C1
Temperature: 70 °C
Reaction time: 11 h
Yield: 100.9 %

Procedure:
A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of 3-hydroxypyrrolidine, 3.6 ml of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and 20 ml of tetrahydrofuran was heated under stirring under nitrogen atmosphere in an oil bath at 70° C. for 11 hours. The reaction mixture was separated with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silicagel column chromatography with 10–30% ethyl acetate/hexane, to give 5.9 g of 2-bromo-6-(3-hydroxypyrrolidin-1-yl)pyridine.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]#CCO)[CH3:2].C[C:10]([CH3:12])=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O.C[C:23](C)=[O:24]>O>[CH3:23][O:24][C:10](=[O:11])[C:12]#[C:2][CH2:1][O:3][CH2:4][CH3:5]
Reactant: CCOCC#CCO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOCC#CC(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 4-ethoxy-but-2-yn-1-ol (1 g, 8.76 mmol) in acetone (26 mL) at 0° C. was added dropwise Jones reagent. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with methyl acetate. The organic layers were combined, dried (Na2SO4), and concentrated. The resulting 4-ethoxy-but-2-ynoic acid was methylated (TMSCHN2 (2 M), MeOH/toluene, room temperature, 3 hours) to afford 0.66 g of the title compound as a clear oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[N:5][C:6](Cl)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[CH3:1][N:2]([CH3:16])[C:3]1[N:4]=[N:5][C:6]([C:22]2[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(C)c1cc(-c2ccccc2)c(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)c1cc(-c2ccccc2)c(-c2ccc(C=O)cc2)nn1
Temperature: 110 °C

Procedure:
N,N-dimethyl 6-chloro-5-phenylpyridazin-3-amine (1-2; 120 mg, 0.51 mmol) was dissolved in dry dioxane (3 mL) and 4-formylphenyl boronic acid (136 mg, 0.91 mmol). 2 M aqueous Na2CO3 (0.75 mL) and palladium(0) tetrakis-triphenylphosphine (66 mg, 0.058 mmol) were then added. This mixture was degassed, the vessel sealed and heated at 110° C. for 24 hours. The cooled reaction was diluted with water and the product extracted into ethyl acetate, the extract dried over anhydrous NaSO4, filtered and evaporated. The product was purified by chromatography on silica gel and elution with a 25-65% ethyl acetate/hexane gradient to give 4-[6-(Dimethylamino)-4-phenylpyridazin-3-yl]benzaldehyde (1-3). NMR (CDCl3): δ9.98 (1H, s), 7.74 (2H, d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.35 (3H, m), 7.19 (2H, d, J=8 Hz), 6.76 (1H, s), 3.29 (6H, s); m/e (m+1): 304.2
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:29])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CCCc1ccccc1
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Product: CCOC(=O)C(c1nsc(NC(=O)OC(C)(C)C)n1)C(O)CCc1ccccc1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 1.4 ml (~10 mMol) of dihydrocinnamaldehyde for 5 days in the manner described in Example 29 and, after working up by aqueous extraction, the product was chromatographed on 25 g of silica gel using toluene/ethyl acetate (4:1) and separated into the erythro and threo forms.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13]([O-:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K+].[I-].[Na+]>CN(C=O)C.CCOCC>[C:21]([O:20][P:13]([O:25][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 4-(bromomethyl)benzoate (1200 mg, 5.24 mmol), potassium di-tert-butyl phosphate (1431 mg, 5.76 mmol) and sodium iodide (785 mg, 5.24 mmol) were combined in DMF (3.00 mL) under nitrogen. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ether, washed with 10% LiCl solution and brine, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc) to provide Preparation 55A (571 mg, 1.593 mmol, 30%): 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.53-7.37 (m, 2H), 5.05 (d, J=7.5 Hz, 2H), 3.92 (s, 3H), 1.48 (d, J=0.4 Hz, 18H).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH3:4][C:5]1([CH3:26])S[C@@H:8]2[C@H:10]([NH:13][C:14]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:15])[C:11](=[O:12])[N:7]2[C@H:6]1[C:23]([OH:25])=[O:24].[CH3:27]O>C(O)(C)(C)C.[Pt]>[CH3:27][O:25][C:23]([C:6]([N:7]1[C:11](=[O:12])[C@@H:10]2[C@H:8]1[O:15][C:14]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[N:13]2)=[C:5]([CH3:26])[CH3:4])=[O:24]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CO
Agent: [Pt]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC(C)(C)O
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Reaction time: 2.5 h
Yield: 87 %

Procedure:
Magnesium chloride (36 mg) was dissolved in a mixture of 2.5 ml of methanol and 0.5 ml of tertbutyl alcohol. To the solution was added 53 mg of methyl ester of penicillin G to prepare an electrolyte. With platinum electrodes (1 cm2) dipped into the electrolyte, electrolysis was continued for 150 minutes (about 6 F) at a temperature of less than 0° C. and 3 to 8 V by applying constant current of 10 mA. Thereafter, the reaction mixture was stirred for about 30 minutes and extracted with chloroform. The extract was treated in the same manner as in Example 1, giving 41 mg of contemplated compound in 87% yield. The results of instrumental analyses were found identical with those of Example 1.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12](Cl)=[O:13].S(Cl)(Cl)=O.Cl>ClCCl>[C:1]([NH:6][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:9]([O:8][CH3:7])[CH:10]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CCC(C)(C)N
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCC(C)(C)NC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
30 ml of tert-amylamine are added at 10° C. to a solution of 27 g of 3-methoxy-4-nitrobenzoyl chloride (obtained from 25 g of the corresponding acid and thionyl chloride at reflux for 4 hours, followed by evaporation under vacuum) in 250 ml of dichloromethane. The reaction mixture is stirred for 30 minutes at 20° C., 100 ml of a 1N hydrochloric acid solution are then added, the organic phase is separated by settling, washed and dried over MgSO4, the solvent is then evaporated and the residue is chromatographed on silica gel, elution being carried out with dichloromethane, to obtain 31 g of the expected product; M.p.=65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:22])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C(=O)O)c1OC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(=O)Cl)c1OC
Yield: 86.3 %

Procedure:
To a solution of 2,3-dimethoxybenzoic acid (10.9781 mmol, 2.0 g) in CH2Cl2 (20 mL) with a drop of DMF, was added oxalyl chloride (10.9781 mmol, 957.702:1) dropwise at RT After 2 hrs the reaction mixture was concentrated in vacuo to afford 2,3-dimethoxybenzoyl chloride (1.9 g, 90%):
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]CC)=[O:13])[CH:10]=2)[NH:5][CH:4]=1)#[N:2].OO.NC(N)=[O:21].[OH-].[Na+]>CO.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)(=[O:21])[NH2:2]
Reactant: NC(N)=O
Reactant: CCOC(=O)c1ccc2[nH]cc(C#N)c2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=O)c1c[nH]c2ccc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of ethyl 3-cyano-1H-indole-5-carboxylate (1.05 g, 4.89 mmol) in methanol (12 mL) was added to a 0° C. solution of urea hydrogen peroxide (4.74 g, 48.9 mmol) and sodium hydroxide (11.7 mL of a 2.5 M solution in water, 29.3 mmol). The mixture was allowed to warm to room temperature and stir overnight. An additional 2 mL of a 2.5 M solution of sodium hydroxide was added and the reaction was left stirring 4 hours. The mixture was concentrated and acidified to pH 2 using 6 M hydrochloric acid. The resulting precipitate was filtered off and dried under vacuum at 60° C. to give the title compound (915 mg, 92%). 1H NMR (400 MHz, DMSO-d6, δ): 12.46 (br. s., 1 H), 11.84 (s, 1 H), 8.85 (s, 1 H), 8.12 (d, J=2.5 Hz, 1 H), 7.75 (dd, J=8.6, 1.6 Hz, 1 H), 7.50-7.63 (m, 1 H), 7.47 (d, J=8.6 Hz, 1 H), 6.88 (br. s., 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[N:5](C(=O)C(F)(F)F)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:34])[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[CH2:17][CH2:16]3)=[O:14])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: Cc1cccnc1N1CCN(C(=O)Nc2ccc3c(c2)N(C(=O)C(F)(F)F)CCC3(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cccnc1N1CCN(C(=O)Nc2ccc3c(c2)NCCC3(C)C)CC1
Temperature: 60 °C

Procedure:
A suspension of N-(4,4-dimethyl-1-trifluoroacetyl-1,2,3,4-tetrahydroquinol -7-yl)-4-(3-methyl-2-pyridyl)-piperazine-1-carboxamide (100 mg, 0.210 mmol) and potassium carbonate (87 mg, 0.631 mmol) in methanol (5 ml) and water (5 ml) was heated at 60° C. for 3 h. After this period, the solvents were evaporated in vacuo and the residue partitioned between DCM (15 ml) and water (10 ml). The aqueous layer was re-extracted with DCM (2×15 ml) and then the combined organic layers dried (Na2SO4) and the solvents evaporated in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.16 (dd, 1H), 7.43 (dd, 1H), 7.05 (d, 1H), 6.88 (dd, 1H), 6.75 (d, 1H), 6.44 (dd, 1H), 6.29 (br, 1H), 3.85-3.95 (br, 1H), 3.55-3.65 (m, 4H), 3.25-3.30 (m, 2H), 3.15-3.25 (m, 4H), 2.29 (s, 3H), 1.65-1.70 (m, 2H), 1.26 (s, 6H). MS (ES): MH+ 380.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>CN(C=O)C>[CH:1]1([NH:9][C:15]2[CH:16]=[CH:17][CH:18]=[C:11]([F:10])[C:12]=2[C:13]#[N:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1c(F)cccc1F
Reactant: NC1CCCCCCC1
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1NC1CCCCCCC1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 66.2 %

Procedure:
Cyclooctylamine (1.4 mL; 10 mmol) was added dropwise to a solution of 2,6-difluorobenzonitrile (1.39 g, 10 mmol) in DMF (6 ml) at 0° C. The reaction mixture was stiffed at room temperature for 4.5 hours. The reaction mixture was added to vigorously stirred ice water (40 ml) and extracted with ethyl acetate. Solvent was removed to yield 1.63 grams of 2-cyclooctylamino-6-fluorobenzonitrile.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=[C:8]([Br:18])[C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[N+:19]([O-])([OH:21])=[O:20]>>[N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:10]([N+:19]([O-:21])=[O:20])[CH:9]=[C:8]([Br:18])[C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(=O)Nc1ccc(Br)c2c1CC(N=[N+]=[N-])CC2
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1c([N+](=O)[O-])cc(Br)c2c1CC(N=[N+]=[N-])CC2
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of N-(7-azido-4-bromo-5,6,7,8-tetrahydronaphthalen-1-yl)-acetamide (1.5 g) was cooled in an ice bath and treated with fuming nitric acid (2 mL). After stirring for 2 h the solvent was removed by rotoevaporation and water was added to the residue to give a solid. The product was collected by filtration and dried (1.1 g, 81% yield).
Reaction SMILES: F[C:2]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[CH:19]=[CH:18]3)[C:12]([CH:25]=[CH2:26])=[C:11](F)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:28][C:29]([CH3:32])([O-:31])[CH3:30].[K+]>C1COCC1>[C:29]([O:31][C:2]1[N:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH3:24])[CH:19]=[CH:18]3)[C:12]([CH:25]=[CH2:26])=[C:11]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])([CH3:32])([CH3:30])[CH3:28]
Reactant: C=Cc1c(-c2ccc3c(ccn3C)c2)nc(F)c(C(=O)OC(C)(C)C)c1F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1c(-c2ccc3c(ccn3C)c2)nc(OC(C)(C)C)c(C(=O)OC(C)(C)C)c1OC(C)(C)C
Yield: 196.4 %

Procedure:
Into a solution of tert-butyl 2,4-difluoro-6-(1-methyl-1H-indol-5-yl)-5-vinylnicotinate (72 mg, 0.2 mmol) in THF (1.0 mL) at −78° C. was added a solution of potassium tert-butoxide (1.0 M×0.48 mL, 0.48 mmol). The temperature was allowed to rise to room temperature and the reaction was quenched with saturated NH4Cl. The mixture was extracted with ethyl acetate. The organic layers were combined, dried, evaporated and purified by silica chromatography (0-10% ethyl acetate in hexanes) to give tert-butyl 2,4-di-tert-butoxy-6-(1-methyl-1H-indol-5-yl)-5-vinylnicotinate (94 mg, 47%).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:9][SH:10])[C:6]([OH:8])=O)(=[O:3])[CH3:2].OC1C2N=NNC=2C=CC=1.C1CCC(N=C=NC2CCCCC2)CC1.C([O:40][C:41](=[O:54])[C:42]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][C:43]=1[O:49]C(C)(C)C)(C)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][CH:5]([CH2:9][SH:10])[C:6]([NH:48][C:46]1[CH:45]=[CH:44][C:43]([OH:49])=[C:42]([CH:47]=1)[C:41]([OH:54])=[O:40])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1cc(N)ccc1OC(C)(C)C
Reactant: CC(=O)NC(CS)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)NC(CS)C(=O)Nc1ccc(O)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To the solution of 2-acetylamino-3-mercapto-propionic acid (3.0 mmol) in 50 mL of dimethylformamide, hydroxybenzotriazole (3.3 mmol) and DCC (3.3 mmol) were added with stirring at 0° C. for 1 h. To the reaction mixture, 4 or 5-amino-2-tert-butoxy-benzoic acid tert-butyl ester (3) (3.0 mmol) was added and stirred mechanically for 3 h at 0° C. and 72 h at room temperature. After filtration, the filtrate was evaporated under reduced pressure to remove the solvent. The oily residue thus obtained was dissolved in ethyl acetate; the organic layer was washed with brine, dried on anhydrous MgSO4, filtered and the solvent evaporated. The crude intermediate 4 was treated with a solution of TFA (40%) in CH2Cl2. After 2 h the solvent was removed to obtain compound (5) as a crude residue. The residue was loaded on a silica gel open column and eluted with CH2Cl2/MeOH (8/2), from which 4 or 5-(2-Acetylamino-3-mercapto-propionylamino)-2-hydroxy-benzoic acid (5), compound of Formula XI, was obtained (78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13](O)[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:46]=[C:44]1[C:43]2[C:42](=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:41](=[O:51])[N:45]1[CH:13]1[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)C(N2C(=O)c3ccccc3C2=O)C1
Yield: 84 %

Procedure:
To a tetrahydrofuran solution (10 mL) of tert-butyl 4-(4-fluorophenyl)-5-hydroxy-5,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.41 mmol) synthesized in Reference Synthesis Example 354, triphenylphosphine (0.894 g, 3.41 mmol), and phthalimide (0.501 g, 3.41 mmol), diisopropyl azodicarboxylate (1.9 M, toluene solution) (1.97 mL, 3.75 mmol) was added dropwise and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, the reaction solution was concentrated and the resultant residue was purified by silica gel column chromatography to obtain the title compound (1.21 g, yield 84%).