Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.O.C1C(=O)N([Br:42])C(=O)C1>C1COCC1.CO>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:42])=[CH:17][C:16]=2[Cl:21])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.6 %

Procedure:
6-(2-Chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5carboxylic acid methyl ester 7b (55 mg, 0.172 mmol) is dissolved in 1:1 THF/MeOH (2 mL) and cooled to −780C under an atmosphere of nitrogen. TsOH.H2O (49 mg, 0.258 mmol) is added followed by NBS (31 mg, 0.174 mmol). After 10 minutes, the reaction mixture is warmed to 0° C. and then 2 hours later warmed to room temperature. After 16 hours, the reaction mixture is quenched by the addition of 10% Na2S2O3 and diluted with ethyl acetate and water. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure. The crude product is triturated with methylene chloride to give 58 mg (85%) of pure desired product as a tan solid.
Reaction SMILES: CS(C)=O.[CH2:5]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].[CH3:29]I>O>[CH2:5]([C:20]1[CH:21]=[C:22]([O:26][CH3:29])[CH:23]=[CH:24][CH:25]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CI
Reactant: CCCCCCCCCCCCCCCc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Into a 2-liter round-bottomed flask was placed 500 milliliters (ml) of dimethyl sulfoxide, 100 grams (g) of 3-(n-pentadecyl)phenol (0.33 mol), and 73.55 g of potassium hydroxide (1.31 mol). To this mixture, 93.5 g of methyl iodide (0.66 mol) was added drop wise with stirring at room temperature. After the addition, the reaction mixture was stirred for a further 6 hours. Then the reaction mixture was poured into deionized water (1.5 liters). The organic material was extracted by addition of diethyl ether. The diethyl ether layer was separated, washed with water, dried over anhydrous sodium sulfate, and finally evaporated to afford the crude product as a viscous fluid. This material was purified by silica gel column chromatography using petroleum ether as the eluent to furnish 3-(n-pentadecyl)anisole (104.6 g, 97% of theoretical yield) having a melting range of 27-28° C.
Reaction SMILES: [N+](C1C=C(C(C)=CC=1)C(O)=O)([O-])=O.[N+:14]([C:17]1[CH:18]=[C:19]([C:24]([CH3:27])=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21])([O-:16])=[O:15].Cl.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C.CO>[Br:29][CH2:27][C:24]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1CBr

Procedure:
3-Nitro-6-methylbenzoic acid (2-1) (Aldrich) was converted into methyl 3-nitro-6-methylbenzoate (2-2) using the standard procedure of MeOH and HCl gas. To a mixture of methyl 3-nitro-6-methylbenzoate (2-2) (2.0 g, 10.3 mmol) and N-bromosuccinimide (1.64 g, 9.23 mmol) in CHCl3 was added AIBN (20 mg) and this was then photolysed at reflux for 4 hours. The reaction was cooled, filtered and the filtrate evaporated to dryness. Chromatography of the residue (silica, hexane/EtOAc 92:8) afforded 2-3 as a solid (1.56 g). Rf (silica; hexane/EtOAc 10:1)=0.25. ##STR57##
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH3:13])[C:6]2=O.[BH4-].[Na+].CO.OS(O)(=O)=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[CH2:6]2
Reactant: CC1Cc2c(Br)ccc(Br)c2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1=Cc2c(Br)ccc(Br)c2C1
Reaction time: 3 h
Yield: 98.4 %

Procedure:
In a 250 ml round bottom flask 19.2 g (63 mmol) 4,7-Dibromo-2-methyl-indan-1-one were dissolved in 70 ml of toluene at 50° C. Then 2.63 g (1.1 eq.) sodium borohydride were added. At 50° C. 11 ml (4.3 eq.) methanol were added dropwise over a period of 30 min. Stirring was continued at 50° C. for 3 h (complete conversion) and then 50 ml water and 50 ml of 2M H2SO4 were added. The aqueous phase was extracted 2 times with 100 ml toluene. The combined organic layers were washed with 50 ml 2M H2SO4 and 50 ml of a sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. 200 ml toluene and 200 mg p-toluene sulfonic acid were added and the solution was heated on a Dean-Stark-trap for 90 min. 50 ml of a saturated sodium bicarbonate solution were added. The aqueous layer was extracted 2 times with 50 ml toluene each. The combined organic layers were washed with 50 ml of a saturated sodium bicarbonate solution and 50 ml of a sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo to yield 17.8 g (62 mmol, 98%) of the desired indene as a slightly brown oil. 1H-NMR (500 MHz, CDCl3): δ=7.48, 7.35 (2×d, 2H, aromatic), 6.49 (s, 1H, indenyl-C═CH), 3.32 (s, 2H, benzylic), 2.12 (2, 3H, CH3) ppm.
Reaction SMILES: [C:1]([NH:3][C:4](=[O:7])[O:5][CH3:6])#[N:2].[C:8]1(N)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14]>>[N:2]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:1]=1[NH:3][C:4]([O:5][CH3:6])=[O:7]
Reactant: Nc1ccccc1N
Reactant: COC(=O)NC#N
Product: COC(=O)Nc1nc2ccccc2[nH]1
Yield: 94 %

Procedure:
The salt of methyl cyanocarbamate with o-phenylenediamine (1.0 parts) is heated at 145°-50° C. for 10 minutes. This treatment gives 0.86 parts (94% yield) of 2-benzimidazolecarbamic acid, methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH:10]([NH2:13])([CH3:12])[CH3:11].[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH:13][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1cc(Cl)nc(N)n1

Procedure:
600 g of 2-amino-4,6-dichloro-pyrimidine (3.66 mols) are added to 3000 cc of alcohol, 395 g of isopropylamine (8.05 mols) are added, and the mixture is slowly heated to 80° during the course of 2 hours while stirring. After the material is dissolved, the solution is heated under reflux for 3 hours. The alcohol is then distilled off and the residue dissolved in dilute sulphuric acid. The solution must give a clearly acid reaction. The solution is shaken out several times with chloroform. A layer of 3000 cc of chloroform is subsequently placed under the aqueous solution and the solution is made alkaline with a caustic soda solution (pH 11), whereby the temperature should not exceed 35°. After shaking out the chloroform phase is separated and the aqueous phase is again shaken out with chloroform. The combined chloroform solution is dried with Glauber's salt after washing with water and the chloroform is evaporated. After standing for a short time, the oily residue crystallizes. The product may be recrystallized as described in Example 1 for purposes of purification.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.P(OCCCC)(OCCCC)(OCCCC)=O>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: C/C=C/C=O
Agent: CCCCOP(=O)(OCCCC)OCCCC
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 116 °C
Yield: 88.9 %

Procedure:
First, 8.07 g (113 mmol) of crotonaldehyde and 9.69 g (58.0 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.45 g (5.80 mmol) of tributyl phosphate was added. Then the mixture was heated under reflux for 4 hours while agitating at an internal temperature of 116° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.3 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 99%, yield of 88% based on benzenesulfonyl cyanide).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([O:21][C:22](=[O:23])[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4 aminopyridine (0.6 g, 6.37 mmol) in dichloromethane (15 ml) is treated with triethylamine (0.89 ml, 6.37 mmol) followed by phenylchloroformate (0.80 ml, 6.37 mmol) and then stirred at room temperature for 3 days. The reaction mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is dried over magnesium sulphate and evaporated to afford pyridin-4-yl-carbamic acid phenyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(C(Cl)=O)=O.[C:19]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Into a 1-L 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-nitrobenzoic acid (167 g, 999.29 mmol, 1.00 equiv) in dichloromethane (400 mL) and ClCOCOCl (317.5 g, 2.50 equiv). This was followed by the addition of N,N-dimethylformamide (1 mL) dropwise with stirring. The resulting solution was stirred for 4 h at room temperature. The mixture was concentrated under vacuum. To the residue was added a solution of PhNH2 (93 g, 1.00 equiv) in dichloromethane (400 mL), triethylamine (415 mL, 3.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The resulting mixture was washed with 2×500 mL of HCl (10%) and 1×500 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was diluted with 500 mL of petroleum ether/ethyl acetate=5:1. The solids were collected by filtration. This resulted in 205 g (85%) of 4-nitro-N-phenylbenzamide as light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 7.12-7.17 (m, 1H), 7.32-7.41 (m, 2H), 7.78-7.81 (m, 2H), 8.16-8.21 (m, 2H), 8.36-8.42 (m, 2H), 10.58 (s, 1H); MS (ESI) m/z 243 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].I[CH2:19][CH2:20][CH3:21].C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CCCI
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCN1CCN(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
A mixture of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (Example 135, step A) (0.50 g, 2.1 mmol) and 1-iodopropane (0.72 g, 4.22 mmol) was stirred in acetonitrile (42 mL) at rt under N2. To this mixture was added NaHCO3 (0.27 g, 2.5 mmol). The reaction was then heated to reflux and stirred for 24 h. The reaction was cooled to rt, concentrated under vacuum and the residue chromatographed on silica gel to give the title compound of step A (206 mg, 0.74 mmol, 35%) as a yellow oil. MS (ESI): 280 [M+H]+.
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[Cl:20][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCCOc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a flask was added 41.5 grams (g.) (0.3 mole) of 2-phenoxyethanol, 50 ml of toluene and 3.93 g. of pyridine, then 39.3 g. (0.33 mole) of thionyl chloride dropwise while stirring at room temperature. The exothermic reaction was heated at 50°-60° C. for two hours. After cooling to room temperature, the resulting salt was filtered and washed with methylene chloride. The filtrate was washed several times with aqueous sodium bicarbonate, dried using sodium sulfate, and then concentrated to obtain 39 g. of the 1-chloro-2-phenoxyethane as a yellow oil (83% yield).
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[OH-].[Li+].OO>CO.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To a stirred solution of N-Cbz-L-Leu-L-Leu-OCH3 (6.0 g, 14.6 mmol) in MeOH/H2O (3:1) (60 mL) at R. T. was added lithium hydroxide monohydrate (LiOH.H2O) (1.0 g, 43.9 mmol) and hydrogen peroxide (H2O2) (30% weight in H2O) (4.5 mL, 43.9 mmol). The reaction mixture was stirred for 3.5 h and then quenched with 10% HCl. The resulting mixture was extracted with EA (3×20 mL). The combined organic extracts were washed with sat. NaCl (2×10 mL), dried (MgSO4) and concentrated in vacuo to afford N-Cbz-L-Leu-L-Leu-OH as a white solid (5.0 g, 90.5%): 1H NMR (CDCl3, 300 MHz) δ 0.89-0.92 (t, 12H, J=3.0 Hz), 1.48-1.71 (m, 6H), 4.11-4.13 (m, 1H), 4.55-4.62 (m, 1H), 5.09 (s, 2H), 5.64 (d, 1H, J=9.0 Hz), 6.83 (d, 1H, J=9.0 Hz), 7.33-7.40 (m, 5H) ppm.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.C([O:12]OC(C)(C)C)(C)(C)C.C(OCCCC)(=O)C.[C:26]([OH:31])(=[O:30])[C:27]([CH3:29])=[CH2:28]>O>[C:26]([O-:31])(=[O:30])[C:27]([CH3:29])=[CH2:28].[C:1]([O-:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:12])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)OOC(C)(C)C
Solvent: O
Solvent: CCCCOC(C)=O
Product: C=C(C)C(=O)[O-]
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a 4-neck, 500 ml round bottom flask equipped as in Example 1 were added 50 g (0.51 mole) maleic anhydride, 8.0 g di-t-butyl peroxide and 150 g n-butyl acetate. The reaction system was purged with nitrogen and heated to reflux (about 120° C.). Once at reflux, 44 g (1.51 mole) methacrylic acid was added continuously to the solution over a 1-hour period. Reflux was maintained for an additional 7 hours. Then 220 g of water was added to the polymerization solution and the resulting mixture was held at about 90° C. for 1 hour. Agitation was stopped, the layers were allowed to separate, and the upper organic layer was decanted. The lower aqueous layer was reheated to and held at reflux (100° C.) for 6 hours, then atmospherically distilled to remove about 100 g of distillate and produce a 43 weight percent aqueous solution of homogeneous hydrolyzed methacrylate/maleate copolymer in 92 weight percent yield.
Reaction SMILES: C(OC([NH:8][C:9]1([CH3:37])[C:13]2([CH2:15][CH2:14]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1)=O)(C)(C)C.[ClH:38]>C(O)(C)C>[ClH:38].[NH2:8][C:9]1([CH3:37])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:16]2[C:25]([O:26][CH3:27])=[C:24]3[C:19]([C:20](=[O:35])[C:21]([C:32]([OH:34])=[O:33])=[CH:22][N:23]3[C@@H:28]3[CH2:30][C@@H:29]3[F:31])=[CH:18][C:17]=2[F:36])[CH2:10]1
Reactant: COc1c(N2CC3(CC3)C(C)(NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Solvent: CC(C)O
Product: COc1c(N2CC(C)(N)C3(CC3)C2)c(F)cc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 55 °C
Yield: 92 %

Procedure:
7-[7-(tert-Butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptan-5-yl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in which configuration of the tert-butoxycarbonylamino group in the substituent at position 7 is the same as the one produced in Example 9 (267.2 g) was suspended in isopropyl alcohol (1.6 L), and 6N hydrochloric acid (405 mL, 2.43 mol) was added to the suspension while the suspension was stirred in an oil bath at 55° C. The mixture was stirred at the same temperature for 3.5 hours, and after allowing to cool to room temperature, isopropyl alcohol (2.4 L) was added. The reaction vessel was cooled in a water bath at 5° C., and the mixture was stirred at the same temperature for 13 hours. The precipitated crystals were collected by filtration, and after air drying for several hours, the crystals were dried under reduced pressure at 40° C. to obtain 223.3 g (471 mmol, 92%) of the target compound as a yellow powder.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C([O:16][C:17]1[CH:22]=[CH:21][C:20]([S+:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)(C)(C)C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([S+:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: O
Solvent: CO
Product: Oc1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 108 %

Procedure:
A mixture of 25 g of (4-tert-butyloxyphenyl)diphenylsulfonium p-toluenesulfonate, 0.5 g of p-toluenesulfonic acid monohydrate, and 75 g of methanol was stirred at 80° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated in vacuum, to which 100 g of methylene chloride and 50 g of deionized water were added. The organic layer was separated, washed with water, and concentrated in vacuum. To the concentrate, 100 g of MIBK was added. This was concentrated in vacuum again, obtaining 24 g of the target compound, (4-hydroxyphenyl)diphenylsulfonium p-toluenesulfonate as oily matter. Yield 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: Oc1c(Cl)cc(Cl)cc1I
Reactant: C#Cc1ccc(OC)cc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 2,4-Dichloro-6-iodo-phenol [2040-83-7] (2.0 g, 6.9 mmol), 4-Methoxyphenylacetylene (0.91 g, 6.9 mmol), PdCl2P(PH3)2 (0.15 g), and CuI (50 mg) in DMF/Diethylamine (20 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH, filtered to give 85 as a solid (0.80 g, 42%): Mp=172-174° C.; 1H NMR (CDCl3) δ 7.82 (d, 2 H, J=8.1 Hz), 7.41 (d, 1 H, J=1.8 Hz), 7.24 (d, 1 H, J=1.9 Hz), 7.00 (d, 2 H, J=8.8 Hz), 6.84 (s, 3 H), 3.87 (s, 3 H); MS 293/295 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].Cl[CH2:21][C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][CH2:21][C:22]#[N:23])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N#CCCl
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A mixture of (+) 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-2,3-dihydro-1H-inden-1-one (3.29 g, 11 mmole), chloroacetonitrile (1.25 g, 16.5 mmole), and potassium carbonate (3.04 g) in dimethylformamide (30 ml) was stirred at 60°-65° for three hours. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as an oil (3.8 g).
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)([Cl:15])=O>CN(C)C=O>[Cl:15][C:9]1[C:4]2[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1cc2c(Cl)ncnc2cn1
Reaction time: 0.5 h

Procedure:
A suspension of 6-fluoropyrido[3,4-d]pyrimidine-4(3H)-one (U.S. patent application Ser. No. 08/358,352, 1994) (1.65 g) in 50 mL thionyl chloride and several drops of dimethyl formamide was heated under reflux until a clear solution was obtained (20 minutes), and then for a further 30 minutes. The volatiles were removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with aqueous Na2CO3. The solvent was dried and removed to give crude 4-chloro-6-fluoropyrido[3,4-d]pyrimidine which was dissolved in 2-propanol (50 mL) containing 3-bromoaniline (2.1 g). The mixture was heated under reflux for 15 minutes to give a precipitate, which was redissolved by the addition of triethylamine. After the addition of water, the solution was concentrated and cooled to give 4-[(3-bromophenyl)amino]-6-fluoropyrido[3,4-d]pyrimidine, (2.29 g), mp (MeOH) 219.5-221° C.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([C:16](=[O:24])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[CH:11][C:10]=1[O:25][CH3:26]>CN(CN(C)C)C>[Cl:8][C:9]1[C:14]([Cl:15])=[C:13]([C:16](=[O:24])[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH2:1])[CH:12]=[CH:11][C:10]=1[O:25][CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(=O)Cc2ccccc2)c(Cl)c1Cl
Agent: CN(C)CN(C)C
Product: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (100 ml.) is added dropwise to a suspension of 2,3-dichloro-4-phenylacetylanisole (29.5 g., 0.01 mole) in bis(dimethylamino)methane (100 ml.) under nitrogen with cooling to maintain the reaction mixture temperature below 60° C. The reaction mixture is stirred at 25° C. for 2 hours, and poured into ice water (1500 ml.) to precipitate 7.4 g. of 2,3-dichloro-4-(2-phenylacryloyl)-anisole which melts at 87°-89° C.