Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:13].[N+:24]([O-])([OH:26])=[O:25]>CC(O)=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:24]([O-:26])=[O:25])=[CH:4][C:3]=1[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)=[O:13]
Reactant: COc1ccc(COC(=O)c2ccc3ccccc3c2O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc(COC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61782.3 %

Procedure:
A warm vigorously stirred solution of 2 (25.4 g, 0.082 mmol) in AcOH (260 mL) was cooled to 25° C. and treated in one portion with a solution of HNO3 (70% w/w, 18.6 g, 0.20 mmol) in AcOH (25 mL). The temperature rose to 35° C. (controlled with external cooling) and a solid separated. After stirring for a further 10 min at 30° C., the mixture was cooled to 0° C. The precipitate was collected, washed with cold AcOH and iPr2O, and recrystallised from CH2Cl2 /petroleum ether to give 4-methoxybenzyl 1-hydroxy-4-nitronaphthalene-2-carboxylate (3) (17.9 g, 61%) mp 163-164° C. 1H NMR [(CD3)2SO] δ 12.46 (br s, 1H, OH), 8.60 (s, 1H, H-3), 8.60 (d, J=8.6 Hz, 1H, H-5), 8.47 (d, J=8.3 Hz, 1H, H-8), 7.97 (br t, J=7.8 Hz, 1H, H-6), 7.79 (br t, J=7.7 Hz, 1H, H-7), 7.50 (d, J=8.6 Hz, 2H, H-2',6'), 7.00 (d, J=8.7 Hz, 2H, H-3',5'), 5.32 (s, 2H, CH2), 3.78 (s, 3H, OCH3). Anal. Calculated for C19H15NO6 : C, 64.6; H, 4.3; N, 4.0. Found: C, 64.7; H, 4.0; N, 4.2%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CN(C=O)C>O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@@H:9]([O:12][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)[C@H]1CC[C@@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 3 g of cis-4-hydroxy-cyclohexanecarboxylic acid ethyl ester, 3 g of imidazole, 33 g of tert-butyldimethylsilyl-chloride, and 6 mL of DMF was stirred under inert atmosphere overnight. The mixture was diluted with 250 mL of water and extracted into 3×50 mL portions of ether. The combined ether extracts were washed with 2×50 mL of water, dried over magnesium sulfate and concentrated under reduced pressure. Drying under vacuum overnight gave 4.5 g of product as a colorless oil: 1H NMR (400 MHz, CDCl3) 4.1 (dd, 2H), 3.58 (m, cis isomer, 0.85H), 2.2 (m, 1H), 1.95 (m, 4H), 1.6 (m, 1H), 1.5 (m, 1H), 1.22 (m, 6H), 0.9 (s, 9H), 0.04 (s, 6H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1(Cl)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
In the drybox, 14.4 mg (0.087 mmol) of (Me3C)2PH(O) from Experiment 2, 20.0 mg (0.0218 mmol) of Pd2(dba)3 and 4.0 mL of 1,4-dioxane were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperature overnight. Next, 651 mg (2.0 mmol) of CSCO3 and 146.3 mg (1.2 mm) of PhB(OH)2 were added into the mixture above, followed by syringing 122 μl (1.2 mmol) of PhCl into the reactor. The resulting mixture was refluxed for 24 h. The reaction mixture was then cooled to room temperature, chromatographed on silicon gel using ethyl acetate/hexane (5% volume ratio) as eluant. The eluate was concentrated by rotary evaporation followed by high vacuum to yield 163 mg (88% yield) of biphenyl. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.77 (d, J=7.75 Hz, 4H), 7.60 (t, J=7.65 Hz, 4H), 7.50 (t, J=7.38 Hz, 2H).ppm. 13C NMR (125 MHz, CDCl3): δ141.2, 128.7, 127.2, 127.1 ppm.
Reaction SMILES: F[C:2]1[N:23]=[CH:22][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=3)[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CS(C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:9]2[C:4]3[CH:3]=[C:2]([NH:31][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)[N:23]=[CH:22][C:5]=3[N:6]=[CH:7][N:8]=2)=[CH:12][C:13]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COc1ccc(CN)cc1
Reactant: Fc1cc2c(Nc3ccc(F)c(C(F)(F)F)c3)ncnc2cn1
Solvent: CS(C)=O
Product: COc1ccc(CNc2cc3c(Nc4ccc(F)c(C(F)(F)F)c4)ncnc3cn2)cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A stirred solution of compound 163 (14.30 g, 43.87 mmol) in DMSO (90 mL) was treated with slow addition of 4-methoxybenzylamine (57.3 mL, 482.52 mmol) under nitrogen at 70° C. The resultant mixture was stirred at 70 to 75° C. for 48 h, then cooled to room temperature and poured into a beaker of ice-water (1 L) with stirring. The resulted solid was collected by filtration, washed with water and dried in a vacuum oven (45° C.) for 2 h. The crude product was triturated with CH2Cl2 to provide N4-(4-fluoro-3-(trifluoromethyl)phenyl)-N6-(4-methoxybenzyl)pyrido[3,4-d]pyrimidine-4,6-diamine (166) (14.40 g, 74%) as a yellow solid, m.p. 202-204° C. 1H NMR [(CD3)2SO] δ 9.83 (s, 1H), 8.77 (s, 1H), 8.38 (s, 1H), 8.27-8.30 (m, 1H), 8.21-8.24 (m, 1H), 7.55 (t, J=9.7 Hz, 1H), 7.28-7.34 (m, 3H), 7.17 (s, 1H), 6.86-6.90 (m, 2H), 4.50 (d, J=6.3 Hz, 2H), 3.71 (s, 3H). Anal. Calcd for C22H17F4N5O: C, 59.59; H, 3.86; N, 15.79%. found: C, 59.31; H, 4.07; N, 15.46%.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl.[OH-].[Na+]>O>[CH2:25]([C:26]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2[nH]1
Temperature: 15 °C
Reaction time: 5 h

Procedure:
Into a four-necked flask of 2 l capacity were charged 54.0 g (0.5 mol) of o-phenylenediamine, 142 g (0.5 mol) of stearic acid and 500 ml of 4N-hydrochloric acid, and a reaction was effected for 5 hours while refluxing the reaction solution. Then, 500 ml of water was added to the reaction mass, and the resulting solution was neutralized up to a pH of 9.2 at a temperature of not higher than 15° C. with a 20% aqueous solution of sodium hydroxide. Then, the resulting mixture was stirred at a temperature of not higher than 15° C. for 1 hour, and then filtered. The filter cake was washed with water to obtain the aimed 2-heptadecylbenzimidazole in an yield of 139.5 g (78.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([Cl:21])=[CH:14][C:3]=1[NH:4]S(C1C=CC=CC=1)(=O)=O>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([Cl:21])=[CH:14][C:3]=1[NH2:4]
Reactant: O=[N+]([O-])c1cc(Cl)c(NS(=O)(=O)c2ccccc2)cc1Cl
Agent: O=S(=O)(O)O
Product: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.44 mole (154 g) of 2,5-dichloro-4-nitro-N-benzenesulphonylaniline prepared in the previous stage is suspended in 600 ml of concentrated sulphuric acid. After 24 hours' stirring at ambient temperature the reaction mixture is poured onto 5 kg of ice. The expected product precipitates. After filtering, washing to neutrality and drying, it melts at 156° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C(OC([N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH:25]=[C:24]1[CH2:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH2:38])[C:34]1=[O:39])=O)(C)(C)C>>[O:39]=[C:34]1[C@@H:35]([NH:38][S:12]([C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)(=[O:14])=[O:13])[CH2:36][CH2:37][N:33]1[CH2:32][C:24]1[NH:23][C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH:25]=1
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2cnccc21
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Product: O=C1[C@@H](NS(=O)(=O)c2ccc(-c3ccc(Cl)s3)s2)CCN1Cc1cc2cnccc2[nH]1

Procedure:
The title compound is prepared as described in EXAMPLE 56, Part A using 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride and 2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester as starting material. The crude product can be purified by column chromatography eluting with 5% MeOH/CH2Cl2to give the title compound as a white solid or used in the subsequent step after an aqueous work-up without further purification. Ion spray MS, [M+H]+=593, 595, Cl pattern.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([N:10]=C=O)([CH3:9])[CH3:8])(=[O:3])[CH3:2]>Cl>[C:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[C:7]([NH2:10])([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)(C)N=C=O)c1
Agent: Cl
Product: CC(=O)c1cccc(C(C)(C)N)c1
Temperature: 0 °C
Yield: 54.8 %

Procedure:
3-Acetyl-α, α-dimethylbenzyl isocyanate 3 (1000 mg, 4.92 mmol) in 8N HCl (30 mL) were refluxed for 30 min. The reaction mixture was cooled to 0° C. and then washed with diethyl ether. The aqueous portion was neutralized with a 10% NaOH solution and extracted with diethyl ether (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography eluting with methanol/chloroform to give 24 as a yellow oil (478 mg, 55%). 1H NMR (CDCl3, 400 MHz) δ 1.57 (s, 6H), 2.61 (s, 3H), 3.72 (s, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 8.14 (s, 1H).
Reaction SMILES: C([Li])CCC.BrC1C=CC=CC=1[C:13]1[CH:14]=[CH:15][C:16]2[N:17](C3C=CC=CC=3)[C:18]3[C:23]([C:24]=2[CH:25]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3.[Br:32][C:33]1[CH:34]=[C:35]([C:40]2([C:53]3[CH:58]=[C:57]([Br:59])[CH:56]=[C:55]([Br:60])[CH:54]=3)[C:52]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:46]3[C:41]2=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:36]=[C:37]([Br:39])[CH:38]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[C:35]([C:40]2([C:53]3[CH:58]=[C:57]([Br:59])[CH:56]=[C:55]([Br:60])[CH:54]=3)[C:52]3=[CH:51][C:50]4[N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:16]5[C:15]([C:49]=4[CH:48]=[C:47]3[C:46]3[C:41]2=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:14][CH:13]=[CH:25][CH:24]=5)[CH:36]=[C:37]([Br:39])[CH:38]=1
Reactant: Brc1ccccc1-c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)c3ccccc3-c3ccccc32)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1cc(Br)cc(C2(c3cc(Br)cc(Br)c3)c3ccccc3-c3cc4c5ccccc5n(-c5ccccc5)c4cc32)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
24.0 ml (60 mmol) of n-butyllithium (2.5 N in hexane) are added dropwise to a solution, cooled to −78° C., of 23.9 g (60 mmol) of 3-(2-bromophenyl)-N-phenylcarbazole in 500 ml of THF, the mixture is subsequently stirred at −78° C. for a further 30 min., and a solution of 38.0 g (60 mmol) of 9,9-bis-(3,5-dibromophenyl)fluorene in 100 ml of THF is then added dropwise. When the addition is complete, the mixture is allowed to warm to room temperature, the THF is removed in vacuo, the residue is taken up in 500 ml of glacial acetic acid, 5 ml of hydrogen bromide are added, and the suspension is heated under reflux for half an hour. After cooling, the solid is filtered off with suction, washed three times with 300 ml of ethanol and recrystallised once from toluene/ethanol. Yield: 36.2 g (45 mmol), 75.3%, purity about 97% (HPLC).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1OCCCCCOC(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCc1cccc(C(C)=O)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A solution of 4.22 g (12.06 mmol) of 2-[[5-(acetoxy)pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester and 0.1 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was stirred and refluxed for 3.5 hr and stirred at room temperature for 21 hr. Most of the methanol was removed in vacuo and the residue was diluted with water and worked-up with ether in the usual manner (the combined ether extracts were additionally washed with saturated aqueous sodium bicarbonate). The product was purified by flash chromatography on silica gel, eluting with 1:2 hexane-ethyl acetate. There was obtained 3.6 g (97%) of 2-[[5-(acetoxy)pentyl]oxy]phenyl]-2-propenoic hydroxypentyl)oxy]-5-acetylbenzenepropanoic acid methyl ester as a viscous oil.
Reaction SMILES: CC([NH:9][S:10](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:12])=[O:11])(C)CC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15](/[CH:14]=[CH:13]/[S:10]([NH2:9])(=[O:11])=[O:12])[CH:16]=1
Reactant: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)/C=C/c1cccnc1
Yield: 72.8 %

Procedure:
(E)-2-pyridin-3-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (3.63 g, 12.3 mmol) was stirred for 3 hours in a 1:1 mixture of trifluoroacetic acid and dichloromethane (40 mL). The solvent was concentrated in vacuo to afford a yellow oil. The oil was dissolved in dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL), dried over MgSO4, filtered and concentrated in vacuo to afford (E)-2-pyridin-3-yl-ethenesulfonic acid amide as a pale yellow solid (1.65 g, 73%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Intermediate 4 (34.29 g, 94.60 mmol) in tetrahydrofuran (234 mL) and methanol (234 mL) was added 1 N aq sodium hydroxide (473 mL). The solution was stirred at room temperature for 16 h. The solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 3 N aqueous hydrochloric acid was added dropwise to pH 2. The resulting slurry was filtered, and the solid was washed with water (300 mL, then 100 mL). The solid was dried by azeotropic removal of water first with toluene, then heptane (7×100 mL), followed by heating to 70° C. under reduced pressure to afford (+/−)-4-(1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid (Intermediate 5). 1H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.4 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.66-7.58 (m, 3H), 7.40 (t, J=7.6 Hz, 1H), 5.56 (dd, J=6.0, 8.6 Hz, 1H), 2.49 (s, 3H), 2.24-2.10 (m, 1H), 2.08-1.95 (m, 1H), 1.66-1.52 (m, 1H), 1.52-1.39 (m, 1H), 1.03 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:13])=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].C(O)(=[O:16])C.OO>O1CCCC1>[F:13][C:5]1[C:6]([OH:16])=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)c1cccc(B(O)O)c1F
Agent: OO
Solvent: C1CCOC1
Product: CC(=O)c1cccc(O)c1F
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of (3-acetyl-2-fluorophenyl)boronic acid (10.0 g, 0.055 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 5 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 1-(2-fluoro-3-hydroxy-phenyl)-ethanone (8.50 g, 100%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:27]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: COc1cccc2c1CNC2
Solvent: CN(C)C=O
Product: COc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn4c3c1OCC4C)C2
Yield: 51.8 %

Procedure:
131 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 224 mg of 4-methoxyisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 99 mg of the target compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH:7]2[CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl>CN(C=O)C.O>[CH2:26]([N:9]1[CH2:8][CH:7]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH3:2])[CH:5]=2)[CH2:10]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc2c(c1)C(CCNC(C)=O)CNC2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(CCNC(C)=O)CN(Cc1ccccc1)C2
Temperature: 125 °C

Procedure:
The compound obtained in Example 4 (740 mg; 2.5 mmol) and potassium carbonate (720 mg; 5 mmol) are suspended in 20 ml of DMF, and then benzyl bromide (0.37 ml; 3 mmol) is added to the solution. The reaction mixture is heated at 125° C. for 4 hours with stirring. The solution is poured into 50 ml of water, acidified with 6N HCl and washed with ethyl acetate. The aqueous phase is then rendered alkaline with potassium carbonate and extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue so obtained is purified by chromatography on silica gel (eluant: dichloromethane with the progressive addition of methanol until the proportions 9/1 are reached). The purified oil precipitates. The precipitate so formed is recrystallised from a 7/3 toluene/cyclohexane mixture to yield the title product in the form of a white solid.
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH3:36])[C:30]([N:32]([O:34][CH3:35])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH3:36])[C:30]([N:32]([O:34][CH3:35])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CON(C)C(=O)[C@H](C)N
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](C)C(=O)N(C)OC)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 1.21 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 254-2 (4.31 mmol, crude form) as starting materials, respectively 946 mg (Isomer A, colorless amorphous) and 686 mg (Isomer B, colorless amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [F:1][CH:2]([F:10])[O:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C([Li])CCC.Cl>O1CCCC1>[F:1][CH:2]([F:10])[O:3][C:4]1[CH:9]=[C:8]([B:15]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)Oc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OC(F)F)c1
Reaction time: 0.17 h
Yield: 57.6 %

Procedure:
A solution of 3-(difluoromethoxy)benzene (3.0 g) and triisopropoxyborane (2.78 g) in tetrahydrofuran (15 ml) was cooled to −78° C. under argon atmosphere, and thereto was added a solution of n-butyl lithium (1.59 M hexane solution, 9.3 ml). The mixture was stirred at same temperature for 10 minutes, warmed, and further stirred at room temperature overnight. Thereto was added 3N aqueous hydrochloric acid solution (10 ml), and the mixture was stirred at room temperature for 5 minutes. The mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from hexane to give 3-difluoromethoxybenzene-boronic acid (1.6 g) as colorless crystals.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[CH:9][C:8]=1[C:19]#[N:20].[OH-:21].[Na+]>>[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[CH:9][C:8]=1[C:19]([NH2:20])=[O:21]
Reactant: [OH-]
Reactant: Cc1ccccc1-n1ncc(C#N)c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccccc1-n1ncc(C(N)=O)c1N
Temperature: 40 °C
Reaction time: 2 h

Procedure:
300 ml of 96% strength sulphuric acid are cautiously added to 40.0 g (201.8 mmol) of 5-amino-1-(2-methylphenyl)-1H-pyrazole-4-carbonitrile (Example 9A) while cooling in ice. The mixture is then heated to 40° C. and stirred for 2 hours at this temperature. After cooling, it is poured into 2 l of ice-water and cautiously neutralized with 50% strength sodium hydroxide solution. After extraction with ethyl acetate three times (2 l each time) the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulphate, and the solvent is distilled off under reduced pressure. 36.0 g (82% of theory) of product (purity >90%) are obtained and are employed without further purification in subsequent reactions.
Reaction SMILES: [C:1]1([CH2:9]O)[C:2]([CH2:7][OH:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[OH:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH2:9][Br:12]
Reactant: OCc1ccccc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: OCc1ccccc1CBr
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1,2 benzenedimethanol (1.41 g, 10 mmol), carbontetrabromide (3.648 g, 11 mmol), triphenylphosphine (2.885 g, 11 mmol) in dry methylene chloride (50 ml) was stirred at rt over 2 days under argon. The solvent was removed under reduced pressure and the residue chomatographed (flash silica gel, 1:1 t-butyl methyl ether:hexanes) to afford the title compound as a white solid. (0.99 g, 49%)