Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][CH2:17][CH2:16]2.C([O:24][B:25](OCC)[O:26]CC)C.[Cl-].[NH4+]>O1CCCC1>[CH2:18]1[C:19]2[C:15](=[CH:14][C:13]([B:25]([OH:26])[OH:24])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1
Reactant: CCOB(OCC)OCC
Reactant: Brc1ccc2c(c1)CCC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2c(c1)CCC2
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium in hexane (13.2 mL of 1.6 M, 21 mmol) is added to a stirred solution of 5-bromo-indane (1.06 g, 4 mmol) in dry tetrahydrofuran (30 mL) at −75° C. under an argon atmosphere. The mixture is stirred for 30 min at −65° C., then treated with triethylborate (3.07 g, 21 mmol) and stirred for 60 min at −50° C. The resulting mixture is allowed to warm to 0° C. and then treated with a saturated aqueous solution of ammonium chloride (60 mL) and extracted with ethyl acetate (2×80 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography (silica gel, 50% ethyl acetate in hexaen) and recrystallised from ethyl acetate-hexane to give indan-5-boronic acid as a colourless crystalline solid.
Reaction SMILES: I[Si](C)(C)C.O1CCCC1.C1(C[O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:33]=[C:32]4[C:28]([C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:30][NH:31]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)C=CC=CC=1>C(#N)C>[OH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:33]=[C:32]3[C:28]([C:29]([NH:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[N:30][NH:31]3)=[CH:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)ccc12
Agent: C[Si](C)(C)I
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(O)cc3)ccc12
Temperature: 82 °C
Reaction time: 17 h

Procedure:
0.15 cm3 of iodotrimethylsilane and then 5 cm3 of tetrahydrofuran are added to 200 mg of N-[6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide, described previously, in 7.5 cm3 of acetonitrile, and the medium is heated at about 82° C. for 2 hours. 0.15 cm3 of iodotrimethylsilane is added and heating is continued for 17 hours. The reaction medium is then evaporated to dryness under reduced pressure (2 kPa; 40° C.). The residue is taken up in 75 cm3 of ethyl acetate, and this mixture is then washed with 2×50 cm3 of saturated aqueous sodium sulphate solution and with 50 cm3 of saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and then evaporated under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 1.5 cm), eluting with ethyl acetate and collecting 30 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is washed with 3×5 cm3 of diisopropyl ether. It is filtered off on a sinter funnel and, after drying (90 Pa; 40° C.), 100 mg of N-[6-(4-hydroxyphenyl)]-1H-indazol-3-yl]butanamide are thus obtained in the form of a white solid melting at about 235° C.
Reaction SMILES: [F:1][CH2:2][O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH2:14])[S:11][N:10]=1)[C:6]([NH2:8])=[O:7].[CH:15](O)=[O:16].C(OC(=O)C)(=O)C>>[F:1][CH2:2][O:3][N:4]=[C:5]([C:9]1[N:13]=[C:12]([NH:14][CH:15]=[O:16])[S:11][N:10]=1)[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(=NOCF)c1nsc(N)n1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: NC(=O)C(=NOCF)c1nsc(NC=O)n1
Yield: 61.4 %

Procedure:
To a suspension of 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl) acetamide (anti-isomer) (3.51 g, 16 mmol) in 99% formic acid (14.73 g, 320 mmol), acetic anhydride (4.90 g, 48 mmol) was added, and the mixture was reacted at 40° C. for 50 hrs, and then cooled to below 10° C. to separate crystals. The crystals were collected by filtration and washed with cold methanol (10 ml) on Nutsche. The crystals in DMF (16 ml) were heated to dissolve and the resulting solution was dispersed in methanol (32 ml), and then cooled, filtered and dried to give 2-fluoromethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl) acetamide (syn-isomer) (2.43 g, yield: 61.4%). The content obtained by HPLC: 99.0% (anti-isomer: 0.2%).
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:17]2[C:16](=[O:20])[C:15]3[C:6](=[CH:7][C:8]4[C:13]([CH:14]=3)=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:5](=[O:21])[C:4]=2[CH:3]=1.[Na+].[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CS(C)=O>[C:23]1([S:29]([C:2]2[CH:19]=[CH:18][C:17]3[C:16](=[O:20])[C:15]4[C:6](=[CH:7][C:8]5[C:13]([CH:14]=4)=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:5](=[O:21])[C:4]=3[CH:3]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=S([O-])c1ccccc1
Reactant: O=C1c2ccc(F)cc2C(=O)c2cc3ccccc3cc21
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccc(S(=O)(=O)c3ccccc3)cc2C(=O)c2cc3ccccc3cc21

Procedure:
1 g (3.62 mmol) of 2-fluoro-naphthacene-5,12-dione, 0.89 g (5.43 mmol) of benzenesulfinic acid sodium salt (sodium benzenesulfinate) and 10 ml of DMSO are stirred at 100° C. for 3 hours. After cooling, the mixture is poured onto water. The crystals are filtered off and dissolved in THF/toluene. The solution is dried over sodium sulfate and evaporated. The residue is recrystallized from THF/toluene/pentane. Yield: 1.35 g (94%), melting point >260° C.
Reaction SMILES: Br.[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.C(O[CH:23]=[C:24]([C:30](=[O:43])[C:31]1[CH:36]=[C:35]([F:37])[C:34]([N+:38]([O-:40])=[O:39])=[C:33]([CH3:41])[C:32]=1F)[C:25]([O:27][CH2:28][CH3:29])=[O:26])C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:9]=[C:8]([F:10])[C:7]([O:11][CH3:12])=[CH:6][C:4]=1[N:5]1[C:32]2[C:31](=[CH:36][C:35]([F:37])=[C:34]([N+:38]([O-:40])=[O:39])[C:33]=2[CH3:41])[C:30](=[O:43])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23]1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Reactant: COc1cc(N)c(F)cc1F
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2cc(OC)c(F)cc2F)c2c(C)c([N+](=O)[O-])c(F)cc2c1=O
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
2,4-Difluoro-5-methoxyaniline monohydrobromide (780 mg) and a solution of triethylamine (328 mg) in chloroform (10 ml) were added dropwise to a solution of ethyl 3-ethoxy-2-(2',5'-difluoro-3'-methyl-4'-nitrobenzoyl)acrylate (2.0 g) in chloroform (10 ml) at 0° C. After the mixture was stirred for 10 minutes, the solvent and the like were distilled off. Anhydrous potassium carbonate (510 mg) was added to a solution of the whole amount of the residue in N,N-dimethylformamide (10 ml), and the mixture was stirred at 70° C. for 5 hours. Ethyl acetate and water were added to the reaction mixture to collect an organic layer. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. Ethanol was added to the residue to disperse it therein, and filtration was conducted to obtain the title compound (660 mg) as a pale yellow powder.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:28][N:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[S:36][C:37]([C:41]([OH:43])=O)=[C:38]([CH3:40])[N:39]=2)[C:30]1=[O:44]>>[F:24][C:25]1[CH:26]=[C:27]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:28][N:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:35]2[S:36][C:37]([C:41]([NH2:7])=[O:43])=[C:38]([CH3:40])[N:39]=2)[C:30]1=[O:44]
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3cc(F)cc(F)c3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-2-(3-(3,5-difluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 212-213° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.31 (br s, 2H), 7.18-7.07 (m, 3H), 4.57 (d, J=16.3 Hz, 1H), 4.39 (d, J=16.3 Hz, 1H), 4.22 (dd, J=10.0, 9.1 Hz, 1H), 3.87-3.79 (m, 1H), 3.58 (dd, J=10.0, 6.6 Hz, 1H), 2.46 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 366.9 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][OH:12])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[O-:21][N+:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][OH:12])=[CH:3][CH:2]=1
Reactant: OCc1ccnc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(CO)c2ccccc21
Temperature: 0 °C
Reaction time: 17.5 h

Procedure:
To a solution of quinolin-4-ylmethanol (0.20 g, 1.26 mmol) dissolved in CH2Cl2 (10 mL), which was cooled to 0° C., was added m-chloroperbenzoic acid (57-86% w/w in H2O, 0.50 mg) in one portion. The reaction was allowed to slowly warm to room temperature while stirring. After 17.5 h, the resulting solid was filtered and washed with CH2Cl2 to yield (1-oxidoquinolin-4-yl)methanol as a white solid. MS (ES+): 176 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[F:9][C:4]1[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
To a stirred solution of 4-bromo-1,2-difluorobenzene (3.5 g, 17.86 mmol) in dry THF was cooled to −78° C., was added a n-BuLi (10.71 mL) slution dropwise. After completion of the addition, the mixture was stirred for 15 min., and triisopropyl borate (6.71 g, 35.71 mmol) was added in one portion. The reaction flask was kept in a cooling bath for 30 min., and warmed to room temperature for 3 hours. The solvent was removed, the residue was dissolved in ether, washed with 1N HCl and water, dried over Na2SO4, filtered, and concentrated in vacuo, the residue was purified by recrystallyzation with CH2Cl2 and hexane to give the pure 3,4-difluorophenylboronic acid (800 mg, 20%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[Cl:38]C1C=C(B(O)O)C=CC=1>>[Cl:38][C:3]1[CH:4]=[C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[CH:6]=[CH:7][CH:2]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2cccc(Cl)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-chlorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.CCOP(OCC)([CH2:18][C:19]#[N:20])=O.CC(C)([O-])C.[K+].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:18]/[C:19]#[N:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(/C=C/C#N)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
7 g of 3,4-dimethoxybenzaldehyde (42.1 mmoles) are dissolved in 84 mL of THF and the solution is cooled to 0° C. 8.2 g of diethyl cyanomethyl phosphonate (7.5 mL, 46.3 mmoles, 1.1 eq.) and subsequently 5.2 g of potassium tert-butoxide (46.3 mmoles, 1.1 eq.) are added little by little. The mixture is stirred for one hour at 0° C. and then overnight at ambient temperature. The reaction mixture is hydrolysed using 175 mL of water and extracted twice with dichloromethane. The organic phases are collected and the solvent is evaporated off under reduced pressure to yield 7.69 g of the title product in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14].S(=O)(=O)(O)O>C1C=CC=CC=1>[CH2:13]([O:9][C:8](=[O:10])[CH:7]=[CH:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[CH3:14]
Reactant: CCO
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: CCOC(=O)C=Cc1ccc(Cl)cc1
Yield: 96.5 %

Procedure:
4-Chlorocinnamic acid (300 g) was suspended in benzene (1200 ml), and ethanol (340 g) and conc. sulfuric acid (14 ml) were added thereto, followed by reflux of the resulting mixture for 15 hours. After the reaction mixture had been washed successively with a diluted aqueous NaCl solution (500 ml), a saturated aqueous sodium hydrogencarbonate solution (500 ml) and a dilute aqueous NaCl solution (500 ml), the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was evaporated under reduced pressure to obtain the title compound (334 g, 97%) as a colorless liquid.
Reaction SMILES: C(O[C@@H:5]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C@H:6]1OC(=O)C)(=O)C.[O:17]=[C:18]1[CH:27]=[CH:26][C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2>C1(C)C(C)=CC=CC=1>[O:17]=[C:18]1[C:27]2[C:26](=[CH:6][C:7]3[C:8]([CH:5]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:25](=[O:28])[C:24]2[CH2:23][CH:22]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][CH2:20][C:19]1=2
Reactant: CC(=O)O[C@@H]1c2ccccc2[C@H]1OC(C)=O
Reactant: COC(=O)C1CCC2=C(C1)C(=O)C=CC2=O
Solvent: Cc1ccccc1C
Product: COC(=O)C1CCC2=C(C1)C(=O)c1cc3ccccc3cc1C2=O
Yield: 81.2 %

Procedure:
A mixture of 240 mg (1.1 mmol) of trans-1,2-diacetoxy-1,2-dihydrobenzocyclobutene and 220 mg (1.0 mmol) of methyl rac-1,2,3,4,5,8-hexahydro-5,8-dioxonaphthalene-2-carboxylate in 20 ml of dry xylene was stirred and heated under reflux under an atmosphere of nitrogen for 18 hours. The solution was evaporated to dryness, the yellow residue was stirred with 100 ml of diethyl ether and the mixture was subsequently filtered to give 260 mg (81%) of methyl rac-1,2,3,4,5,12-hexahydro-5,12-dioxonaphthacene-2-carboxylate in the form of a bright yellow solid of melting point 173°-174° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[O-][CH2:15][CH3:16].[Na+]>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>[C:15]1([CH:16]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(c1ccc(F)cc1)C(F)(F)F
Reactant: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: Fc1ccc(C(=Cc2ccccc2)C(F)(F)F)cc1
Yield: 91 %

Procedure:
4'-Fluoro-2,2,2-trifluoroacetophenone (F. E. Herkes et al.: J. Org. Chem. 32, 1311-18 (1967)) is reacted with benzyl-triphenyl-phosphonium chloride in the presence of an ethanol solution of sodium ethoxide. 1-Phenyl-3,3,3-trifluoro-2-(4-fluorophenyl)-propene is obtained with a yield of 91%; b.p.: 110°-114° C./0.2 mm Hg, m.p.: 43°-45° C.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:15]2[CH:14]=[CH:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[C:7]([O:18][CH3:19])[CH:8]=2.C(N(CC)CC)C.[CH2:27]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>C1COCC1>[CH2:27]([C:39]1[CH:40]=[CH:41][C:42]([S:45]([O:1][N:2]=[C:3]2[C:4]3[CH:5]=[CH:6][C:7]([O:18][CH3:19])=[CH:8][C:9]=3[C:10]3[C:15]2=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)(=[O:47])=[O:46])=[CH:43][CH:44]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)-c1cc(OC)ccc1C2=NO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)ON=C2c3ccc(OC)cc3-c3cc(OC)ccc32)cc1
Yield: 51.4 %

Procedure:
As described under 11.3., 5.1 g (0.02 mol) of 9-hydroxyimino-3,6-dimethoxyfluorene are reacted at 0° C., in the presence of 3.0 g (0.03 mol) of triethylamine in 100 ml THF, with 5.6 g (0.022 mol) of 4-dodecylbenzenesulfonyl chloride. The crude product obtained after isolation is purified by flash chromatography on silica gel (eluant: petroleum ether/ethyl acetate 4:1). 5.8 g (51.3%) of 9-(4-dodecyl-phenylsulfonyloxyimino)-3,6-dimethoxyfluorene are obtained in the form of a viscous yellow oil. The UV spectrum (acetonitrile) of the substance shows absorption bands with a maximum at 315 nm (ε=21100) that extend to 443 nm. Elemental analysis: C33H41NO5S (563.76)
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15](O)=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1.C[CH2:21][N:22](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.CN>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:14]([C:15]([NH:22][CH3:21])=[O:16])=[C:13]([CH3:18])[N:12]=[CH:11][CH:10]=2)=[C:4]([F:19])[CH:3]=1
Reactant: Cc1nccc(-c2cc(F)c(Cl)cc2F)c1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2cc(F)c(Cl)cc2F)ccnc1C
Reaction time: 0.17 h
Yield: 52.8 %

Procedure:
To the stirred solution of 4-(4-chloro-2,5-difluorophenyl)-2-methylnicotinic acid (1.7 g, 4.02 mmol) in DMF (0.5 mL) was added DIEA (2.81 mL, 16.06 mmol), HOBT (1.230 g, 8.03 mmol), EDC (1.155 g, 6.02 mmol) at 0° C. followed by addition of methylamine hydrochloride (0.488 g, 7.23 mmol). After stirring for 10 min, the ice bath was removed and the reaction mixture was allowed to stir overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (10 mL) and washed with water (10 mL) followed by brine (10 mL). The organic layer was separated and dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford 4-(4-chloro-2,5-difluorophenyl)-N,2-dimethylnicotinamide (1 g, 2.123 mmol, 53% crude yield) as a brown solid which was taken to the next step without purification. LC/MS (ESI) m/e 297.3 [(M+H)+, calcd for C14H12ClF2N2O 297.1]; LC/MS retention time (method B): tR=0.76 min.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Br:8][C:9]1[S:13][C:12]([S:14](Cl)(=[O:16])=[O:15])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:14]([C:12]1[S:13][C:9]([Br:8])=[CH:10][CH:11]=1)(=[O:16])=[O:15]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Br)s1)N(CCO)CCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
To a stirred solution of diethanolamine (1.45 g, 13.8 mmol) in THF (20 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) and triethylamine (0.71 ml, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.98 g, 77%) as a white solid. MS (ISP) 330.0 [(M+H)+], mp 70° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][O:30][C:31]([NH:33][C@@H:34]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C:35](O)=[O:36])=[O:32].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:22]([C@H:2]([NH:1][C:35]([C@@H:34]([NH:33][C:31](=[O:32])[O:30][CH3:29])[C@@H:38]([CH3:41])[CH2:39][CH3:40])=[O:36])[C@@H:3]([OH:21])[CH2:4][C@@H:5]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:20])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of the product from Example 6A (0.50 g, 1.30 mmol) in THF (13 mL) was treated with the product from Example 5A (0.30 g, 1.59 mmol), DEPBT (0.45 g, 1.50 mmol), and N,N-diisopropylethylamine (1.1 mL, 6.31 mmol), stirred at 25° C. for 16 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated to give the title compound, used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([F:29])[CH:18]=1)[N:9]=[C:8]2[NH:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36](C([O-])=O)[N:35]=[CH:34]2.[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1.O>CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([C:10]2[N:9]=[C:8]([NH:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[NH:36][N:35]=[CH:34]4)[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:6]=3)[N:11]=2)[CH:22]=[CH:21][C:20]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4c(cnn4C(=O)[O-])c3)c2cc1OCCCl
Reactant: C1CCNC1
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nc(-c3ccc(-c4ccccc4)c(F)c3)nc(Nc3ccc4[nH]ncc4c3)c2cc1OCCN1CCCC1
Temperature: 75 °C
Yield: 84.2 %

Procedure:
A mixture of 5-(6-(2-chloroethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-7-methoxyquinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.200 g, 0.31 mmol) and pyrrolidine (0.385 g, 5.41 mmol) in DMSO (1.5 mL) was heated at 75° C. for 1.5 h. The mixture was allowed to cool to RT, upon which it was poured into water (100 mL). The solid that formed was collected via filtration and purified by preparative TLC (SiO2, CH2Cl2:MeOH 9:1) to give the desired compound 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine (0.15 g, 0.261 mmol, 84%). MS 575.4 (M+1) HPLC retention time 5.40 mins.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1.C(O)CC>O>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1
Solvent: O
Solvent: CCCO
Product: O=C(Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1)c1cccc(Cl)c1
Temperature: 4 °C
Yield: 30.6 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-chlorobenzoic acid (1.6 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-chlorophenyl)-1,8-naphthyridine (1.8 g). The product obtained by precipitation in water (2.2 g; m.p. approximately 190° C.) is dissolved in boiling propanol (400 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with propanol (3×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Chlorophenyl)-1,8-naphthyridin-2-yl]-3-chlorobenzamide (0.85 g), m.p. 222°-224° C., is obtained.