Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH:5]([C:13]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=1[F:23])[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])[CH3:4].N.[CH2:25]([Mg][Cl:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Cl-].[NH4+]>O1CCCC1.O>[ClH:33].[CH2:25]([C:7]1([OH:12])[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH:5]([N:3]([CH3:2])[CH3:4])[C:13]1[C:14]([F:23])=[C:15]([F:22])[C:16]([F:21])=[C:17]([F:20])[C:18]=1[F:19])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CN(C)C(c1c(F)c(F)c(F)c(F)c1F)C1CCCCC1=O
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1c(F)c(F)c(F)c(F)c1F)C1CCCCC1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 19.4 %

Procedure:
The base was freed from 3.0 g (8.39 mmole) of the hydrochloride of 2-(dimethylaminopentafluorophenylmethyl) cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of ammonia solution (25 vol. %), extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 2.5 g (7.8 mmole) of this base were dissolved in 12 ml of tetrahydrofuran, added dropwise to 4.7 ml (9.3 mmole) of benzylmagnesium chloride (2 M solution in tetrahydrofuran) while cooling in an ice bath, and then stirred for 15 hours at RT. The reaction mixture was worked up by adding 10 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 15 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 2.46 g of crude base (76.4% of theory) were obtained, from which 0.68 g of 1-benzyl-2-(dimethylaminopentafluorophenylmethyl)cyclohexanol, hydrochloride (19.4% of theory) was obtained according to the procedure described in Example 1 (3rd Stage). The hydrochloride decomposes on heating above 100° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20].BrCC(OCC)=O>CC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc2c(Cl)nccc2c1
Reactant: CCOC(C)=O
Agent: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(Cl)nccc2c1
Temperature: 60 °C

Procedure:
To a dry 40 mL vial equipped with a stir bar was added 1-chloroisoquinolin-6-ol (200 mg, 1.11 mmol) and potassium carbonate (231 mg, 1.67 mmol). To the vial was added dry ethyl acetate (6 mL) followed by ethyl 2-bromoacetate (0.148 mL, 1.34 mmol). The vial was sealed and then heated at 60° C. for 2 h. The mixture was cooled to room temperature, diluted with acetone, and then filtered. The filtrated was concentrated and the resulting solid residue was subjected to SiO2 chromatography (hexanes:EtOAc 85:15 to 70:30) to afford ethyl 2-((1-chloroisoquinolin-6-yl)oxy)acetate as a colorless, crystalline solid (296 mg, 66%). 1H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (d, J=9.3 Hz, 1H), 8.22 (d, J=5.8 Hz, 1H), 7.49 (d, J=5.8 Hz, 1H), 7.40 (dd, J=9.3, 2.8 Hz, 1H), 7.04 (d, J=2.5 Hz, 1H), 4.79 (s, 2H), 4.32 (q, J=7.3 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); MS: MS m/z 266.15 (M++1).
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]23[O:21][CH2:20][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:16][O:15]3)=[CH:10][CH:9]=1)#[CH:7].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O1CCCC1>[Si:25]([C:7]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]23[O:15][CH2:16][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:20][O:21]3)=[CH:12][CH:13]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC12COC(c3ccc(C#C[Si](C)(C)C(C)(C)C)cc3)(OC1)OC2
Reaction time: 0.17 h

Procedure:
n-Butyllithium (0.79 ml of 1.6M solution, in hexane) was added to a stirred solution of 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane (0.25 g.) in dry tetrahydrofuran (15 ml) at 0°, under nitrogen. The reaction mixture was stirred at 0° for 10 minutes. t-Butyldimethylsilyl chloride (0.23 g.) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated in vacuo. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC), eluting with 2:3 dichloromethane: hexane saturated with ammonia. 1-[4-(2-t-Butyldimethylsilylethynyl)phenyl]-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane was obtained as pale yellow crystals (0.32 g.)
Reaction SMILES: C(=O)=O.CC(C)=O.[CH2:8]([C:24]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]=1[OH:38])[C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=1[OH:23].C(N(CC)CC)C.Cl[SiH2:47]Cl>O1CCCC1>[C:30]([C:28]1[CH:27]=[C:26]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:25]2[O:38][SiH2:47][O:23][C:10]3[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:12][C:13]([C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:14][C:9]=3[CH2:8][C:24]=2[CH:29]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: Cl[SiH2]Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)O[SiH2]Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Yield: 57.2 %

Procedure:
In a flame-dried flask equipped with a dry ice-acetone filled Dewar condenser and a sintered glass inlet, 42.5 grams (0.1 mole) 2,2'-methylene-bis(4,6-di-t-butylphenol) and 20.2 grams (0.2 mole) triethylamine dissolved in 100 ml tetrahydrofuran are treated slowly with 11.1 grams (0.11 mole) dichlorosilane. Filtration and recrystallization from acetonitrile-toluene gave 25.9 grams (57% yield) of a white solid mp 189°-192° C. The 1H NMR spectrum is consistent with the product.
Reaction SMILES: [CH3:1][C@@:2]1([OH:13])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH:9][CH3:10])[C:3]1([CH3:12])[CH3:11].[C:14](Cl)(=[O:16])[CH3:15]>>[CH3:1][C@@:2]1([O:13][C:14](=[O:16])[CH3:15])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH:9][CH3:10])[C:3]1([CH3:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: CC=CC[C@@H]1CC[C@@](C)(O)C1(C)C
Product: CC=CC[C@@H]1CC[C@@](C)(OC(C)=O)C1(C)C

Procedure:
Using the procedure of Example 15, 2 g of (1R,S) 1,2,2-trimethyl-3-(2-butenyl)-cyclopentanol and 15 ml of acetyl chloride were reacted to obtain 1.8 g of (1R,S) 1,2,2-trimethyl-1-acetyloxy-3-(2-butenyl)-cyclopentane.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[C:24](=[O:32])[CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[O:9])([CH3:6])([CH3:5])[CH3:4].O.Cl>O1CCCC1.C(O)C>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:41]=[CH:42][CH:43]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1)[C:24](=[O:32])[CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)CCC(=O)N(Cc1ccc(O)cc1)c1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N(Cc2ccc(O)cc2)C(=O)CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Aqueous 1 N sodium hydroxide solution (8 ml, 8 mmols) was added to a solution of ethyl N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl)succinamate (2.57 g, 4 mmols) in tetrahydrofuran (10 ml) and ethanol (10 ml). The resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then acidified with 1 N hydrochloric acid added thereto. Then, this was extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an amorphous solid of N-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]-N-(4-hydroxybenzyl) succinamic acid (1.47 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.I[C:28]1[C:36]2[C:31](=[N:32][CH:33]=[N:34][C:35]=2[NH2:37])[N:30]([C@H:38]2[CH2:43][CH2:42][C@@H:41]([N:44]3[CH2:49][CH2:48][N:47]([CH3:50])[CH2:46][CH2:45]3)[CH2:40][CH2:39]2)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:37][C:35]1[N:34]=[CH:33][N:32]=[C:31]2[N:30]([C@H:38]3[CH2:43][CH2:42][C@@H:41]([N:44]4[CH2:45][CH2:46][N:47]([CH3:50])[CH2:48][CH2:49]4)[CH2:40][CH2:39]3)[N:29]=[C:28]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=5[N:6]=4)=[CH:15][CH:14]=3)[C:36]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccc(Cl)cc6s5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 90 °C
Yield: 25.8 %

Procedure:
Procedure for Suzuki coupling: A mixture of N-(6-chloro-1,3-benzothiazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.116 g, 0.30 mmol), cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.106 g, 0.24 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.014 g, 0.012 mmol) in ethylene glycol dimethyl ether (3.0 mL), sodium carbonate (0.064 g, 0.60 mmol), and water (1.5 mL) in a sealed Schlenk flask were heated at 90° C. for 24 h. The mixture was cooled, diluted with water (10 mL) and extracted with methanol/dichloromethane (1:19, 3×20 mL). The combined organic fractions were dried (magnesium sulfate), filtered, concentrated and purified by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 7.8-10.0 min) to afford cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-6-chloro-1,3-benzothiazol-2-amine as a yellow powder (0.036 g, 0.062 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.42 min; MS (MH)+ 574.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1.BrC(C1C=CC2OCCOC=2C=1)C=C.[OH-].[K+].[CH2:31]([OH:35])[CH2:32][CH2:33][OH:34]>CS(C)=O>[OH:34][CH2:33][CH2:32][CH2:31][O:35][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: OCCCO
Reactant: BrC/C=C/c1ccc2c(c1)OCCO2
Agent: C=CC(Br)c1ccc2c(c1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCCCOC/C=C/c1ccc2c(c1)OCCO2

Procedure:
Following the procedure described in example 7§D, but starting from a mixture of trans-2,3-dihydro-6-(3-bromoprop-1-en-1-yl)benzo[1,4]dioxine and 2,3-dihydro-6-(1-bromoallyl)benzo[1,4]dioxine (650 mg), 296 mg of potassium hydroxide (296 mg 85% wt) and 1,3-propanediol (298 μL) in dimethylsulfoxide (1.8 mL) gives 280 mg of trans-2,3-dihydro-6-[3-(3-hydroxypropoxy)prop-1-en-1-yl]benzo[1,4]dioxine as a yellow oil used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[O:26].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:25](=[O:26])[NH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[CH3:14]
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1=C(O)N(C)S(=O)(=O)c2cscc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 3 hours with 0.82 g (4.6 mmol) of 2-methyl-4-nitrophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-methyl-4-nitrophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 186°-188° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][C:13]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].Cl>ClC1C=CC=CC=1Cl.C1(C)C=CC=CC=1>[CH3:22][C:20]1[CH:19]=[CH:18][C:14]([C:15](=[O:16])[C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[C:13]([CH3:12])[CH:21]=1
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(F)cc2)c(C)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a suspension of anhydrous aluminum chloride (16.2 g) dispersed in 1,2-dichlorobenzene (150 ml) was added fluorobenzene (13 g), and thereto was added dropwise 2,4-dimethylbenzoyl chloride (17.0 g) at 0-20° C. The mixture was stirred at 10-30° C. for 1 hr and heated to 80° C. The mixture was stirred for 1 hr, cooled again and poured into 6N hydrochloric acid. The reaction mixture was diluted with a great excess toluene and partitioned. The obtained organic layer was washed successively with 5% aqueous sodium hydroxide solution and water, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane-ethyl acetate as eluent to give nearly pure 1,3-dimethyl-4-(4′-fluorobenzoyl)benzene (19.4 g, 85%) as pale-yellow oil. The spectrum data of this oil were the same as those confirmed in Example 7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH2:11][CH2:12][OH:13].[CH:14](O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:14][N:10]([CH2:11][CH2:12][OH:13])[C:3]=2[CH:4]=1
Reactant: O=CO
Reactant: COc1ccc(N)c(NCCO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2ncn(CCO)c2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((2-amino-5-methoxyphenyl)amino)ethanol (914 mg, 5.01 mmol) in THF (30 mL), formic acid (0.19 mL, 5.01 mmol) was added. After stirring at 80° C. for 30 min the reaction was allowed to reach rt and basified with conc. aq.NaHCO3-solution. The aq. layer was extracted with DCM (5×). The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 2-(6-methoxy-1H-benzo[d]imidazol-1-yl)ethanol as a brown oil which was used as such in the next step. LC-MS conditions B: tR=0.30 min, [M+H]+=193.13.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2.O[CH2:39][CH2:40][O:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C>[F:13][C:14]1[C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([O:36][CH2:39][CH2:40][O:41][C:42]4[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=4)=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[N:26][CH:25]=2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[C:17]([CH3:37])[NH:18]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1O
Reactant: OCCOc1ccncc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCCOc1ccncc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
DEAD (0.19 ml, 1.2 mmol) was added dropwise to a solution of 4-(4-fluoro-2-methylindol-5-yloxy)-7-hydroxy-6-methoxycinnoline (0.2 g, 0.6 mmol), (prepared as described in Example 4), 4-(2-hydroxyethoxy)pyridine (0.125 g, 0.9 mmol), (J. Chem. Soc. Perkin II, 1987, 1867), and triphenylphosphine (0.31 g, 1.2 mmol) in DMF (4 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum to give an oil that crystallised on standing. The solid was triturated with methylene chloride, filtered, washed with methylene chloride and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)cinnoline (90 mg, 33%).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:19]([CH:20]=1)=[N:18][C:17]1[C:12](=[CH:13][CH:14]=[C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)[CH:16]=1)[CH:11]=2.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[ClH:2].[ClH:1].[ClH:2].[CH:26]([NH:29][CH:23]([CH3:24])[CH2:22][O:21][C:15]1[CH:14]=[CH:13][C:12]2[C:17]([CH:16]=1)=[N:18][C:19]1[C:10](=[CH:9][CH:8]=[C:7]([O:6][CH2:5][CH:4]([NH:18][CH:17]([CH3:12])[CH3:16])[CH3:3])[CH:20]=1)[CH:11]=2)([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: ClCCCOc1ccc2cc3ccc(OCCCCl)cc3nc2c1
Agent: Cl
Product: CC(C)NC(C)COc1ccc2cc3ccc(OCC(C)NC(C)C)cc3nc2c1

Procedure:
The compound is prepared from 3,6-bis(3-chloropropoxy)acridine hydrochloride and isopropylamine as described in Example 15.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH3:13])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:10]=[CH:11][C:12]=1[CH2:13][Br:32])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C

Procedure:
To 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-methylphenyl)-1,3-benzoxazole (1.46 g, 4.3 mmol) in CCl4 (50 mL) was added NBS (770 mg, 4.3 mmol) and benzoyl peroxide (50 mg). The reaction mixture was refluxed for 6 h, cooled to rt, and CCl4 was removed in vacuo. The residue was dissolved in EtOAc (50 mL), washed with H2O (50 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-bromomethylphenyl)-1,3-benzoxazole as light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:8]([CH2:9][CH3:10])=[N:7][C:6]2[N:11]([CH2:14][CH3:15])[N:12]=[CH:13][C:5]=2[C:4]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)=[O:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[CH2:14]([N:11]1[C:6]2=[N:7][C:8]([CH2:9][CH3:10])=[C:3]([CH2:2][NH:1][C:31]([C:30]3[CH:34]=[CH:35][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)=[O:32])[C:4]([NH:16][CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:5]2[CH:13]=[N:12]1)[CH3:15]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 100.2 %

Procedure:
To a solution of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-amine (1.02 g, 3.0 mmol) in DCM (30 mL) was added 4-[(methyloxy)carbonyl]benzoic acid (0.541 g, 3.0 mmol), HBTU (1.37 g, 3.6 mmol), and Et3N (0.843 mL, 6.0 mmol) This mixture was stirred at room temperature for 23 h. It was diluted with DCM (30 mL), which was washed with H2O (30 mL) and dried over Na2SO4, filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 1.40 g (quantitative). LC-MS m/z 466 (M+H)+.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Cl[Si](CC)(CC)CC.[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37](=[O:47])[C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[CH:35]=3)[N:30]([CH3:48])[C:29](=[O:49])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1>C1COCC1.O>[Cl:20][C:21]1[CH:22]=[C:23]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([OH:47])([C:11]4[N:7]([CH3:6])[CH:8]=[N:9][CH:10]=4)[C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[CH:35]=3)[N:30]([CH3:48])[C:29](=[O:49])[CH:28]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Reactant: Cn1ccnc1
Agent: CC[Si](Cl)(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1cncc1C(O)(c1ccc([N+](=O)[O-])cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Reaction time: 0.25 h
Yield: 26.9 %

Procedure:
n BuLi (1.6M in hexane) (4.4 ml, 0.0071 mol) was added dropwise at −70° C. to a solution of 1-methyl-1H-imidazole (0.0071 mol) in THF (8 ml) under N2 flow. The mixture was stirred for 15 minutes. ClSiEt3 (0.0073 mol) was added dropwise at −70° C. The mixture was stirred for 15 minutes. BuLi (1.6M in hexane) (3.9 ml, 0.0062 mol) was added dropwise at −70° C. The mixture was stirred at −70° C. for 15 minutes. A solution of 4-(3-chlorophenyl)-1-methyl-6-(4-nitrobenzoyl)-2(1H)-quinolinone (described in Example A3d) (0.0040 mol) in THF (15 ml) was added. The mixture was stirred at −70° C. for 15 minutes, poured out into H2O and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2; 15–40 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from diethyl ether. The precipitate was filtered off and dried, yielding 0.54 g (27%) of (±)-4-(3-chlorophenyl)-6-[hydroxy(1-methyl-1H-imidazol-5-yl)(4-nitrophenyl)methyl]-1-methyl-2(1H)-quinolinone, mp. 230° C.