Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2=[N:21][N:22](COCC[Si](C)(C)C)[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)=[C:11]2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.O.N>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[CH:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:26][CH2:27][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:29][CH2:30]3)[C:11]=2[N:10]=1
Reactant: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n(COCC[Si](C)(C)C)nc12
Agent: N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(C)(=O)=O)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 30 ml round-bottomed flask equipped with a septum having a top-mounted argon intake is charged with 47 mg of 5-(2,6-difluorophenyl)-3-([1-(methylsulphonyl)piperidin-4-yl]amino}-2-{[2-(trimethylsilyl)ethoxy]methyl}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline in 4 ml of DCM. After cooling to 0° C. using an ice bath, 0.47 ml of TFA is added and the mixture is stirred at RT for 3 h. It is concentrated under RP and the solid obtained is taken up in 25 ml of water and 0.75 ml of 0.75M aqueous ammonia solution. It is extracted with AcOEt, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and methanol (92.5/7.5 by vol.). This gives 6 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-7-ethynyl-2H-pyrazolo[4,3-c]isoquinoline (yellow solid). MS (E/1); m/z=481 (M+); 1H NMR: 1.66 (m, 2 H) 2.11 (m, 2 H) 2.87 (s, 3 H) 2.91 (m, 2 H) 3.56 (m, 2 H) 3.79 (m, 1 H) 4.37 (s, 1 H) 6.10 (d, J=8.3 Hz, 1 H) 7.34 (t, J=7.9 Hz, 2 H) 7.65 (broad s, 1 H) 7.69 (m, 1 H) 7.97 (broad d, J=8.3 Hz, 1 H) 8.42 (d, J=8.3 Hz, 1 H) 12.88 (broad s, 1 H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH3:21])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][NH:17][C@@H:16]([CH2:20][CH3:21])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC[C@@H]1NCCN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@H]1CN(Cc2ccccc2)CCN1
Temperature: 65 °C
Reaction time: 17 h
Yield: 89.6 %

Procedure:
LiAlH4 (1 M solution in THF, 11 mL, 11.0 mmol) was added drop wise to solution of (S)-1-benzyl-3-ethylpiperazine-2-one (0.8 g, 3.66 mmol) in THF (30 mL) at 0° C. The reaction mixture was stirred at 65° C. for 17 h, then cooled 0° C. and quenched sequentially with H2O (0.7 mL), 10% NaOH (1 mL) and H2O (1.5 mL). Diethylether (100 mL) was added to the reaction mixture, and stirring was continued for 1.5 h. The solid was filtered off, the filtrate was concentrated and dried in vacuum to afford (S)-1-benzyl-3-ethylpiperazine (0.67 g, 87%) as an oily solid. 1H NMR and MS consistent.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[S:9][CH:10]=1)(=[O:3])[CH3:2].[Br:21]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[S:9][C:10]=1[Br:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1csc(-c2cccc(C(F)(F)F)c2)n1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCc1nc(-c2cccc(C(F)(F)F)c2)sc1Br
Temperature: 5 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (10 mL) of the crude compound (21 mmol) obtained in Example 64c in acetic acid was slowly added dropwise a solution (10 mL) of bromine (2.5 g, 31 mmol) in acetic acid, and the mixture was stirred at 0-10° C. overnight. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=80/20) to give the title compound (4.0 g, 51%) as a colorless solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].P(Cl)(Cl)([Cl:20])=O>CN(C)C=O>[Cl:20][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=2[O:12][CH3:13])[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1ccc(OC)c2c(O)c(C#N)cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(OC)c2c(Cl)c(C#N)cnc12

Procedure:
A stirred mixture of 1.30 g of 4-hydroxy-5,8-dimethoxy-quinoline-3-carbonitrile, 10 ml of phosphorous oxychloride, and 2 drops of N,N-dimethylformamide was refluxed for 10 minutes and evaporated free of volatile matter. The residue was stirred with 50 ml of water. The product was collected and dried to give 1.74 g of 4-chloro-5,8-dimethoxy-quinoline-3-carbonitrile as a solid, mp 165-167° C.; mass spectrum (EI, m/e): M 248.0346.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:16]=[C:11]3[CH:10]=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:22][N:20]1[CH:21]=[C:17]([C:15]2[CH:16]=[C:11]3[CH:10]=[N:9][NH:8][C:12]3=[N:13][CH:14]=2)[CH:18]=[N:19]1
Reactant: COc1ccc(Cn2ncc3cc(-c4cnn(C)c4)cnc32)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cnc3[nH]ncc3c2)cn1
Temperature: 50 °C

Procedure:
To a solution of 1-(4-methoxybenzyl)-5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine (116) (40 mg, 0.125 mmol) dissolved in chloroform (10 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was heated at 50° C. for 12 h. After completion of the reaction the solvents were removed and diluted with cold water, pH was adjusted to 8 and the aqueous phase extracted with chloroform two times. The organic layer was washed with brine solution and dried over sodium sulphate and the solvents were removed. The crude was passed through 100-200 mesh silica gel eluting the compound at 40% ethyl acetate in hexane as pale yellow solid of 5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine 117 obtained in 10 mg quantity. MS m/z 199.9 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(#N)C>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2)CC1
Reaction time: 5 h
Yield: 125.8 %

Procedure:
To a stirring solution of 1-Boc-piperidine-4-carboxaldehyde (2.4 g, 11.3 mmol) in THF (60 mL) and acetonitrile (15 mL) was added piperazine (4.85 g, 56.3 mmol). After stirring for 5 h, sodium triacetoxyborohydride (2.87 g, 13.5 mmol) was added and the reaction was allowed to stir overnight. The next morning, the solvents were removed by rotary evaporation and the residue was dissolved in ethyl acetate, washed twice with satd aq. NaHCO3, followed by water, then dried over MgSO4, filtered and concentrated in vacuo. The residue was then chromatographed over silica gel, eluting with a step gradient of 2% through 15% (2 N ammonia/methanol) in dichloromethane. The product containing fractions were combined and concentrated in vacuo to give 4.03 g (48%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.C(O)(=O)CCCCCCCCCCC.C(Cl)(=O)CCCCCCCCCCC.[C:33]([N:46]=[C:47]=[S:48])(=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[C:66]([F:71])[CH:65]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[O:61][CH3:62])[N:57]=[CH:56][CH:55]=[C:54]2[O:63][C:64]1[CH:70]=[CH:69][C:67]([NH:68][C:47]([NH:46][C:33](=[O:45])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[S:48])=[C:66]([F:71])[CH:65]=1
Reactant: CCCCCCCCCCCC(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: CCCCCCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCC(=O)O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Temperature: 100 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available dodecanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and dodecanoyl isothiocyanate was prepared using the resultant dodecanoyl chloride as a starting compound according to the description of the literature. Dodecanoyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (60 mg, yield 68%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=1)[S:13]([C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[OH-].[Na+:40]>C(O)C>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][C:3]=1[N:12]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=1)[S:13]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O-:22])=[O:21])=[CH:25][CH:26]=1)(=[O:15])=[O:14].[Na+:40]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2ncc3ccccc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)ncc2ccccc12
Yield: 97.4 %

Procedure:
A suspension of ethyl 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]-amino}sulfonyl)benzoate (1.11 g, 2.04 mmol) prepared in Example 1 and 2 mol/L aqueous sodium hydroxide solution (1.02 ml, 2.04 mmol) in ethanol (20.4 ml) was heated to reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue is washed with diethyl ether and pentane to give sodium 4-({(4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoate (1.07 g, 94%) as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:20].[F:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH:27][S:28]([C:31]2[C:32](Br)=[N:33][CH:34]=[CH:35][CH:36]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>ClCCl.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>[F:21][C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH:27][S:28]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[C:3](=[O:20])[CH2:4]4)[CH:36]=2)(=[O:29])=[O:30])=[CH:24][CH:23]=1
Reactant: CN1C(=O)Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: O=S(=O)(NCc1ccc(F)cc1)c1cccnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C(=O)Cc2cc(-c3cncc(S(=O)(=O)NCc4ccc(F)cc4)c3)ccc21
Temperature: 100 °C

Procedure:
To 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 3a (124 mg, 0.45 mmol) was added bromo-pyridine-3-sulfonic acid 4-fluoro-benzylamide (140 mg, 0.41 mmol), tripotassium phosphate (260 mg, 1.25 mmol) and DMF (2.5 mL). The reaction mixture was degassed and placed under an argon atmosphere, at which time tetrakis(triphenylphosphine)palladium(0), (23 mg, 0.02 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 60 minutes. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (heptane-ethyl acetate, 20 to 100%) to furnish 5-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyridine-3-sulfonic acid 4-fluoro-benzylamide; HRMS: (ESI) m/z 412.1136 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.17 (s, 3H), 3.65 (s, 2H), 4.12 (s, 2H), 7.03 (t, J=8.8 Hz, 2H), 7.14 (d, J=8.1 Hz, 1H), 7.25 (dd, J=8.6, 5.6 Hz, 2H), 7.65 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 8.20 (t, J=2.3 Hz, 1H), 8.44 (t, J=6.3 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 9.04 (d, J=2.3 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[C:14]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+]>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:21]3[CH:22]=[CH:23][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=3)[CH:3]=[CH:4][C:5]=2[CH3:13])[C:9]1=[O:11]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(Cl)c2c1CC(C)C2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-c2ccc(C(C)(C)C)cc2)c2c1CC(C)C2=O
Temperature: 80 °C

Procedure:
13.4 (68.8 mmol) of 7-chloro-2,4-dimethyl-1-indanone (1c), 14.71 g (82.6 mmol) of 4-tert-butylphenylboronic acid, 16.05 g (151 mmol) of sodium carbonate, 188 ml of ethylene glycol and 30.7 ml of water were placed under a protective gas atmosphere in a reaction vessel and heated to 80° C. While stirring vigorously, a freshly prepared catalyst solution of 77 mg (0.343 mmol) of palladium acetate, 1.7 ml (1.01 mmol) of an aqueous TPPTS solution (0.6 molar) in 25 ml of water was added to the reaction components and the reaction mixture was refluxed for 3 hours until the reaction was complete. After cooling to room temperature, the ethylene glycol phase was extracted three times with a total of 900 ml of toluene. The combined toluene phases were washed twice with a total of 250 ml of sodium chloride solution and dried over 150 g of sodium sulfate. Removal of the solvent, drying of the residue and subsequent distillation in an oil pump vacuum gave 18.59 g of (1d).
Reaction SMILES: C(O[C:4]([C:6]1([C:29]([O:31]CC)=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5])C.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH2:40]>C(O)C>[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][N:40]([CH2:39][C:35]1[O:34][CH:38]=[CH:37][CH:36]=1)[C:4]([C:6]1([C:29]([OH:31])=[O:30])[O:10][C:9]2[CH:11]=[CH:12][C:13]([CH2:15][CH:16]([NH:18][CH2:19][CH:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[OH:21])[CH3:17])=[CH:14][C:8]=2[O:7]1)=[O:5]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2O1
Reactant: NCc1ccco1
Solvent: CCO
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)N(Cc1ccco1)Cc1ccco1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
A mixture of 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-ethyl ester (2.4 g, 5 mmol) and 2-furanylmethylamine (10 mL, excess) was refluxed in ethanol for 48 h. The reaction mixture was concentrated and the residue obtained was extracted with chloroform:methanol (3:1). It was washed with water and dried over anhydrous MgSO4. The organic layer was filtered and concentrated. The residue obtained was chromatographed over silica gel eluted with 9:1 chloroform:methanol to yield a brown solid; mp 50; yield 400 mg; 14%; M+H 581.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([NH:9][C:10](=[O:19])[O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CC(=O)CC>[CH2:12]([O:11][C:10]([NH:9][C:5]1[C:6](=[O:8])[N:7]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
A slurry of benzyl N-(6-methyl-2-oxo-1,2-dihydro-3-pyridinyl)carbamate (preparation 3) (20 g, 78 mmol) in 2-butanone (500 ml) was treated with K2CO3 (53.9 g, 94 mmol) and further 2-butanone (100 ml). The resultant mixture was treated cautiously with tert-butyl 2-bromoacetate (15.2 ml, 94 mmol) and stirred at room temperature for 18 hr. The solvent was evaporated and the crude material was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate, the combined organic layers washed with sat aq brine and dried over Na2SO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave the crude product which was purified by recrystallisation from ethyl acetate:hexane to give the desired product (white solid, 15.1 g, 52%). 1H NMR (CDCl3) δ: 1.40 (s, 9H), 2.20 (s, 3H), 4.70 (s, 2H), 5.20 (s, 2H), 6.05 (d, 1H), 7.40 (m, 5H), 7.70 (s, br, 1H), 7.90 (d, 1H). LRMS m/z=373.6 (M+1)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:5]1[CH:34]=[CH:33][C:8]2[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)[C:10](=[O:12])[S:11][C:7]=2[CH:6]=1>C(OCC)C>[CH3:1][O:2]/[N:3]=[C:4](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[C:5]1[CH:34]=[CH:33][C:8]2[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([O:27][CH2:28][C:29]([F:31])([F:30])[F:32])[C:24]([OH:26])=[O:25])=[CH:20][CH:21]=3)[C:10](=[O:12])[S:11][C:7]=2[CH:6]=1
Reactant: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(OCC(F)(F)F)C(=O)O)cc1
Solvent: CCOCC
Product: CO/N=C(/c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(OCC(F)(F)F)C(=O)O)cc1

Procedure:
The compound obtained in Example 62 is taken up in the diethyl ether. The filtrate is recovered and evaporated to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O.Cl.[NH2:23][CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]2[C:8]=1[C:16](=[O:18])[N:23]([CH:24]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:25]1=[O:26])[C:10]2=[O:12]
Reactant: NC1CCC(=O)NC1=O
Reactant: O=C(O)c1cccc(OCc2cccc(F)c2)c1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4cccc(F)c4)c3C2=O)C(=O)N1
Yield: 89.8 %

Procedure:
A mixture of 3-(3-fluoro-benzyloxy)-phthalic acid (1.9 g, 6.7 mmol), alpha-amino-glutarimide hydrochloride (1.2 g, 7.0 mmol) in pyridine was refluxed overnight. The mixture was evaporated and the residue was purified by flash column chromatography (methanol/methylene chloride) to give 4-(3-fluoro-benzyloxy)-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione as a white solid (2.3 g, 89% yield); HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 60/40 CH3CN/0.1% H3PO4, 2.22 min (99.9%); mp, 241-243° C.; 1H NMR (DMSO-d6) δ 2.01-2.08 (m, 1H, CHH), 2.55-2.62 (m, 2H, CH2), 2.83-2.95 (m, 1H, CHH), 5.11 (dd, J=6, 12 Hz, 1H, CH), 5.40 (s, 2H, CH2), 7.15-7.87 (m, 7H, Ar), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.77, 69.11, 113.61, 113.90, 114.52, 114.80, 115.71, 116.70, 120.13, 122.96, 122.99, 130.49, 130.60, 133.25, 137.05, 139.08, 139.18, 155.21, 160.59, 163.81, 165.33, 166.74, 169.89, 172.73. Anal Calcd For C20H15N2O5F: C, 62.83; H, 3.95; N, 7.33; F 4.97. Found: C, 62.72; H, 3.75; N, 7.27; F, 5.02.
Reaction SMILES: [N:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[CH:12]=[C:13]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:26]=3[N:27]=2)[CH:14]=[C:15]([F:17])[CH:16]=1>N1C=CC=CC=1>[F:17][C:15]1[CH:14]=[C:13]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]=[CH:23][N:24]=[C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[C:26]=3[N:27]=2)[CH:12]=[C:11]([NH:10][S:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:8])=[O:7])[CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncnc2ccc(-c3cc(N)cc(F)c3)nc12
Reactant: O=S(=O)(Cl)N1CCCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1ncnc2ccc(-c3cc(F)cc(NS(=O)(=O)N4CCCC4)c3)nc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
Pyrrolidine-1-sulfonyl chloride (CAS 1689-02-7) (56 mg, 0.92 mmol) was added to a solution of tert-butyl 6-(3-amino-5-fluorophenyl)pyrido[3,2-d]pyrimidin-4-ylcarbamate (33-A) (300 mg, 0.84 mmol) in pyridine at ice bath. After the reaction mixture was stirred at 60° C. for 4 h, it was partitioned between water and EtOAc and purified by prep-TLC (PE:EtOAc=2:1) to give title product (250 mg, 61%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26][C:27]([C:30](O)([CH3:32])[CH3:31])([CH3:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>C1C=CC=CC=1.CCCCCC>[CH3:31][C:30]1([CH3:32])[C:27]([CH3:29])([CH3:28])[O:26][CH:17]([C:16]2[CH:19]=[CH:20][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:14]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:15]=2)[O:18]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=Cc1ccc(OCCCCCc2ccccc2)c(-c2cccs2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(C)OC(c2ccc(OCCCCCc3ccccc3)c(-c3cccs3)c2)OC1(C)C
Temperature: 25 °C
Yield: 808.4 %

Procedure:
Step-1: In a 500 mL 3-necked flask equipped with a stir-bar and condenser was placed 4-((5-phenylpentyl)oxy)-3-(thiophen-2-yl)benzaldehyde (Intermediate 7) (4.9 g, 1.4 mmol), pinacol (6.6 g, 5.6 mol) and p-toluenesulfonic acid (0.8 g, 4.2 mmol) in benzene (125 mL). The resulting mixture was refluxed for 1 h. TLC analysis (EtOAc: hexane; 1:1) showed the reaction was complete. The reaction was cooled to room temperature, washed with saturated NaHCO3 (2×75 mL), brine (1×75 mL), filtered through 1PS filter paper and concentrated under reduced pressure to give a brown oil. The oil was flash chromatographed over silica gel (100 g) with anhydrous sodium sulfate (20 g) on top packed with hexane. The column was eluted with 12×50 mL of 15% EtOAc in hexane. The product was eluted to give 5.1 g (81%) 4,4,5,5-tetramethyl-2-(4-((5-phenylpentyl)oxy)-3-(thiophen-2-yl)phenyl)-1,3-dioxolane (Intermediate 8) as a yellow oil. HPLC analysis showed a purity of ˜97%. NMR (CDCl3) δ 7.8 (s, 1H), 7.55 (d, 1H), 7.1-7.4 (m, 8H), 6.95 (d, 1H), 6.0 (s, 1H), 4.1 (t, 2H), 2.7 (t, 2H), 1.95 (m, 2H), 1.7 (m, 2H), 1.6 (m, 2H), 1.35 (d, 12H).