Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:37]2[CH:49]=[CH:48][C:40]([CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:11]1([N:8]2[C:9]3[CH:10]=[C:2]([C:37]4[CH:38]=[CH:39][C:40]([CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:48][CH:49]=4)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]4[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=4[CH3:26])=[O:17])[C:5]=3[CH:6]=[N:7]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
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: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.25 g, 0.56 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.20 g, 0.67 mmol) and Pd(PPh3)4 (0.032 g, 0.027 mmol) in 1,4-dioxane (4 mL) and purged with argon for 10 min. 2M Na2CO3 solution (0.22 g, 2.03 mmol) was then added to it before a further argon purge for 10 min. The reaction mixture was stirred at 100° C. for 3 h. After completion of the reaction, water was added and extraction carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give -cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (68.4% yield). LCMS: 540.25 (M+1)+; HPLC: 99.15% (@ 254 nm) (Rt; 5.583); 1H NMR (DMSO-d6, 400 MHz) δ 11.51 (bs, 1H), 8.62 (t, 1H, J=4.8 Hz), 8.36 (s, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.80 (d, 2H, J=8 Hz), 7.43 (d, 2H, J=8 Hz), 5.88 (s, 1H), 5.34-5.31 (m, 1H), 4.38 (d, 2H, J=4.8 Hz), 3.59-3.58 (m, 4H), 3.52 (s, 2H), 2.38 (m, 4H), 2.21 (s, 3H), 2.11 (s, 3H), 2.04-1.99 (m, 2H), 1.88 (m, 4H), 1.72-1.69 (m, 2H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:28])[C:21](=[CH:26][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23])(=[O:16])[CH3:15]>C(OCC)(=O)C>[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:28])[C:21](=[CH:26][C:27]=1[Br:1])[C:22]([O:24][CH3:25])=[O:23])(=[O:16])[CH3:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(NC(C)=O)cc1O
Temperature: 72.5 °C
Yield: 44.4 %

Procedure:
N-Bromosuccinimide (0.94 g, 5.3 mmol) was added to an N,N-dimethylformamide (8 ml) solution of methyl 4-acetylaminosalicylate (I-248) (1.1 g, 5.0 mmol), followed by stirring with heating under reflux at 70 to 75° C. for 2 hours and a half. After cooling to room temperature, ethyl acetate was added, followed by washing twice with saturated brine and drying over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with chloroform/methanol (100:1) gave the entitled compound (0.64 g, 45%) as a pale red solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:42][C:18]3=[N:19][C:20]([CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[CH:22]=[C:17]3[C:16]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:11][CH:10]=1>ClC(Cl)C>[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:42][C:18]3=[N:19][C:20]([CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[C:21]([C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[CH:22]=[C:17]3[C:16]=2[C:43](=[O:46])[NH:44][CH3:45])=[CH:11][CH:10]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(CCC(F)(F)F)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(CCC(F)(F)F)c(-c3cccc(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
TFA (2.24 ml, 29.0 mmol) was added to a stirring solution of tert-butyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoate (315 mg, 0.581 mmol) in dichloroethane (5.81 ml) at rt. The reaction was allowed to stir for 1 h at rt and then was concentrated to dryness azeotroping with toluene to give the expected product 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridin-5-yl)benzoic acid (189 mg, 0.389 mmol, 67% yield) consistent by LCMS and NMR. LC-MS retention time: 2.89 min; m/z (MH+): 487. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 3u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. 1H NMR (400 MHz, DMSO-d6) δ 13.16 (br. s, 1H), 8.55-8.47 (m, 1H), 8.10-8.02 (m, 3H), 8.00-7.96 (m, 2H), 7.74 (d, J=7.8 Hz, 1H), 7.69-7.62 (m, 1H), 7.42 (t, J=8.9 Hz, 2H), 3.05-2.96 (m, 2H), 2.85-2.70 (m, 5H).
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[S:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>CCCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:3])[C:13]2[CH:14]=[CH:15][S:11][C:12]=2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4]1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: c1ccsc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2sccc21
Temperature: 40 °C

Procedure:
90 g of 2,5-dimethyl-2,5-dichlorohexane and 195 ml of thiophene are dissolved in 400 ml of hexane. 54 ml of titanium tetrachloride are slowly added dropwise thereto while cooling with ice, the mixture is warmed to 40° C. for 1.5 hours, again cooled with ice and the dark red mixture is treated cautiously with ice-water. The mixture is extracted three times with ether, the organic phase is washed with saturated sodium bicarbonate solution, dried and evaporated. The thus-obtained black oil is firstly filtered over silica gel (eluting agent hexane) and subsequently distilled in a water-jet vacuum. There are obtained 18.5 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethylbenzo[b]thiophene as a colorless liquid, b.p. 95°-96° C./10 mm.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:18][NH2:19])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.C[Si](C)(C)Cl.[S:34](Cl)(=[O:37])(=[O:36])[NH2:35].Cl>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([SH:17])[CH2:14][C@H:13]2[CH2:18][NH:19][S:34](=[O:37])(=[O:36])[NH2:35])=[O:11])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: NS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)NC[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of crude (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-aminomethyl-4-mercaptopyrrolidine (3.3 g: 10.18 mmole) in dichloromethane (100 ml) at -78° C., triethylamine (2.84 ml: 2.2 eq.) and trimethylchlorosilane (3.12 ml: 2.2 eq.) are dropwise added. After stirring for 20 minutes, triethylamine (4.25 ml: 3 eq.) and 1M-sulfamoyl chloride in dichloromethane (25 ml: 2.5 eq.) are dropwise added to the mixture. After 20 minutes stirring, the reaction mixture is acidified with hydrochloric acid, warmed to room temperature, and extracted with dichloromethane. The extract is washed with water, and 1N-hydrochloric acid (10 ml) and methanol (30 ml) are added thereto. The solution is stirred at room temperature for 30 minutes. The reaction mixture is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-sulfamoylaminomethyl-4-mercaptopyrrolidine (2.65 g). Yield: 66.7%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH:10][C:4](=[O:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=O)Cl
Reactant: Cc1cccc(C)c1N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COCC(=O)Nc1c(C)cccc1C
Yield: 56.9 %

Procedure:
55 g (0.5 mol) of methoxyacetyl chloride were added dropwise to a solution of 61 g (0.5 mol) of 2,6-dimethylaniline and 50.5 g (0.5 mol) of triethylamine in 250 ml of toluene at 5° to 15° C., while stirring and cooling. The mixture was subsequently stirred at 20° C. for 2 hours, filtered and concentrated and the residue was taken up in water. The aqueous mixture was extracted with methylene chloride and the extract was dried over sodium sulphate and concentrated by distilling off the solvent. The residue was distilled under a high vacuum. 55 g (57% of theory) of 2,6-dimethyl-N-methoxyacetyl-aniline of boiling point 122°-132° C./0.1 mm Hg and of melting point 61°-63° C. were obtained. ##STR177##
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7](=[O:17])[N:6]([CH3:18])[CH2:5]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:18][N:6]1[CH2:5][CH:4]([CH2:3][CH2:2][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:9]2=[N:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]2[C:7]1=[O:17]
Reactant: CN1CC(CCCl)c2nc3ccccc3n2C1=O
Reactant: C1COCCN1
Product: CN1CC(CCN2CCOCC2)c2nc3ccccc3n2C1=O
Temperature: 60 °C

Procedure:
To 20 mL of morpholine was added 3.5 g (0.0133 mol) of 4-(2-chloroethyl)-3,4-dihydro-2-methylpyrimido[1,6-a]benzimidazol-1(2H)-one. The reaction mixture was heated in 60° C. for 24 hrs. The excess morpholine was removed by rotary evaporation and finally by high vacuum (0.5 mm Hg ~60° C.). The residue was dissolved in ~100 mL of CH2Cl2 washed with 3×50 ml of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was crystallized from isopropyl ether to give 2.7 g (65%) of analytically pure crystals, mp 111°-12° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][N:16]=2)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])[CH3:4]>CO.C(Cl)(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)[C:28]=3[CH3:29])=[O:23])=[CH:17][N:16]=2)[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1(c2ccc(NC(=O)c3cnn(-c4ccc(C)cc4)c3C)cn2)CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1(c2ccc(NC(=O)c3cnn(-c4ccc(C)cc4)c3C)cn2)CCC(O)CC1
Reaction time: 4 h
Yield: 70.7 %

Procedure:
Sodium borohydride (131 mg) was added at −78° C. to a solution of 1-[5({[5-methyl-1-(4-methylphenyl)-1H-pyrazol-4-yl]carbonyl}amino)pyridin-2-yl]-4-oxocyclohexanecarboxylic acid ethyl ester (400 mg) in methanol (6.0 ml) and chloroform (3.0 ml) and stirred at the same temperature for four hours. After the reaction, a saturated aqueous solution of ammonium chloride, the solvent was evaporated and extracted with chloroform three times. The organic solution was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was recrystallized (n-hexane/ethanol) to give the titled compound (284 mg) as a white solid. MS (ESI) m/z: 463 (M+H)+.
Reaction SMILES: C1(S([C:10](=[CH:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=2)[C:11]([NH:13][CH3:14])=[O:12])(=O)=O)C=CC=CC=1.[N-:31]=[N+:32]=[N-:33]>>[CH3:30][C:27]([C:18]1[CH:17]=[C:16]([C:15]2[NH:31][N:32]=[N:33][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[CH:21]=[C:20]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:19]=1[OH:26])([CH3:28])[CH3:29]
Reactant: CNC(=O)C(=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)S(=O)(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Product: CNC(=O)c1nn[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
reacting the product of step b) with a metal azide to yield 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-3H-[1,2,3]triazole-5-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([CH2:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:18]1([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:6]
Reactant: NCC1(c2cccnc2)CCCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC1(c2cccnc2)CCCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and C-(1-pyridin-3-yl-cyclopentyl)-methylamine. LCMS (MH+): m/z=348.9, tR (minutes, Method A)=1.16
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:22][CH3:23])[N:13]2C2CCCCO2)=[C:9]([NH2:24])[N:8]=1)[CH3:2].[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[NH:8][C:9]([NH2:24])=[C:10]2[C:14]([N:15]=1)=[N:13][C:12]([O:22][CH3:23])=[N:11]2)[CH3:2]
Reactant: CCOCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCOCCOc1nc2nc(OC)nc-2c(N)[nH]1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2-{[2-(Ethyloxy)ethyl]oxy}-8-(methyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (4.78 g, 14.2 mmol) was dissolved in MeOH (30 ml) and TFA (7.5 ml) was added with stirring at 0° C. The mixture was left standing at room temperature for 1 day. A white solid was formed. The solid was filtered off and washed with ethyl acetate and dried in vacuo. This gave product (4 g, 80.5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C1CCCCC1.[CH2:25]([O:32][C:33]1[C:34]([CH2:44][CH:45]=[O:46])=[CH:35][C:36]([Cl:43])=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([O:32][C:33]1[C:34]([CH2:44][CH:45]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[S:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[CH:3]=2)[OH:46])=[CH:35][C:36]([Cl:43])=[C:37]2[C:42]=1[N:41]=[CH:40][CH:39]=[CH:38]2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(-c2cccc(Br)c2)s1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(C(O)Cc3cc(Cl)c4cccnc4c3OCc3ccccc3)c2)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a stirring solution of 2-(3-bromo-phenyl)-5-methyl-thiophene (0.395 mmol) in tetrahydrofuran (4 mL) at −78° C. was slowly added a 2M solution of n-butyllithium in cyclohexane (0.435 mmol, 1.1 eq.). The resulting solution was stirred 30 min at −78° C. and solid [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (0.395 mmol) was added. Stirring at −78° C. was continued for 10 min and the reaction was allowed to warm to room temperature and was stirred 1 h. The reaction mixture was then quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give a yellow oil that was purified by column chromatography using 20% ethyl acetate/hexanes to give the final product as a light yellow solid (0.18 mmol, 46%). MS (ESI) m/z 486.4.
Reaction SMILES: [F:1][C:2]1[C:3]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45].O>CN(C)C=O>[F:1][C:2]1[C:3]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])=[CH:4][C:5]([S:9]([N:12]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[C:6]([O:8][CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(N2C(=O)c3ccccc3C2=O)cc1S(=O)(=O)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 5-fluoro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)phenol (0.46 g) and cesium carbonate (0.48 g) in N,N-dimethylformamide (5 mL) was added 1-bromo-2-(tert-butyl-dimethylsilyloxy)ethane (0.25 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane n-hexane/ethyl acetate=1/1) to give 5-fluoro-2-(2,3,4,5-tetrahydro-1H-1-benzoazepin-1-yl-sulfonyl)-4-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-1-[2-(tert-butyldimethylsilyloxy)ethoxy]-benzene (66 mg). This material was dissolved in tetrahydrofuran (3 mL). To the solution was added hydrazine monohydrate (0.026 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was cooled to room temperature, and diluted with ethyl acetate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (52 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][CH2:45][O:46][CH2:47][CH3:48]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[C:18](=[O:36])[N:17]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOCCBr
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CCOCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4-[7-(2-Butynyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg) and potassium carbonate (15 mg) were dissolved in N,N-dimethylformamide (1.2 ml), and 2-bromoethylethyl ether (12 μl) was added to the solution. The mixture was stirred at 60° C. for 2 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the organic layer was concentrated by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (2:1). The obtained 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. A quarter of the obtained 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 3.2 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:20])[CH3:19])[C:12]([O:14]CC)=[O:13])=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([O:17][CH:18]([CH3:19])[CH3:20])[C:12]([OH:14])=[O:13])=[CH:8][CH:9]=2)=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOC(=O)C(Cc1ccc(CCO)cc1)OC(C)C
Product: CC(C)OC(Cc1ccc(CCOC(=O)Nc2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
Using ethyl 3-[4-(2-hydroxyethyl)phenyl]-2-isopropoxypropanoate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([NH:25][C:26]([NH:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:16])[CH:14]=[CH:13][N:12]=1)=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1ccccc1CCc1ccnc(N)c1
Solvent: ClCCl
Product: Cc1ccccc1CCc1ccnc(NC(=O)NC(=O)c2ccccc2)c1
Temperature: 65 °C

Procedure:
4-(2-o-Tolyl-ethyl)-pyridin-2-ylamine (100 mg, 0.47 mmol) is dissolved in methylene chloride (3 mL). Then benzoyl isocynate (100 mg, 0.71 mmol) is added. The resulting mixture is sealed and heated at 65° C. for 1 hour. The solvent is then removed to give 225 mg of crude which is used in the next step without purification.