Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])CC)C.O[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:31])=[CH:26][CH:25]=1.C[CH:39]([O:41]C(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1.[OH-].[Na+]>>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:22][CH2:21][CH2:20][O:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][CH:5]([O:41][CH3:39])[C:4]([OH:3])=[O:18])=[C:10]([O:16][CH3:17])[CH:11]=2)=[CH:25][CH:26]=1)(=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCCO)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: CCOC(=O)C(CC)Cc1ccc(O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc(OCCCOc2ccc(C(=O)c3ccccc3)cc2)ccc1CC(OC)C(=O)O

Procedure:
A mixture solution of 2-(4-Hydroxy-2-methoxy-benzyl)-butyric acid ethyl ester from Example 188, Step C and [4-(3-Hydroxy-propoxy)-phenyl]-phenyl-methanone were allowed to react under the Standard Mitsounobu coupling conditions B (DIAD/toluene) to give the corresponding coupled product which by the Standard hydrolysis procedure C (NaOH) yield the title compound. MS (ES) for C27H28O7 [M+H]+: 465.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([F:23])([CH:10]([O:15][Si](CC)(CC)CC)[C:11]([F:14])([F:13])[F:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[C:1]([N:4]1[CH2:5][CH2:6][C:7]([F:23])([CH:10]([OH:15])[C:11]([F:13])([F:12])[F:14])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C(F)(F)F)C1(F)CCN(C(C)=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(F)(C(O)C(F)(F)F)CC1

Procedure:
By use of 1-acetyl-4-fluoro-4-[2,2,2-trifluoro-1-(triethylsiloxy)-ethyl]piperidine (294 mg, 0.822 mmol) dissolved in tetrahydrofuran (5 mL) and a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (1.23 mL, 1.23 mmol), the mixture was stirred and reacted at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with ethyl acetate was performed, followed by drying over anhydrous sodium sulfate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:24][C:25](=[O:37])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([C:35]#[N:36])([CH3:34])[CH3:33])[CH:27]=3)[CH:19]=[CH:20][C:21]=1[C:22]#[N:23])[N:9]=2)=[O:4].C(N(CC)CC)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>O1CCCC1.C(OCC)(=O)C>[C:35]([C:32]([C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:24][C:18]1[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[C:16]([O:15][C:10]2[N:9]=[C:8]3[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)=[N:14][C:13]3=[CH:12][CH:11]=2)[CH:17]=1)=[O:37])([CH3:34])[CH3:33])#[N:36]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(NC(=O)CCl)sc4n3)c2)c1
Reactant: CN1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)ccc4C#N)nc3s2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
N-[3-({2-[(Chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-cyanophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (136 μL, 0.99 mmol) and 1-methylpiperazine (109 μL, 0.99 mmol) were added, and the mixture was stirred at 60° C. for 8 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether/hexane to give the title compound (93 mg, 47%) as a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[N:8]([CH2:33][CH2:34][CH3:35])[C:9](=[O:32])[C:10]2[NH:11][C:12]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)=[N:13][C:14]=2[N:15]=1)C.[Li+].[OH-]>C1COCC1.CO.O>[O:32]=[C:9]1[N:8]([CH2:33][CH2:34][CH3:35])[C:7]([O:6][CH2:5][C:4]([OH:36])=[O:3])=[N:15][C:14]2[N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[CH:20]=3)[NH:11][C:10]1=2
Reactant: CCCn1c(OCC(=O)OCC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1c(OCC(=O)O)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O

Procedure:
A mixture of {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-acetic acid ethyl ester (56 mg, 0.11 mmol), LiOH:6H2O (14 mg, 0.33 mmol) and THF:MeOH:Water (3:2:1) (1 ml) were stirred for 3 hours at ambient temperature. Organic volatiles were evaporated and the residue was acidified with 1N HCl to obtain {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-yloxy}-acetic acid as an off white solid (20 mg, 38%)
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27](O)[CH:26]=C(O)[N:24]=2)=[CH:19][CH:18]=1.[CH2:31]([Cl:33])Cl>>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[C:27]([Cl:3])[CH:26]=[C:31]([Cl:33])[N:24]=2)=[CH:19][CH:18]=1
Reactant: ClCCl
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2nc(O)cc(O)n2)cc1
Solvent: CN(C)c1ccccc1
Product: COc1ccc(-c2nc(Cl)cc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
126 ml of phosphoroxy chloride (POCl3) and then 57 ml of N,N-dimethyl aniline are added dropwise over 30 minutes to 54.5 g of 2-p-methoxyphenyl-4,6-dihydroxypyrimidine with cooling, such that the temperature does not exceed 45° C. The reaction mixture is then stirred for 2 hours at room temperature and subsequently refluxed for 2 hours. The reaction mixture is then concentrated by rotary evaporation and the residue is triturated in 2 liters of iced water. The solid product is isolated by filtration, dissolved in 1.5 liters of methylene chloride and the solution is treated with fuller's earth and dried. The methylene chloride solution is filtered and concentrated. The residue is recrystallised from ethanol, affording 51 g of crystalline 2p-methoxyphenyl-4,6-dichloropyrimidine with a melting point of 127°-128° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>O1CCCC1.C(OCC)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: OCCCCCCCCCCCc1ccc(O)cc1
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)c1ccccc1
Solvent: CCOCC
Product: C=CC(=O)OCCCCCCCCCCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53 %

Procedure:
2.5 ml of acryloylchloride was added to a solution of 7.4 g of 4-(11-hydroxyundecyl)-phenol (D) and 3.9 ml of N,N-dimethylaniline in 60 ml of tetrahydrofuran, cooled in an ice bath. After stirring for three hours at room temperature, the solution was diluted with 60 ml of diethyl ether and extracted subsequently with 100 ml of water, 100 ml of 2.4 N HCl and 100 ml of a saturated NaCl solution. 4.74 g of 4-(11-acryloyloxyundecyl)phenol (G, 53%) was obtained as a brown powder after drying over magnesium sulphate, evaporating and washing with ligroin.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9](Br)[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]2.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[C:24]1([C:2]2[CH:10]=[C:9]([C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=3)[CH:8]=[C:7]3[C:3]=2[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:6]3)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)cc(Br)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)cc(-c3ccccc3)c12
Temperature: 25 °C

Procedure:
Ethyl 4,6-dibromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (0.244 g, 0.5 mmol), phenylboronic acid (0.147 g, 1.2 mmol, 2.4 equiv.) and potassium phosphate trihydrate (0.400 g, 1.5 mmol, 3.0 equiv.) were mixed together in a 10 ml microwave vial. The vial was purged with Argon and trans-dichlorobis(triphenylphosphine)-palladium (II) (0.021, 0.03 mmol, 6 mol %) and 5 ml of dry dioxane were added to the mixture. The microwave vial was capped and irradiated at 100 watt, 150° C., under pressure up to 10 bars. Then it was allowed to cool down to rt, and toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 20% of ethyl acetate/cyclohexane as eluent to yield a light-beige-colored solid in 60-70%. 1H-NMR (DMSO-d6) δ 1.09, 1.32 (each t, 3H, 3J=7.1 Hz, CH3); 2.11 (m, 2H, 2′-H); 2.84 (m, 2H, 1′-H); 3.89, 4.33 (each q, 2H, 4J=7.1 Hz, CH2); 7.12 (d, 1H, 2J=1.6 Hz, 7-H); 7.35 (t, 1H, 3J=7.4 Hz, Ph-ring); 7.43 (m, 7H, Ph-ring); 7.67 (d, 1H, 2J=0.9 Hz, 5-H); 7.68 (d, 1H, 2J=1.6 Hz, Phenyl-ring); 11.84 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 14.2, 14.3 (2CH3, each C═OOCH2CH3); 20.5 (C-2′); 34.8 (C-1′); 59.5, 60.5 (2CH2, each C═OOCH2CH3); 109.6 (C-5); 121.1 (C-7); 121.8 (C-3); 123.6 (C-2); 124.7 (C-3a); 127.0 (C-2″, C-6″); 127.4 (C-4″′); 127.5 (C-4″); 128.0 (C-3″′, C-5″′); 129.0 (C-3″, C-5″); 129.1 (C-2″′, C-6″′); 136.7 (C-7a); 137.4 (C-4), 137.6 (C-6); 140.7 (C-1″); 140.8 (C-1″′); 161.5 (2′-CO2Et); 171.7 (2-CO2Et). LC-MS (m/z): 442 [M]+, 440 [M]−. Purity (LC-MS): 96%.
Reaction SMILES: [CH2:1]([O-:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Li+].C(O)CCCCCCC.C([Li])CCC.Br[C:26]1[C:31]([F:32])=[CH:30][C:29]([Br:33])=[CH:28][N:27]=1>CCCCCC.O1CCCC1>[Br:33][C:29]1[CH:30]=[C:31]([F:32])[C:26]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:27][CH:28]=1
Reactant: CCCCCCCC[O-]
Reactant: Fc1cc(Br)cnc1Br
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCCCCCCCO
Product: CCCCCCCCOc1ncc(Br)cc1F

Procedure:
Lithium octanolate (prepared in advance from 13.02 g (100.00 mmol) of 1-octanol and 69 ml (110.00 mmol) of a 1.6 molar n-butyllithium solution in n-hexane at 0° C. in 40 ml of tetrahydrofuran) and 25.49 g (100.00 mmol) of 2,5-dibromo-3-fluoropyridine are refluxed for 7 hours in 40 ml of tetrahydrofuran. The mixture is subsequently partitioned between aqueous sodium chloride solution and ether, and the ether phase is washed twice with aqueous sodium chloride solution, dried over sodium sulfate, filtered and freed from solvent. Chromatographic purification (silica gel/hexane: ethyl acetate 9:1) gives 18.19 g (59.80 mmol) of 5-bromo-3-fluoro-2-octyloxypyridine. ##STR23##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:13]([C:12]1[CH:21]=[CH:22][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:23](=[O:25])[CH3:24])=[CH:10][CH:11]=1)(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(2-Aminophenylamino)benzophenone (Compound 101, 0.58 g, 2 mmol) was dissolved in acetic anhydride (10 ml) and the solution was stirred at room temperature for 3 hours. The precipitate that forms after 75 min was filtered off and washed with water to afford the title compound.
Reaction SMILES: Br[C:2]1[N:3]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH:32]3CC3)=[CH:24][CH:23]=2)[C:4]([S:7]CC(NC2C=CC(C(O)=O)=CC=2Cl)=O)=[N:5][N:6]=1.Cl.NNC(N)=N.C([N:44](C(C)C)CC)(C)C.CN(C)[CH:52]=[O:53]>>[NH2:44][C:2]1[N:3]([C:22]2[C:27]3[C:26](=[CH:31][CH:30]=[C:29]([O:53][CH3:52])[CH:28]=3)[C:25]([CH3:32])=[CH:24][CH:23]=2)[C:4]([SH:7])=[N:5][N:6]=1
Reactant: CN(C)C=O
Reactant: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)Nc1ccc(C(=O)O)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: N=C(N)NN
Product: COc1ccc2c(C)ccc(-n3c(N)nnc3S)c2c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
Compound 7 (1.0 g, 4.4 mmol) was dissolved in 10 mL of dimethylformamide, aminoguanidine hydrochloride salt (723 mg, 6.5 mmol) and diisopropyl ethylamine (1.14 mL, 6.5 mmol) were added and the mixture stirred at 50° C. for 18 hours. The mixture was then concentrated and to the resulting residue was added 2M aqueous sodium hydroxide solution (10 mL). The mixture was stirred at 50° C. for 18 hours and then cooled to room temperature. The resulting mixture was then neutralized with aqueous 1N HCl and the precipitate (product) collected to give 5-amino-4-(7-methoxy-4-methylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol (8). (1.14 mg, 91% yield)
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([SH:14])[CH2:9]1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>CN(C=O)C.O>[CH3:7][C:8]1([CH3:15])[CH2:13][CH2:12][CH2:11][CH:10]([S:14][C:17]2[N:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)[CH2:9]1
Reactant: CC1(C)CCCC(S)C1
Reactant: N#Cc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CCCC(Sc2ccc(C#N)cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Add potassium tert-butoxide (777 mg, 6.94 mmol) to a solution of 3,3-dimethylcyclohexanethiol (1 g, 6.94 mmol) in DMF (10 mL) and stir at room temperature for 10 min. Add 6-chloro-nicotinonitrile (547 mg, 3.96 mmol) and warm the solution to 60° C. for 18 h. Cool the mixture, dilute with water (100 mL) and extract with EtOAc (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil that solidifies on standing to a white solid (0.37 g, 38%).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27](O)=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:37]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-].C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:1]([NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([N:17]2[C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([C:27]([NH2:37])=[O:28])[C:21]=3[C:20]3=[N:30][O:31][C:32]([CH3:33])=[C:19]3[C:18]2=[O:34])[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(=O)O)c21
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cccc(C(N)=O)c21
Reaction time: 8 h
Yield: 47.6 %

Procedure:
To a solution of Example 598, (0.05 g, 0.11 mmol), EDCI (0.032 g, 0.165 mmol), and HOBt (0.023 g, 0.165 mmol) in DMF (1.5 ml) under N2 was added NH4Cl (0.009 g, 0.165 mmol) and diisopropylamine (0.046 ml, 0.33 mmol). The reaction was stirred overnight. The mixture was diluted with EtOAc, washed (1.0 N HCl saturated with NaCl), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexanes/EtOAc gradient) gave the title compound (0.024 g, 48%). MS(ES+) (m/z) 459.1 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.ClCCl.Cl[S:38]([C:41]1[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>C(N(CC)CC)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:38]([C:41]3[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=3)(=[O:39])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (150 mg, 0.31 mmol, 1.00 equip), dichloromethane (20 mL), triethylamine (0.5 mL), and methyl 5-(chlorosulfonyl)thiophene-2-carboxylate (76 mg, 0.32 mmol, 1.00 equip). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylate as a yellow solid. LCMS (ES, m/z) 682 [M+H]+
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][CH2:21][CH2:22][O:23][C:24](=[O:27])[CH2:25]Br)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CC(O)=O.[OH-].[Na+].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][C:16]([NH:20][CH2:21][CH2:22][O:23][C:24](=[O:27])[CH2:25][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[CH:17][CH:18]=3)[CH2:13][O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=C(CBr)OCCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(CN1CCOCC1)OCCNc1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
A mixture of bromo-acetic acid 2-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-ylamino]-ethyl ester (35 mg, 0.082 mmol) in morpholine (1 ml) was stirred at room temperature for 1.5 hours. The mixture was poured into 2% AcOH aqueous solution (50 ml) with stirring. The mixture was then basified with NaOH solution. The solid was filtered, washed with water, dried under vacuum to give morpholin-4-yl-acetic acid 2-[1-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-ylamino]-ethyl ester as a yellow solid (18 mg, 51%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23](S(C)(=O)=O)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C1COCC1>[CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23]([N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCNCC2)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
The resin (A3), 0.0214 mmol) was suspended in THF (1 ml) and NEt3 (14 mg, 0.14 mmol). To this mixture was added piperazine (21 mg, 0.128 mmol) and shaking continued for 18 h. The resin was washed with THF (2×1 min), DMF (3×1 min, 60° C.) and with DCM (3×1 min) at rt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]([O:22]C)=O)[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH3:18])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:19]=1.O.[NH4+:25]>>[F:1][C:2]1[CH:3]=[C:4]([C:20]([NH2:25])=[O:22])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][NH:17][CH3:18])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:19]=1
Reactant: CNCc1ccc(-c2nc3cc(F)cc(C(=O)OC)c3o2)cc1
Reactant: [NH4+]
Solvent: O
Product: CNCc1ccc(-c2nc3cc(F)cc(C(N)=O)c3o2)cc1
Yield: 22 %

Procedure:
Methyl 5-fluoro-2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxylate (25 mg, 0.06 mmol) in ammonium water (2 mL) was stirred at 30° C. for 17 hr and the solvents were evaporated; the residue was purified by pre-HPLC to obtain 5-fluoro-2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide as a white solid (4 mg, yield 22%). 1H-NMR (400 MHz, MeOD-d4) δ 2.07 (s, 1H), 2.41 (s, 3H), 3.85 (s, 2H), 7.52-7.55 (m, 2H), 7.57-7.61 (m, 2H), 8.25-8.27 (d, J=7.6 Hz, 2H); LC-MS (ESI) m/z 300 [M+1]+.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]([CH3:11])=[C:3]1[CH3:12].[H-].[K+].[H][H].[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>O>[CH3:1][CH:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([Si:18]([CH3:20])([CH3:19])[CH3:17])[C:5]=2[C:4]([CH3:11])=[C:3]1[CH3:12]
Reactant: [H][H]
Reactant: C[Si](C)(C)Cl
Reactant: CC1=C(C)C(C)C2=C1CCCC2
Agent: [H-]
Agent: [K+]
Solvent: O
Product: CC1=C(C)C(C)C2=C1C([Si](C)(C)C)CCC2
Reaction time: 48 h

Procedure:
19.6 g of 1,2,3-trimethyl-4,5,6,7-tetrahydroindene as obtained in Example 1-(3) was dissolved in 70 mL of tetrahydrofuran anhydride. Then the resultant solution was added dropwise at room temperature to 200 mL of suspension of 7.2 g of potassium hydride in tetrahydrofuran anhydride. After the elapse of 1.5 hour, the mixed solution was gradually heated and the reaction was continued under refluxing with heating for 4 hours. When hydrogen was no longer generated, the reaction solution was restored to room temperature, incorporated with 19.6 g of trimethylsilyl chloride and stirred for two days and nights. Subsequently water was added to the reaction liquid to stabilize the excess potassium hydride, then the organic phase was separated, extraction was carried out from the water phase by the use of ethyl ether and the mixture of the extract and the aforesaid organic phase was dried with magnesium sulfate anhydride. Lastly, vacuum distillation was performed to recover 22.7 g of 1,2,3-trimethyl-4,5,6,7-tetrahydroindenyltrimethylsilane.