Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].C1N=C[N:36](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:33])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH3:32])[CH:21]=1)[CH2:16][C:17]([NH2:36])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC(F)F
Yield: 78.8 %

Procedure:
3-(4-Acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide was prepared by the procedure of Example 6 from 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.5 g, 1.1 mmol), CDI (0.19 g, 1.2 mmol) and NH4OH (0.1 ml, 1.2 mmol) in THF (30 ml) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionamide as white solid (0.40 g, 80%): mp 178-180° C.; 1HNMR (CDCl3): δ1.44 (t, J=7.0 Hz, 3H, OCH2CH3), 2.26 (s, 3H, CH3CO), 3.03 (dd, J=5, 15 Hz, 1H, CH2), 3.70 (dd, J=10, 15 Hz, 1H, CH2), 4.09 (q, J=7.0 Hz, 2H, OCH2CH3), 5.38 (broad, 1H, NH2), 5.61 (broad, 1H, NH2), 5.76-5.83 (m, 1H, CHN), 6.83 (t, JH-F=75 Hz, 1H, CF2H), 7.06-7.14 (m, 3H, Ar), 7.46 (d, J=7.5 Hz, 1H, Ar), 7.65 (t, J=7.5 Hz, 1H, Ar), 7.74 (d, J=7.5 Hz, 1H, Ar), 9.45 (s, 1H, NHCO). 13CNMR (DMSO-d6): 14.4, 24.2, 36.7, 50.0, 64.2, 93.9, 112.5, 113.2, 116.7, 116.7, 118.0, 119.4, 121.2, 125.9, 131.4, 135.8, 136.4, 137.6, 139.0, 149.7, 167.2, 168.2, 169.2, 171.0; Anal Calcd for C22H21F2N3O6: C, 57.27; H, 4.59; N, 9.11. Found: C, 57.04; H, 4.41; N, 8.93.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([OH:16])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[OH-].[K+].C1(C)C=CC=CC=1>O>[CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:15]([O:16][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH2:14][CH2:13][CH2:12][O:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CCCO[C@H]1COCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCO[C@H]1CCCO[C@H]1COCc1ccccc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
A mixture of 1.037 g of dl-cis-2-benzyloxymethyltetrahydropyran-3-ol (prepared as described in Preparation 33), 1.709 g of hexadecyl bromide, 0.77 g of potassium hydroxide and 15 ml of toluene was heated, with stirring, at 120° C. for 10 hours. At the end of this time, the reaction mixture was cooled and then poured into water. The aqueous layer was extracted twice with diethyl ether. The organic layer and the extracts were combined, washed with water, dried over anhydrous magnesium sulfate and condensed by evaporation under reduced pressure. The resulting oily residue (3.3 g) was subjected to column chromatography through 50 g of silica gel. The fraction eluted with a 1:10 by volume mixture of diethyl ether and hexane gave 1.455 g of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([CH3:21])[CH:13]=1>CN(C=O)C.O>[CH3:21][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19])[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: Nc1cc(O)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccnc(N)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution of 2-aminopyridin-4-ol (355 mg, 3.22 mmol) in DMF (4.0 mL) at 0° C. under nitrogen was added portionwise sodium hydride (60% dispersion in mineral oil, 193 mg, 4.83 mmol) and the reaction mixture warmed to RT for 2 hr, The mixture cooled to 0° C. and a solution of 4-fluoro-2-methyl-1-nitrobenzene (500 mg, 3.22 mmol) in DMF (2.0 mL) was added, dropwise and the reaction mixture warmed to RT for 16 hr. The resulting mixture was diluted with water (20 mL) and was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (20 mL), then dried (MgSO4) and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, 25% EtOAc in DCM, isocratic elution) to afford 4-(3-methyl-4-nitrophenoxy)pyridin-2-amine as a yellow solid (351 mg, 44%); Rt 1.20 min (Method 2); m/z 246 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.N1C=CC=CC=1.[Br:16]Br>C(Cl)Cl>[Br:16][C:7]1[CH:8]=[C:2]([Cl:1])[CH:3]=[C:4]([CH3:9])[C:5]=1[NH2:6]
Reactant: BrBr
Reactant: Cc1cc(Cl)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Cl)cc(Br)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
2.83 g (20 mmol) of 4-chloro-2-methyl aniline and 1.74 g (22 mmol) of pyridine were dissolved in 20 ml DCM. 3.20 g (20 mmol) of bromine were added dropwise under cooling. The reaction mixture was stirred for 2 h at rt. The solvent was removed and the residue was dissolved in diethyl ether. The organic layer was washed with water, dried over sodium sulfate, filtered and the solvent was evaporated. The crude product was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 3.91 g (89%) of 2-bromo-4-chloro-6-methyl aniline as a light green solid. 1H NMR (CDCl3, 300 MHz): δ 7.30 (s, 1H), 6.99 (s, 1H), 4.04 (br s, 2H), 2.19 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[C:16]([CH:17]2[CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:20])(=O)C.O>CO>[Cl:20][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]2[CH2:18][CH2:19]2)[C:11]=1[OH:10]
Reactant: CC(=O)Oc1c(Cl)cccc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1c(Cl)cccc1C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
Potassium carbonate (21.3 g, 154 mmol) was added to a solution of 2-chloro-6-cyclopropylphenyl acetate (16.3 g, 77 mmol) in methanol (80 ml) at once and the mixture was stirred at room temperature for 90 minutes. After water (240 ml) was added to the reaction mixture, the resulting mixture was concentrated by an evaporator to remove most of methanol. The obtained mixture was cooled to 0° C. and 4M hydrochloric acid was added thereto to make pH to 2 or lower such that the temperature of the mixture did not exceed 25° C. This was extracted with a 10% ethyl acetate-90% hexane (V/V) solvent mixture. The organic layer was combined and washed with a saturated aqueous NaCl solution, followed by drying with anhydrous sodium sulfate (90 g). After the solid was removed by filtration, the filtrate was concentrated to obtain a pale brown oil. This oil was purified by silica gel column chromatography (use of 120 g of Wakogel C-100E) to obtain 10.1 g of 2-chloro-6-cyclopropylphenol.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]4[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=4[CH3:20])[C:5]=3[C:4]=2[CH:3]=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][C:27]=1[O:41][CH3:42]>>[OH:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:24])[C:13](=[O:23])[N:14]([C:15]5[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=5[CH3:20])[C:5]=4[C:4]=3[CH:3]=2)=[CH:28][C:27]=1[O:41][CH3:42]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: Cc1nn(C)c(C)c1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1cc(-c2ccc3ncc4c(c3c2)n(-c2c(C)nn(C)c2C)c(=O)n4C)ccc1O

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-3-methyl-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate H, 39 mg, 0.100 mmol) and 4-hydroxy-3-methoxyphenylboronic acid pinacol ester (Aldrich, Buchs, Switzerland, 30 mg, 0.120 mmol) to give the title compound as a lightly yellow foam. (HPLC: tR 2.50 min (Method A); M+H=430 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.23 (s, 1H), 8.93 (s, 1H), 8.06-7.99 (m, 1H), 7.92-7.85 (m, 1H), 7.51-7.46 (m, 1H), 7.03-6.96 (m, 1H), 6.94-6.89 (m, 1H), 6.87-6.81 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.58 (s, 3H), 2.08 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([Cl:28])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
3,4-dibenzyloxybenzoic acid (3.1 g. 9.3 mmol) was combined with pyridine (5 drops, catalytic) and thionyl chloride (15 ml, 205 mmol). The solution was heated at reflux for 4 h, cooled, and excess thionyl chloride removed under reduced pressure. The crude product was dissolved in benzene (50 ml), and stripped of solvent under vacuum. The benzoyl chloride (theoretical yield 3.4 g) was then dissolved in dichloromethane and used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:10]([CH3:11])[O:9][C@@H:6]([O:7]C)[CH2:5][C@H:4]1[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15].O>C(O)(=O)C>[CH3:1][O:2][C@H:3]1[C@H:10]([CH3:11])[O:9][C@@H:6]([OH:7])[CH2:5][C@H:4]1[NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15]
Reactant: CO[C@H]1C[C@@H](NC(=O)C(F)(F)F)[C@@H](OC)[C@H](C)O1
Solvent: O
Solvent: CC(=O)O
Product: CO[C@H]1[C@H](C)O[C@@H](O)C[C@H]1NC(=O)C(F)(F)F
Temperature: 100 °C
Yield: 98.1 %

Procedure:
To a solution of 1.76 g; 6.5 mmol of compound VI in 35 ml of acetic acid there were added 140 ml of water. The solution was then heated at 100° C. for 1 hour. The solvent was then evaporated off and the residue was recrystallized from carbon tetrachloride to give 1.64 g (yield 98%) of 4-O-methyl-2,3,6-trideoxy-3-trifluoroacetamido-α-L-ribohexopyranose (VII); m.p. 113°-115° C.; [α]D23° =-61.5° (c=0.5 in CHCl3); mass spectrum; m/e 257 (M+). The p.m.r. spectrum showed absoption at: 1.27 (d, CH3 --C--5), 2.96 (dd, J=9.5 and 4.0 Hz, C--4--H), 3.44 (s, CH3O), 4.00 (dq, J=6.5 and 9.5 Hz, C--5--H), 4,69 (m, C--3--H) and 5.32 (broad s, WH =6.0 Hz, C--1--H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.C[O:13][C:14](=[O:43])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3Br)[CH:25]=2)=[CH:19][C:18]=1[CH3:42]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:32]1[CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=[CH:36][C:31]=1[O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:14]([OH:43])=[O:13])=[C:18]([CH3:42])[CH:19]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: COc1ccccc1-c1cc(C(F)(F)F)ccc1Oc1cccc(Oc2ccc(CCC(=O)O)c(C)c2)c1

Procedure:
The title compound is prepared according to Example 89 by using 2-methoxyphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 102 mg (64%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H25O5F3 522, found 523 (M+1, 100%).
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C-:12]#[N:13].[K+]>CN(C=O)C.[OH-].[Na+]>[O:5]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:11]2[CH:2]([C:12]#[N:13])[CH2:3][CH2:4]1
Reactant: [C-]#N
Reactant: ClC1CCOc2ncccc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#CC1CCOc2ncccc21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-3,4-dihydro-2H-pyrano[2,3-b]pyridine (18.7 mmol) in 60 mL DMF was added KCN (56.1 mmol) and the mixture was stirred at 90° C. overnight. After cooling to RT, the mixture was diluted with aq. 0.5 M NaOH solution and extracted 3 times with EtOAc. The combined organic layers were washed again with aq. 0.5 M NaOH solution and once with brine. The organic phase was dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (4/1) to EtOAc gives the desired compound as yellow oil.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:13](=O)[CH2:14][C:15](=O)[CH3:16])[C:9]([CH3:19])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:13]([C:10]3[C:9]([CH3:19])=[N:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[OH:12])=[CH:14][C:15]([CH3:16])=[N:29]2)=[CH:24][CH:23]=1
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)CC(=O)C1C(=O)N(c2ccccc2)N=C1C
Agent: Cl
Product: Cc1cc(-c2c(C)nn(-c3ccccc3)c2O)n(-c2ccc(F)cc2)n1

Procedure:
Prepare the title compound from 1-[1-phenyl-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-4-yl]-butane-1,3-dione and 4-fluorophenyl hydrazine hydrochloride according to the procedure of Example 28.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:12]([C:5]4[C:6]([C:8]([F:11])([F:10])[F:9])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=4)=[O:13])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3cnc(Cl)nc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2-chloro-4-trifluoromethylpyrimidine-5-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (35% yield). 1H NMR (300 MHz, CDCl3) δ 8.77, 8.08, 7.97, 7.01, 4.06-3.68, 3.55, 3.39, 1.50, 0.76-0.71, 0.48-0.42, 0.10-0.05.
Reaction SMILES: [OH:1][CH:2]([CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][Si](C)(C)C)[CH:23]=1)[CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][CH2:19][CH:2]([OH:1])[CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)#[CH:29]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)CNCc1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cccc(CNCC(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To tert-butyl 3-hydroxy-1-phenyl-4-(3-((trimethylsilyl)ethynyl)benzylamino)butan-2-ylcarbamate in a mixture of THF (2 ml) and MeOH (2 ml), 1M K2CO3 (0.25 ml) was added and the reaction mixture was stirred at rt for 18 h. Then solvent was removed, crude residue was redissolved in ethyl acetate, washed with water, brine and dried. Column purification yielded tert-butyl 4-(3-ethynylbenzylamino)-3-hydroxy-1-phenylbutan-2-ylcarbamate in 85% yield.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH2:16][C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)=[N+:13]=[N-:14]>>[ClH:1].[S:19]1[CH:20]=[CH:21][C:17]([CH2:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)=[CH:18]1
Reactant: [N-]=[N+]=NCCc1ccsc1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(CCc3ccsc3)nn2)c[nH]1
Yield: 47.2 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.078 g, 0.45 mmol) was reacted with 3-(2-Azido-ethyl)-thiophene (0.083 g, 0.543 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(2-Thiophen-3-yl-ethyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.069 g, 47%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 7.33 (s, 1H), δ 7.19 (dd, 1H), δ 6.85 (d, 1H), δ 6.72 (d, 1H), δ 6.06 (s, 1H), δ 4.45 (t, 2H), δ 3.08 (t, 2H), δ 2.79 (t, 2H), δ 2.59 (t, 2H), ppm 13C (75 MHz, CD3OD) δ 149.3, 147.0, 137.7, 132.1, 127.7, 125.8, 122.4, 121.9, 110.6, 50.8, 30.7, 26.6, 24.8 ppm; HRMS (ESI) calcd for C13H17N6S (M+) 289.1229. found 289.1231.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH:36](Br)([CH3:38])[CH3:37]>>[CH:36]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])([CH3:38])[CH3:37]
Reactant: CC(C)Br
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: COc1cc2c(cc1OC)C(Cc1ccc(OC(C)C)c(OC)c1)N(CC(=O)NCc1ccccc1)CC2

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with isopropyl bromide
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[CH3:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH:7]=[CH:8]1
Reactant: Cc1cccc2cc[nH]c12
Reactant: Cc1c[nH]c2ccccc12
Product: Cc1cccc2ccn(C)c12
Yield: 90 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-methylindole for the 3-methylindole, the title compound (1.95 g, 90%) was obtained as a light-colored oil: MS (ES) m/e 146.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[N:28][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:24]2[CH:29]=[N:28][C:27]([N:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[C:11]=1[CH3:12]
Reactant: CC1(C)OB(c2ccc(N3CCNCC3)nc2)OC1(C)C
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCNCC3)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine (0.583 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperazin-1-yl)pyridin-3-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=375.1 (M+1).
Reaction SMILES: N12CCCN=C1CCCCC2.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].[CH2:34]([N:42]=[C:43]=[O:44])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>CC#N>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:43]([NH:42][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:44])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1
Reactant: CCCCCCCCN=C=O
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCNC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.33 h
Yield: 56.2 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.29 g, 1.90 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione hydrochloride (0.6 g, 1.85 mmol) in CH3CN (50 mL). After stirring for 20 min, octyl isocyanate (0.44 g, 2.77 mmol) was added. The mixture was stirred at room temperature for 17 hours. The slurry mixture was filtered and the solid was recrystallized from methanol to give N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(octylamino)carboxamide (0.46 g, 56%) as a white solid: mp 160-162° C.; 1H NMR (DMSO-d6) δ 11.14 (s, 1H), 7.85-7.68 (m, 3H), 6.43 (t, J=6.0 Hz, 1H), 6.13 (t, J=5.6 Hz, 1H), 5.18-5.11 (dd, J=5.3 and 12.5 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H), 3.02-2.83 (m, 3H), 2.64-2.50 (m, 2H), 2.08-2.04 (m, 1H), 1.36-1.24 (m 12H), 0.85 (t, J=6.2 Hz, 3H); 13C NMR (DMSO-d6) δ 172.75, 169.82, 167.57, 167.03, 157.99, 141.19, 134.57, 133.33, 131.50, 126.95, 121.61, 48.82, 39.32, 38.83, 31.21, 30.93, 29.92, 28.73, 28.69, 26.37, 22.07, 21.98, 13.93; Anal. Calcd. For C23H30N4O5: C, 62.43; H, 6.83; N, 12.66. Found: C, 62.27; H, 6.94; N, 12.54.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[CH3:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]3)=[C:4]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate (1.20 g, 2.68 mmol, 1.00 equiv), (3-methylphenyl)boronic acid (0.730 g, 5.37 mmol, 2.00 equiv), Pd(PPh3)4 (0.310 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.10 g, 7.96 mmol, 2.97 equiv), dioxane (12 mL), and water (2 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to provide 1.00 g (81% yield) of tert-butyl 4-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 459 [M+H]+.