Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(-c2nc3ccccc3o2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of methyl 4-(benzoxazol-2-yl)-benzoate (0.20 g, 0.8 mmol) in THF (8 mL) at −78° C. was added a solution of DIBAL-H (4.0 mL, 1.0 M in THF, 4.0 mmol). The reaction was allowed to warm to room temperature, stirred for 1 h and quenched with a saturated potassium sodium tartrate solution (15 mL). The biphasic mixture was stirred vigorously for 1 h, the phases separated and the organic layer dried (MgSO4), filtered and concentrated to give the title alcohol (0.16 g, 89%). 1H NMR (CDCl3) δ 1.80 (t, 1H (Oh)), 4.82 (d, 2H, J=6.0 Hz), 7.36 (m, 2H), 7.55 (d, 2H, J=8.4 Hz), 7.60 (m, 1H), 7.78 (m, 1H), 8.26 (d, 2H, J=8.4 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][CH:7]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)[CH3:2].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>CN(C=O)C.C(#N)C>[CH2:1]([O:3][C:4](=[O:29])[CH:5]=[CH:6][CH:7]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:8][C:9]1[N:10]=[CH:11][N:12]([CH2:32][CH:33]=[CH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1c[nH]cn1)NC(=O)CCCCCCc1ccccc1
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C=CC(Cc1cn(CC=Cc2ccccc2)cn1)NC(=O)CCCCCCc1ccccc1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
The 5-(1H-Imidazol-4-yl)-4-(7-phenyl-heptanoylamino)-pent-2-enoic acid ethyl ester (100 mg, 0.25 mmol) in DMF (1 mL) was treated with NaH (10 mg, 60%, 0.25 mmol) at room-temperature. After 5 minutes cinnamyl bromide (50 mg, 0.25 mmol) was added, and the solution stirred overnight. Analytical HPLC showed the product was a 60:40 mixture of τ (required) and π (undesired) isomers respectively. The solution as taken up into water and acetonitrile and subject to reverse phase HPLC (30% B to 100% B over 25 min). The product, a mixture of both isomers, was obtained as an oil (88 mg, 68%), ESMS 514 (M+H+). 13C NMR δ 174.72, 174.67, 174.22, 171.69, 170.52, 166.20, 145.85, 142.93, 138.31, 138.16, 137.81, 137.45, 134.89, 134.81, 133.37, 132.86, 131.49, 131.39, 129.26, 128.98, 128.52, 128.34, 127.04, 125.68, 122.23, 119.68, 119.61, 119.54, 118.93, 114.55, 63.08, 61.90, 60.91, 60.79, 57.59, 54.77, 52.59, 52.53, 51.49, 50.21, 37.04, 36.14, 35.99, 33.44, 31.44, 29.61, 29.18, 29.13, 29.03, 28.97, 25.67, 25.62, 25.46, 14.27, 14.05.
Reaction SMILES: CC1N=CC=CC=1C(N)=O.[C:11]([C:15]1[N:20]=[C:19]([CH3:21])[C:18]([CH:22]([NH2:24])[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[CH:32][N:31]([CH2:34][C:35](O)=[O:36])[C:30]=2[C:38]=1[F:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[C:11]([C:15]1[N:20]=[C:19]([CH3:21])[C:18]([CH:22]([NH:24][C:35](=[O:36])[CH2:34][N:31]2[C:30]3[C:38]([F:39])=[C:26]([F:25])[CH:27]=[CH:28][C:29]=3[N:33]=[CH:32]2)[CH3:23])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: Cc1nc(C(C)(C)C)ccc1C(C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ncccc1C(N)=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(C(C)(C)C)ccc1C(C)NC(=O)Cn1cnc2ccc(F)c(F)c21

Procedure:
The title compound was synthesized according to the procedure described for the synthesis of 2-methylnicotinamide, starting from [1-(6-tert-butyl-2-methylpyridin-3-yl)ethyl]amine (intermediate 32) (31.5 mg, 0.16 mmol), 6,7-difluorobenzimidazole-1-acetic acid (35 mg 0.16 mmol) HATU (38 mg, 0.18 mmol) and DIPEA (71 μl, 0.41 mmol). Water was added and the reaction concentrated. The mixture was partitioned between ethyl acetate and water, and extracted 3 more times with ethyl acetate. The product was then purified by silica gel flash chromatography with acetone/hexanes (Yield 25 mg, 40%). 1H NMR (400 MHz, CD3OD-D4) d ppm 1.32 (s, 9 H), 1.47 (d, J=7.03 Hz, 3 H), 2.53-2.57 (m, 3 H), 5.04-5.15 (m, 2 H), 5.15-5.22 (m, 1 H), 7.16 (ddd, J=11.43, 8.79, 7.52 Hz, 1 H), 7.28 (d, J=8.20 Hz, 1 H), 7.41 (dd, J=8.89, 3.61 Hz, 1 H), 7.68 (d, J=8.20 Hz, 1 H), 8.11 (s, 1 H) MS [MH+] calc. 387.1996 found 387.3.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:36]([CH:33]3[CH2:35][CH2:34]3)=[O:37])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)C1CC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, cyclopropanecarbonyl chloride (20 mg, 192 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (11.8 mg, 38% of theory).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:40]4[C:39](=[CH:38][CH:37]=[C:36]([CH3:35])[CH:41]=4)[NH:42][C:22]=3[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Product: Cc1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 4-methylphenylhydrazine hydrochloride: ESMS m/e: 539.1 (M+H)+.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl.O>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(COc2ccccc2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of methyl 4-(phenoxymethyl)benzoic acid (420 mg, 1.84 mmol), 1-hydroxybenzotriazole (373 mg, 2.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (530 mg, 2.75 mmol), triethylamine (0.8 mL, 5.7 mmol) were dissolved in dichloromethane (20 mL). The mixture was stirred at room temperature for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (280 mg, 1.84 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours. To the resultant mixture, water (10 mL) was added and then extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried over sodium sulfate, filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:4) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(phenoxymethyl)benzamide (Compound I-11) as a white solid (300 mg, 45%). LRMS (M+H+) m/z: calcd 362.16. found 362. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.49 (s, 1H), 8.37 (t, J=5.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.31 (t, J=7.8 Hz, 2H), 7.04-6.96 (m, 3H), 5.88 (s, 1H), 5.17 (s, 2H), 4.32 (d, J=5.1 Hz, 2H), 2.20 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH:13]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH2:22][C:23]([OH:25])=[O:24])[CH:19]=3)[CH2:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cc1ccc2c(c1)CC(CNS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 80 °C
Yield: 91.1 %

Procedure:
Suspended in 50 ml of 1N sodium hydroxide were 16.5 g of ethyl [2-[(4-chlorophenyl)sulfonylaminomethyl]indan-5-yl]-acetate, and the suspension was heated at 80° C. for 1 hour. After cooling, hydrochloric acid was added to the suspension to acidify it. A crystal deposited was collected by filtration. The crystal was recrystallized from 80% ethanol to obtain 14.0 g of the title compound as a colorless needle crystal. Yield: 91%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:17]([NH:18][C:19]([C:21]2[NH:22][C:23]([CH2:27][CH3:28])=[C:24]([Cl:26])[N:25]=2)=[O:20])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:43]1[S:44][C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]([CH3:48])[N:47]=1>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:17]([NH:18][C:19]([C:21]2[NH:22][C:23]([CH2:27][CH3:28])=[C:24]([Cl:26])[N:25]=2)=[O:20])[CH2:16][CH2:15][N:14]([C:43]2[S:44][C:45]([C:49]([O:51][CH2:52][CH3:53])=[O:50])=[C:46]([CH3:48])[N:47]=2)[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: CCc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2NC(=O)OCc2ccccc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](NC(=O)OCc3ccccc3)C2)nc1C
Yield: 84.2 %

Procedure:
The same operation as in Example (1h) was performed using tert-butyl trans(±)-3-{[(benzyloxy)carbonyl]amino}-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidine-1-carboxylate obtained in Example (79d) (85 mg, 0.17 mmol), sodium carbonate (160 mg, 1.51 mmol) and ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (55 mg, 0.22 mmol), to obtain 82.3 mg of the title compound as a yellow solid (85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:8])[NH:5][CH:6]=1.Br[CH2:21][CH2:22]Br>>[Br:1][C:2]1[CH:3]=[C:4]2[C:7](=[O:8])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)[CH2:22][CH2:21][N:5]2[CH:6]=1
Reactant: COc1ccc(NC(=O)c2cc(Br)c[nH]2)cc1OC
Reactant: BrCCBr
Product: COc1ccc(N2CCn3cc(Br)cc3C2=O)cc1OC

Procedure:
Following the procedure described in Example 1 step D, the product of step A (140 mg) was alkylated with 1,2-dibromoethane to yield 143 mg of the title compound. MS (ESI) 351, 353 (M+H)−.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]([C:28]4[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=4)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[NH:18][C:17]3=[O:37])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.[Pd]>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]([C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=4)([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:18][C:17]3=[O:37])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(c2ccccc2)(c2ccc([N+](=O)[O-])cc2)C(=O)N1CCCN1CCC(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(C2(c3ccccc3)NC(=O)N(CCCN3CCC(c4ccccc4)CC3)C2=O)cc1

Procedure:
3-[3-(4-phenyl-1-piperidyl) propyl]-5-(4-nitrophenyl)-5-phenylhydantoin (17.5 g, 0.035 mole) in 200 ml of glacial acetic acid and 0.6 g of Pd/C (10%) was reduced on the Parr shaker. The theoretical amount of hydrogen was taken up. The mixture was filtered and concentrated. The concentrate in aqueous methanol was made basic with NH4OH. The solid was recrystallized from aqueous dimethylformamide-methanol and twice from aqueous dioxane.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([O:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:6]([N:20]=[C:21]2[S:25][C:24](=[O:26])[N:23](C=O)[NH:22]2)=[C:5]([F:29])[CH:4]=1>CO.CC(C)=O>[Cl:2][C:3]1[C:8]([O:9][C:10]2[C:15]([C:16]([F:18])([F:19])[F:17])=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:7][C:6]([N:20]=[C:21]2[S:25][C:24](=[O:26])[NH:23][NH:22]2)=[C:5]([F:29])[CH:4]=1
Reactant: O=Cn1[nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)sc1=O
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: O=c1[nH][nH]c(=Nc2cc(Oc3ncccc3C(F)(F)F)c(Cl)cc2F)s1
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
A solution of 10% hydrochloric acid in methanol (8 ml) was added to a solution of 5-[4-chloro-2-fluoro-5-(3-trifluoromethyl-2-pyridyloxy)phenylimino]-3-formyl-1,3,4-thiadiazolidin-2-one (3.3 g) in acetone (60 ml). After stirring for 0.5 hour, the solvents were removed and the residue processed. A minimal amount of ethanol was used to dissolved the residue and hexane added to induce crystallization. The crystals were filtered off and dried to give the product (1.0 g, 36%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>O>[OH:2][C:1]1[CH:8]=[CH:7][C:5]([O:6][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc(OCCOc2ccccc2)cc1
Yield: 85 %

Procedure:
To 100 ml of water were added 40 g of hydroquinone, 20 g of β-bromophenetole and 6 g of potassium hydroxide and the mixture was subjected to reaction at 80° C. for about 2 hours. The solid precipitated was filtered and washed with warm water. The unreacted materials were extracted with alkali for removal. The remaining insoluble solids were removed by filtration and the filtrate was neutralized with hydrochloric acid. The solid precipited was filtered, washed with water and recrystallized from ethyl alcohol, giving 1-(4-hydroxyphenoxy)-2-phenoxy ethane in a yield of 85%. M.p. 156° C.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([O:12][C:13](=[O:45])[CH:14]([CH2:40][CH2:41][CH2:42][CH2:43][OH:44])[CH2:15][C:16]1([C:21](=[O:39])[NH:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:11])([CH3:10])[CH3:9].Cl>N1C=CC=CC=1>[C:8]([O:12][C:13](=[O:45])[CH:14]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:15][C:16]1([C:21](=[O:39])[NH:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)C(CCCCO)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)OCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Valeryl chloride (0.2 ml, 1.98 mmole) was added dropwise to a stirred, ice cold solution of 3-{1-[(cis-4-benzyloxycarbonylcyclohexyl)carbamoyl]cyclopentyl}-2-(4-hydroxybutyl)propanoic acid t-butyl ester (0.7 g, 1.32 mmole) in dry pyridine (5 ml). The mixture was allowed to stand overnight at room temperature and ice was added, the pH was adjusted to 3 by the addition of 2N hydrochloric acid and the mixture was extracted with diethyl ether. The organic extract was dried (Na2SO4) and evaporated to give a gum which was chromatographed on silica eluting with hexane containing increasing proportions of diethyl ether to give the title product as a gum. Found: C,70.06; H,8.91; N,2.58. C36H55NO7 requires C,70.44; H,9.03; N,2.28%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[C@@H:10]([CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]1[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[N:29]=1.CC([O-])=O.[K+].O1CCOCC1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.O>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:18]3[CH:17]=[C:16]([C@H:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH3:26])[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[N:29]=2)=[CH:51][CH:50]=1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)n2)cc1
Temperature: 100 °C
Yield: 61.3 %

Procedure:
A 1-L round-bottomed flask was charged with (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (11.90 g, 32.4 mmol), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (Example 51; 13.72 g, 35.6 mmol), KOAc (10.18 g, 104 mmol), dioxane (180 mL), and water (36.0 mL). Nitrogen gas was bubbled through the mixture for 10 min. Bis-(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (2.295 g, 3.24 mmol) was added and a reflux condensor was attached to the flask. The mixture was heated at 100° C. under nitrogen overnight (17 h). After cooling to ambient temperature, water was added and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (330 g of silica gel, 5% to 75% EtOAc/hexanes) to give tert-butyl(3S)-4-((1R)-1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (13.35 g, 19.87 mmol, 61.3% yield) as a light-yellow foam. m/z (ESI, +ve) 672.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.39-8.46 (m, 1H) 8.19-8.24 (m, 1H) 7.19-7.25 (m, 4H) 6.83-6.90 (m, 4H) 4.82 (d, J=11.93 Hz, 4H) 3.97-4.07 (m, 1H) 3.81 (s, 3H) 3.80 (br s, 1H) 3.79 (s, 3H) 3.31-3.44 (m, 2H) 3.08-3.18 (m, 1H) 2.69-2.77 (m, 1H) 2.55 (s, 3H) 2.42-2.48 (m, 2H) 1.39-1.46 (m, 12H) 1.00 (d, J=6.26 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>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.COCCOC>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]2=[O:23])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
2-(5-(3-Bromophenyl)pent-4-ynyl)isoindoline-1,3-dione (0.31 g, 0.84 mmol), phenyl boronic acid (206 mg, 1.68 mmol), and Pd (PPh3)4 (0.23, 0.2 mmol) were taken into DME (5 mL) and stirred at 80° C. for two hours. The reaction was then quenched with saturated NaHCO3 and the resulting mixture extracted with EtOAc, washed with brine, then dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was purified on normal phase chromatography (Heptane/EtOAc) to yield 2-(5-(biphenyl-3-yl)pent-4-ynyl)isoindoline-1,3-dione. MH+ 366.3
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC=CC=3C(O)=O)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1([CH3:57])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49]CC)=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]#[C:55][CH3:56])=[CH:33][CH2:32]1>>[CH3:30][C:31]1([CH3:57])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:44]=[CH:45][C:46]([C:47]([OH:49])=[O:48])=[CH:52][CH:53]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]#[C:55][CH3:56])=[CH:33][CH2:32]1
Reactant: CC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccccc3C(=O)O)cc21
Product: CC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 75 mg (0.20 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-propynyl)naphth-2-yl)ethynyl]benzoate (Compound 92) was converted to the title compound (pale yellow solid) using 42 mg (2 ml, 1.0 mmol) of LiOH (0.5 M aqueous solution).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:43][C:42]2[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Fc1ccc(CCl)cc1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccc(F)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-fluorobenzyl chloride (0.36 mL) as starting materials, 5-benzyloxy-N-({1-[(4-fluorophenyl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.76 g) was obtained.