Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C([Sn](CCCC)(CCCC)[C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)CCC.[F-].[K+].O>C1(C)C=CC=CC=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>[CH3:13][C:4]1[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]2=[C:2]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(-c3ccco3)n1)C(=O)OCC2
Temperature: 0 °C
Yield: 77.6 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.265 mmol) and Pd(PPh3)4 (146 mg, 0.127 mmol) were dissolved in 12 mL of anhydrous toluene, dropwisely added with 2-(tributylstannyl)furan (0.80 mL, 2.530 mmol) and then heated to reflux for about 15 hours under the nitrogen atmosphere. The mixture was added with 15 mL of 2% KF solution and 20 mL of distilled water while stirring at 0° C. and then extracted twice with 50 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (5% EtOAc/MC) was performed on the resulting residue and 225 mg (78%) of 6-methyl-8-furan-2-yl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13](O)[CH3:14]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12])=[CH2:14]
Reactant: CCO
Reactant: Cc1c(Br)ccc2c1COC2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4-methyl-2-benzofuran-1(3H)-one (598 mg, 4.47 mmol), potassium vinyl trifluoroborate (507 mg, 2.23 mmol), PdCl2(dppf)-CH2Cl2 Adduct (182 mg, 0.223 mmol), and TEA (0.622 mL, 4.47 mmol) were added to 10 mL ethanol in a 20 mL microwave tube. The tube was sealed and degassed, then heated to 140° C. for 20 min. Analysis by LC-MS showed product peak. The reaction mixture was diluted with ethyl acetate, washed with brine twice, dried and evaporated to dryness. The crude product was purified by MPLC chromatography using a 120 g Redi-sep column and 0-80% ETOAC/Hexane solvent system to yield 5-ethenyl-4-methyl-2-benzofuran-1(3H)-one. LC-MS: M+1=175.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH2:22][CH3:23])=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Temperature: 80 °C
Reaction time: 72 h

Procedure:
2-Phenyl-4-quinolone-6-carboxylic acid (1.3 grams) obtained in Example 2 is dissolved in 80 ml of ethanol and 0.5 ml of concentrated sulfuric acid. The solution is stirred for three days at 80° C., water is added thereto, crystals which separate out therefrom are collected by filtration. These are washed with water and dried to give 1.4 grams of ethyl 2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting at above 300° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH3:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH3:13])([CH3:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)(C)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 13.3 %

Procedure:
Ethyl-2,2-dimethyl-7-bromoheptanoate (7.0 g, 0.026 mol) was treated with 4-chlorobenzenesulphonamide (9.9 g, 0.052 mol) and potassium carbonate (21.5 g, 0.016 mol) by the method described in Example 5(ii) to give the title compound (1.3 g) as an oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]=[CH2:8])[CH:2]1[O:4][CH2:3]1.C([O-])([O-])=[O:10].[Na+].[Na+]>O>[CH2:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][OH:10])[CH:7]=[CH2:8]
Reactant: C=CCOCC1CO1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCOCC(O)CO
Temperature: 80 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
A 5,000 mL, 3-necked flask fitted with a mechanical stirrer, thermometer and 500 mL addition funnel was charged with water (2,000 mL) and 70% aqueous HClO4 (2.0 mL), then heated to 80° C. Allyl glycidyl ether (500 g, 4.38 mol) was added in one portion and the reaction mixture stirred for 12 hours. The mixture was neutralized by addition of 5% aqueous Na2CO3 to pH=8. The water was evaporated in vacuo to leave 550 g of crude product, which was distilled to yield 498 g (86%) of pure 3-allyloxy-1,2-propanediol: bp 76°-83° C. (0.4 mm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]=[C:30]=[S:31])[CH:25]=[C:26]([Cl:28])[CH:27]=1>C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][C:30](=[S:31])[NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[O:6])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(NC(=O)c2ccc(OC)c(N)c2)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccc(OC)c(NC(=S)Nc3cc(Cl)cc(Cl)c3)c2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 79.6 %

Procedure:
A mixture of 3-amino-4-methoxy-N-(4-methoxyphenyl)-benzamide from Example 3 (0.681 g, 2.50 mmol) in ethyl acetate (80 mL) was heated briefly to 60° C. then filtered to clarity and mixed with 3,5-dichlorophenyl isothiocyanate (0.511 g, 2.50 mmol). The reaction was allowed to stand for 3 days at room temperature then concentrated to two-thirds volume and allowed to stand overnight. Filtration afforded the product (0.948 g); m.p 175-182° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:24]C)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:10]=2)[CH:8]=1)#[N:2].[N:26]([Sn](CCCC)(CCCC)CCCC)=[N+:27]=[N-:28].C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[NH2:16][CH2:15][C:11]1[CH:10]=[C:9]([C:7]2[C:6]([OH:24])=[CH:5][CH:4]=[C:3]([C:1]3[NH:2][N:28]=[N:27][N:26]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(C#N)cc1-c1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: NCc1cccc(-c2cc(-c3nnn[nH]3)ccc2O)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
tert-Butyl (5′-cyano-2′-methoxy-biphenyl-3-yl-methyl)-carbamate (0.73 g, 2.16 mmol), prepared as in Reference 19, and azidotributyltin (0.9 mL, 3.2 mmol) was dissolved in toluene (5 mL) and the solution was refluxed for 14 hours. The mixture cooled to room temperature and then workup with ethyl acetate and 1N HCl gave a slurry. The slurry was dried by rotovap and then triturated with hexanes. The solids were collected by filtration and treated with hydrobromic acid (48% aqueous, 15 mL). The mixture was refluxed for 14 hours at 120° C. and then diluted with water (50 mL). The dilution was dried by lyophilization to give 3′-aminomethyl-5-(1H-tetrazol-5-yl)-biphenyl-2-ol (0.4 g).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)#[CH:17]>>[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19]1)#[CH:17]
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: C#CC1CCCNC1
Agent: Cl
Product: C#CC1CCCN(c2nnc(N)nc2-c2ccccc2)C1
Yield: 1.5 %

Procedure:
6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (10 mg, 2%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.60 g, 2.40 mmol) and 3-ethynyl piperidine HCl (0.42 g, 2.87 mmol) according to the general procedure of Example 2.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10])=[CH:4][C:3]=1[CH3:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][O:10][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][C:3]=1[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(OC[C@@H](C)CO)cc(C)c1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(OC[C@@H](C)COS(C)(=O)=O)cc(C)c1Br

Procedure:
(S)-3-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propan-1-ol (130 mg), methanesulfonyl chloride (0.073 mL) and triethylamine (0.264 mL) are stirred in 5 mL of dichloromethane at room temperature overnight. The reaction mixture is washed with citric acid saturated aqueous solution and with brine. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound, used in the next step without further purification. Yield: 148 mg.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[CH3:11][O-:12].[Na+]>CN(C=O)C>[CH3:11][O:12][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(I)nc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-3-methoxy-6-iodopyridine (11-3, 34 g, 162 mmol) in DMF (65 mL) was added sodium methoxide (37 mL, 162 mmol) and heated to 100° C. The mixture was stirred for 10 minutes and partitioned between saturated NaHCO3 and DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica (0 to 20% EtOAc in hexanes) to afford the title compound (11-4) as a white powder. ESI+MS [M+H]+ C7H8INO2: 265.8 found, 266.0 required
Reaction SMILES: [CH3:1][C:2]([CH3:5])([CH3:4])[CH3:3].[Mg].II.Br[CH2:10][CH2:11][CH:12]=[CH2:13]>O1CCCC1>[CH3:1][C:2]([CH3:5])([CH3:4])[CH2:3][CH2:13][CH2:12][CH:11]=[CH2:10]
Reactant: CC(C)(C)C
Reactant: C=CCCBr
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCCC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2,2-Dimethylpropane (15.1 g, 0.10 mol) in dry tetrahydrofuran (80 ml) was added dropwise to a mixture of magnesium turnings (2.43 g, 0.10 mol) in dry tetrahydrofuran (20 ml) containing a single crystal of iodine, at such a rate so as to maintain the solvent at reflux. The resulting solution was allowed to cool to room temperature and decanted from the residual magnesium under nitrogen into a fresh flask. The solution was diluted with dry tetrahydrofuran (150 ml), cooled to -20° C. under an atmosphere of nitrogen treated with cuprous bromide dimethyl sulphide complex and stirred for 20 minutes. The resulting solution was then treated with 4-bromo-1-butene (13.5 g, 0.10 mol) and stirred at -20° C. for 16 hours and then at 20° C. for 4 hours. The reaction mixture as quenched with saturated aqueous ammonium chloride solution (10 ml), diluted with ether (200 ml) and washed with an aqueous solution of ammonia (2×200 ml of 10%). The solution was dried over sodium sulfate and distilled at atmospheric pressure to yield 6,6-dimethyl- 1-heptene as a colourless oil, having a boiling point of 120°-125° C., and the following structural characteristics:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[N:19]=[C:20](S(C)(=O)=O)[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[C:32]([O:36][C:37](=[O:43])[NH:38][CH2:39][CH2:40][CH2:41][NH2:42])([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C>>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[CH:17]=[C:18]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)[N:19]=[C:20]([NH:42][CH2:41][CH2:40][CH2:39][NH:38][C:37](=[O:43])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])[C:15]4=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[O:31])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CS(=O)(=O)c1nc(-c2ccncc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCNc1nc(-c2ccncc2)cn2c(-c3ccc(C(=O)NC4CC4)cc3)cnc12
Temperature: 170 °C
Yield: 16.9 %

Procedure:
0.1 mmol N-cyclopropyl-4-[8-(methylsulfonyl)-6-(pyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl]benzamide (intermediate example 9-2) (1 mL, 0.1 M in NMP), 0.2 mmol tert-butyl(3-aminopropyl)carbamate (0.4 mL, 0.5 M in NMP, 2 eq) and 0.3 mmol DIPEA (41 μL, 3 eq) were combined in a sealed vial and heated at 170° C. under microwave irradiation for 60 min. After cooling, the solution was filtered and subjected to preparative HPLC to give 8.9 mg tert-butyl [3-({3-[4-(cyclopropylcarbamoyl)phenyl]-6-(pyridin-4-yl)imidazo[1,2-a]pyrazin-8-yl}amino)propyl]carbamate (11%): 1H-NMR (300 MHz, d6-DMSO): δ=8.58 (2H, d), 8.54 (1H, d), 8.32 (1H, s), 8.02-7.93 (3H, m), 7.87-7.76 (4H, m), 6.83 (1H, tr), 3.58 (2H, m), 3.01 (2H, m), 2.86 (1H, m), 1.77 (2H, m), 1.32 (9H, s), 0.68 (2H, m), 0.55 (2H, m) ppm; UPLC-MS: RT=0.90 min; m/z (ES+) 528.6 [MH+]; required MW=527.6.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[N:51]1([CH2:57][C:58]([N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)=[O:59])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:54]3[CH2:53][CH2:52][N:51]([CH2:57][C:58](=[O:59])[N:60]4[CH2:61][CH2:62][CH2:63][CH2:64]4)[CH2:56][CH2:55]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(CN1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1)N1CCCC1
Yield: 58.9 %

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (300 mg, 1.14 mmol) obtained in Step 6 of Example 1, N-methylmorpholine (0.25 mL, 2.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (305 mg, 1.59 mmol), 1-hydroxybenzotriazole monohydrate (200 mg, 1.48 mmol) and 2-(piperazin-1-yl)-1-(pyrrolidin-1-yl)ethanone (337 mg, 1.71 mmol) in a similar manner to Step 7 of example 1, was triturated in mixed solvent of ethyl acetate/methanol to obtain Compound 121 (298 mg, 60%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([CH:26]([C:39]([NH2:41])=[O:40])[C:27]2[CH:38]=[CH:37][C:30]([C:31]([O:33][CH2:34][CH2:35][OH:36])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl.C(N(CC)CC)C>[N:10]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH:22]([CH:26]([C:39]([NH2:41])=[O:40])[C:27]2[CH:38]=[CH:37][C:30]([C:31]([O:33][CH2:34][CH2:35][O:36][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH3:25])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(c1ccccc1N1CCCCC1)C(C(N)=O)c1ccc(C(=O)OCCOC(=O)c2cccnc2)cc1
Temperature: 20 °C

Procedure:
A solution of 0.7 gm (4.68 m mol) of nicotinic acid chloride in 20 ml of methylene chloride was rapidly added dropwise to a stirred solution of 2.0 gm (4.56 m mol) of 2-hydroxyethyl 4-[(1-(2-piperidino-phenyl)-1-butyl)-aminocarbonylmethyl]-benzoate in 40 ml of methylene chloride and 0.7 ml (4.81 m mol) of triethylamine. The resulting mixture was stirred at 20° C. for two and one-half hours and then extracted with water, and the organic phase was subsequently dried, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel [toluene/acetone (5:1)].
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)=[O:4].[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CO>[CH2:14]([O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]=[CH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:12][CH:11]=1)[CH3:15]
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CCOc1ccc(C=CC(=O)OC)cc1

Procedure:
This ester was treated with excess ethyl iodide in the presence of potassium carbonate in refluxing dry acetone for 48 hours. A moderate yield of methyl p-ethoxycinnamate was obtained as white crystals from methanol, mp 68°-70° C.: λmaxCCl4 5.8, 6.09, 6.22, 6.6, 8.0, 8.56, 9.53, 10.15, and 10.08 μ. Reduction of methyl p-ethoxycinnamate in benzene with LAH gave a 50% yield, after recrystallization from methanol, of p-ethoxycinnamyl alcohol, mp 85° C.: λmax CCl4 2.75, 6.2, 6.61, 6.75, 8.93, 9.2, 9.55, 9.97, 10.3, 10.85, and 11.87 μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(F)c(F)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-difluoro-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:10])[CH2:8][CH3:9].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[O:21][CH2:22][CH2:23][CH2:24]Cl>CS(C)=O.O>[CH2:7]([NH:10][CH2:24][CH2:23][CH2:22][O:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]=1)[CH2:8][CH3:9]
Reactant: CCCN
Reactant: ClCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCNCCCOc1ccc2ccccc2c1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-propylamine (0.28 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 8 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-propyl-(3-(naphthalen-2-yloxy)propyl)amine, solid, m.p. 112° C., (yield 0.51 gm, 91.2%).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9](N)=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1.S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+]>O>[N:1]1[N:2]([C:6]2[CH:12]=[CH:11][C:9]([OH:14])=[CH:8][CH:7]=2)[N:3]=[N:4][CH:5]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(-n2ncnn2)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(-n2ncnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The crude 4-(2H-tetrazol-2-yl)aniline (60 mg, 0372 mmol) was suspended in water (2 mL) and sulfuric acid (0.2 mL) before cooling to 0° C. An aqueous solution of sodium nitrite (26 mg, 0.565 mmol) in water (2 mL) was added. The mixture was stirred at 0° C. for 30 min. Additional water (1 mL) and sulfuric acid (0.37 mL) was added and the mixture heated at 120° C. for 1 hour. The reaction was then cooled and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, concentrated and purified by preparative TLC eluting with 30% ethyl acetate/hexanes to give the desired phenol product as yellow solid. LRMS calc: 162.1; obs: 163.2 (M+1).
Reaction SMILES: [NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(#N)C>[NH2:1][C:2](=[O:16])[C@@H:3]([NH:5][C:6]1[N:11]=[C:10]([N:21]2[CH2:22][CH2:23][CH:18]([OH:17])[CH2:19][CH2:20]2)[N:9]=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=1)[CH3:4]
Reactant: OC1CCNCC1
Reactant: C[C@H](Nc1cc(C(N)=O)nc(Cl)n1)C(N)=O
Solvent: CC#N
Product: C[C@H](Nc1cc(C(N)=O)nc(N2CCC(O)CC2)n1)C(N)=O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-chloropyrimidine-4-carboxamide (compound 37-6) (243 mg, 1 mmol), 4-hydroxylpiperidine (101 mg, 1 mmol), and TEA (0.17 mL, 1.2 mmol) was dissolved in acetonitrile (5 mL) and stirred at 70° C. for 1 hr, extracted with EtOAc (2×20 ml), and dried over MgSO4. The ethyl acetate was removed via rotary evaporator and the crude (S)-6-((1-amino-1-oxopropan-2-yl)amino)-2-(4-hydroxypiperidin-1-yl)pyrimidine-4-carboxamide (compound 37-7) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]=2)[CH2:22][NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:27]=3)[CH2:22][NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NCc2ccc(-c3ccccc3)cc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2ccc(-c3ccccc3)cc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-6-phenyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared. The product was purified by LC 2000 chromatography, eluting with ethyl acetate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([C:17]([O:19][N:20]([CH3:22])[CH3:21])=[O:18])=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1.CS([C:27]1[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=1)(=O)=O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([C:17]([O:19][N:20]([CH3:22])[CH3:21])=[O:18])=[C:12]([O:16][C:27]3[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[N:28]=3)[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CN(C)OC(=O)c1c(O)cccc1-c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2cccc(-c3ccc(Br)cc3)c2C(=O)ON(C)C)n1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
At 10° C., 0.30 g (0.01 mol) of sodium hydride (80% strength) is added to a solution of 3.35 g (10 mmol) of 3-(4-bromophenyl)-2-(N,N-dimethylaminooxycarbonyl)-phenol in 25 ml of dried dimethylformamide, and the mixture is stirred for 3 hours at 30° C. Subsequently, 2.18 g (0.01 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine is added and the mixture stirred for 12 hours at room temperature. Working up in accordance with Example 4 gives a colorless solid.