Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CC[CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.OC([C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=1)[C:50]#[N:51])C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH:39]([N:34]1[C:33]([C:27]2[N:26]=[C:25]3[C:24]4[CH:42]=[CH:43][C:21]([O:20][CH:17]([C:47]5[CH:48]=[C:49]([CH:52]=[CH:53][CH:54]=5)[C:50]#[N:51])[CH3:14])=[CH:22][C:23]=4[O:32][CH2:31][CH2:30][N:29]3[CH:28]=2)=[N:37][C:36]([CH3:38])=[N:35]1)([CH3:41])[CH3:40]
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(O)c1cccc(C#N)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)c4cccc(C#N)c4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 6.9 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (300 mg, 0.92 mmol), 3-(1-hydroxyethyl)benzonitrile (390 mg, 2.65 mmol) and triphenylphosphine (600 mg, 2.28 mmol) in dioxane (10 mL) was added dropwise DIAD (449 ul, 2.28 mmol) and the reaction mixture was stirred at RT for 18 h under an argon atmosphere. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in EtOAc). The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was stirred in aq. NaOH (2M) for 15 min and then was filtered off. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 50-100% 0.1% HCO2H in acetonitrile/water) affording 191 (29 mg, 7%). LCMS: RT 4.81 min [M+H]+ 455.2. 1H NMR (DMSO, 400 MHz): δ 8.26 (1H, d, J=8.97 Hz), 7.93-7.89 (1H, m), 7.82-7.74 (3H, m), 7.60 (1H, t, J=7.78 Hz), 6.80 (1H, dd, J=9.00, 2.57 Hz), 6.57 (1H, d, J=2.54 Hz), 5.87-5.75 (1H, m), 5.66 (1H, q, J=6.38 Hz), 4.49-4.40 (4H, m), 2.25 (3H, s), 1.59 (3H, d, J=6.35 Hz), 1.45 (6H, d, J=6.60 Hz)
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:11][CH:10]2[N:12]([CH3:13])[CH:6]([CH2:7][CH2:8][CH2:9]2)[CH2:5]1.[C:14]1([C:20]2[O:21][C:22]3[C:23](=[C:25]([C:29](O)=[O:30])[CH:26]=[CH:27][CH:28]=3)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:13][N:12]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH:4]([NH:3][C:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:22]3[O:21][C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:24][C:23]=13)=[O:30])[CH2:5]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccccc4)nc13)C2
Yield: 40 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride and 2-phenylbenzoxazole-4-carboxylic acid using conditions similar to those described for Step C in Example 1. This compound was obtained in 40% yield as a white solid; mp 182-185° C.; 1H NMR (300 MHz, CDCl3) δ 9.18 (d, J=6.5 Hz, 1H), 8.25 (m, 2H), 8.19 (dd, J=7.8, 0.9 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H), 7.55-7.65 (m, 3H), 7.47 (t, J=8.0 Hz, 1H), 4.71-4.58 (m, 1H), 3.30 (m, 2H), 2.76 (m, 2H), 2.69 (s, 3H), 2.38-1.33 (m, 8H); MS (APCI) m/z 376 [M+H]+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2]1.N1C=CC=CC=1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>C(Cl)Cl>[C:34]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:2]1)(=[O:37])[CH2:35][CH3:36]
Reactant: CCC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)N1CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
Piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.150 g, 0.38 mmol) was dissolved in 2 mL of DCM and pyridine was added (0.120 mL/1.54 mmol). Propionyl chloride (0.05 mL, 5.4 mmol) was added dropwise to the solution and the resulting mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and was quenched by addition of saturated solution of NaHCO3. The aqueous layer was extracted once with DCM and the combined organics were dried (MgSO4), filtered and, concentrated. The crude was purified by SiO2 chromatography using DCM/(DCM:MeOH:NH4OH; 60:10:1) 75% DCM) to give 0.130 g of 1-(1-propionyl-piperidin-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (76% yield).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:18]1CCO[CH:19]1[C:23]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:47])[N:28]2[CH2:35][C:36]1[CH:37]=[N:38][C:39]([C:42]2[CH:46]=[CH:45][S:44][CH:43]=2)=[CH:40][CH:41]=1>CC(C)=O.O>[CH3:34][O:33][C:30]1[C:29]2[N:28]([CH2:35][C:36]3[CH:37]=[N:38][C:39]([C:42]4[CH:46]=[CH:45][S:44][CH:43]=4)=[CH:40][CH:41]=3)[C:27](=[O:47])[CH2:26][CH2:25][C:24]=2[C:23]([CH:19]=[O:18])=[CH:32][CH:31]=1
Reactant: COc1ccc(C2OCCO2)c2c1N(Cc1ccc(-c3ccsc3)nc1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C=O)c2c1N(Cc1ccc(-c3ccsc3)nc1)C(=O)CC2
Yield: 111.6 %

Procedure:
Pyridinium p-toluenesulfonate (PPTS) (0.24 g) was added to a mixed solution of 5-(1,3-dioxolan-2-yl)-8-methoxy-1-(6-thiophen-3-ylpyridin-3-ylmethyl)-3,4-dihydro-1H-quinolin-2-one (0.4 g) in acetone (8 ml) and water (4 ml), followed by heating under reflux 1.5 hours. The resulting mixture was concentrated under reduced pressure, subjected to extraction with dichloromethane, washed with water, washed with a saturated sodium chloride solution, dried over sodium sulfate, filtrated, and concentrated under reduced pressure to thereby obtain 0.4 g (yield: quantitative) of 8-methoxy-1-(6-thiophen-3-ylpyridin-3-ylmethyl)-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a light brown amorphous solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:58])([C:54]([F:57])([F:56])[F:55])[C:24]([F:53])([F:52])[C:25]([F:51])([F:50])[C:26]([F:49])([F:48])[C:27]([F:47])([F:46])[O:28][C:29]([F:45])([F:44])[C:30]([F:43])([F:42])[O:31][C:32]([F:41])([F:40])[CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38]Br>>[CH2:1]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:32]([O:31][C:30]([F:42])([F:43])[C:29]([F:44])([F:45])[O:28][C:27]([F:46])([F:47])[C:26]([F:48])([F:49])[C:25]([F:50])([F:51])[C:24]([F:52])([F:53])[C:23]([F:22])([F:58])[C:54]([F:57])([F:55])[F:56])([F:41])[F:40])=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: FC(F)(COCCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining 5-octyl-2-(4-hydroxyphenyl)pyrimidine (1.03 g, 3.61 mmol) and 4-(2-(2-(tridecafluorohexyloxy) tetrafluoroethoxy)-2,2-difluoroethoxy)-1-bromobutane (2.68 g, 4.02 mmol; prepared from 1,4-dibromobutane and 2-(2-(tridecafluorohexyloxy) tetrafluoroethoxy)-2,2-difluoroethanol). The resulting crude product was isolated essentially as described in Example 3 and further purified by recrystallization from cyclohexane/ethyl acetate to yield 1.85 g of purified product.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH3:33])/[C:27]([O:29]CC)=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>C(O)C.C(OCC)C>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22](/[CH:25]=[C:26](\[CH2:32][CH3:33])/[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)O)cc2)c1
Temperature: 50 °C
Yield: 84 %

Procedure:
268 mg (6.7 mmol) of sodium hydroxide are added to a solution of 284 mg (0.67 mmol) of ethyl 2-[1-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate in 10 mL of ethanol. The reaction mixture is heated at 50° C. for 15 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the solid obtained is taken up in ethyl ether, filtered off and dried. 222 mg (84%) of 2-[1-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]meth-(E)-ylidene]butyric acid are obtained in the form of a white powder with a melting point of 150-152° C.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C(Cl)[Cl:11]>>[Cl:11][CH:8]([CH3:9])[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: CCC(=O)CC(=O)OC
Reactant: ClCCl
Product: COC(=O)CC(=O)C(C)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-oxopentanoic acid, methyl ester (Aldrich, 26.0 mL, 207.2 mmol) in methylene chloride (300 mL) was added in portions, N,N,N-trimethyl(phenyl) methanaminium dichloroiodanuide (75.71 g, 217.5 mmol). The reaction mixture was stirred at room temperature (rt) for 2 h, then washed with saturated sodium thiosulfate, brine, dried over magnesium sulfate and concentrated. The crude product was used directly in next step (23 g, 67.4%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)=[NH:10])=[O:7])([CH3:4])[CH3:3].[OH-].[Na+]>CO>[CH3:4][C:2]([O:5][C:6]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)=[NH:10])=[O:7])([CH3:1])[CH3:3]
Reactant: COC(=O)c1ccc(C(=N)NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.3 %

Procedure:
To a solution of the compound prepared in Example 17 (0.20 g, 0.72 mmol) in methanol (10 mL) was added 1 M aqueous sodium hydroxide (5 mL). The reaction was stirred at room temperature for 1 h. The mixture was concentrated and the resulting aqueous residue was diluted with ethyl acetate. The aqueous layer was acidified with 1 M hydrochloric acid to pH 4-5 and extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried and concentrated to give the title compound (0.208 g, >99%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][N:22]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23]1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][N:22]1[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[N:23]1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: Cc1cc(C)n(CC(N)C(=O)O)n1
Product: Cc1cc(C)n(CC(Nc2nc3ccc(Cl)cc3cc2C(=O)O)C(=O)O)n1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(3,5-dimethyl-pyrazol-1-yl)-propionic acid to provide the title compound in good yield.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([I:18])=[CH:16][C:15]([CH2:19][CH3:20])=[CH:14][C:13]=1[CH:21]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.I[Si](C)(C)C.C(O)C>ClCCl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([NH:27][CH:21]([C:13]2[CH:14]=[C:15]([CH2:19][CH3:20])[CH:16]=[C:17]([I:18])[C:12]=2[O:11][CH2:10][CH2:9][OH:8])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:29][CH:30]=1)#[N:35]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(I)c1OCCOCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(I)c1OCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 7.1 g of ethyl (RS)-[2-(2-benzyloxy-ethoxy)-5-ethyl-3-iodo-phenyl]-(4-cyano-phenylamino)-acetate in 50 ml of dichloromethane was treated with 7.29 g of iodotrimethylsilane. After 12 hours at room temperature the same amount of iodo-trimethylsilane was added and the mixture was stirred for 18 hours at room temperature. Then, ethanol was added. The reaction mixture was concentrated, poured on to ice/aqueous sodium bisulphite solution and extracted with ethyl acetate. The organic phases were washed with aqueous sodium hydrogen carbonate solution and ice-water, dried over sodium sulphate and concentrated. Crystallization of the residue gave 3.8 g of ethyl (RS)-(4-cyano-phenylamino)-[5-ethyl-2-(2-hydroxy-ethoxy)-3-iodo-phenyl]-acetate. Chromatography of the mother liquor on silica gel gave an additional 1.83 g of product; MS (ISP) m/z 495 (M+H)+, 517 (M+Na)+.
Reaction SMILES: [C:1]([CH:6]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=[O:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O:3][CH2:4][CH3:5])=[O:2].[O-]CC.[Na+].[C:32]1([CH2:38][CH2:39][CH2:40][CH2:41]I)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>COCCOC>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:41][CH2:40][CH2:39][CH2:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:20][CH:19]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OCC
Reactant: ICCCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CCCCc1ccccc1)(CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 56.1 %

Procedure:
Ethyl 2-carboethoxy-4[4'-(4"-chlorophenyl)phenyl]-4-oxobutanoate (0.40 g, 1.02 mmol) was added in one portion at rt to a solution of sodium ethoxide (0.08 g, 1.12 mmol) in DME (1 mL). After 15 min, 4-phenyl-1-iodobutane (0.24 g, 0.93 mmol) in DME (3 mL) was added. The resulting solution was stirred for 18 h. The solvent was concentrated in vacuo and the resulting oil dissolved in CH2Cl2 (100 mL) and washed with water (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×50 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel using a gradient of ethyl acetate/hexane (10% to 25% ethyl acetate) as the eluent to afford a crystalline solid which was recrystallized with hexane and ethyl acetate to afford 1-[4'-(4"-chlorophenyl)phenyl]-3,3-dicarboethoxy-1-oxo-7-phenylheptane (0.272 g, 28%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:18])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Br[C:21]1[CH:22]=[C:23]([C:26]#[N:27])[O:24][CH:25]=1>>[CH3:18][C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:19]=[C:2]([C:21]3[CH:22]=[C:23]([C:26]#[N:27])[O:24][CH:25]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(Br)co1
Product: CC1(c2cccs2)OCC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5-methyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromofuran-2-carbonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 10.09 (s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 7.61 (m, 2H), 7.54 (dd, J=4.9, 1.0 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 6.97 (dd, J=5.4, 3.9 Hz, 1H), 6.84 (dd, J=3.4, 1.0 Hz, 1H), 4.16 (d, J=15.6 Hz, 1H), 4.00 (d, J=15.6 Hz, 1H), 2.07 (s, 3H); MS (ES) m/z 351 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C>C(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:13]1
Reactant: CCOC(=O)COC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Solvent: CCO
Product: CCOC(=O)COC1CCNCC1
Yield: 74.2 %

Procedure:
A solution of 36.4 g (0.131 mole) of ethyl 2-(1-benzyl-4-piperidyloxy)-acetate in 200 ml of absolute ethanol was reacted with hydrogen at 50° C in the presence of 3.5 g of 5% palladized charcoal until the theoretical amount of hydrogen was absorbed and the catalyst was filtered off. The ethanol was evaporated off and the residue was distilled to obtain 18.2 g (74% yield) of ethyl 2-(4-piperidyloxy)-acetate as a clear oil boiling at 102° C at 0.1 mm Hg and having a refractive index nD20 = 1.4665.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:18]=[N:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][NH2:14])=O)=[C:4]([CH3:19])[CH:3]=1.I.CS[CH:23]([NH2:25])[NH2:24].O>N1C=CC=CC=1>[NH2:25][C:23]1[NH:24][C:11]([C:10]2[CH:15]=[CH:16][N:17]=[CH:18][C:9]=2[NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[CH3:19])=[N:13][N:14]=1
Reactant: CSC(N)N
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)NN
Agent: I
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(I)ccc1Nc1cnccc1-c1nnc(N)[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
A reaction mixture of 3-(4-Iodo-2-methyl-phenylamino)-isonicotinic acid hydrazide (120 mg, 0.33 mmol, 1 eq) and C-Methylsulfanyl-methanediamine hydroiodide (104 mg, 0.47 mL, 1.45 eq) in pyridine (2 mL) in sealed tube was heated to 140° C. while stirring for 4 hrs. After cooling, it was poured into water, extracted with EtOAc, and the combined organic fractions, dried over anhydrous MgSO4. After filtration and solvent removal the remaining crude product was subjected to silica gel column chromatography (eluent:Hexane EtOAc=1:1) to afford the desired product (35 mg). [4.26 min; 393(M+1)]
Reaction SMILES: CO.[N+:3]([C:6]1[CH:31]=[CH:30][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:8][CH:7]=1)([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[CH:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:11])=[CH:30][CH:31]=1
Reactant: O=C(Nc1cc(CCc2ccccc2)ccc1C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 mg of 5% palladium-carbon was added to a mixed solution of 1.0 mL of methanol and 2.0 mL of ethyl acetate containing 7.0 mg of 2-(4-nitrobenzamido)-4-phenethylbenzoic acid and stirred under hydrogen atmosphere at room temperature for 2 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure to obtain 4.0 mg of 2-(4-aminobenzamido)-4-phenethylbenzoic acid as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:19][CH2:20][CH:21]([NH2:24])[CH2:22][CH3:23]>>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:1])[C:3]([NH:24][CH:21]([CH2:22][CH3:23])[CH2:20][CH3:19])=[O:5]
Reactant: CCC(N)CC
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncnc2)cc1
Product: CCC(CC)NC(=O)C(C)(C)c1ccc(-c2cncnc2)cc1
Yield: 67 %

Procedure:
Prepared in a similar manner to Example 20 starting from 2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and pentan-3-amine. Yield: 67%. 1H NMR (400 MHz, dMSO): δ 0.71-0.75 (m, 6H), 1.26-1.42 (m, 4H), 1.49 (s, 6H), 3.57-3.59 (m, 1H), 6.91-6.93 (d, 1H), 7.45-7.48 (d, 2H), 7.77-7.79 (d, 2H), 9.14 (s, 2H), 9.17 (s, 1H); MS+H (312).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C.[OH-].[Na+]>>[C:30]([C:27]([C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:14]1[CH:15]=[CH:16][C:17]([CH3:18])=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:32])([CH3:29])[CH3:28])#[N:31]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2c1
Yield: 10.6 %

Procedure:
Using N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (0.31 g, 0.70 mmol) produced in Example A32(iv), 2-chloro-2-oxoethyl acetate (0.55 g, 4.0 mmol), and 8N aqueous sodium hydroxide solution (1 mL), and in the same manner as in Example A30, the title compound (37 mg, 11%) was obtained as a pale-yellow powder.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[C@H:12]([CH3:26])[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=1[CH2:45][C:46](O)=[O:47].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:20][CH2:21][C:22]([OH:24])([CH3:25])[CH3:23])[C@H:12]([CH3:26])[N:11]1[C:46](=[O:47])[CH2:45][C:38]1[CH:39]=[C:40]([O:43][CH3:44])[CH:41]=[CH:42][C:37]=1[Cl:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(CCC(C)(C)O)cccc21
Reactant: COc1ccc(Cl)c(CC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cl)c(CC(=O)N2[C@@H](CO[Si](C)(C)C(C)(C)C)Cc3c(CCC(C)(C)O)cccc3[C@@H]2C)c1

Procedure:
Dissolve 4-[(1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl]-2-methyl-butan-2-ol (0.36 g, 0.95 mol in dichloromethane (9.5 mL). Add diisopropylethylamine (499 μL, 2.86 mmol). Add 2-(2-chloro-5-methoxy-phenyl)acetic acid (229.5 mg, 1.14 mmol). Add O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (561 mg, 1.40 mmol) and stir at ambient temperature overnight. Dilute the reaction mixture with dichloromethane and wash with water and brine, dry over sodium sulfate, filter, and concentrate under reduced pressure to give a brown oil. Purify the residue by silica gel chromatography, eluting with acetone: hexanes (gradient, 0-20%) to give the title compound as an opaque oil (0.46 g, 0.82 mmol). MS (m/z): 560.2 (M+1).