Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:43]([NH:51][NH2:52])(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17]([NH:52][NH:51][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:19])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NNC(=O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (754 μmol) of N-Boc-L-phenylalanine were dissolved in 8 ml of DMF mixed with 131 μl (754 μmol) of N,N-diisopropylethylamine, 346 mg (2261 μmol) of HOBt, 434 mg (2261 μmol) of EDC, and 411 mg (3015 μmol) of benzoyl hydrazine. The reaction composition was stirred at RT overnight, then evaporated, and the residue purified over preparative HPLC. The yield was 313 mg (95% purity, 100% o. th.) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[N:6]=[C:5]([NH2:7])[N:4]([C:8]([NH:10][CH3:11])=[S:9])[N:3]=1)(=[O:14])[CH3:13]
Reactant: CNC(=S)n1nc(N)nc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CNC(=S)n1nc(NC(C)=O)nc1N
Reaction time: 66 h
Yield: 80 %

Procedure:
To the compound (3.00 g) obtained in Example 31 and pyridine (25 ml) was gradually added dropwise acetic anhydride (2.1 ml) under ice-cooling. The mixture was stirred at 0° C.-room temperature for 66 hours and the resulting crystals were collected by filtration. The crystals were washed with hexane-ethyl acetate and dried to give 2.98 g of white powdery crystals (yield 80%).
Reaction SMILES: BrC1C=C(F)C=C2C=1C=CC(=O)N2.[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](=[O:25])[NH:22]2)=[C:17]([F:26])[CH:16]=1.[H-].[Na+].CS(O[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:37]1)(=O)=O.FC1C=C2C(N=CC(=O)N2CCN2CCC(NC(=O)OC(C)(C)C)CC2)=CC=1>C(OCC)(=O)C>[Br:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21](=[O:25])[N:22]2[CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][CH:39]([NH:42][C:43](=[O:44])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:38][CH2:37]2)=[C:17]([F:26])[CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: O=c1ccc2c(F)cc(Br)cc2[nH]1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: O=c1ccc2c(Br)cc(F)cc2[nH]1
Agent: [H-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(Br)cc32)CC1
Yield: 14.3 %

Procedure:
A mixture of 5-bromo-7-fluoroquinolin-2(1H)-one and 7-bromo-5-fluoroquinolin-2(1H)-one (Intermediate 177 and 178, 3.0 g, 9.4 mmol) was reacted with sodium hydride (60% in oil, 0.20 g, 5.0 mmol) and 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6, 9.4 mmol) as described for Intermediate 141. Chromatography on silica gel with a gradient of 50-75% ethyl acetate in hexanes gave 0.63 g (33%) of the regioisomeric product mixture, which was carried on without further purification to the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].S(Cl)([Cl:13])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:13])=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccc(Cl)c1
Yield: 90 %

Procedure:
A solution of 3-chlorobenzoic acid (30 g, 191.61 mmol) in thionyl chloride (200 ml) was stirred overnight at 90° C. The resulting mixture was concentrated under vacuum to afford 3-chlorobenzoyl chloride as light yellow oil (30 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:15]([C:14]2[CH:20]=[CH:21][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:3]=1
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: Cc1cc(Cl)ccn1
Product: COc1ccc(C(=O)Cc2cc(Cl)ccn2)cc1

Procedure:
2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone was synthesized from 4-chloro-2-picoline (10 g, 78.4 mmol) and ethyl 4-methoxybenzoate (14.1 g, 78.4 mmol) as described in Example 12 to give the product as a mixture of enol and keto tautomers. MS m/z 262 (M+1).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].CN(C)[CH:25]=[O:26]>O1CCCC1>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:25]=[O:26]
Reactant: COc1cc(F)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1c(Br)ccc(F)c1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.7 %

Procedure:
1.6 M Solution of n-butyllithium in hexanes (3.35 mL, 5.36 mmol) was added dropwise to a solution of N,N-diisopropylamine (0.960 mL, 6.85 mmol) in tetrahydrofuran (10 mL) at −78° C. and the resultant reaction mixture was stirred at −78° C. for 10 min. A solution of 1-bromo-4-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) in tetrahydrofuran (2 mL) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. N,N-dimethylformamide (0.412 mL, 5.32 mmol) was added to the reaction mixture dropwise at −78° C. and the reaction mixture was stirred at −78° C. for 1 h. Reaction mixture was quenched with saturated ammonium chloride, warmed to 20° C., and diluted with ether and 1M aqueous solution of HCl. Layers were separated and the aqueous layer was and re-extracted with ether. The combined organic layers were washed with brine, dried with magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (727 mg, 64%) as a yellow solid. LCMS calculated for C8H7BrFO2 (M+H)+: m/z=233.0, 235.0. found: 233.0, 234.8.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:35])[C:23]1[CH:32]=[C:31](Br)[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[NH2:34].[CH3:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:25]=[C:24]([NH2:34])[C:23]([C:22]([O:21][CH3:20])=[O:35])=[CH:32][C:31]=1[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH3:36]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1cc(Br)c(C(=O)OC)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CCOCC
Product: COC(=O)c1cc(-c2ccccc2C)c(C(=O)OC)cc1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
A solution of palladium acetate (260 mg, 1.16 mmol) and triphenylphosphine (1.21 g, 4.63 mmol) was stirred for 10 minutes at ambient temperature and then the product of Example 319A (11.1 g, 38.6 mmol), 2-methylphenylboronic acid (5.77 g, 42.4 mmol), ethanol (18 mL) and aqueous 2M sodium carbonate (157 mL) were added. The reaction mixture was warmed to reflux and stirred for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with ether. The aqueous phase was extracted with ether. The combined organic layers were washed with water, dried, filtered and concentrated in vacuo to give an orange oil. Chromatography on silica gel (25% ethyl acetate-hexanes) gave the desired compound (9.6 g, 83%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:44])([F:43])[CH:19]([CH3:42])[CH:20]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][C:37]=3[F:40])[C:32]2=[O:41])=[CH:26][CH:25]=1)[C:21](O)=[O:22].O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:44][C:18]([F:17])([F:43])[CH:19]([CH3:42])[CH:20]([C:24]1[CH:25]=[CH:26][C:27]([CH2:30][N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][C:37]=3[F:40])[C:32]2=[O:41])=[CH:28][CH:29]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: CC(C(C(=O)O)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C(C(=O)Nc1cccc(CCC(=O)OC(C)(C)C)c1)c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
215.3 mg (0.89 mmol) of tert-butyl 3-(3-aminophenyl)propanoate were added to a solution of 280.0 mg (0.71 mmol) of 4,4,4-trifluoro-2-{4-[(4-fluoro-1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methylbutanoic acid and 114.8 mg (0.85 mmol) of 1-hydroxy-1H-benzotriazole hydrate in 1.4 ml of DMF. At 0° C., 308 μl (1.77 mmol) of DIEA and then, a little at a time, 296.2 mg (0.78 mmol) of HATU were added to the resulting mixture. The reaction mixture was then slowly warmed to RT and subsequently stirred at RT for 2.5 h. The mixture was added to water and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water gradient). This gave 333 mg (78.6% of theory) of the title compound.
Reaction SMILES: C(OC(N[C@H](CCCCNC(OC(C)(C)C)=O)C(NCCC([O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1)=O)=O)=O)(C)(C)C.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1>CO>[OH:17][CH:18]([CH2:19][N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)[CH2:42][O:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27]3[C:28]([O:36][CH3:37])=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:26]=3[CH2:25][CH2:24][C@H:23]([NH:38][C:39](=[O:41])[CH3:40])[C:22]=2[CH:42]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCNC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc1[C@@H](NC(C)=O)CC2
Solvent: CO
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OCC(O)CN3CCOCC3)cc1[C@@H](NC(C)=O)CC2
Yield: 55 %

Procedure:
A solution of N-[(5S)-3-(2,3-epoxypropoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (1) (0.092 g; 0.22 mmol) and morpholine (40 μl; 0.44 mmol) in methanol was heated at reflux for 4 hours. After evaporation to dryness the residue was purified by flash chromatography eluting with dichloromethane/ethanol (90/10) to give N-[(5S)-3-(2-hydroxy-3-morpholinopropoxy)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide as a yellow foam.
Reaction SMILES: [C:1](/[C:3](=[C:9]1\[CH2:10][C:11]([CH3:15])([CH3:14])[CH2:12][CH2:13]\1)/C(OCC)=O)#[N:2].[C-:16]#[N:17].[Na+]>CCO>[C:1]([CH2:3][C:9]1([C:16]#[N:17])[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10]1)#[N:2]
Reactant: [C-]#N
Reactant: CCOC(=O)/C(C#N)=C1\CCC(C)(C)C1
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CCC(C#N)(CC#N)C1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with a stir bar and a reflux condenser, containing (E)-ethyl 2-cyano-2-(3,3-dimethylcyclopentylidene)acetate (9.5 g, 46 mmol) in EtOH (50 mL), was added sodium cyanide (2.3 g, 46 mmol). The reaction mixture was refluxed for 24 h, cooled to RT and concentrated to dryness. The residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organics was dried with Na2SO4, concentrated to dryness and subjected to FCC to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 2.75 (s, 2H), 2.41-2.33 (m, 1H), 2.19 (d, J=15 Hz, 1H), 2.03-1.93 (m, 1H), 1.85-1.63 (m, 3H), 1.20 (s, 3H), 1.11 (s, 3H).
Reaction SMILES: [BH4-].[Na+].Cl.[CH2:4]([NH:7][CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10](=[O:19])[CH2:9]1)[CH:5]=[CH2:6].C(O)C.[OH-].[Na+]>O>[CH2:4]([NH:7][CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH:10]([OH:19])[CH2:9]1)[CH:5]=[CH2:6]
Reactant: C=CCNC1CCc2ccccc2C(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCNC1CCc2ccccc2C(O)C1
Temperature: 20 °C
Yield: 98.4 %

Procedure:
7.3 g of sodium borohydride was added over 30 minutes at 15° C to a solution of 7.3 g of the product of Step A in 7 3 ml of ethanol and 7.3 ml of water and the mixture was stirred for an hour at 20° C. The mixture was made alkaline with concentrated sodium hydroxide and the ethanol was evaporated. Water was added thereto and the mixture was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to dryness to obtain 6.2 g of 7-allylamino-5ξ-hydroxy-6,7,8,9-tetrahydro [5H] benzocycloheptene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=[C:17]4B3OC(C)(C)C(C)(C)O3)=[N:12][N:13]=2)=[CH:5][CH:4]=1.Br[C:45]1[N:50]=[C:49]([N:51]2[CH2:56][CH2:55][N:54]3[C:57]([CH3:60])=[N:58][N:59]=[C:53]3[CH2:52]2)[CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.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>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[S:10][C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][CH:18]=[C:17]4[C:45]3[CH:46]=[CH:47][CH:48]=[C:49]([N:51]4[CH2:56][CH2:55][N:54]5[C:57]([CH3:60])=[N:58][N:59]=[C:53]5[CH2:52]4)[N:50]=3)=[N:12][N:13]=2)=[CH:42][CH:43]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(B3OC(C)(C)C(C)(C)O3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Reactant: Cc1nnc2n1CCN(c1cccc(Br)n1)C2
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: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNc2nnc(-c3ccc4[nH]cc(-c5cccc(N6CCn7c(C)nnc7C6)n5)c4c3)s2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A glass microwave reaction vessel was charged with N-(4-methoxybenzyl)-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-thiadiazol-2-amine (90.0 mg, 0.146 mmol) and 7-(6-bromopyridin-2-yl)-3-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (64.4 mg, 0.219 mmol) in p-dioxane/H2O (3:1, 2.0 mL) followed by potassium carbonate (40.3 mg, 0.292 mmol) and Pd(PPh3)4 (8.43 mg, 7.30 μmol). The reaction was stirred and heated in a microwave at 100° C. for 15 min, then 120° C. for 15 min. The mixture was diluted with DCM and washed with brine, dried, filtered and concentrated to give the crude material. MS (ESI, pos. ion) m/z: 550 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[NH:7][C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].C(N(C(C)C)CC)(C)C.Br[CH2:24][C:25]#[C:26][CH3:27]>CN(C)C=O.O>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:24][C:25]#[C:26][CH3:27])[C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CC#CCBr
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 40.00 g of 3-methyl-8-bromoxanthine, 36 ml of diisopropylethylamine and 23.00 g of 1-bromo-2-butyne in 500 ml of N,N-dimethylformamide is stirred at room temperature for three hours. 1 ml of 1-bromo-2-butyne is then added again and the mixture is stirred at room temperature for a further hour until the reaction is complete. For work-up, the reaction mixture is diluted with 400 ml of water. The resulting precipitate is filtered off with suction, washed with water, cold methanol and diethyl ether and dried.
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:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.[CH3:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[CH:25]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=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:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[N:18]=[CH:25]/[C:21]2[S:22][CH:23]=[CH:24][C:20]=2[CH3:19])=[N:2]1
Reactant: Cc1ccsc1C=O
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccsc1/C=N/c1ccccc1C=Cc1n[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Compound 2 (0.060 g, 0.25 mmol) was dissolved in toluene (3.0 mL) and the solution was added with 3-methylthiophene-2-carbaldehyde (55 μL, 0.51 mmol), p-toluenesulfonic acid (small amount), followed by stirring at 60° C. for 2 hours. Then, the reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was triturated in ethanol to obtain Compound 160 (76 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cc(OC2CCNCC2)c2cc(F)ccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(OC2CCN(S(C)(=O)=O)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of [6-fluoro-4-(piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (80 mg, 0.25 mmol) and methanesulfonyl chloride (58 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was added triethylamine (63.6 mg, 0.63 mmol). After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 10-50% ethyl acetate in petroleum ether) to afford [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (82 mg, 83%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([F:35])[C:41]=5[F:42])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(F)c1F
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5F)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2,3-difluoro-phenylboronic acid. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.[CH2:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].S(=O)(=O)(O)O>O>[C:1]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCOC(=O)c1cc(O)c(O)c(O)c1
Yield: 75 %

Procedure:
A mixture of 30 g of tara (about 0.1 mole of bound gallic acid), 120 g (0.95 mole) of n-octanol and 3 g of anhydrous sulfuric acid was heated at 140° C. for 7 hours with continuous removal of the water of reaction, after which the mixture was washed neutral with water and then evaporated down to give the crude n-octyl gallate in the form of an oil. The purity of the product was 65% and the yield was 75%, calculated as pure ester.
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:32])=[CH:33][CH:34]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 46.1 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methyl)amino]benzoic acid (143 mg) synthesized in Example 71 (2) and ethyl 3-(methylamino)propanoate (45.9 mg) to give the title compound (77.4 mg, 46%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1.CCN(CC)CC.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C1COCC1.CN(C1C=CN=CC=1)C.CCOCC>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[CH2:5][CH:4]=[CH:3][CH2:2]2)=[O:19])=[CH:16][CH:15]=1
Reactant: C1=CNCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)N1CC=CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Pyrroline (4 mL, 54 mmol) was dissolved in THF (100 mL), Et3N (14 mL, 100 mmol) was added. The mixture was cooled to 0° C. 4-chloro-benzoyl chloride (7.6 mL, 60 mmol) was added very slowly at 0° C. Catalytic amount of DMAP was added too. Finally the reaction mixture was stirred at 0° C. to RT for overnight. The reaction mixture was diluted with ether and filtered to remove white solid of Et3N.HCl. Then evaporated to remove solvent and triturated with hexane/ether to give white solid 10.3 g with ratio of unsaturated/saturated about 3/1 by NMR. Then triturated with hexane/ether again to give 6.68 g white solid with ratio of unsaturated/saturated about 3.7/1 by NMR. 1H-NMR (300 MHz, CDCl3): δ 4.3 (4H, d), 5.80 (2H, d), 7.40 (4H, dd)