Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC[C@@H](N[C:11](=[O:26])[C@:12]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[CH3:25][C@@:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:11]([OH:26])=[O:28]
Reactant: CC(C)(C)CC[C@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@](C)(C(=O)O)c1ccccc1
Yield: 90 %

Procedure:
To a solution of Example 48A (4.48 g, 12.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3×200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.66 g, 90%). 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9 H) 1.09 m, 2 H) 1.56 (s, 3 H) 1.99 m, 2 H) 7.33 m, 5 H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[C:16]2[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:28][CH3:29])[CH:15]=2)[N:10]=1>C(O)(C)(C)C.CCOCC>[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([O:30][CH3:31])=[C:14]([O:28][CH3:29])[CH:15]=3)[N:10]=[C:9]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:18]=2)=[CH:20][CH:21]=1)([CH3:27])[CH3:26]
Reactant: Oc1ccccc1
Reactant: COc1cc2nc(Cl)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COc1cc2nc(Oc3ccccc3)nc(-c3ccc(C(C)C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
216 mg (2.30 mmol) phenol and 11 mg (0.44 mmol) are dissolved in 2 ml t-butanol and the resulting solution is stirred for 3 h at rt. After that time 80 mg (0.23 mmol) 2-chloro-4-(4-isopropyl-phenyl)-6,7-dimethoxy-quinazoline is added and the solution is stirred at 85° C. overnight. The reaction mixture is diluted with ether and extracted with brine. The organic layer is dried and evaporated. After chromatography (hexane/ethyl acetate the product is obtained as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([SH:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13]I>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]([C:9]#[N:10])=[C:6]([S:8][CH3:13])[N:7]=1
Reactant: CSc1nc(N)nc(S)c1C#N
Reactant: CI
Solvent: CC(C)=O
Product: CSc1nc(N)nc(SC)c1C#N
Temperature: 80 °C

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4-mercapto-6-methylsulfanyl-pyrimidine-5-carbonitrile (3:50 mg, 2.5 mmol, 1.0 eq.), methyl iodide (8.2 mmol), and acetone (10 mL). The reaction mixture was heated at 80° C. for 5 min. The precipitate was filtered and gave to white solid. No further purification was necessary (312 mg, 58%). LC-MS: (ES+) m/z 213 (M+1). 1H-NMR, Varian 400 MHz (DMSO-d6) δ 2.52 (s, 3H), 2.46 (s, 3H) ppm
Reaction SMILES: [O-:1][S:2](S([O-])=O)=[O:3].[Na+].[Na+].O.[CH:10]([C:13]([C:16]([C:19]([C:22]([C:25]([CH2:28]I)([F:27])[F:26])([F:24])[F:23])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11]>C(#N)C>[CH:10]([C:13]([C:16]([C:19]([C:22]([C:25]([CH2:28][S:2]([OH:1])=[O:3])([F:26])[F:27])([F:23])[F:24])([F:20])[F:21])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11]
Reactant: FC(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CI
Reactant: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=S(O)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 70 °C
Yield: 94 %

Procedure:
Na2S2O4 (260 mg, 3.0 mmol) was poured into a 20 ml flask and the inside of the flask was replaced with argon. Water (5.0 ml) was added thereto and then, H(CF2)6CH2I (442 mg, 1.0 mmol) was added dropwise using acetonitrile (5.0 ml). After ten-hour stirring at 70° C., purification was conducted by adding 3N—HCl to the reaction product, extracting with ether, extracting into water layer with an aqueous solution of saturated NaHCO3, again making the solution acidic with hydrochloric acid and then extracting into ether layer. After distilling off the solvent, drying was carried out under reduced pressure to obtain H(CF2)6CH2SO2H (359 mg, 0.94 mmol).
Reaction SMILES: C([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.CN1CCOCC1.ClC(OCC(C)C)=O.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]=[CH:39][CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH2:50])=[CH:44][C:43]=2[O:51][CH3:52])=[CH:34][CH:33]=1.Cl>O1CCCC1>[NH2:8][C@@H:9]([CH:10]([CH3:11])[CH3:12])[C:13]([NH:50][CH2:49][CH2:48][C:45]1[CH:46]=[CH:47][C:42]([O:41][CH2:40][CH2:39][CH2:38][C:35]2[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][CH:36]=2)=[C:43]([O:51][CH3:52])[CH:44]=1)=[O:15]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(CCN)ccc1OCC=Cc1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cc(CCNC(=O)[C@@H](N)C(C)C)ccc1OCCCc1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
BOC-L-Valine (31.4 g) and N-methylmorpholine (15.9 ml) are dissolved in tetrahydrofuran (250 ml) and cooled to −20° C. Isobutyl chloroformate (18.9 ml) is added dropwise during 20 minutes. The resulting mixture is stirred for 15 min and allowed to warm to −7° C. It is then cooled again to −20° C. and a solution of 2-{4-[3-(4-chloro-phenyl)-allyloxy]-3-methoxy-phenyl}-ethylamine (41.7 g) in tetrahydrofuran (150 ml) is added dropwise during 40 min. The reaction mixture is stirred at room temperature during 4 hours. 1M Hydrochloric acid (500 ml) is added carefully. It is extracted with ethyl acetate (2×500 ml). The organic layers are washed with 1M hydrochloric acid (500 ml) and brine (500 ml), dried (MgSO4) and evaporated. The residue is dissolved in tetrahydrofuran (500 ml) and hydrogenated over palladium (5% on charcoal, 0.14 g) at room temperature and normal pressure. The reaction mixture is filtered and evaporated. The residue is dissolved in dioxane (130 ml) and added dropwise to 4M sulfuric acid (650 ml). The resulting mixture is stirred for 8 hours at +50° C. After cooling it is extracted with diethyl ether (2×1000 ml). The aqueous phase is saturated with potassium carbonate and then extracted with diethyl ether (2×1500 ml). The organic layers are dried (K2CO3) and evaporated. (S)-2-Amino-N-(2-{4-[3-(4-chloro-phenyl)-propoxy]-3-methoxy-phenyl}-ethyl)-3-methyl-butyramide is obtained.
Reaction SMILES: CO.O.C[O:5][C:6](=[O:23])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][CH3:22])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[OH-].[Na+:25]>O>[Na+:25].[CH3:22][O:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([O-:23])=[O:5])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1
Reactant: COCCN1CCN(c2ccc(C(=O)OC)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCN1CCN(c2ccc(C(=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To 4 ml of MeOH/H2O (1:1) is added 0.52 g (1.87 mmol) of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl]benzoic acid methyl ester and 0.078 g (1.96 mmol) of NaOH (30%). The resulting reaction mixture is stirred 1 hour at 80° C., then cooled to room temperature and diluted with H2O. The H2O-layer is extracted 3 times with diethyl ether and then lyophilised to yield 0.47 g of 4-[4-(2-methoxy-ethyl)-piperazin-1-yl)-benzoic acid sodium salt as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Cl:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([S:1][C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=3)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][N:28]2[C:31]2[CH:32]=[N:33][N:34]([CH2:36][CH2:37][CH3:38])[CH:35]=2)=[CH:24][CH:23]=1
Reactant: CCCn1cc(-n2ccc3ccc(Cl)cc32)cn1
Reactant: CCOC(=O)c1cccc(S)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.4 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (372 mg, 2.03 mmol) in CH2Cl2 (20 mL) under inert atmosphere was added NCS (271 mg, 2.03 mmol) at 0° C.; warmed to RT and stirred for 45 min. To this, compound 2 (500 mg, 1.93 mmol) was added at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (40 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 3 (700 mg, 83%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.89 (s, 1H), 7.76-7.74 (m, 1H), 7.72 (s, 1H), 7.68 (s, 1H), 7.49-7.47 (m, 2H), 7.40 (s, 1H), 7.24-7.23 (m, 2H), 7.15 (d, J=8.4 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.01-1.96 (m, 2H), 1.34 (t, J=7.2 Hz, 3H), 1.00 (t, J=7.2 Hz, 3H); LC-MS (ESI): 72.2%; m/z 440.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.87 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.C(=O)(O)[O-].[Na+].[NH2:14][C:15]1[N:16]=[N:17][C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21]>O.C(O)C>[CH3:22][C:18]1[CH:19]=[C:20]([CH3:21])[C:15]2[N:16]([CH:3]=[CH:4][N:14]=2)[N:17]=1
Reactant: Cc1cc(C)c(N)nn1
Reactant: COC(CBr)OC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2nccn2n1
Reaction time: 16 h
Yield: 44.6 %

Procedure:
A mixture of 25 g (148 mmol) of bromoacetaldehyde dimethyl acetal, 5 mL of water and 5 mL of 48% HBr was refluxed 2 h. After cooling, it was poured into 50 mL of ethanol. Solid sodium bicarbonate was added until bubbling ceased. The mixture was filtered and to the filtrate was added 7.5 g (61 mmol) of 3-amino-4,6-dimethylpyridazine. After stirring 16 h, the ethanol was removed with a rotary evaporator. The residue was triturated with ethanol to give a brown solid which was dissolved in water and washed with dichloromethane. The aqueous layer was brought to pH 9 with sodium bicarbonate and extracted with dichloromethane. Drying (Na2SO4) and solvent removal with a rotary evaporator gave 4 g of the title compound as a brown solid, m.p. 70°-74° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[C:15]=2[F:22])=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O-])([O-])=O.[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])(=O)=O>C(C(C)=O)C>[CH2:1]([C:8]1[CH:13]=[N:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:33][CH:34]([F:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:16]([F:21])[C:15]=2[F:22])=[N:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1cnc(-c2ccc(O)c(F)c2F)nc1
Reactant: CCCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCc1cnc(-c2ccc(OCC(F)CCCCCC)c(F)c2F)nc1

Procedure:
0.08 mol of 5-heptyl-2-(2,3-difluoro-4-hydroxyphenyl)pyrimidine, together with 11.6 g of K2CO3 and 25.6 g of optically active 2-fluoro-1-octyl tosylate in 70 ml of methyl ethyl ketone, are refluxed for 12 hours under a protective gas atmosphere. The reaction mixture is then hydolysed [sic], and the product is then worked up in a customary manner and purified by chromatography, to give optically active 5-n-heptyl-2-[2,3-difluoro-4-(2-fluorooctyloxy)phenyl]pyrimidine of melting point 56° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:39])([F:38])[F:37])[CH3:29])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][CH:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]([F:37])([F:38])[F:39])[CH3:29])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1
Reactant: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 44, 10.18 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide and 4.61 g of tetra-n-butylammonium fluoride (˜75% in H20) in 670 ml THF yield the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][O:28][CH2:29][C:30]([OH:32])=O)=[C:21]([C:34]([O:36]C)=[O:35])[CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:33])[CH2:27][O:28][CH2:29][C:30]([N:3]([CH2:1][CH3:2])[C:4]2[CH:5]=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH:7]=[CH:8][C:9]=2[CH3:10])=[O:32])=[C:21]([CH:20]=1)[C:34]([OH:36])=[O:35]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: CCNc1cc(-c2ccc(F)cc2)ccc1C
Product: CCN(C(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccc(F)cc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-4′-fluoro-4-methylbiphenyl-3-amine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-[((2-[ethyl(4′-fluoro-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:40])C(=O)C1>C(Cl)Cl.O>[Cl:40][C:7]1[N:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)[C:9]2[C:5]([C:6]=1[S:20][C:21]1[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Solvent: O
Solvent: ClCCl
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirred solution of ethyl 3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate 6 (100 mg, 0.21 mmol) in CH2Cl2 (3 mL) was added NCS (33.7 mg, 0.25 mmol) at RT under inert atmosphere. After 8 h stirring, additional NCS (33.7 mg, 0.25 mmol) was added at RT and stirred again for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 9-11% EtOAc/Hexanes to afford compound 7 (50 mg, 47%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71-7.67 (m, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.4, 6.0 Hz, 1H), 7.04-6.97 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.04-1.93 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H); LC-MS (ESI): 98.8%; m/z 510.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.94 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[S:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CSC(CCCCN=[N+]=[N-])CCCc1cccnc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CSC(CCCCN)CCCc1cccnc1
Temperature: 25 °C
Reaction time: 52 h

Procedure:
To a solution of 0.1 g (0.28 mmol) ethyl 8-azido-4-[3-(3-pyridyl)propyl]-3-thia-octanoate in 0.7 mL tetrahydrofuran is added 0.082 g triphenylphosphine followed by 0.01 mL water. The mixture is stirred at room temperature for 52 hours and then evaporated to give ethyl 8-amino-4-[3-(3-pyridyl)-propyl]-3-thia-octanoate, NMR (CDCl3) delta 4.2 (q,2H), 3.2 (s,2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:20][CH3:21])=[N:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]2)=[CH:7][CH:6]=1)=[O:4].O>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH2:20][CH3:21])=[N:10][N:11]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CCc1nn(C2C=CCCC2)c2cc(C(=O)OC)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nn(C2CCCCC2)c2cc(C(=O)OC)ccc12
Reaction time: 0.75 h
Yield: 94.8 %

Procedure:
A mixture of 417 mg (1.47 mmol, 1.0 equiv) 1-cyclohex-2-enyl-3-ethyl-1H-indazole-6-carboxylic acid methyl ester and 50 mg of 10% Pd/C, 50% water wet in 20 mL ethyl acetate was placed on a Parr® hydrogenation appartus and shaken under 45 psi H2 for 45 minutes. The reaction mixture was filtered through Celite®, and the filtrate concentrated on a rotary evaporator and dried at high vacuum, room temperature to give 399 mg (95%) of a clear oil: HRMS calcd for C17H22N2O2+H: 287.1759. Found: 287.1783.
Reaction SMILES: [CH2:1]([C:6]1[C:11]([CH:12]=[CH:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Li+].[OH-]>C1COCC1.O>[CH2:1]([C:6]1[C:11]([CH:12]=[CH:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=[C:8]([C:18]([F:21])([F:19])[F:20])[N:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1nc(C(F)(F)F)ccc1C=CC(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCc1nc(C(F)(F)F)ccc1C=CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a suspension of compound 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid, methyl ester (366 mg, 1.22 mmol) in THF (3 ml) was added a solution of 1 N-LiOH (3.0 ml), and the mixture was stirred for 3 hours at room temperature. The resulting residue was dissolved in H2O and then washed with EtOAc, acidified with 1N HCl to pH 1˜2. The solution was extracted three times with methylene chloride and then dried over anhyd. MgSO4 and concentrated in vacuo to give 3-(2-pentyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (340 mg, 97%).
Reaction SMILES: CO.[O:3]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:19][C:20](=[O:30])[CH2:21]/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[O:3]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:19][C:20](=[O:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(C/C=C/c1ccccc1)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(CCCc1ccccc1)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1.3 mg of 10% palladium-carbon was added to a mixed solution of 1.0 mL of methanol and 1.0 mL of ethyl acetate containing 10 mg of 4-phenoxy-2-((E)-4-phenyl-3-butenamido)benzoic acid and stirred under hydrogen atmosphere at room temperature for 6 hours. After insoluble were removed by filtration, the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 4.6 mg of 4-phenoxy-2-(4-phenylbutanamido)benzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13]CC)=O)=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH:16]1([C:19]2[C:27]3[C:26]([NH2:28])=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)[N:20]=2)[CH2:18][CH2:17]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[C:19]([CH:16]3[CH2:18][CH2:17]3)=[N:20][N:21]4[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[O:13])=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)ccn12
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A mixture of ethyl 7-chloroimidazo[1,2-a]pyridine-3-carboxylate (10.0 g, 44.5 mmol) and 3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-amine (12.4 g, 44.5 mmol) in THF (100 mL) was cooled to 0° C. using an ice/water bath. A solution of 1.0M lithium bis(trimethylsilyl)amide (102 mL, 102 mmol) was added slowly over 40 minutes keeping the internal temperature below 5° C. The mixture was stirred at 0° C. for 30 minutes, diluted with IPA (100 mL), and then concentrated under reduced pressure. The residue was diluted with IPA (100 mL) and concentrated under reduced pressure. The residue was dissolved in IPA (100 mL) and treated with a 10% aqueous ammonium chloride solution (200 mL) to give a slurry which was filtered and dried to give 7-chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a light brown solid (18.4 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[N:26]=[C:27]=[O:28]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27](=[O:28])[N:16]([C:14]1[CH:15]=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:11]=[CH:12][N:13]=1)[CH3:17]
Reactant: O=C=Nc1c(Cl)cccc1Cl
Reactant: CNc1cc(Nc2ccc(F)cc2F)ncn1
Product: CN(C(=O)Nc1c(Cl)cccc1Cl)c1cc(Nc2ccc(F)cc2F)ncn1

Procedure:
The title compound is prepared analogously as described in Example 105B from N-(2,4-difluoro-phenyl)-N′-methyl-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([O:14]CC(C)=C)=[CH:10][C:11]=2[CH3:13])[CH2:6][CH:5]1[CH3:20])(=[O:3])[CH3:2]>C(N(CC)C1C=CC=CC=1)C.C(OCC)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([OH:14])=[C:10]([CH2:8][C:7]([CH3:12])=[CH2:6])[C:11]=2[CH3:13])[CH2:6][CH:5]1[CH3:20])(=[O:3])[CH3:2]
Reactant: C=C(C)COc1cc(C)c2c(c1C)CC(C)N2C(C)=O
Solvent: CCOCC
Solvent: CCN(CC)c1ccccc1
Product: C=C(C)Cc1c(C)c2c(c(C)c1O)CC(C)N2C(C)=O
Yield: 174.2 %

Procedure:
A solution of 1-acetyl-2,3-dihydro-2,4,7-trimethyl-5-[(2-methyl-2-propenyl)oxy]-1H-indole (3.8 g, 14.7 mmol) in N,N-diethylaniline (30 ml) was stirred for 2 hours at 200° C. under nitrogen atmosphere. The reaction mixture was diluted with diethyl ether, and washed with 1N hydrochloric acid, water and saturated brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain 3.5 g of the title compound as an oil.