Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:44]([OH:52])(=[O:51])[CH:45]([CH2:47][C:48]([OH:50])=[O:49])[OH:46].[H][H]>O1CCCC1.CCOCC>[CH2:21]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:51][C:44](=[O:52])[CH:45]([CH2:47][C:48]([OH:50])=[O:49])[OH:46])=[O:17])=[CH:19][CH:20]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC(=O)C(O)CC(=O)O)cc1

Procedure:
To a warm solution of N-carbobenzyloxy-4-(hexadecylamino)benzoyl chloride and 1.3 g. (1 eq) triethylamine in 100 ml. ether is treated with 2 g. (14.9 m moles) malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated over 600 mg. 10% Pd(C) at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetic acid to yield the title compound as a tan, crystalline mass.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:48]=[CH:47][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH:37]([C:40]([O:42]C(C)(C)C)=[O:41])[CH2:36]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:15][CH:14]=1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[NH:28][CH:27]=[C:26]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:39][CH2:38][CH:37]([C:40]([OH:42])=[O:41])[CH2:36]4)=[O:30])[CH:25]=3)[CH:19]=2)=[CH:47][CH:48]=1)=[O:11]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCC(C(=O)OC(C)(C)C)C5)c[nH]4)c3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCC(C(=O)O)C5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylate (22 mg, 0.033 mmol) in 2 ml of methylene chloride was added 1 ml of TFA. The mixture was stirred at room temperature for 16 hours, and evaporated to dryness under reduced pressure. The residue was re-dissolved in 2 ml of methanol and poured into 10 ml of water with vigorous stirring. Saturated NaHCO3 solution was added dropwise until pH=7. The precipitates were filtered, washed with water and dried in vacuo to give 1-(3-{[(5-{4-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}propyl)pyrrolidine-3-carboxylic acid as light reddish solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-])=[CH:7][C:6]=2[N:16]=1)[CH3:2].[NH4+:30].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:30][C:7]1[C:6]2[N:16]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: [NH4+]
Reactant: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-[2-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (14.3 g, 35.8 mmol) in 90 mL of CH2Cl2 was treated with 90 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (7.05 g, 37.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature. After 30 min, the reaction was treated with 90 mL of CH2Cl2 and 90 mL of water. The organic portion was then washed with 1% Na2CO3 solution (2×), water, brine, dried over Na2SO4 and concentrated. The resulting solid was triturated in ether and filtered to yield 9.35 g of tert-butyl 2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light tan solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1.CC(O)=O>C1COCC1>[CH3:38][C:37](=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([OH:28])=[CH:34][CH:33]=1
Reactant: CC(=O)CCc1ccc(O)cc1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=Cc1ccccc1)CCc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (10.9 g, 25.1 mmol, 1.2 equiv.) in THF (35 mL), was added potassium-t-amylat (1.7 M in toluene, 20 mL, 34.0 mmol, 1.7 equiv.) at 25° C. 4-(4-Hydroxyphenyl)butan-2-one (3.3 g, 20.1 mmol, 1.0 equiv.) in THF (5 mL) was added to the red suspension, and the mixture was stirred at 70° C. for 30 min. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was diluted with hexanes (50 mL). The organic phase was washed with H2O (2×30 mL) and MeOH/H2O (8:2, 2×20 mL) and concentrated. The residue was purified by flash chromatography on SiO2 to yield 2.10 g (44%) of the title compound as a white solid.
Reaction SMILES: OC(C(Cl)(Cl)Cl)[CH2:3][C:4]1[N:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12.[OH-:29].[Na+].[CH2:31]([OH:33])[CH3:32]>>[C:31](/[CH:32]=[CH:3]/[C:4]1[N:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)([OH:29])=[O:33]
Reactant: OC(Cc1nnccc1-c1c(-c2ccccc2)nn2ccccc12)C(Cl)(Cl)Cl
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)/C=C/c1nnccc1-c1c(-c2ccccc2)nn2ccccc12

Procedure:
To an ethanol (12 ml) solution of 3-[3-{2-hydroxy-3,3,3-trichloropropyl)pyridazin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (1.20 g) was added 24% aqueous sodium hydroxide solution (4.8 ml), and refluxed for 5 hours. The reaction mixture was evaporated in vacuo and added 10% hydrochloric acid (12 ml). The precipitates were collected by filtration to give 3-[3-{(E)-2-carboxyvinyl}pyridazin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.64 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCN(C(=O)c1ccc(F)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Yield: 81.6 %

Procedure:
The title compound was prepared as described in Example 24. A, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol) and 4-fluorobenzoyl chloride (0.475 g, 3.0 mmol) to provide the title compound (0.786 g, 82% yield): ES-MS (m/z) 482 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11]([O:13]CC)=[O:12])=[O:7])[CH3:4].O>C(O)C.CC(C)=O>[CH2:3]([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11]([OH:13])=[O:12])=[O:7])[CH3:4]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.7 %

Procedure:
Add a solution of 0.709 g (17.72 mmol) sodium hydroxide in 7.38 mL ethanol to a solution of (+/−)-trans-cyclopropane-1,2-dicarboxylic acid diethyl ester (3.00 g, 16.11 mmol) in 36.9 mL acetone. Stir at room temperature for 24 hours. Pour reaction mixture into 100 mL water and extract with ethyl acetate (1×70 mL). Acidify the aqueous layer with 5N HCl and concentrate under reduced pressure. Add ethyl acetate and filter the resulting slurry. Concentrate the filtrate under reduced pressure to provide the desired compound (2.26 g, 88.7%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[N:18][CH3:19])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]2.[BH4-].[Na+]>C(O)(C)C>[OH:1][CH2:2][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH2:17][NH:18][CH3:19])=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: CN=Cc1c2ccccc2c(CO)c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CNCc1c2ccccc2c(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.9 %

Procedure:
10-(hydroxymethyl)-9-((methylimino)methyl)anthracene (1.00 g, 4.0 mmol) was slurried in 25 mL isopropanol. NaBH4 (0.454 g, 12.0 mmol) was added as a solid and the solution was stirred at room temperature for 72 h. The mixture was filtered on a sintered-glass frit and the solvent was removed under reduced pressure to yield 10 as a bright yellow powder (0.853 g, 86% yield): 1H NMR (300.13 MHz, CD3OD) δ 2.55 (s, 3H), 4.64 (s, 2H), 5.56 (s, 2H), 7.55 (m, 4H), 8.38 (m, 2H), 8.50 (m, 2H); 13C—{1H} NMR (75.4 MHz, CD3OD) δ 133.4, 133.0, 131.6, 131.5, 126.9, 126.7, 126.2, 125.7, 57.2, 47.9, 36.5.
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[O:3][Si:4]([CH3:18])([CH3:17])[O:5][Si:6]([CH3:16])([CH3:15])[O:7][Si:8]([CH3:14])([CH3:13])OC(=O)C.[C:21]([OH:26])(=[O:25])[C:22]([CH3:24])=[CH2:23]>>[CH3:1][Si:2]([CH3:19])([CH3:20])[O:3][Si:4]([CH3:18])([CH3:17])[O:5][Si:6]([CH3:16])([CH3:15])[O:7][Si:8]([CH3:13])([CH3:14])[O:25][C:21](=[O:26])[C:22]([CH3:24])=[CH2:23]
Reactant: C=C(C)C(=O)O
Reactant: CC(=O)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C
Product: C=C(C)C(=O)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C

Procedure:
5 g of nonamethyl-1-acetoxy-tetrasiloxane prepared as described in reference example of EP-0839869 and 2.31 g of commercial methacrylic acid (ATOFINA Norsocryl® MAA) are mixed at room temperature. Acetic acid is then distilled under reduced pressure (45° C./13 hPa) to afford nonamethyl-1-methacryloyloxy-tetrasiloxane.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[CH:6]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].Cl.Cl.[N:31]1([CH2:35][CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32]1>O1CCCC1.C(N(CC)CC)C.CN(C)C=O>[F:1][C:2]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:20]([N:39]2[CH2:40][CH2:41][CH:36]([CH2:35][N:31]3[CH2:34][CH2:33][CH2:32]3)[CH2:37][CH2:38]2)=[O:21])[CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: C1CN(CC2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(CN2CCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(2-Fluoro-4-nitrophenoxy)pyridin-2-ylamine (60 mg) was dissolved in tetrahydrofuran (3 ml) under a nitrogen atmosphere, and then triethylamine (0.101 ml) and phenyl chloroformate (0.0908 ml) were added thereto while cooling in an ice water bath, followed by warming to room temperature and stirring for 1.5 hrs. The solution was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (30 ml), water (30 ml), brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, to which was added N,N-dimethylformamide (3 ml). 4-(Azetidin-1-ylmethyl)piperidine dihydrochloride (192 mg) and triethylamine (0.235 ml) were added thereto, followed by stirring for 8 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and a saturated aqueous solution of ammonium chloride (50 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (50 ml), water (50 ml), and brine (50 ml), and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:1, then ethyl acetate). Fractions containing the target compound were concentrated to provide the titled compound (34 mg) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+]>CO.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][S:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:36])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CCCCCSCCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCS(=O)CCCCCCCCCC1c2ccc(O)cc2SCC1(C)c1ccc(O)cc1
Yield: 55.1 %

Procedure:
A solution of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-(9-pentylthiononyl)thiochroman (178 mg, 0.355 mmol) and sodium periodate (83 mg, 0.390 mmol) in methanol (20 ml) and water (5 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was quenched with water and then diluted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated. The concentrate was purified with preparative chromatography on silica gel plate (hexane:ethyl acetate=1:1) to obtain 101 mg (yield: 55%) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[N:27]1([CH2:33][CH2:34][O:35][C:36]2[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=2)[CH:39]=O)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:39]([C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:35][CH2:34][CH2:33][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:37]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1cccc(OCCN2CCOCC2)c1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4cccc(OCCN5CCOCC5)c4)nc23)CC1)Nc1nccs1
Temperature: 85 °C

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide (0.060 g, 0.15 mmol, 1 eq) in EtOH (2.6 mL) and DMF (0.35 mL), 3-(2-morpholin-4-ylethoxy)benzaldehyde (0.039 g, 0.17 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.45 mL, 0.45 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.018 g, 21%); 1H-NMR (500 Mz, DMSO-d6): 2.68-2.85 (m, 6H), 3.41 (s, 2H, NCH2CO), 3.55-3.65 (m, 4H), 3.71-3.80 (m, 4H), 4.12-4.25 (s, 2H), 7.06-7.12 (m, 1H), 7.23 (d, J=3.5 Hz, 1H, thiazole H-5 or thiazole H-4), 7.40-7.50 (m, 2H, thiazole H-4 or thiazole H-4 and ArH), 7.75-7.82 (m, 2H, ArH), 8.13 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.70-12.10 (br s, 1H, NHCO), 13.18 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.62 min—583/585 [(M+H)+, Cl isotopic pattern].
Reaction SMILES: [C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:27]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[CH:32][CH:31]=3)=[O:28])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1COCC1.[OH-].[Na+].Cl>CO>[C:1]1([C@H:11]([NH:13][CH2:14][CH:15]2[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([C:27]([O:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=3)=[O:28])[CH2:16]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](NCC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To 232 mg of 4-(methoxycarbonyl)phenyl 3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate were added 6.0 mL of THF, 3.0 mL of methanol, and 3.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. After neutralizing by addition of 3.0 mL of 1 M hydrochloric acid, the reaction mixture was concentrated under reduced pressure. To the residue was added water, followed by extraction with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol). This was dissolved in a small amount of chloroform, and hexane was added thereto. Then, the precipitate was isolated by filtration, and dried under reduced pressure at 50° C. to obtain 66 mg of 4-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}oxy)benzoic acid as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([NH2:21])[CH:13]=[CH:14][C:15]=1[O:16][C:17]([F:20])([F:19])[F:18].Cl.Cl[C:24](OC(Cl)(Cl)Cl)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:21]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]([F:19])([F:18])[F:20])=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=1)=[C:24]=[O:25]
Reactant: Nc1ccc(OC(F)(F)F)c(-c2nc3ccccc3o2)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C=Nc1ccc(OC(F)(F)F)c(-c2nc3ccccc3o2)c1
Yield: 70.4 %

Procedure:
A solution of 3-benzoxazol-2-yl-4-trifluoromethoxyphenylamine (210 mg, 0.71 mmol) in 5 mL of dry toluene was stirred while 1.15 mL of 3.1N hydrochloric acid in ethyl acetate was added. The precipitate was concentrated by evaporation. Another 5 mL of toluene was added followed by evaporation. This procedure was repeated 3 times to remove excess of hydrochloric acid. The amine hydrochloride was dissolved in 5 mL of toluene and trichloromethyl chloroformate (0.853 mL, 7.1 mmol) was added. The mixture was refluxed overnight under a nitrogen atmosphere, evaporated at 70° C. followed by stripping with dry toluene. 2-(5-Isocyanato-2-trifluoromethoxyphenyl)benzoxazole (160 mg, 70%) was obtained as crystals and used immediately to synthesize the title compound.
Reaction SMILES: [Na+].[CH:2]1([N:5]2[C:9]([C:10]([O-])=[O:11])=[C:8]([C:13]3[CH:14]=[N:15][C:16]([N:19]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)[CH2:4][CH2:3]1.[N:45]1([CH:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:2]1([N:5]2[C:9]([C:10]([N:53]3[CH2:54][CH2:55][CH:50]([N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:51][CH2:52]3)=[O:11])=[C:8]([C:13]3[CH:14]=[N:15][C:16]([N:19]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:17][CH:18]=3)[N:7]=[C:6]2[C:34]2[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:38][CH:39]=2)[CH2:3][CH2:4]1
Reactant: O=C([O-])c1c(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1c(-c2ccc(N(Cc3ccccc3)Cc3ccccc3)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1)N1CCC(N2CCCC2)CC1
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 0.12 g (0.2 mmol) of 3-cyclopropyl-5-(6-dibenzylamino-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid sodium salt and 0.03 g (0.2 mmol) of 4-pyrrolidin-1-yl-piperidine in 1 ml of DMF was added 83 microliters (0.6 mmol) of triethylamine and 0.08 g (0.2 mmol) of HATU. The mixture was stirred for 1 h after which time it was evaporated to dryness, the residue was partitioned between CH2Cl2 and saturated sodium hydrogen carbonate solution, the organic phase was dried with sodium sulfate and concentrated. Purification by flash column chromatography [MeOH/CH2Cl2 5:95] afforded 0.1 g (79%) of the title compound as a colorless solid. MS: 721.3 (MH+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[NH2:14][C:15]1[N:20]=[C:19]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([Cl:31])[N:16]=1>C1COCC1.CCOC(C)=O.O>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:18]=[C:17]([Cl:31])[N:16]=[C:15]([NH2:14])[N:20]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCN3)n1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.5 h

Procedure:
A solution of 226 mg (1.21 mMol) 3-trifluoromethyl-phenylisocyanat in 5 ml THF is added dropwise to 302 mg (1.15 mMol) 5-(2-amino-6-chloro-pyrimidin-4-yloxy)-2,3-dihydro-indole (Step 24.2) in 5 ml THF. After 30 min, the reaction mixture is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; EtOAc/hexane 1:4→2:5) gives the title compound: MS: [M+1]+=450; TLC(hexane/EtOAc 3:2): Rf=0.08; HPLC: AtRet=15.6.