Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][C:44](=[O:46])[CH3:45])[CH2:10]2)=[CH:5][CH:4]=1.B.O1CCCC1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@@H:11]([CH2:42][CH2:43][CH:44]([OH:46])[CH3:45])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: B
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(C)O)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to procedure 29a, 800 mg of 4-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-butan-2-one and 3.0 ml of borane-tetrahydrofuran complex (1N in tetrahydrofuran) are used to afford the title compound as a yellow oil. Rf=0.22 (EtOAc-heptane 2:1); Rt=5.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C@@H:9]([CH3:12])[CH2:10]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(N(CC)CC)C.N=[PH3]>[OH-].[Na+].C(#N)C>[CH3:10][C@H:9]1[CH2:12][NH:1][C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8]1
Reactant: C[C@@H](CO)Nc1ccccc1N
Agent: BrC(Br)(Br)Br
Agent: N=[PH3]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@H]1CNc2ccccc2N1
Temperature: 35 °C
Reaction time: 0.17 h
Yield: 41.6 %

Procedure:
A 1-L round bottomed flask containing (S)-2-(2-aminophenylamino)propane-1-ol (5.12 g, 30.8 mmol) was charged with acetonitrile (400 mL). The solution was concentrated partially in order to azeotropically dry the solution (ca. 100 mL of acetonitrile were removed). Triphenylphosphine (17.77 g, 67.8 mmol) was added, and once the triphenylphosphine had dissolved, carbon tetrabromide (22.47 g, 67.8 mmol) was added. The internal temperature gradually increased to a high of 35° C. After 10 min, triethylamine (18.89 mL, 136 mmol) was added. After 15 min, the reaction mixture was heated to 80° C. After 4 h, heating was discontinued and the reaction mixture stirred at rt overnight. The reaction mixture was diluted with aqueous sodium hydroxide and the mixture stirred at rt until hydrolysis of the iminophosphorane was complete. The mixture was extracted with dichloromethane. The dichloromethane extract was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel. The product-containing fractions were concentrated to afford (S)-2-methyl-1,2,3,4-tetrahydroquinoxaline (1.9 g, 41%). MS (ESI, pos. ion) m/z 149 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:27])[CH2:16][NH:17][C:18]3[N:23]=[C:22]([C:24]([NH2:26])=[O:25])[CH:21]=[CH:20][N:19]=3)[CH2:10][CH2:9]2)[CH:7]=1.Cl>CO>[NH2:26][C:24]([C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:17][CH2:16][CH2:15][NH:26][C:24]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([NH:17][CH2:16][CH:15]([OH:27])[CH2:14][N:11]3[CH2:10][CH2:9][N:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:28][CH3:29])[CH2:13][CH2:12]3)[N:23]=2)=[O:25])[N:23]=1)=[O:25]
Reactant: COc1ccc(Cl)cc1N1CCN(CC(O)CNc2nccc(C(N)=O)n2)CC1
Agent: Cl
Solvent: CO
Product: COc1ccc(Cl)cc1N1CCN(CC(O)CNc2nccc(C(=O)NCCNc3nccc(C(N)=O)n3)n2)CC1

Procedure:
4.7 g. (11.16 mmol) of (±)-2-[[3-[4-(5-chloro-2-methoxyphenyl) piperazin-1-yl]-2-hydroxypropyl]amino]pyrimidine-4-carboxamide and 450 ml of methanol are introduced into a 1 l round-bottomed flask, a stream of gaseous hydrochloric acid is passed through for a few minutes and the mixture is heated at the reflux temperature of the methanol for 2 h.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1C=CC=CC=1N>>[F:23][C:24]1[CH:2]=[CH:3][CH:4]=[CH:5][C:1]=1[NH:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: Nc1ccccc1F
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2ccccc2F)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (2-fluorophenyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.18 (s, 3H), 4.38 (bs, 2H), 6.84 (bs, 1H), 6.96-7.22 (m, 5H), 7.45-7.78 (m, 3H), 8.15 (bs, 1H); MS (ESI) m/z 324.5 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:18][C:19]1[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][Cl:39])[C:34](Cl)=[O:35]>N1C=CC=CC=1>[Cl:30][CH2:31][CH2:32][N:33]([CH2:37][CH2:38][Cl:39])[C:34]([O:26][CH2:25][C:23]1[CH:22]=[CH:21][C:20]([N+:27]([O-:29])=[O:28])=[C:19]([CH2:18][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:24]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1cc(CO)ccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Reactant: O=C(Cl)N(CCCl)CCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C[C@@H](Cc1cc(COC(=O)N(CCCl)CCCl)ccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Adapting a literature known protocol (Fex, et al., U.S. Pat. No. 3,299,104), tert-butyl(3R)-4-[5-[bis(2-chloroethyl)carbamoyloxymethyl]-2-nitro-phenyl]-3-(tert-butoxycarbonylamino)butanoate (20b) is prepared through carbamoylation of tert-butyl(3R)-3-(tert-butoxycarbonylamino)-4-[5-(hydroxymethyl)-2-nitro-phenyl]butanoate (20a) (731 mg, 2.0 mmol) with commercial N,N-bis(2-chloroethyl)carbamoyl chloride (439 μL, 614 mg, 3.0 mmol) in anhydrous pyridine (15 mL) at about 0° C. The reaction mixture is stirred with gradual warming to room temperature. The reaction is monitored by TLC and/or LC/MS to completion. Excess of the carbamoyl chloride is destroyed with crushed ice. Aqueous work-up followed by purification through silica gel column chromatography afford the title compound (20b).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=1)(=O)=O.C[Sn](C)C.C[Sn](C)C.FC(F)(F)S(O[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)(=O)=O.[Cl-].[Li+]>O1CCOCC1.CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([C:7]2[CH:8]=[C:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:36]=1
Reactant: O=S(=O)(Oc1cccnc1)C(F)(F)F
Reactant: CCOC(=O)Cc1cccc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)Cc1cccc(-c2cccnc2)c1

Procedure:
To a solution of 2.04 g (6.5 mmol) of ethyl m-(trifluoromethylsulfonyloxy)-phenylacetate in 33 ml dioxane is added 1.33 ml (6.5 mmol) hexamethylditin followed by 1.49 g (6.6 mmol) 3-(trifluoromethylsulfonyloxy)-pyridine, 0.827 g (19.5 mmol) lithium chloride and 0.15 g (0.13 mmol) tetrakis-(triphenylphosphine) palladium(0). The mixture is then heated at 90° for 62 h, diluted with ether and washed with 10% aqueous ammonia followed by water and brine. The organic layer is dried, filtered, evaporated and the residue is purified by flash chromatography using 1:1 ether/hexane as eluent to give ethyl m-(3-pyridyl)-phenylacetate; IR (CH2Cl2): 1731 cm-1.
Reaction SMILES: [C:1]1(=O)N(CCCCNC2CC3C(=CC=CC=3OC)OC2)C(=O)C2=CC=C[CH:27]=[C:2]12.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH:34]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:51](=[O:52])[CH2:50][C:49]([CH3:54])([CH3:53])[CH2:48][C:47]1=[O:55])[CH2:35][O:36]2>>[CH3:29][O:30][C:31]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:32]=1[CH2:33][CH:34]([N:41]([CH2:1][CH2:2][CH3:27])[CH2:42][CH2:43][CH2:44][CH2:45][N:46]1[C:47](=[O:55])[CH2:48][C:49]([CH3:53])([CH3:54])[CH2:50][C:51]1=[O:52])[CH2:35][O:36]2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)c3ccccc3C1=O)CO2
Reactant: COc1cccc2c1CC(NCCCCN1C(=O)CC(C)(C)CC1=O)CO2
Product: CCCN(CCCCN1C(=O)CC(C)(C)CC1=O)C1COc2cccc(OC)c2C1
Yield: 77 %

Procedure:
Using the procedure described in Example 2, but replacing the compound of Example 1 by the compound of Example 16, the expected product is obtained.
Reaction SMILES: [C:1](OCC)(=O)CC(OCC)=O.[H-].[Na+].[C:14]([C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](Cl)[N:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCOCC1>[C:14]([C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([CH3:1])[N:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc([N+](=O)[O-])c(C(=O)c2ccccc2)n1
Reaction time: 0.25 h

Procedure:
They were added to a solution of 16.8 grams of diethyl malonate in 75 ml. of dioxane with stirring and under a nitrogen atmosphere 3.3 grams of sodium hydride (80%) and then stirring continued for 15 minutes more. Then there were added in portions 26.3 grams of 2-benzoyl-3-nitro-6-chloropyridine and then stirring was continued at 70° C. for two hours more. The precipitated deeply colored sodium salt of the dicarbethoxymethyl compound was filtered off with suction. Five grams of this compound were boiled under reflux in a mixture of 25 ml. of concentrated hydrochloric acid and 25 ml. of methanol for 90 minutes, the solution filtered hot and the filtrate treated with water to the point of turbidity. The desired product crystallized out.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(Cl)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-azetidin-1-yl-4-chloro-phenyl)-carbamic acid tert.-butyl ester (Example J16) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) according to the general procedure M. Obtained as a yellow solid (142 mg).
Reaction SMILES: [C@@H:1]1([C:10]([OH:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O>C(OC(=O)C)(=O)C>[C:10]1(=[O:11])[C@@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]2[C:7](=[O:9])[O:12]1
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)[C@@H]2CCCC[C@@H]12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
(1R,2R)-Cyclohexane-1,2-dicarboxylic acid (150 mg, 0.87 mmol) was suspended in acetic anhydride (2 mL) and stirred at 80° C. for 1 hour. The mixture was cooled, concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give (3aR,7aR)-hexahydro-2-benzofuran-1,3-dione as a white solid. It was taken up in DMF (5 mL), 8-fluoro-2,3,4,5-tetrahydropyrido[4,3-B]indole (166 mg, 0.87 mmol) was added and the solution stirred at room temperature for 3 hours. 1-Aminocyclopropanecarbonitrile hydrochloride (114 mg, 0.96 mmol) was added followed by triethylamine (0.36 mL, 2.61 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 499 mg, 0.96 mmol) and the mixture stirred overnight. DMF was removed in vacuo and the residue partitioned between DCM (2×30 mL) and 50% brine (10 mL). The combined organics were treated with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (magnesium sulphate), concentrated in vacuo and adsorbed onto silica for purification by flash chromatography (0-80% ethyl acetate/isohexane). To purify further, the sample was triturated twice with anhydrous diethyl ether (2×5 mL), filtered and dried under vacuum. This gave (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide as a white solid (24.0 mg, 7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:33]1[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1>>[CH2:38]([N:36]1[CH:37]=[C:33]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:24])=[O:25])[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:13][CH:12]=4)=[CH:10][C:3]=23)[C:34]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:51])[N:48]([CH3:50])[CH3:49])=[CH:42][CH:41]=2)=[N:35]1)[CH3:39]
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccc(N3CCOCC3)cc2)cc2c(Br)ccnc21
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc(N4CCOCC4)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with 4-bromo-2-[4-(4-morpholinyl)phenyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 676.4
Reaction SMILES: [CH3:1][C:2]([C:4]([CH2:7][CH3:8])([CH3:6])[CH3:5])=[O:3].[CH:9]#[CH:10].Cl>O1CCCC1>[CH3:1][C:2]([OH:3])([C:4]([CH3:6])([CH3:5])[CH2:7][CH3:8])[C:9]#[CH:10]
Reactant: CCC(C)(C)C(C)=O
Reactant: C#C
Agent: Cl
Solvent: C1CCOC1
Product: C#CC(C)(O)C(C)(C)CC
Reaction time: 0.5 h
Yield: 85 %

Procedure:
50 g of tert-amyl methyl ketone were dissolved in 50 ml of tetrahydrofuran and the solution was added dropwise at 0° C. to 330 ml of a 1.5 molar acetylene Grignard solution in tetrahydrofuran. After 30 min, the mixture was hydrolyzed with 2N hydrochloric acid, the organic phase was separated, the solvent was removed and the residue was then fractionally distilled. 52 g (85%) of 3,4,4-trimethylhex-1-yn-3-ol were obtained (b.p.: 110° C./175 mbar).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:35]([C@@H:37]2[CH2:40][C@H:39]([CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[CH2:38]2)=[O:36])=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:35]([C@@H:37]2[CH2:40][C@H:39]([CH2:41][C:42]([OH:44])=[O:43])[CH2:38]2)=[O:36])=[O:22])[CH:12]=[C:13]([F:19])[C:14]=1[Si:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cooled TFA (2 mL) was added to tert-butyl 2-(cis-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (130 mg, 0.22 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. The pH of the reaction mixture was adjusted to 6 with cooled aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (78 mg, 0.146 mmol, 65.9%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:34])([F:33])[F:32])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:31]([F:32])([F:33])[F:34])[O:16][N:15]=[C:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]([OH:29])=[O:28])=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed methanol (20 mL), methyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalene-1-carboxylate (200 mg, 0.40 mmol, 1.00 equiv), 15% NaOH (5 mL). The resulting solution was stirred for 2 h at 70° C. in an oil bath. The reaction mixture was cooled. The resulting mixture was concentrated under vacuum. The solids were collected by filtration and washed with 10 mL H2O. Then the solid was dried under infrared light. This resulted in 150 mg (77%) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]naphthalene-1-carboxylic acid as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[N:26]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:33][CH2:32][CH2:31][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: NCCN1CCCC1
Product: O=C(NCCN1CCCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-(1-pyrrolidinyl)ethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.61 (1H, br), 8.28 (1H, br s), 7.36 (1H, s), 7.30 (2H, m), 7.14 (2H, t, J=8.8 Hz), 4.04 (2H, s), 3.41 (2H, m), 2.56 (2H, t, J=6.4 Hz), 2.54-2.48 (4H, m), 1.68 (4H, m); ES+ MS: 411 (M+H+, 100).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16]>CN1CCCC1=O>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH3:16])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCN(C)C
Solvent: CN1CCCC1=O
Product: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
A mixture of 4-fluoronitrobenzene (0.35 g, 2.5 mmol) and N,N,N′-trimethylethylenediamine (1.5 g, 1.9 mmol) in N-methylpyrrolidinone (10 mL) is heated for 19 hours in a 100° C. shaking block. After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The organic phase is washed four times with water and with saturated aqueous sodium chloride solution and then concentrated under reduced pressure to give N,N,N′-trimethyl-N′-(4-nitrophenyl)ethane-1,2-diamine as a brown semisolid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1.C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:6]1[S:7][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC[C@H]1O[C@H](S)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranose (287 mg, 0.79 mmol) in dichloromethane (6 ml) was added cholest-5-en-3β-yl 6-iodohexyl ether (470 mg, 0.79 mmol) and triethylamine (0.11 ml, 0.79 mmol). After stirring under dry nitrogen atmosphere overnight at room temperature, the solvent was removed at reduced pressure and the residue chromatographed on silica gel eluted with 5-25% ethyl acetate in hexanes to give 6-(cholest-5-en-3β-yloxy)hexyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranoside (0.36 g, 55% yield), m.p. 103°-103.5° C. This product was dissolved in 1:1 (v/v) ethanol-tetrahydrofuran (10 ml) and treated with a suspension of Bio-Rad AG-1-X2 OH- ion-exchange resin (2.5-3 fold excess) in ethanol (5 ml). After stirring a room temperature for 45 minutes, the resin was filtered and washed with warm tetrahydrofuran (3×5 ml), and the combined filtrates concentrated to give 6-(5-cholesten-3β -yloxy)hexyl 1-thio-α-D-mannopyranoside (250 mg, 91% yield) as needles from warm tetrahydrofuran, m.p. (endothermic transitions) 64-64, 81-82, and 226°-227° C.