Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[C:8](OC(=O)C)(=[O:10])[CH3:9].CCN(CC)CC.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:8]([O:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)C(C)(C)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(C)=O
Temperature: 10 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
A mechanically stirred 3 l round-bottomed flask under an atmosphere of nitrogen was charged with 3-hydroxy-3-methyl-2-butanone (100.0 g, 979 mmol) and CH2Cl2 (900 ml). A solution of acetic anhydride (92.4 ml, 979 mmol) and CH2Cl2 (50 ml) was added over 10 min and the resulting solution was cooled to 10° C. DMAP (5.98 g, 49 mmol) was added in one portion followed by Et3N (205 ml, 1.47 mol) over 50 min while maintaining an internal temperature below 16° C. After the addition, the mixture was aged for 16 h at room temperature. The resulting solution was poured onto MeOH (200 ml) and after 15 min 2N HCl (400 ml) was added. The phases were separated and the organic phase was washed with water (500 ml) then saturated NaHCO3 (500 ml) then dried over Na2SO4. The solvent was removed under diminished pressure to provide 3-acetoxy-3-methyl-2-butanone as a golden oil (132.5 g): 1H NMR (CDCl3, 400 MHz) δ 2.12 (3H, s), 2.09 (3H, s), 1.47 (6H, s); 13C NMR (CDCl3, 100.61 MHz) δ 206.6, 170.2, 83.5, 23.4, 23.2, 21.0.
Reaction SMILES: [Cl:1][C:2]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=O)[CH:13]=[CH:14][CH:15]=1.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CC#N>[ClH:1].[Cl:1][C:2]1[C:37]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[O:19])[CH:13]=[CH:14][CH:15]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1)N1CCOCC1
Yield: 108.2 %

Procedure:
2-(3-{3-[[2-chloro-3-(trifluoromethyl)benzyl)(2,2-diphenylethyl)-amino]-propoxy}-phenyl acetic acid (50 mg, 0.086 mmole) and morpholine (8.7 mg, 0.10 mmole) were dissolved in CH3CN (2 ml). BOP reagent (44 mg, 0.10 mmole) was added followed by Et3N (20 mg, 0.20 mmole). The resultant mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure. The residue was partitioned between EtOAc and aqueous Na2CO3 (5%) solution. The organic layer was separated, dried over MgSO4 and concentrated. In cases where the product required further purification, a preparative Gilson HPLC was used (YMC CombiPrep ODS-A, 50×20 mm, 20 ml/min, 30–90% CH3CN over 15 minutes). The HCl salt was made by adding HCl (in ether) to an ether solution of the product and then evaporation of the solvent to give a yellow solid (32 mg, 54%). MS(ES) m/e 651.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH:3]=1.C(N(CC)CC)C.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(#N)C>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:35]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:36])/[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=3[CH:9]=2)[CH:3]=1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)c(=N)s1
Reactant: O=C(Cl)N1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CCCCC2)s1
Temperature: 65 °C

Procedure:
The imine (Example 26A, 30 mg, 0.09 mmol) was dissolved in acetonitrile (1.5 mL). Triethylamine (19 μl, 0.18 mmol) was added followed by the 1-piperidinecarbonyl chloride (0.11 mmol). The reaction was heated at 65° C. overnight. The reaction mixture was cooled down and passed through a Si-amine cartridge (1 g, 1.6 mmol/g) to remove the excess carbamyl chloride eluting with additional acetonitrile. The resulting solution was dried and purified by reverse phase HPLC to supply the titled compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (4H), 1.53 (2H), 2.20 (3H), 3.43 (4H), 7.24 (1H), 7.63 (2H), 7.83 (1H); MS (ESI) m/z 432.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:24]([O:26][C:27](=[O:31])[CH:28]([CH3:30])[NH2:29])[CH3:25].C(N(CC)CC)C>O1CCCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)=[CH:13][C:14]=1[S:19]([NH:29][CH:28]([CH3:30])[C:27]([O:26][CH2:24][CH3:25])=[O:31])(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CCOC(=O)C(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)NS(=O)(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 58 %

Procedure:
4.0 g of 3-chloro-2-(4-chloro-3-chlorosulfonylphenyl)-5-trifluoromethylpyridine, 2.4 g of D,L-alanine ethyl ester hydrochloride and 5.2 g of triethylamine in 50 ml of anhydrous tetrahydrofuran were stirred at 23° C. for 18 hours, after which the mixture was concentrated. The residue was taken up in 100 ml of methylene chloride. The solution was extracted twice with 30 ml of water each time, dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel with cyclohexane/ethyl acetate (4:1) resulted in 2.8 g of a colorless oil. Yield: 58%;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH:12][C:13](=[O:16])[CH2:14][CH3:15].[CH2:17](O)C>ClCCl.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:17])[C:13](=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)Nc1cc([N+](=O)[O-])ccc1OC
Reactant: CCO
Agent: [Pd]
Solvent: ClCCl
Product: CCC(=O)N(C)c1cc([N+](=O)[O-])ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of 340 mg of N1-(2-methaxy-5-nitrophenyl)-N1, N2, N2-trimethylethane-1,2-diamine (2) in 20 mL of ethanol containing 5% w/w of Pd—C (10%) was subjected to hydrogenation (1 atm, balloon) for 1.5 h. The contents of the flask were passed through a short pad of celite and washed with MeOH. The filtrate was evaporated under reduced pressure and crude amine obtained was carried over to the next reaction without further purification. Thiocarbodiimidazole (260 mg, 1.46 mmol) was added to the crude amine in dichloromethane (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, and concentrated. The crude product was then purified by flash chromatography on silica gel to give N1-(5-isothiocyanato-2-methoxyphenyl)-)-N1, N2, N2-trimethylethane-1,2-diamine (3) (110 mg, 0.42 mmol, 31%).
Reaction SMILES: [Cl:1]C[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].[CH3:18]C(C)=O>>[Cl-:1].[CH2:11]([N+:13]([CH2:18][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:4]=[CH2:3])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]
Reactant: CCN(CC)CC
Reactant: CC(C)=O
Reactant: ClCC=Cc1ccccc1
Product: C=Cc1ccccc1C[N+](CC)(CC)CC
Product: [Cl-]

Procedure:
10 mass % of chloromethyl styrene and 20 mass % of triethyl amine. were reacted in acetone solvent at 40° C. for 40 hours to obtain N,N,N-triethyl(vinylphenyl)methyl ammonium chloride. This was cooled to −5° C., recrystallized and isolated, followed by dissolving the same in toluene at a concentration of 10 mass %, and 0.005 mass % of 2,2-azobis(2-methyl butyronitrile) was further dissolved therein. After nitrogen bubbling, this solution was subjected to polymerization at 50° C. for 72 hours. The solution after polymerization was reprecipitated by pouring the same in excessive amounts of methanol followed by drying to obtain a solid matter. This solid matter was dissolved in tetrahydrofuran at a concentration of 40 mass %, and the solvent was dried after impregnation of porous membrane (polyethylene-based, having weight average molecular weight of 250,000, membrane thickness of 25 μm, average pore diameter of 0.03 μm and porosity of 37%). This operation was repeated several times to produce an anion-exchange membrane 5 including a quaternary ammonium group having a halogeno ion as its counterion.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[C:16]4[CH:17]=[CH:18][C:19]([B:21]5[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]5)=[CH:20][C:15]=4[S:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:34]=[CH:35][C:36]2[N:40]=[C:39]([C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[NH:38][C:37]=2[CH:53]=1.C(=O)([O-])[O-].[K+].[K+].ClC(Cl)C>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.C1(C)C=CC=CC=1.C(COC)OC>[CH3:27][C:24]1([CH3:26])[C:23]([CH3:28])([CH3:29])[O:22][B:21]([C:19]2[CH:18]=[CH:17][C:16]3[C:12]4[CH:11]=[CH:10][C:9]([C:33]5[CH:34]=[CH:35][C:36]6[N:40]=[C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[NH:38][C:37]=6[CH:53]=5)=[CH:30][C:13]=4[S:14][C:15]=3[CH:20]=2)[O:25]1
Reactant: CC1(C)OB(c2ccc3c(c2)sc2cc(B4OC(C)(C)C(C)(C)O4)ccc23)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2[nH]1
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: Cc1ccccc1
Solvent: COCCOC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)sc3cc(B5OC(C)(C)C(C)(C)O5)ccc34)cc2[nH]1
Temperature: 85 °C
Yield: 62.2 %

Procedure:
A mixture of 3,7-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-dibenzo[b,d]thiophene (3.6 g, 8.2 mmol), (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.31 mg, 0.27 mmol), 2M aqueous potassium carbonate solution (5 mL, 10 mmol), dimethoxyethane (25 mL), toluene (5 mL) and dichloroethane (2.5 mL) was degassed under a stream of argon for 15 minutes. The reaction was heated to 85° C. for 2 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-tert-butyl 2-(6-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)dibenzo[b,d]thiophen-3-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 62%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:78])[C@@H:7]([NH:13][C:14](=[O:77])[CH2:15][CH2:16][C@@H:17]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[NH:18][C:19](=[O:69])[CH2:20][CH2:21][C@@H:22]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[NH:23][C:24](=[O:61])[CH2:25][CH2:26][C@@H:27]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[NH:28][C:29](=[O:53])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:92]1[C:97](=[O:98])[CH2:96][CH2:95][C:93]1=[O:94])=[N+](C)C)C>C(#N)C>[O:94]=[C:93]1[CH2:95][CH2:96][C:97](=[O:98])[N:92]1[O:11][C:10](=[O:12])[CH2:9][CH2:8][C@H:7]([NH:13][C:14](=[O:77])[CH2:15][CH2:16][C@@H:17]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[NH:18][C:19](=[O:69])[CH2:20][CH2:21][C@@H:22]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[NH:23][C:24](=[O:61])[CH2:25][CH2:26][C@@H:27]([C:54]([O:56][C:57]([CH3:58])([CH3:59])[CH3:60])=[O:55])[NH:28][C:29](=[O:53])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:78]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
(S)-2-((S)-4-tert-Butoxycarbonyl-4-{(S)-4-tert-butoxycarbonyl-4-[(S)-4-tert-butoxycarbonyl-4-(17-tert-butoxycarbonylheptadecanoylamino)butyrylamino]butyrylamino}butyrylamino)pentanedioic acid 1-tert-butyl ester (0.1 g, 0.09 mmol) was activated with TSTU (29.8 mg, 0.099 mmol) in acetonitrile solution at RT for 1 h using the same method for activation and work up as described above. This afforded 100 mg crude activated product which could be used as such for insulin acylation without further purification. LC-MS (electrospray): m/z=1208 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:22])([C:19]([OH:21])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:31][C:32]1[O:33][C:34](=[O:38])[O:35][C:36]=1[CH3:37]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:22])([C:19]([O:21][CH2:37][C:36]1[O:35][C:34](=[O:38])[O:33][C:32]=1[CH3:31])=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([OH:18])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: Cc1oc(=O)oc1CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Yield: 31 %

Procedure:
A solution of N-(t-butoxycarbonyl)-3-hydroxy-α-methyltyrosine (760 mg, 2.44 mmol), triethylamine (263 mg, 2.60 mmol) and 4-bromomethyl-5-methyl-1,3-dioxol-2-one (500 mg, 2.60 mmol) in dimethylformamide, 10 mL, is stirred at 60° C. for 3 hours under nitrogen. Most of the dimethylformamide is removed at 50°-60° C. and 0.1 mm and the residue is partitioned between saturated sodium bicarbonate solution, 10 mL, and ethyl acetate, 50 mL. The ethyl acetate extract is washed with water saturated with sodium sulfate, filtered and concentrated at 40°-45° C. and 15 mm. Flash chromatography of the residue over 40 g of silica gel 60 (230-400 mesh) with 3% methanol-97% chloroform as eluent affords 320 mg of the desired ester.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[O:2].[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16].[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2([C:43]([F:46])([F:45])[F:44])[O:31][N:30]=[C:29]([C:32]3[CH:41]=[CH:40][C:35]([C:36]([NH:38][OH:39])=[O:37])=[C:34]([CH3:42])[CH:33]=3)[CH2:28]2)[CH:23]=[C:24]([Cl:26])[CH:25]=1>O1CCCC1>[F:13][C:14]([F:18])([F:17])[CH2:15][NH:16][C:1]([O:39][NH:38][C:36](=[O:37])[C:35]1[CH:40]=[CH:41][C:32]([C:29]2[CH2:28][C:27]([C:22]3[CH:23]=[C:24]([Cl:26])[CH:25]=[C:20]([Cl:19])[CH:21]=3)([C:43]([F:44])([F:46])[F:45])[O:31][N:30]=2)=[CH:33][C:34]=1[CH3:42])=[O:2]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NO
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NOC(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
In a solution of 0.16 g of carbonyl diimidazole in 2 ml of tetrahydrofuran, 0.10 g of 2,2,2-trifluoroethylamine was added, and stirred at room temperature for 1 hour. Then, a solution of 0.10 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzhydroxamic acid in 2 ml of tetrahydrofuran was added in the reaction mixture, and continued to stir at room temperature further for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, 10 ml of water was added in the residue, and extracted with ethyl acetate (10 ml×1). The organic phase was washed with 5 ml of 2N hydrochloric acid aqueous solution, dehydrated and dried with saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled under reduced pressure. The residue was purified with silica gel thin-layer chromatography (Kanto Chemical Co., Ltd.: PLC plates silica gel 60 F254 20×20 cm layer thickness 2 mm) that was developed with ethyl acetate-hexane (1:1) to obtain 0.12 g of the aimed product as white crystal.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]=1[C:23]([O:25]CC)=[O:24]>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:3]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(Cc2ccccc2)nc2c(C(F)(F)F)cccc2c1O
Solvent: CCO
Product: O=C(O)c1c(Cc2ccccc2)nc2c(C(F)(F)F)cccc2c1O
Yield: 83.9 %

Procedure:
Using the procedure of Step E of Example 6, a mixture of 9.4 g of the product of Step D, 25.2 ml of 36° Be sodium hydroxide and 51 ml of 95% ethanol was refluxed for 6 hours to obtain 7.3 g of 4-hydroxy-2-phenylmethyl-8-trifluoromethyl-quinoline-3-carboxylic acid melting at 252° C which was used as is for the next step.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[CH2:20][C:21]1[CH:29]=[CH:28][C:24]2[O:25][CH2:26][O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>CN(C=O)C.C(Cl)Cl.CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([NH:12][CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]4[CH:29]=[CH:28][C:24]5[O:25][CH2:26][O:27][C:23]=5[CH:22]=4)[CH2:14]3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1cn(-c2ccc(NC3CCCNC3)cc2)cn1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: c1cn(-c2ccc(NC3CCCN(Cc4ccc5c(c4)OCO5)C3)cc2)cn1
Temperature: 50 °C

Procedure:
3-[(4-(Imidazol-1-yl)phenyl)amino]piperidine (330 mg, 1.36 mmol) was dissolved in DMF and then treated with 5-chloromethyl-1,3-benzodioxole (1.0 eq.), K2CO3 (2.5 eq.) and Nal (0.1 eq.). The resulting mixture was heated at 50° C. for 1 hour. Filtration of the mixture and evaporation of the solvent in vacuo gave a crude product (411 mg). Flash column chromatography on silical gel with 1-2.5% methanol in methylene chloride afforded 3-[(4-(imidazol-1-yl)phenyl)amino]-1-[(1,3-benzodioxol-5-yl)methyl]piperidine (110 mg), 1H NMR(CDCl3) 7.70 (s, 1), 7.10 (m, 4), 6.80 (s, 1), 6.70 (m, 2), 6.60 (d, 2), 5.90 (s, 2), 4.30 (m, 1), 3.60 (m, 1), 3.40 (AB q, 2), 2.70 (m, 1), 2.40 (m, 3), 1.50-1.80 (m, 4) ppm.
Reaction SMILES: C([C:5]1[CH:6]=[CH:7][C:8]([NH:14][CH:15]=[O:16])=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)CCC.[CH:17]([O:20][C:21]([NH:23]C1C=CC(N)=C([N+]([O-])=O)C=1)=[O:22])([CH3:19])[CH3:18].C(C1C=CC(N)=C([N+]([O-])=O)C=1)CCC>>[CH:15]([NH:14][C:8]1[CH:7]=[CH:6][C:5]([NH:23][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[O:22])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])=[O:16]
Reactant: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCCCc1ccc(NC=O)c([N+](=O)[O-])c1
Agent: CCCCc1ccc(N)c([N+](=O)[O-])c1
Product: CC(C)OC(=O)Nc1ccc(NC=O)c([N+](=O)[O-])c1

Procedure:
In a similar manner to that described above for the preparation of 5-n-butyl-2-formamido-1-nitrobenzene but substituting an equimolecular quantity of 4-isopropoxycarbonylamino-2-nitroaniline for the 4-n-butyl-2-nitroaniline, there was obtained 2-formamido-5-isopropoxycarbonylamino-1-nitrobenzene, m.p. 168°-170° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][C:14]([C:20]([NH:22][O:23]C3CCCCO3)=[O:21])=[CH:15][CH:16]=2)[CH2:11]1)=[O:9].[ClH:30]>CO>[ClH:30].[OH:23][NH:22][C:20]([C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:19][N:10]([C:8](=[O:9])[CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:11]2)=[CH:16][CH:15]=1)=[O:21]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CN(C(=O)Cc1ccccn1)CC2
Agent: Cl
Solvent: CO
Product: O=C(NO)c1ccc2c(c1)CN(C(=O)Cc1ccccn1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 130 mg 2-(pyridin-2-ylacetyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide in 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid is stirred overnight at ambient temperature. Subsequently, the reaction mixture is evaporated. The residue is dissolved in a mixture of water and acetonitrile and lyophilized. 105 mg of the title compound are obtained. MH+=312.1
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH3:18].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28].[H-].[Na+]>CN(C=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[C:9]([CH3:18])[N:8]2[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1-c1ccccc1
Yield: 77.3 %

Procedure:
1-([1,1′-Biphenyl]-2-ylmethyl)-4-hydroxy-2-methyl-1H-indole (767 mg, 2.45 mmol) was alkylated by treating with 0.23 mL (2.45 mmol) of methyl bromoacetate and 98 mg (2.45 mmol) of 60% NaH/mineral oil in DMF as described in Example 1, Part E. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 730 mg (77% yield) of [[1-([1,1′-biphenyl]-2-ylmethyl)-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, 99-101° C.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@H:7]2[CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]([C:19](=[O:35])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[CH2:8]2)=[C:4]([CH3:38])[CH:3]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C@H:7]2[CH2:11][NH:10][C@H:9]([C:19]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)=[O:35])[CH2:8]2)=[C:4]([CH3:38])[CH:3]=1
Reactant: Cc1cc(F)ccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
The (2S,4R)-tert-butyl 4-(4-fluoro-2-methylbenzyl)-2-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidine-1-carboxylate (826 mg, 1.59 mmol) was dissolved in methylene chloride (5 mL) and then trifluoroacetic acid (5 mL) was added to the solution. The mixture was stirred at ambient temperature for 1 hour, concentrated in vacuo and dried under high vacuum to give (2S,4R)-4-(4-fluoro-2-methylbenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide trifluoroacetic acid (826 mg, 1.54 mmol, 100%) as a yellow oil.