Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[CH2:33]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][OH:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+]>C(OCC)(=O)C.O.O1CCOCC1>[CH2:33]([N:40]1[CH2:44][CH2:43][CH2:42][C@@H:41]1[CH2:45][O:46][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: OC[C@H]1CCCN1Cc1ccccc1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1OC[C@H]1CCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 50.1 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (300 mg), [(2R)-1-benzylpyrrolidin-2-yl]methanol (251 mg), 18-crown-6 (346 mg), potassium t-butoxide (147 mg), and dioxane (3 mL) was stirred at 100° C. for 5 hours. To the mixture were added water and ethyl acetate, followed by liquid separation. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; ethyl acetate:chloroform=1:1) to obtain 5-{[(2R)-1-benzylpyrrolidin-2-yl]methoxy}-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (201 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH:17]=[CH:18][C:19](=[O:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>[Zn]>[OH:21][C:19]([CH3:20])([CH:18]=[CH:17][CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)C=CCCc1ccc(OCc2ccccc2)cc1
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccccc2)cc1

Procedure:
Using 25.83 g of 6-(p-benzyloxyphenyl)-3-hexen-2-one, 11.3 ml of ethyl bromoacetate and 6.63 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example I (a) affording 29.6 g of ethyl 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-4-heptenoate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[C@H:41]2[N:37]([CH2:38][CH2:39][CH2:40]2)[CH2:36][C:35]2[CH:42]=[C:43](/[CH:46]=[CH:47]/[C:48](O)=[O:49])[CH:44]=[N:45][C:34]=2[NH:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>CO>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:48](=[O:49])/[CH:47]=[CH:46]/[C:43]1[CH:44]=[N:45][C:34]2[NH:33][C:32](=[O:31])[C@H:41]3[N:37]([CH2:38][CH2:39][CH2:40]3)[CH2:36][C:35]=2[CH:42]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Reactant: CNCc1cc2ccccc2n1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN1CCC[C@H]1C(=O)N2
Yield: 23 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (S)-(E)-3-(10-oxo-2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-benzo[f]azulen-6-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (91 mg, 23%) was prepared as a tan powder: [α]25D +197.70 (c 1.00, methanol); 1H NMR (300 MHz, DMSO-d6) δ 12.51 (br s, 1H), 11.28 (s, 1H), 8.83-8.74 (m, 1H), 8.32-8.25 (m, 1H), 7.65-7.60 (m, 1H), 7.51-7.32 (m, 3H), 7.15-6.98 (m, 2H), 6.43-6.18 (m, 1H), 5.07-4.86 (m, 2H), 4.46-4.21 (m, 3H), 3.73-3.62 (m, 4H), 3.18-2.87 (m, 5H), 2.08-1.88 (m, 3H); MS (ESI) m/e 430 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BrH:17].BrBr.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:17][CH:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: Br
Reactant: O=C(Cc1ccccc1)c1ccc(F)cc1
Agent: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(c1ccc(F)cc1)C(Br)c1ccccc1
Temperature: 19 °C
Reaction time: 0.08 h

Procedure:
Methylene chloride (1 L) is taken in a 4 necked RB flask equipped with mechanical strring rod, pressure equalization funnel and a CaCl2 guard tube. 100 g (0.466 mol) of 1-(4-Fluorophenyl)-2-phenyl ethanone is introduced in to the above flask and stirred for 5 minutes to obtain a clear solution.2 ml of a 30% hydrobromic acid in acetic acid is then added, followed by gradual addition of a cold solution of bromine (73 g, 0.456 mole) in 200 ml of methylene chloride at 26±2° C. Bromine solution is added in such a manner that it is consumed instantly as indicated by colouration of reaction mixture. After addition of bromine solution the reaction mixture is cooled to 19±1° C., treated with 5% aqueous sodium sulphite (200 ml) and stirred for about lhr at 21.5±3.5° C. The organic layer is then separated and is subjected to the above operation twice with 5% aqueous sodium sulphite (2×200 ml). The organic layer is then stirred with 5% aqueous sodium bicarbonate (200 ml) for about 1 hr at 21.5±3.5° C. and separated. The organic layer is finally stirred with 5% aqueous sodium chloride(200 ml) and separated. The organic layer is dried over sodium sulphate and filtered. Methylene chloride is removed by distillation and the syrup thus obtained solidified on standing in to a pale orange coloured solid. Yield 129 g (94.8%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C.Cl>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:28][CH3:29])=[C:5]([CH3:30])[O:4][N:3]=1
Reactant: COc1cc2c(NCc3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Yield: 5.4 %

Procedure:
To a solution of this nitro intermediate (2.5 g, 24.82 mmol) in a mixture of ethanol (20 ml) and HCl (3.8 ml), was added portionwise SnCl2.2H2O (5.6 g, 24.82 mmol). The reaction mixture was heated to 40° C. for 1 h, then hydrolysed with sodium hydroxide N and extracted with DCM. The organic phase was washed with water, dried and concentrated to give the title compound as a brown powder (0.5 g, 17.8%). (APCI-MS) m/z: 376 MH+, Rt 2.46 min. 1H NMR (300 MHz, DMSO-d6, ppm) δ: 8.56 (d, 1H), 8.29 (s, 1H), 7.77 (dd, J=7.8, 7.6 Hz, 1H), 7.54 (s, 1H), 7.53-7.51 (m, 1H), 7.31-7.25 (m, 1H), 5.31 (s, 2H), 4.46 (d, J=7.2 Hz, 2H), 3.78 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C.C(O)(=O)C>C(O)C>[CH2:15]([O:14][C:12]([C:11]1[CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20](=[O:19])[N:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2)=[O:13])[CH3:16]
Reactant: CCOC(=O)Cc1ccccn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(=O)OCC)c2ccccn2c1=O
Reaction time: 1 h

Procedure:
To a solution of sodium ethoxide (sodium, 151 mg) in ethanol (20 ml) was added ethyl pyrid-2-ylacetate (1 ml) at room temperature and the mixture was stirred for 1 hour at the same temperature. To the mixture was added diethyl ethoxymethylenemalonate (1.33 ml) at room temperature and the mixture was stirred at room temperature overnight. To the mixture was added acetic acid (0.75 ml) at room temperature and the precipitate was filtered and washed with water to give 1,3-diethoxycarbonyl-4H-quinolizin-4-one (896 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH2:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:23](O)=O>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([F:14])[C:7]2[N:13]=[CH:23][NH:10][C:8]=2[CH:9]=1)=[O:22]
Reactant: O=CO
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N)c(F)c1Nc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.3 %

Procedure:
4-Amino-3-fluoro-5-nitro-2-phenylamino-benzoic acid methyl ester 26a (16.70 g, 54.71 mmol), formic acid (250 mL, 6.63 mol) and 20% Pd(OH)2/C (9.00 g, 16.91 mmol) in ethanol (250 mL) are stirred at 40° C. for two hours under N2 and then at 95° C. for 16 hours. The reaction mixture is cooled to room temperature and filtered through Celite rinsing with ethyl acetate. The filtrate is concentrated under reduced pressure to give a yellow solid. The solid is triturated with diethyl ether to give 13.47 g (86%) of the desired product as a tan solid. MS APCI (+) m/z 286 (M+1) detected; MS APCI (−) m/z 284 (M−1) detected.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[C:19]([F:29])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1.C1C=C([O:36]O)C(C(O)=O)=C(C(O)=O)C=1>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH+:9]([O-:36])[CH2:10][C@H:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[C:19]([F:29])[CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3)c(F)c2)C(=O)O1)c1ccc(Cl)s1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Product: O=C1O[C@H](C[NH+]([O-])C(=O)c2ccc(Cl)s2)CN1c1ccc(N2CCOCC2)c(F)c1

Procedure:
is obtained by treating 5-chloro-N-{[(5S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-2-thiophenecarboxamide from Example 1 with the magnesium salt of monoperoxyphthalic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[C:5]([Br:19])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.N1C=CC=CC=1>ClCCl>[Br:19][C:5]1[C:6]([CH3:18])=[C:7]([C:2]([NH:1][S:27]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:3][CH:4]=1)[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: Cc1c(Br)ccc(N)c1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(Br)ccc(NS(=O)(=O)c2ccc(F)cc2)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
A solution of Example 126B (2.57 g, 7.13 mmol), 4-fluorobenzenesulfonyl chloride (1.92 g, 7.8 mmol) in dichloromethane (40 mL) was treated with pyridine (1.44 mL, 17.8 mmol), stirred for 48 hours at ambient temperature, washed with 1N HCl (2×30 mL). The organic solution was dried (MgSO4), filtered, and concentrated. The resulting solid was triturated twice with hexanes to provide the desired product (3.10 g, 91.2%). 1H NMR (DMSO-d6) δ 2.19 (s, 3H), 5.25 (s, 2H), 6.86 (d, 2H), 7.35-7.46 (m, 7H), 7.63 (d, 1H), 7.75 (m, 2H), 10.07 (s, 1H). MS (ESI(−)) m/e 476, 478 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.S(=O)(=O)(O)O.[N+:16]([O-])([OH:18])=[O:17].[OH-].[K+]>>[N+:16]([C:8]1[N:6]2[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: Brc1ccc2nccn2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2ccc(Br)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 24 gms. (0.122 mole) of 6-bromoimidazo [1,2-a] pyridine in 80 ml. of concentrated sulfuric acid is treated dropwise with 24 ml. of concentrated nitric acid while maintaining a temperature of 15° C. with external cooling. When the addition is complete, the reaction mixture is stirred at room temperature for 1/2 hour and poured onto 450 gm. of ice. The ph of the mixture is adjusted to ph 4 with aqueous potassium hydroxide and the resultant solids are collected by filtration. The filter cake is washed with water and dried. Recrystallization from methylene chloride-hexane yields pure 3-nitro 6-bromoimidazo [1,2-a] pyridine m.p. 160°-161° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:29]([NH2:31])=[O:30])=[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][N:20]3[CH2:25][CH2:26][O:27][CH3:28])[N:14]=1.[C:32](OC(=O)N[C@H]1CCCCC[C@H]1N)(C)(C)C.C(OC(=O)N[C@H]1CCCC[C@H]1N)(C)(C)C>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:32][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:29]([NH2:31])=[O:30])=[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][N:20]3[CH2:25][CH2:26][O:27][CH3:28])[N:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCC[C@H]1N
Reactant: COCCn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)cccc21
Agent: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Product: COCCn1ccc2c(Nc3nc(N[C@@H]4CCCCC[C@@H]4N)nnc3C(N)=O)cccc21

Procedure:
In accordance with Example 3 (Steps 1 to 4), 1-(2-methoxyethyl)-1H-indol-4-amine obtained in Example 46 was used instead of 1-methyl-1H-indol-4-amine, and tert-butyl((1S,2R)-2-aminocycloheptyl)carbamate obtained in the above-described Step was used instead of tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate to obtain the titled compound as a light yellow solid.
Reaction SMILES: Cl.ClC1[N:4]([C:12]2[CH:30]=[CH:29][C:15]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=C2.[C:31]([Cl:36])(=O)[C:32](Cl)=O.[CH3:37][NH2:38]>C(Cl)Cl>[CH3:37][NH:38][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][CH2:17][O:16][C:15]2[CH:14]=[CH:13][C:12]([N:4]3[C:31]([Cl:36])=[C:32]4[C:6]([CH:11]=[CH:10][CH:9]=[CH:8]4)=[N:5]3)=[CH:30][CH:29]=2)[CH2:25][CH2:24]1)=[O:28]
Reactant: O=C(O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Reactant: CN
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)C1CCN(CCCOc2ccc(-n3nc4ccccc4c3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.7 %

Procedure:
To a solution of 1-{3-[4-(3-chloro-indazol-2-yl)-phenoxy]-propyl}-piperidine-4-carboxylic acid hydrochloride (0.11 g, 0.25 mmol) in methylene chloride (11 mL) was added oxalyl chloride (0.12 g, 0.98 mmol) at room temperature, and stirred at room temperature for 3h. After the solvent was removed, the acid chloride was dissolved in THF and methylamine (40% in H2O, 3.8 g, 49 mmol) was added in one portion. The resulting reaction was stirred at room temperature for 3 h, and the THF was removed. The product was collected on a filter and air-dry for 8 h to provide the title compound (0.1 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.71(d, J=10.8 Hz, 1H), 7.62-7.56 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.14 (m, 2H), 7.04 (d, J=12 Hz, 2H), 5.48 (br, 1H), 4.10 (t, J=6 Hz, 2H), 3.00 (br d, J=12 Hz, 1H), 2.82 (d, J=4.8 Hz, 3H), 2.52 (t, J=6 Hz, 2H), 2.10-1.73 (m, 9H), LC/MS (APCI) m/z: 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:35])([CH2:29][N:30]1[CH:34]=[N:33][CH:32]=[N:31]1)[C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11].[C:36](=[O:47])([O:40][CH2:41][CH:42]1[O:46][CH2:45][CH2:44][CH2:43]1)[O:37][CH2:38][I:39]>C(#N)C>[I-:39].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:35])([C@H:10]([N:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[C:13]1=[O:28])[CH3:11])[CH2:29][NH+:30]1[CH2:34][N:33]([CH2:38][O:37][C:36]([O:40][CH2:41][CH:42]2[O:46][CH2:45][CH2:44][CH2:43]2)=[O:47])[CH:32]=[N:31]1
Reactant: O=C(OCI)OCC1CCCO1
Reactant: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Product: C[C@@H](N1CCN(c2ccc(-n3cnnn3)cc2)C1=O)[C@](O)(C[NH+]1CN(COC(=O)OCC2CCCO2)C=N1)c1ccc(F)cc1F
Product: [I-]
Temperature: 50 °C
Reaction time: 15 h
Yield: 50.1 %

Procedure:
To a mixture of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-tetrazol-1-yl)phenyl]-2-imidazolidinone (0.5 g) and acetonitrile (10 ml) was added iodomethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (0.594 g), and the mixture was stirred for 15 hours at 50° C. The reaction mixture was subjected to silica gel flush chromatography (eluent: ethyl acetate→acetate→acetone/ethanol=10/1), and the fraction containing the desired compound was concentrated under reduced pressure. The residue was subjected to ODS column chromatography (eluent:methanol/water=3/2). The fraction containing the desired compound was concentrated and the residue was lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,3,4,5-tetrahydrofurfuryl)oxycarbonyloxymethyl]-1H-1,2,4-triazolium iodide (Compound 30, 0.4 g) as a colorless powder. The product was dissolved in water (15 ml), and the solution was subjected to ion-exchange resin [Dowex 1×8 (Cl− type)]. The fraction containing the desired compound was concentrated under reduced pressure, and lyophilized to give 1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-tetrazol-1-yl)phenyl]-1-imidazolidinyl]butyl]-4-[(2,3,4,5-tetrahydrofurfuryl)oxycarbonyloxymethyl]-1H-1,2,4-triazolium chloride (Compound 21 , 0.24 g) as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([C:12]3[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N([OH:34])N=NC=2C=1.CC[N:37]([CH:41](C)C)C(C)C.CC(C)(C)CCN>CN(C=O)C.O>[C:1]1([C:7]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:19][C:20]=3[C:41]([NH2:37])=[O:34])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1ccc(-c2nc(-c3ccccc3)no2)cc1
Agent: CC(C)(C)CCN
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1-c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 124.7 %

Procedure:
To a solution of 4-(3-phenyl-1,2,4-oxadiazol-5-yl)benzoic acid (200 mg, 0.75 mmol) in DMF (2 mL) was added EDC (167 mg, 0.90 mmol), HOBt (122 mg, 0.90 mmol), DIPEA (200 mg, 1.50 mmol) and 3,3-dimethylbutylamine (113 mg, 1.12 mmol). The reaction was stirred at room temperature for 18 h. The reaction was diluted with water (10 mL) and isolated the white precipitate by vacuum filtration to afford N-(3,3-dimethylbutyl)-4-(3-phenyl-1,2,4-oxadiazol-5-yl-benzamide (248 mg, 95%). 1H-nmr (400 MHz, CDCl3) δ 8.31 (d, J=8 Hz, 2H), 8.23-8.17 (m, 2H), 7.95 (d, J=8 Hz, 2H), 7.59-7.52 (m, 3H), 6.12 (s, 1H), 3.57-3.51 (m, 2H) 1.62-1.58 (m, 2H), 1.02 (s, 9H); MS (ESI) m/z 349.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:6]2[C:7]([O:12][C:13]3[N:18]=[CH:17][C:16]([NH:19][C:20]([C@H:22]([NH:25][C:26](=[O:32])OC(C)(C)C)[CH2:23][CH3:24])=[O:21])=[CH:15][N:14]=3)=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]=2[O:4][CH2:3]1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>Cl.C(O)(C)C.C(OCC)(=O)C>[CH2:23]([C@H:22]1[NH:25][C:26](=[O:32])[N:19]([C:16]2[CH:15]=[N:14][C:13]([O:12][C:7]3[C:6]4[C:2]([CH3:33])([CH3:1])[CH2:3][O:4][C:5]=4[C:10]([CH3:11])=[CH:9][CH:8]=3)=[N:18][CH:17]=2)[C:20]1=[O:21])[CH3:24]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2ccc(C)c3c2C(C)(C)CO3)nc1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC[C@H]1NC(=O)N(c2cnc(Oc3ccc(C)c4c3C(C)(C)CO4)nc2)C1=O
Temperature: 35 °C
Yield: 89.6 %

Procedure:
1,1-dimethylethyl {(1R)-1-[({2-[(3,3,7-trimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]propyl}carbamate (Intermediate 191, 213 mg, 0.47 mmol) was dissolved in HCl 5-6 N in isopropanol (1 mL) and the resulting solution was heated to 35° C. for 30 minutes. The reaction mixture was then concentrated under vacuum, the residue diluted with ethyl acetate (50 mL) and an aqueous 5% solution of K2CO3 (30 mL). Two phases were separated and the organic layer was washed with an aqueous saturated solution of ammonium chloride (30 mL), dried over Na2SO4 and concentrated under vacuum. The resulting crude was dissolved in ethyl acetate (10 mL) and triethylamine was added (0.23 mL, 1.64 mmol). The reaction mixture was cooled to 0-5° C. and a solution of triphosgene (55 mg, 0.185 mmol) in ethyl acetate (5 mL) was added drop wise in 10 minutes. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with brine dried over Na2SO4 and concentrated under vacuum. The residue was purified purified by flash chromatography on silica gel using cyclohexane/ethyl acetate 50:50 as eluent affording the title compound (161 mg) as a white solid.
Reaction SMILES: CCOC(/N=N/C(O[CH2:11][CH3:12])=O)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[F:28][C:25]([F:26])([F:27])[C:20]([C:17]1[CH:16]=[CH:15][C:14]([NH2:13])=[CH:19][CH:18]=1)([O:29][CH2:34][CH2:35][N:30]1[CH2:12][CH2:11][CH2:33][CH2:32][CH2:31]1)[C:21]([F:22])([F:23])[F:24]
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC(O)C1CCCCN1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(C(OCCN2CCCCC2)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
DEAD (366 mg, 2.1 mmol) was added drop-wise to the solution of 2-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (520 mg, 2 mmol), 2-piperidylethan-1-ol (260 mg, 2 mmol) and PPh3 (550 mg, 2.1 mmol) in THF (10 mL). The mixture was stirred for 2 h. The reaction was partitioned between EtOAc and aqueous NaHCO3 solution and the organic phase was washed with brine. After concentrated in vacuo, the organic residue was purified by flash chromatography on silica to give the title intermediate.