Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C@@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[NH2:1][C@H:4]1[C@@H:8]([F:9])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@H](N=[N+]=[N-])C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@@H](F)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask equipped with a magnetic stir bar and a reflux condenser, to a solution of cis-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate (86 mg, 0.374 mmol) in THF (5.5 mL) was added PPh3 on polystyrene (1.6 mmol/g, 280 mg, 0.448 mmol) and water (0.33 mL). The reaction mixture was stirred at 60° C. for 2 h. The mixture was then filtered and the filtrate dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford cis-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate as a colorless oil. LC-MS-conditions 10: tR=0.45 min; [M-CH3+H]+=190.41.
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=O)[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:17]([NH2:18])=[C:16]([O:22][CH3:23])[CH:15]=1>CN1CCCC1=O.ClCCl>[Br:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9]([NH:18][C:17]3[C:19]([CH3:21])=[CH:20][C:14]([Cl:13])=[CH:15][C:16]=3[O:22][CH3:23])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c2cccc(Br)c21
Reactant: COc1cc(Cl)cc(C)c1N
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc(Cl)cc(C)c1Nc1nc2cccc(Br)c2n1C
Temperature: 110 °C
Yield: 84.9 %

Procedure:
To a mixture of 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one 2.32 g (9.69 mmol) and 4-chloro-2-methoxy-6-methylaniline 4.98 g (29.1 mmol) in 0.5 mL of N-methyl-2-pyrrolidone was heated at 110° C. for 2 days. The reaction was cooled to room temperature and diluted with dichloromethane. The mixture was washed with sodium bicarbonate and water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate/hexane (1:1) to give 3.13 g (8.23 mmol, 85%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:10]([NH:11][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH3:13])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(N[C@H](C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(N[C@H](C)c2ccc(F)c(F)c2)c2cccc(N)c2)cc1

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(3-nitrophenyl)-(4-methoxyphenyl)methyl]-[(R)-1-(3,4-difluorophenyl)ethyl]amine (1.27 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (1.52 g) and sodium borohydride (510 mg) were reacted, and the reaction mixture was purified by chromatography through a silica gel column using a 1:8 by volume mixture of ethynyl acetate and toluene as the eluant, to afford isomer A (235 mg,) as a yellow oil and isomer B (240 mg) as a pale yellow oil of the title compound.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]([NH2:13])([CH3:12])[CH3:11].[OH-].[Na+]>C(OCC)(=O)C>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:13][CH:10]([CH3:12])[CH3:11])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CC(C)N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc(Cl)nc(Cl)n1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
A suspension of 369 g of cyanuric chloride in 1000 ml of ethyl acetate is cooled to -15° C. With good stirring, 124 g of isopropylamine are first added dropwise at -20° C. to -10° C. in the course of 21/2 hours, followed by 267 g of a 30% aqueous solution of sodium hydroxide in the course of one hour. The reaction mixture is stirred for a further 11/2 hours at the same temperature, then the organic phase is separated, washed with two 100 ml portions of water and dried over sodium sulphate. The solvent is evaporated, to yield an oil from which the 2,4-dichloro-6-isopropylamino-s-triazine precipitates in crystalline form after stirring with petroleum ether at low temperature. Melting point: 46°-47° C.
Reaction SMILES: N1C=[CH:4][CH:3]=[CH:2]1.[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([CH3:12])[CH:11]=1>>[CH3:12][C:10]1[C:11]2[CH2:4][CH2:3][CH2:2][CH2:6][C:7]=2[NH:8][CH:9]=1
Reactant: Cc1c[nH]c(C)c1
Reactant: c1cc[nH]c1
Product: Cc1c[nH]c2c1CCCC2

Procedure:
Conversion of α-pyrrolecarboxylate esters to α-unsubstituted pyrroles by treatment with phosphoric acid provided a convenient preparation of pyrrole 5b and was extended to 3-n-propyl, 3-n-butyl, and 3-isopropyl derivatives 5d-f of 2,4-dimethylpyrrole 5a. A similar conversion afforded 3-methyl-4,5,6,7-tetrahydroindole 5i from its 2-carboxylate ester derivative 4i. Unsuccessful attempts to extend the method to the preparation of 2,4-dimethyl-3-tert-butylpyrrole 5g led instead to the replacement of both the carboethoxy and tert-butyl groups with hydrogen to give 2,4-dimethylpyrrole 5a. The pyrroles 5g, j, k were obtained from ethyl 3',5'-dimethyl-4-tert-butylpyrrole-2-carboxylate 4g, ethyl 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolecarboxylate 4j, and ethyl 3,4-diethyl-5-methylpyrrole-2-carboxylate 4k by saponification with potassium hydroxide followed by decarboxylation of the free acids in ethanolamine at 180° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:25])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([Br:21])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:22]([NH2:24])=[O:23])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:26]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29](=O)[O:28][C:27]1=O.[N+](O[La](O[N+]([O-])=O)O[N+]([O-])=O)([O-])=O.COC(OC)OC>O1CCCC1.C(OCC)(=O)C.C(OCC)(=O)C.CCCCCC>[Br:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:29](=[O:28])[C:30]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[N:26]=[CH:27]5)[C:3]=4[CH3:25])=[CH:9][N:10]=[C:11]([C:22]([NH2:24])=[O:23])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1
Reactant: Cc1c(N)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(Br)ccc3c12
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: O=[N+]([O-])O[La](O[N+](=O)[O-])O[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(Br)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 90 °C
Yield: 61.5 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxamide (0.243 g, 0.615 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.251 g, 1.537 mmol), tris(nitrooxy)lanthanum, 6H2O (0.080 g, 0.184 mmol), and trimethoxymethane (2.020 mL, 18.44 mmol) in tetrahydrofuran (2 mL) was heated at 90° C. for 16 hr. The mixture was diluted with ethyl acetate (120 mL), washed with water (2×30 mL) and brine (30 mL), and dried over anhydrous MgSO4. The desired product (0.198 g, 0.378 mmol, 61.4% yield) was isolated as a yellow solid by ISCO (40 g silica gel, solid loading, 40-80% ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[C:8](O)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(Cl)(=O)=O.Cl.[NH2:44][C@@H:45]1[C:63](=[O:64])[N:47]2[C:48]([C:60]([OH:62])=[O:61])=[C:49]([S:52][CH2:53][C:54]3[CH:59]=[N:58][CH:57]=[CH:56][N:55]=3)[CH2:50][S:51][C@H:46]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Na+].[Cl-]>CN(C)C(=O)C.CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][C:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)/[C:8]([NH:44][C@@H:45]2[C:63](=[O:64])[N:47]3[C:48]([C:60]([OH:62])=[O:61])=[C:49]([S:52][CH2:53][C:54]4[CH:59]=[N:58][CH:57]=[CH:56][N:55]=4)[CH2:50][S:51][C@H:46]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(SCc3cnccn3)CS[C@H]12
Agent: CS(=O)(=O)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(SCc4cnccn4)CS[C@H]23)cs1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 110.1 %

Procedure:
To a solution of 2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetic acid (3.70 g, 8.61 m mol) in N,N-dimethylacetamide (37 ml) was added potassium carbonate (1.19 g, 8.61 m mol) and methansulfonyl chloride (1.33 ml, 17.2 m mol) at 5° C. The mixture was stirred at 5° C. for 30 minutes. To a solution of 7β-amino-3-[(pyrazin-2-yl)methylthio]-3-cephem-4-carboxylic acid hydrochloride (3.42 g, 8.61 m mol) in DMF (34.2 ml) was added bis(trimethylsilyl)acetamide (14.9 ml, 60.3 m mol), and stirred at 5° C. for 20 minutes. To the solution was added the above-mentioned solution of the activated acid. The mixture was stirred at 5° C. for 1 hour. The reaction mixture was poured into 20% NaCl aq. (350 ml). The precipitates were collected by filtration, washed with water and dried in vacuo to give 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(trityloxyimino)acetamido]-3-[(pyrazin-2-yl)methylthio]-3-cephem-4-carboxylic acid (6.98 g, 9.49 m mol).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=1.[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1>>[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH2:2][C:3]2[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=2)[N:13]=[C:12]([OH:17])[CH:11]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cnc(CCl)c1
Product: Cc1cc(O)nc(SCc2cn(C)cn2)n1
Yield: 60 %

Procedure:
This example was synthesized from 4-(chloromethyl)-1-methyl-1H-imidazole and 6-methyl-2-sulfanylpyrimidin-4-ol following the general procedure as shown in the last step of Example 109. This provided the title compound as a white solid (260 mg, 60% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.60 (s, 3H), 4.24 (s, 2H), 5.97 (bs, 1H), 7.06 (s, 1H), 7.52 (s, 1H); M+237.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:9])[CH2:3][C:2]2=[O:10].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.[H-].[Na+].Cl>CN(C)C=O.O>[F:11][C:12]([F:22])([F:23])[C:13]1[CH:14]=[C:15]([NH:19][C:20]([CH:3]2[C:4](=[O:9])[CH:5]3[CH2:8][CH:1]([CH2:7][CH2:6]3)[C:2]2=[O:10])=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CC(=O)C2CCC1C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)C1C(=O)C2CCC(C2)C1=O

Procedure:
A solution of bicyclo[3,2,1]octane-2,4-dione (0.27 g, 2.0 mmole), 3-(trifluoromethyl) phenyl isocyanate (0.55 ml, 4.0 mmole), and 60% sodium hydride in mineral oil (0.088 g, 2.2 mmole) in dimethylformamide (100 mL) was stirred at 0° C. for 1 hour and then heated at 45–50° C. under nitrogen for 24 hours. After cooling, the mixture was diluted with H2O and treated with 2N aqueous HCl until the mixture was clear. The clear solution was then extracted with dichloromethane. The organic layer was washed with H2O again, dried over anhydrous magnesium sulfate, and concentrated on a rotary evaporator. The residue was purified with by chromatography on silica gel (40% dichloromethane/hexane) to give a clear oily liquid as the expected product. The oily product was crystallized with ethyl acetate/hexane in a dry ice bath to afford the title compound as a white solid, mp=68–69° C.; MS (−) ESI m/z=324 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C(O)(C(F)(F)[F:37])=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:37])[C:20]=2[N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2ccncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-butyl 1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)pyridin-4-yl)piperidine-4-carboxylate prepared according to methods similar to the one depicted in Example 1 was dissolved in DCM (5 mL). TFA (1 mL, 12.98 mmol) was added and the mixture was stirred at RT for 5 hr. The reaction mixture was concentrated to give 1-(3-(2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid as a beige solid that was used in next step without further purification. MS (ES+) 418.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CNC
Product: CN(C)C(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and dimethylamine (0.330 g, 56.6%); MS: 189.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]([CH2:6][C@@H:7]([C:13]([N:15]2[C@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:27])=[O:14])[CH2:8][CH2:9][CH2:10][CH:11]=O)=[CH:4][C:3]=1[CH3:31].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]([CH2:6][C@H:7]([CH2:8][CH2:9][CH2:10][CH2:11][NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=2)[C:13]([N:15]2[C@H:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][O:17][C:16]2=[O:27])=[O:14])=[CH:4][C:3]=1[CH3:31]
Reactant: NCc1ccc(F)cc1
Reactant: Cc1cc(C[C@H](CCCC=O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cc(C[C@H](CCCCNCc2ccc(F)cc2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc(C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a solution of (S)-5-(4-fluoro-3,5-dimethylbenzyl)-6-((R)-4-benzyl-2-oxooxazolidin-3-yl)-6-oxohexanal (0.039 g, 0.0917 mmol) and 4-fluorobenzyl amine (0.014 g, 0.110 mmol) in 3 mL of dichloroethane, was added NaBH(OAc)3 (0.027 g, 0.128 mmol). After stirring at room temperature for overnight, the reaction was quenched with 20 mL of saturated NaHCO3 solution and the reaction mixture was extracted with ethyl acetate (20 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-10% methanol/dichloromethane to give the title compound as light yellow oil (0.030 g, 62% yield). LC-MS: tR=6.9 min; m/z 535 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].FC(F)(F)C(O)=O.[CH3:16][C@H:17]1[CH2:22][NH:21][C@H:20]([CH3:23])[CH2:19][N:18]1[C:24]1[CH:43]=[CH:42][C:27]([O:28][CH2:29][C@@H:30]2[O:35][C:34]3=[N:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][N:33]3[CH2:32][CH2:31]2)=[CH:26][CH:25]=1.Cl[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][C:60]([F:63])([F:62])[F:61])=[CH:55][CH:54]=2)=[CH:48][CH:47]=1.CC(C)([O-])C.[Na+]>O.CN1CCCC1=O>[CH3:16][C@H:17]1[CH2:22][N:21]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][C:60]([F:61])([F:62])[F:63])=[CH:55][CH:54]=3)=[CH:50][CH:51]=2)[C@H:20]([CH3:23])[CH2:19][N:18]1[C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][C@@H:30]2[O:35][C:34]3=[N:36][C:37]([N+:39]([O-:41])=[O:40])=[CH:38][N:33]3[CH2:32][CH2:31]2)=[CH:42][CH:43]=1
Reactant: C[C@@H]1CN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)[C@@H](C)CN1
Reactant: FC(F)(F)Oc1ccc(Oc2ccc(CCl)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)[C@@H](C)CN1Cc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (135 mg) and sodium iodide (146 mg) were added to an N-methylpyrrolidone solution (6 ml) of (R)-7-[4-((2S,5R)-2,5-dimethyl-piperazin-1-yl)phenoxymethyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine trifluoroacetate (343 mg) and 1-(chloromethyl)-4-[4-(trifluoromethoxy)phenoxy]benzene (269 mg), and the mixture was stirred at 60° C. for 3 hours. Sodium tert-butoxide (112 mg) was added to the mixture and stirred at room temperature for 3 hours. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1→ethyl acetate:n-hexane=3:1) to afford the title compound as a pale brown amorphous compound (200 mg).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:10](O)=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8].C1C=CC2N(O)N=NC=2C=1.[NH2:40][C@H:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CC(C)N=C=NC(C)C>C(Cl)Cl>[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C@H:2]([C:10]([NH:40][C@H:41]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:11])[CH2:3][S:4][CH2:5][NH:6][C:7]([CH3:9])=[O:8]
Reactant: CC(=O)NCSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccccc1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(=O)NCSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Fmoc-Cys(Acm)-OH (855 mg, 2 mmol) in 4 ml dry DCM at 0° C., HOBt (270 mg, 2 mmol) was added. Then an ice-cold solution of H-Phg-OtBu (415 mg, 2 mmol) in 4 ml of dry DCM was added. Subsequently, DIC (319 μl, 2 mmol) was introduced dropwise. After 1 h at 0° C. and 4 h at 4° C., the solution was evaporated under vacuum. The residue was dissolved in 50 ml EtOAc and washed with sat. aq. NaHCO3, 0.5 M HCl and water. After drying and evaporation of the organic phase, the residue was chromatographed on silica gel to give the protected dipeptide 1 as a foam. Yield 1.14 g (95%), Rf 0.35 (DCM/MeOH, 95:5). 1H NMR (CDCL3): δ1.45 (9H, s, tBu), 1.92 (3H, s, CH3 Acm), 2.71-3.1 (2H, m, CβH2 Cys), 3.8 (1H, m, CoH Cys) 4.2-4.5 (5H,m, CH2 Acm. CH—CH2 Fmoc), 4.56-4.85 (3H, m, CoH Phg, Fmoc), 5.4 (1H, d, J=7.3 Hz, NH) 6.47 (1H, d, J=8.4 Hz, NH), 7.2-8.05 (14H, Fmoc+Phg aromatic, NH Acm). 13C NMR (CDCl3): δ23.7 (CH2, Acm), 27.7 (3×CH3, tBu), 34.9 (Cβ, Cys), 41.1 (CH2, Acm), 41.9 (CH2, Fmoc), 57.4 (CαPhg), 83.7 (Cq tBu), 119.7-127.5 (aromatic, Fmoc, Phg), 141.0 and 143.6 (4C, Fmoc), 156.6 (CO, Fmoc), 170.2 (CO, Cys), 173.5 (2×CO, Acm, tBu ester).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.2 %

Procedure:
Prepared using General Procedure 12. To a stirred suspension of 4-bromobenzaldehyde (9.88 g, 53.4 mmol) and tert-butyl 2-aminoacetate hydrochloride (8.95 g, 53.4 mmol) in methyl tert-butyl ether (200 mL) were added TEA (8.19 mL, 58.7 mmol) and MgSO4. After stirring at room temperature for 18 h the reaction mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in MeOH (200 mL), cooled to 0° C. in an ice bath and sodium borohydride (4.04 g, 107 mmol) was added portionwise. The reaction mixture was allowed to warm to room temperature and was stirred for 18 h. The reaction mixture was quenched with NaHCO3 (200 mL) and after 3 h extracted into EA (300 mL). The organic layer was washed with brine (2×200 mL), dried over MgSO4 and concentrated in vacuo to afford 11.9 g (74%) of tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60. LCMS-ESI (m/z) calculated for C13H18BrNO2: 300; found 300/302 [M+H]+, tR=2.89 min (Method 10).
Reaction SMILES: [OH:1][C@@H:2]([CH2:36][C@@H:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH2:39])[C@@H:3]([NH:8][C:9]([C@@H:11]([NH:18]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6]>C(Cl)Cl.N1CCCCC1>[NH2:18][C@@H:11]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[C:9]([NH:8][C@@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[C@@H:2]([OH:1])[CH2:36][C@@H:37]([CH:40]([CH3:42])[CH3:41])[CH:38]=[CH2:39])=[O:10]
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C

Procedure:
1.3 g of fluoren-9-ylmethyl [(S)-1-[[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol-4-ylethyl]carbamate in 30 ml of methylene chloride and 2 ml of piperidine were stirred at room temperature for 1.5 hours. Thereafter, the solvent was evaporated and the residue was triturated with hexane. The (S)-α-amino-N-[(1S,2S,4S)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]-imidazole-4-propionamide so obtained was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2].C(OC(C1C=C(C2C=CC([F:43])=CC=2)N(C2C=CC(F)=CC=2)C=1C)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][C:22]([F:43])=[CH:21][CH:20]=2)[C:7]=1[CH2:25][Br:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccccc2)c1CBr
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1C
Product: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccc(F)cc2)c1CBr

Procedure:
Prepared in analogy to that of 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 1,5-Bis-(4-fluoro-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 418 (M−HBr+H+).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.[Li]CCCC.CC[O:29][C:30]([CH:32]([F:34])[F:33])=O>C1COCC1>[Br:1][C:2]1[S:3][C:4]([C:30](=[O:29])[CH:32]([F:34])[F:33])=[CH:5][CH:6]=1
Reactant: Brc1cccs1
Reactant: CCOC(=O)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1ccc(Br)s1)C(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A solution of 2-bromothiophene (0.5 g, 3.00 mmol) in dry THF (5 mL) was cooled to −78° C. and freshly prepared lithium diisopropylamide (prepared from diisopropyl amine (0.5 mL, 3.60 mmol) and nBuLi (2.3 mL, 3.60 mmol, 1.6M in THF) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h. Ethyl difluoro acetate (409 mg, 3.30 mmol) was added dropwise at −78° C. and the reaction mixture was stirred for 1 h, then slowly warmed up to room temperature and quenched with saturated NH4Cl solution. The organic product was extracted with EtOAc and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to get 1-(5-bromothiophen-2-yl)-2,2-difluoroethanone (500 mg, yield 69%). 1H NMR (400 MHz, CDCl3) δ 7.77-7.75 (m, 1H), 7.21-7.20 (d, J=4.1 Hz, 1H), 6.27-6.00 (m, 1H).