Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH2:14][NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][CH:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>C(Cl)Cl>[CH3:20][CH:19]([S:16]([NH:15][CH2:14][CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:35]([CH:33]([CH3:34])[CH3:32])(=[O:37])=[O:36])[CH:3]=2)=[CH:24][CH:23]=1)[CH3:22])(=[O:18])=[O:17])[CH3:21]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(N)c2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2cccc(NS(=O)(=O)C(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 264.3 %

Procedure:
To a solution of {2-[4-(3-aminophenyl)phenoxy]propyl}[(methylethyl)sulfonyl]amine (125 mg, 0.3587 mmol, prepared in example 3) dissolved in methylene chloride (2.5 mL, anhydrous) was added triethylamine (0.125 mL, 0.8968 mmol) under a nitrogen system. The mixture was cooled to 0° C. and 2-propanesulfonyl chloride (0.06 mL, 0.5381 mmol) was added by syringe. The mixture was allowed to warm to room temperature, and stirred overnight, under a nitrogen system. The reaction was quenched with excess water, and the organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, yielding 431 mg viscous oil. Purification was conducted using a Chromatotron®, on a 4000 μm rotor and eluting with a 1:1 hexane:ethyl acetate solvent system, yielding 400 mg of two inseparable coeluting spots. This mixture was purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate, yielding the title compound (16.7 mg, 1%) as a slow crystallizing foam.
Reaction SMILES: [N:1]#[C:2][NH2:3].C[O-].[Na+].CO[C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12]>CO>[C:2]([NH:3][C:9]([CH:13]1[CH2:15][CH2:14]1)=[N:10][C:11]#[N:12])#[N:1]
Reactant: N#CN
Reactant: COC(=NC#N)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#CN=C(NC#N)C1CC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
At 0° C. 8,4 g of cyanamide in 50 ml methanol are added to 36 g of a 30% solution of sodium methylate in methanol and stirred for 30 min. at 10° C. The resulting solution is then cooled to -20° C. and mixed with a solution of 22 g N-cyano-cyclopropanecarboximidic acid methylester in 60 ml methanol. The reaction mixture is then stirred for 30 min. at 20° C. and then evaporated. 100 ml of dioxane is added to the resulting residue which is then concentrated by evaporation. Then again 100 ml of toluene is added and the solution is concentrated at an ambient temperature of 60° C. up to a residual weight of 33 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH2:20]([NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][C:22]#[CH:23].C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Si:13]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:23]#[C:22][CH2:21][CH2:20][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:11]=[CH:10]2)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reactant: C#CCCNC(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C#CCCNC(=O)OCc3ccccc3)ccc2c1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A solution of (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (81, 16.1 g, 47.7 mmol), benzyl but-3-ynylcarbamate (82, 9.0 g, 47.7 mmol), and triethylamine (95 mL) in anhydrous THF (100 mL) was cooled to −78° C. and degassed with argon. The mixture was warmed to room temperature and dichlorobis(triphenylphosphine)palladium(II) (3.3 g, 4.8 mmol) and CuI (1.8 g, 9.6 mmol) were added rapidly in one portion under argon. The mixture was heated at 50° C. for 12 h. The reaction mixture was filtered through a plug of diatomaceous earth and the filtrate was concentrated. The residue was purified by column chromatography (silical gel, 10:1 hexanes/EtOAc) to afford carbamate 83 (8.5 g, 38%) as a thick brown oil: 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.39-7.29 (m, 6H), 7.13 (d, J=2.1 Hz, 1H), 7.07 (dd, J=8.7, 2.4 Hz, 1H), 5.17 (br s, 1H), 5.13 (s, 2H), 3.46 (q, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 1.01 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]([CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:7][C@@H:6]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][CH:32]=[N:33][C:34]=2[NH2:38])(=O)C.O.NN>N1C=CC=CC=1>[C:11]([O:10][C@@H:9]1[C@H:8]([CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:7][C@H:6]([N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][CH:32]=[N:33][C:34]=3[NH2:38])[C@H:5]1[OH:4])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O[C@H]1[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cnc2c(N)ncnc21
Agent: NN
Solvent: c1ccncc1
Solvent: O
Product: Nc1ncnc2c1ncn2[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 68 %

Procedure:
A solution of 9-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)adenine 2 [Ref.: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L., “Synthesis and Antiviral Evaluation of β-L-Xylofuranosyl Nucleosides of the Five Naturally Occurring Nucleic Acid Bases”, Journal of Heterocyclic Chemistry, 1993, 30 (October-November), 1229-1233] (8.30 g, 16.05 mmol) and hydrazine hydrate 98% (234 mL, 48.5 mmol) in a mixture of pyridine/glacial acetic acid (4/1, v/v, 170 mL) was stirred at room temperature for 22 h. The reaction was quenched by adding acetone (40 mL) and stirring was continued for one additional hour. The reaction mixture was reduced to one half of its volume, diluted with water (250 mL) and extracted with chloroform (2×150 mL). The organic layer was washed successively with an aqueous saturated solution of NaHCO3 (3×100 mL) and water (3×100 mL), dried, filtered, concentrated and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-3% MeOH in dichloromethane) to give 3 (5.2 g, 68%) precipitated from diisopropylic ether: 1H NMR (DMSO-d6): δ 4.5-4.9 (m, 4H, H-2′, H-4′, H-5′ and H-5″), 5.64 (t, 1H, H-3′, J2′,3′=J3′,4′=3.5 Hz), 6.3 (br s, 1H, OH-2′), 6.45 (d, 1H, H-1′, J1′,2′=4.6 Hz), 7.3 (br s, 2H, NH2-6), 7.4-7.9 (m, 10H, 2 benzoyls), 8.07 and 8.34 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB) m/z 476 [M+H]+, 136 [BH2]+, (FAB−) m/z 474 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 257 nm (ε 16400), 230 nm (ε 29300), λmin 246 nm (ε 14800); [α]D20 64 (c 1.07, CHCl3). Anal. Calcd for C24H21N5O4 (M=475.45): C, 60.43; H, 4.45; N, 14.73. Found: C, 60.41; H, 4.68; N, 14.27.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]([CH2:19][CH2:20][CH3:21])=[C:14](Cl)[C:13]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>C(O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([NH:28][CH2:27][CH2:26][O:25][CH3:24])[C:13]=2[CH:23]=1
Reactant: CCCc1c(Cl)c2cc(Br)ccc2oc1=O
Reactant: COCCN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCc1c(NCCOC)c2cc(Br)ccc2oc1=O

Procedure:
Triethylamine was added to a solution of 6-bromo-4-chloro-3-propyl-2H-1-benzopyran-2-one (0.5 g), in dry ethanol (10 ml) followed by 2-methoxyethylamine (0.16 ml). The mixture was heated at reflux under nitrogen overnight, evaporated and the residue extracted with ethyl acetate and the extract washed with dilute hydrochloric acid, brine, dried and evaporated under reduced pressure. The residue was triturated with ethanol and light petroleum (b.p. 40-60° C.) to give 6-bromo-4-(2-methoxyethylamino)-3-propyl-2H-1-benzopyran-2-one, m.p. 75-7° C. (compound 21).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:16]([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35]=[C:36]([C@@H:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[C@H:45]([CH:51]([CH3:53])[CH3:52])[NH:46][C:47]([O:49][CH3:50])=[O:48])[NH:37][CH:38]=5)=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[N:21]=2)[CH2:15][C:14]2([CH2:59][CH2:58][N:57](C(OC(C)(C)C)=O)[CH2:56][CH2:55]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:52][CH:51]([CH3:53])[C@H:45]([NH:46][C:47](=[O:48])[O:49][CH3:50])[C:44]([N:40]1[CH2:41][CH2:42][CH2:43][C@H:39]1[C:36]1[NH:37][CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([C:25]3[CH:24]=[CH:23][C:22]([C:20]4[N:21]=[C:17]([CH:16]5[CH2:15][C:14]6([CH2:55][CH2:56][NH:57][CH2:58][CH2:59]6)[CH2:13][N:12]5[C:10](=[O:11])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:8])[CH3:9])[NH:18][CH:19]=4)=[CH:27][CH:26]=3)=[CH:29][CH:30]=2)[N:35]=1)=[O:54]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CC2(CCNCC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
To a solution of 1,1-dimethylethyl 2-{N-[(methyloxy)carbonyl]-L-valyl}-3-(4-{4′-[2-((2S)-1-{N-[(methyloxy)carbonyl]-L-valyl}-2-pyrrolidinyl)-1H-imidazol-4-yl]-4-biphenylyl}-1H-imidazol-2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate (68 mg, 0.08 mmol) in anhydrous CH2Cl2 (1 mL) was added trifluoroacetic acid (0.3 mL) and the reaction stirred at room temperature for 2 h. The reaction was concentrated in vacuo and purified by HPLC eluting with 10-90% acetonitrile/water/0.2% NH4OH to afford the title compound as a tan solid (49 mg, 81% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.56-7.83 (m, 10H) 7.31 (br. s., 2H) 5.00-5.22 (m, 2H) 4.12-4.30 (m, 3H) 4.01 (br. s., 1H) 3.80-3.91 (m, 1H) 3.57-3.70 (m, 6H) 2.76-3.07 (m, 4H) 1.89-2.48 (m, 10H) 1.69-1.81 (m, 1H) 1.61 (br. s., 2H) 0.82-1.09 (m, 15H). HRMS for C44H58N9O6 (M+H)+ calc: 808.4510, found: 808.4509. Purity (LC-MS): 94%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:3]=1
Reactant: COC(=O)C(C)CN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)CNc1cc(Br)ccc1[N+](=O)[O-]
Yield: 59.1 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (9.4 g, 42.7 mmol) in tetrahydrofuran (100 mL) were added methyl 3-amino-2-methylpropanoate (5 g, 42.7 mmol) and potassium carbonate (11.8 g, 85.4 mmol). The reaction mixture was stirred with refluxing for 3 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 3-(5-bromo-2-nitrophenylamino)-2-methylpropanoate as a light yellow solid (8 g, 59%).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.O1[C:17]2([CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:19][CH2:18]2)[O:16]CC1.CC(C)=O.C(=O)(O)[O-].[Na+]>O>[O:16]=[C:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])[CH2:19][CH2:18]1
Reactant: O=C(CC1CCC2(CC1)OCCO2)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(CC(=O)OCc2ccccc2)CC1
Temperature: 55 °C
Reaction time: 15 h
Yield: 85.9 %

Procedure:
p-Toluene sulfonic acidmonohydrate (207 mg, 1.21 mmol) was added to a mixture composed of benzyl 2-(1,4-dioxaspiro[4,5]decan-8-yl)acetate (7.0 g, 24.11 mmol), acetone (220 ml), and water (10 ml) at room temperature, and the mixture was stirred at 55° C. for 15 hr. The mixture was cooled with ice and was adjusted to pH 5 by the addition of solid sodium bicarbonate. The mixture was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=85:15) to give the title compound as a colorless solid (5.1 g, yield 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3.[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:3]4[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=4[F:1])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc(F)c(F)cc3F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(F)c(F)cc4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2,4,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (43 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (42 mg, 0.36 mmol). Methyl iodide (0.023 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 40 mg (89%) of the title compound as a foam. FDMS: m/e=359.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:21])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:22][C:23]1[CH:28]=[C:27]([CH2:29]Cl)[CH:26]=[CH:25][N:24]=1>CN(C)C=O.O>[C:3]([C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:29][C:27]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:22])[CH:28]=3)[C:14]2=[O:21])=[CH:11][CH:12]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC1(C)NC(=O)N(c2ccc(C(C)(C)C)cc2)C1=O
Reactant: ClCc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(Cl)c3)C(C)(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
To a suspension of 1.1 g of sodium hydride in 40 mL of dimethylformamide under argon are successively added 4.9 g of 3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione obtained in stage c) of Example 1 and 4.55 g of 2-chloro-4-(chloromethyl)pyridine. The reaction mixture is stirred for 48 hours at room temperature and then diluted with 260 mL of water. The solid formed is filtered off, rinsed with diisopropyl ether and dried to give 4.61 g of 3-(4-tert-butylphenyl)-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:6]#[N:7].S(=O)(=O)(O)[OH:20].N>ClCCl>[F:1][C:2]([F:17])([F:18])[CH2:3][CH2:4][CH:5]([NH:8][CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:10])[C:6]([NH2:7])=[O:20]
Reactant: CC(NC(C#N)CCC(F)(F)F)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: N
Solvent: ClCCl
Product: CC(NC(CCC(F)(F)F)C(N)=O)c1ccccc1
Temperature: -2.5 °C

Procedure:
5,5,5-Trifluoro-2-(1-phenylethylamino)pentanenitrile (crude mixture of diastereomers from Step B, 1.10 kg) was dissolved in dichloromethane (5.5 L) in a suitable vessel equipped with mechanical stirring, ice bath for cooling and maintained under a blanket of nitrogen. Stirring was started and the reaction mixture was cooled to 0 to −5° C. Concentrated sulfuric acid (1.75 L) was added dropwise over a period of 1 hour into the above mixture, maintaining the temperature below 0° C.; a clear solution was obtained after the addition was complete. The temperature of the reaction mixture was raised to 25 to 27° C. and stirred overnight (12-14 h). Completion of the reaction was determined by HPLC. The reaction mixture was poured slowly over crushed ice (˜15.0 kg) and was neutralized with aqueous ammonia (˜25% by volume). The aqueous layer was separated and extracted with dichloromethane (2×3.0 L). The combined dichloromethane layer was washed with water (1×12.0 L) followed by brine (1×3.0 L). The product rich organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield 0.85 kg (72.0%) of the crude title compound 1H NMR (CDCl3) (400 MHz) (Mixture of diasteromers) δ 1.36 (d&m, 41-1, CH3 (J=8.0 Hz & 1H of CH2), 1.90 (m, 1H of CH2), 2.15 & 2.35 (two m, 1H each of CH2—CF3), 2.80-2.90 (m, 1-H, CH-Ph), 3.60-3.70 (m, 1H, —(CONH2)CH(NH), 5.90 & 6.45 (111 each of CONH2 with minor peaks for other diasteromer), 7.20-7.40 (m, 6H, Ar+NH).
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)[C:2]=1[NH2:1]
Reactant: N#Cc1cccc(Cl)c1N
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cccc1-c1nnn[nH]1
Temperature: 100 °C
Yield: 90 %

Procedure:
To a mixture of 2-amino-3-chlorobenzonitrile (500 mg, 3.3 mmol), sodium azide (4.3 mmol, 1.3 eq.), and triethylamine hydrochloride (4.3 mmol, 1.3 eq.) in a sealed tube, 8 mL of toluene was added. The tube was tightly capped and the reaction was stirred and heated to 100° C. overnight. The mixture was cooled to room temperature, diluted with another 10 mL of toluene, transferred to a separatory funnel and washed 3×20 mL with water. The aqueous extractions were collected and acidified to a pH of 4 with concentrated HCl. The solid was collected by filtration, washed with acetonitrile, and dried under vacuum to afford 581 mg of 2-chloro-6-(1H-tetrazol-5-yl)aniline. MS (EI) for C7H6ClN5: 196 (MH+). Step 2: N-[2-Chloro-6-(1H-tetrazol-5-yl)phenyl]thiophene-2-carboxamide: To a solution of 2-chloro-6-(1H-tetrazol-5-yl)aniline (300 mg, 1.5 mmol) in 8 mL of DCM, DIPEA (3.1 mmol, 2.0 eq.) was added followed by thiophene-2-carbonyl chloride (2.3 mmol, 1.5 eq.). The reaction was stirred at room temperature overnight. The organic solution of the crude reaction mixture was extracted twice with aqueous HCl (0.1 M), twice with aqueous sodium hydroxide (0.1 M), and once with a saturated aqueous solution of sodium chloride. The basic aqueous extractions and final brine extraction were combined and acidified to a pH of 4 with concentrated HCl. The resulting solid was collected by filtration. The material was then washed with acetonitrile, and dried under vacuum to afford 33 mg of desired product. 1H-NMR (400 MHz, d6-DMSO): δ 10.32 (s, 1H), 7.96 (d, 1H), 7.87-7.81 (m, 3H), 7.58 (t, 1H), 7.23 (t, 1H). MS (EI) C12H8ClN5OS: 306 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:34])[C@@H:13]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([OH:32])[C:29]3[C:24](=[CH:25][C:26]([CH3:33])=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C:46]1=[O:50])=[O:44]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:34])[C@@H:13]([NH:19][C:20]([C:22]2[CH:31]=[C:30]([O:32][CH2:42][C:43](=[O:44])[N:45]3[CH2:49][CH2:48][CH2:47][C:46]3=[O:50])[C:29]3[C:24](=[CH:25][C:26]([CH3:33])=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([O:18][C:26]([CH3:33])([CH3:27])[CH3:25])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: O=C(CCl)N1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCCC3=O)c3ccc(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 200 mg of 4-{(S)-4-Carboxy-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 2.5 ml of DMF, 184 mg of cesium carbonate and 91 mg of 1-(2-Chloro-acetyl)-pyrrolidin-2-one was added and the reaction mixture was stirred for 3 days at RT. Then, the reaction mixture was diluted with water and filtered through a chem Elut® cartridge by eluting with ethyl acetate. The solvents were removed under reduced pressure and the isolated crude product was pure enough for the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15](Cl)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.CCN(CC)CC.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2Cl
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a mixture of 10.0 g (37.9 mmol) of 8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine and 1.0 mL of Et3N in 200 mL of dry THF at room temperature and under a nitrogen atmosphere was added 33.0 g of piperazine. The mixture was stirred at room temperature for 22.5 hours and then refluxed for 5.5 hours. It was then cooled to room temperature, poured into 250 mL of 5% aqueous NaOH, and extracted with CH2Cl2 (3×). The combined organic portions were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (2→5% MeOH saturated with ammonia in CH2Cl2) to yield the title compound as a glass.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1.[CH2:14]=[O:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(Br)c(-n2cncn2)c1
Reactant: C=O
Product: OCc1ncnn1-c1cc(F)ccc1Br
Temperature: 150 °C

Procedure:
A suspension of 1-(2-bromo-5-fluorophenyl)-1H-1,2,4-triazole (3.63 g, 15 mmol) in 37% formaline (15 mL) in a sealed vessel was stirred in an oil bath heated at 150° C. for 9.5 h. After cooling, the mixture was extracted with CH2Cl2 (15 mL×2) and the combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residual crude oil was purified by column chromatography (SiO2, 0–7% MeOH/CH2Cl2) followed by trituration with Et2O to obtain 430 mg of the title compound as white crystalline solid: TLC Rf 0.5 (10% MeOH/CH2Cl2); HPLC rt=1.31 min; LC/MS m/z 272/274 (M+H); 1H NMR (CDCl3, 500 MHz) δ ppm 3.67 (1H, br.s, OH), 4.65 (2H, s, 9-OCH2), 7.13–7.22 (1H, m, 5-CH), 7.29 (1H, dd, J=8, 3 Hz, 3-CH), 7.71 (1H, dd, J=9.0, 5.3 Hz, 6-CH), 8.03 (1H, s, 8-CH); 13C NMR (CDCl3, 125.8 Hz) δ ppm 55.3 (9-OCH2), 116.2 (d, J=3.9 Hz, 1-C), 117.4 (d, J=25 Hz, 3-CH), 119.4 (d, J=22 Hz, 5-CH), 134.7 (d, J=8.3 Hz, 6-CH), 137.0 (d, J=10 Hz, 2-C), 151.3 (8-CH), 156.3 (7-C), 161.8 (d, J=252 Hz, 4-CF); HRMS (ESI) calcd for C9H8FBrN3O (M+H) 271.9835. found 271.9828 (δ −2.5 ppm).