Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:34][C:35]([F:41])([F:40])[CH2:36][C:37](O)=[O:38].[NH2:42][C@H:43]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([C:52]([N:54]([CH3:67])[CH:55]3[CH2:60][CH2:59][N:58]([C:61]4[CH:66]=[CH:65][N:64]=[CH:63][CH:62]=4)[CH2:57][CH2:56]3)=[O:53])[CH:50]=2)[CH2:45][CH2:44]1>C1COCC1.ClCCl>[CH3:67][N:54]([CH:55]1[CH2:60][CH2:59][N:58]([C:61]2[CH:66]=[CH:65][N:64]=[CH:63][CH:62]=2)[CH2:57][CH2:56]1)[C:52]([C:49]1[CH:50]=[C:51]2[C:46](=[CH:47][CH:48]=1)[CH2:45][CH2:44][C@H:43]2[NH:42][C:37](=[O:38])[CH2:36][C:35]([F:41])([F:40])[F:34])=[O:53]
Reactant: CN(C(=O)c1ccc2c(c1)[C@H](N)CC2)C1CCN(c2ccncc2)CC1
Reactant: O=C(O)CC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)c1ccc2c(c1)[C@H](NC(=O)CC(F)(F)F)CC2)C1CCN(c2ccncc2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
HATU (168 mg, 0.44 mmol, 1 eq) and DIPEA (200 μl, 1.1 mmol, 2.5 eq) were added to an ice-cooled solution of 3,3,3-trifluoropropionic acid (67.5 mg, 0.528 mmol, 1.2 eq) in THF (5 ml), and the mixture was stirred for 30 min. (R)-3-Amino-N-methyl-N-(1-(pyridin-4-yl)piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (154 mg, 0.44 mmol, 1 eq) was dissolved in THF (2 ml) and added dropwise to the reaction solution, and stirring was carried out for 16 h at RT. The reaction solution was diluted with dichloromethane (100 ml), washed with sat. sodium hydrogen carbonate solution (40 ml), sat. ammonium chloride solution (40 ml), water (40 ml) and sat. NaCl solution (40 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 5% MeOH in dichloromethane), the desired product was obtained in the form of a white solid. Yield: 59% (120 mg, 0.26 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C:10]([C:16]([C:18]2[S:19][C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=2)=[O:17])([CH2:13][CH2:14][CH3:15])[CH2:9]1)=O)(C)(C)C.CO.ClCCl.Cl>CCOCC>[ClH:23].[Cl:23][C:21]1[CH:22]=[C:18]([C:16]([C:10]2([CH2:13][CH2:14][CH3:15])[CH2:11][CH2:12][NH:8][CH2:9]2)=[O:17])[S:19][C:20]=1[CH3:24]
Reactant: CCCC1(C(=O)c2cc(Cl)c(C)s2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CCCC1(C(=O)c2cc(Cl)c(C)s2)CCNC1
Temperature: 25 °C
Yield: 194.6 %

Procedure:
A solution of 3-(4-chloro-5-methyl-thiophene-2-carbonyl)-3-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.16 g, 0.43 mmoles) in a mixed solvent of methanol and dichloromethane (3 ml/3 ml) was added a solution of hydrochloride acid in anhydrous ether (1M, 10 ml). The solution was stirred at room temperature over night, and concentrated under reduced pressure. The residue was triturated with hexanes and diethyl ether to yield (4-chloro-5-methyl-thiophen-2-yl)-(3-propyl-pyrrolidin-3-yl)-methanone hydrochloride as solid (0.129 g, 97%). [M+H]+: 272
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:13]>>[Br:13][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCC1CCCCC1
Reactant: BrP(Br)Br
Product: BrCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 195.2 %

Procedure:
4-Cyclohexyl-butan-1-ol(8.1 ml, 47 mmol) at -5° C. under nitrogen was treated dropwise over 10-15 min with 2.2 ml (23 mmol) of phosphorus tribromide, stirred at 0° C. for 15 min, room temperature for 2 h, then at 100° C. for 1.5 h before cooling to 0° C. The reaction was quenched with 50 g of ice, diluted with 100 ml of brine, and extracted with ether. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and distilled at 2 mm Hg, 100° C., to give 9.84 g (96%) of 1-bromo-4-cyclohexylbutane as a colorless liquid. NMR (CDCl3, TMS) δ 0.6-2.3 (m, 17H), 3.43 (t, J=7 Hz, 2H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:24]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1)([CH3:26])[CH3:25].C(=O)([O-])O.[Na+]>COC(C)(C)C>[CH3:2][O:3][CH:4]=[CH:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH:24]([CH3:26])[CH3:25])=[CH:29][CH:30]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)Oc1ccc(C=O)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COC=Cc1ccc(OC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A suspension of 140 g of methoxymethyl-triphenylphosphonium chloride in 400 ml of tert.-butyl methyl ether is treated with 45 g of potassium tert.-butylate within 5 minutes at 0° C. while gassing with nitrogen and the mixture is stirred for a further 10 minutes. Then, a solution of 41 g of 4-(isopropyloxy)-benzaldehyde in 100 ml of tert.-butyl methyl ether is added dropwise at 0° C. within 30 minutes. The reaction mixture is stirred at room temperature for a further 16 hours and then poured into 750 ml of 0.8N sodium hydrogen carbonate solution. The aqueous phase is separated and back-extracted with diethyl ether. The organic phase is washed neutral with water, dried over magnesium sulphate and concentrated. The residue is suspended in 800 ml of hexane. After cooling to 0° C. the triphenylphosphine oxide is filtered off and the tiltrate is concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) gives 45 g of pure 1-methoxy-2-(4-[isopropoxy]phenyl)ethene.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:5].[CH2:31]([NH2:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C[CH2:39][OH:40]>>[CH2:31]([NH:37][C:39](=[O:40])[NH:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][CH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)=[O:5])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: CCCCCCN
Reactant: CCO
Product: CCCCCCNC(=O)Nc1ccccc1C(=O)NCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 56.9 %

Procedure:
{2-amino-N-[(1-diphenylmethylpiperidin-4-yl)methyl]benzamide and n-hexylamine}: yield 56.9%; mp 168°-169° C. (EtOH); 1H NMR (DMSO-d6)ppm: 0.86 (3H, t), 125-1.83 (15H, m), 2.79 (2H, d), 3.01 (2H, dd), 3.17 (2H, t), 4.26 (1H, s), 6.91 (1H, t), 7.13-7.40 (12H, m), 7.57 (1H, d), 8.21 (1H, d), 8.57 (1H, t), 9.95 (1H, s).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OC1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH:19][C:20]([NH2:22])=[O:21])[CH2:11]C1>O>[C:5]([O:4][CH:1]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]([NH:19][C:20]([NH2:22])=[O:21])[CH2:11][CH2:2]1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)NC1CCC(O)c2ccccc21
Solvent: O
Product: CC(=O)OC1CCC(NC(N)=O)c2ccccc21
Reaction time: 1 h

Procedure:
To 10 ml of acetic anhydride 2.0 g of 1,2,3,4-tetrahydro-4-hydroxy-1-naphthylurea (cis/trans) is added and the mixture stirred for 1 hour. The mixture is poured into water and the title compound collected by filtration. Evaporation of the mother liquor in vacuo affords additional title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H][H].CCOCC.[C:29]([OH:32])(=[O:31])[CH3:30]>[Pt]=O>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([CH2:30][C:29]([OH:32])=[O:31])[CH2:17]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)O
Reactant: [H][H]
Reactant: c1cncc(C2c3ccccc3CCc3ccccc32)c1
Agent: O=[Pt]
Solvent: CCOCC
Product: O=C(O)CN1CCCC(C2c3ccccc3CCc3ccccc32)C1
Yield: 100 %

Procedure:
Dissolved 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-pyridine (0.95 g, 3.5 mmol) in 50 mL of glacial acetic acid. Added platinum oxide catalyst (0.2 g), and shook on Paar shaker at 59 psi of hydrogen pressure for 24 hours. Filtered, and evaporated filtrate. Crystallized product from ether to give 1.14 g (100% yield) of 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-piperidine acetic acid as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:31][C:32](=[O:43])[C@H:33](O)[CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([C:8]1[O:9][C:10]2[CH:29]=[CH:28][CH:27]=[CH:26][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C@@H:33]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]([OH:43])=[O:31])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: COC(=O)[C@H](O)CCc1ccccc1
Product: O=C(O)[C@H](CCc1ccccc1)Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-biphenyl-4-ol, and (R)-(−)-2-hydroxy-4-phenylbutyric acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h, and was obtained as a white solid, mp 152-154° C.; MS m/e 537 (M−H)+;
Reaction SMILES: Cl.[F:2][C:3]1([F:7])[CH2:6][NH:5][CH2:4]1.N1CCCC1.CC(O[C:18]([NH:20][C@@H:21]([C:25]([OH:27])=O)[CH:22]1[CH2:24][CH2:23]1)=[O:19])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH3:44][N:45]1[CH:49]=[C:48]([C:50]2[N:55]=[C:54]3[C:56](C(O)=O)=[CH:57][N:58](COCC[Si](C)(C)C)[C:53]3=[N:52][CH:51]=2)[CH:47]=[N:46]1.C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)C(O)=O>>[CH:22]1([C@@H:21]([NH:20][C:18]([C:56]2[C:54]3[C:53](=[N:52][CH:51]=[C:50]([C:48]4[CH:47]=[N:46][N:45]([CH3:44])[CH:49]=4)[N:55]=3)[NH:58][CH:57]=2)=[O:19])[C:25]([N:5]2[CH2:6][C:3]([F:7])([F:2])[CH2:4]2)=[O:27])[CH2:23][CH2:24]1
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Reactant: Cn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Agent: Cl
Solvent: C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CC(F)(F)C4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting 3,3-difluoroazetidine hydrochloride for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-methyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. Trifluoroacetic acid was used instead of hydrochloric acid for all N-Boc deprotection steps. MS: (M+H)+=416.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:19][C@H:18]([C:20]([O:22]C)=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1.O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[NH:19][C@H:18]([C:20]([OH:22])=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CC[C@H](c2ccc(OCc3ccccc3)cc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (5R)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate (D8, 120 mg, 0.38 mmol) in THF (2.3 ml) was added LiOH monohydrate (26 mg, 0.61 mmol) dissolved in water (1.1 ml) followed by methanol (1.1 ml). The resulting solution was stirred at room temperature for 3 hours (hydrolysis being monitored by HPLC). When hydrolysis was complete, the organic solvent was evaporated under reduced pressure (maintaining the temperature at 38° C.) to give a crude aqueous residue containing the title compound; Rt (HPLC)=3.63 min; MS: (ES/+) m/z: 298 [MH+], C18H19NO3 requires 297).
Reaction SMILES: [CH2:1](OC(OCC)OCC)C.[Si:11]([O:28][CH2:29][CH:30]([OH:33])[CH2:31][SH:32])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[P:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])[O:35]CC.P(Cl)(Cl)Cl>C1(C)C=CC=CC=1.ClCCl.[Cl-].[Zn+2].[Cl-].C1(C)C=CC(S(O)(=O)=O)=CC=1>[Si:11]([O:28][CH2:29][C@@H:30]1[O:33][C@@H:1]([P:34]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:35])[S:32][CH2:31]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)[Si](OCC(O)CS)(c1ccccc1)c1ccccc1
Reactant: CCOP(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOP(=O)(OCC)[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1
Yield: 101.6 %

Procedure:
A solution of triethylorthoformate (0.64 g, 4.33 mmol), 1-t-butyldiphenylsilyloxy-3-mercapto-2-propanol (example 24) (5.00 g, 46.23 mmol) and p-toluenesulfonic acid (20 mg) in toluene (60 mL) was heated to reflux for 2h. The solvent was removed under reduced pressure to give a yellow oil. The oil was dissolved in dichloromethane (20.mL), zinc chloride (20 mg) was added along with triethyl phosphite (0.32 g, 1.93 mmol) at 0° C., followed by the addition of phosphorous trichloride (0.13 g, 0.95 mmol). After stirring at room temperature for 18h the solvent was removed under reduced pressure to give a colourless oil. The crude material was purified by flash chromatography with a mixture of hexanes and ethyl acetate (50:50) to give the compound as a colourless oil (0.97 g) in 67% yield as a mixture of cis and trans isomers (1:3.5). 1H NMR (300MHz, CDCl3) d: 1.03 (s, 9H, t-butyl), 1.32 (t, 6H, J=7.0Hz, CH3), 3.02 (m, 1H, H-4a), 3.18 and 3.24 (2dd, 1H, J=10.0 Hz, 6.0 Hz, H-4b), 3.72 (m, 2H, CH2OSi), 4.20 (m, 4H, CH2 CH3), 4.64 (p, 1H, J=6 Hz, H-5), 5.25 and 5.27 (2d, 1H, 2 JHP =9 Hz, H-2), 7.38 and 7.63 (m, 10H, Ar-H).
Reaction SMILES: C([O:5][C:6]([C@H:8]1[C@H:11]([CH2:12][CH3:13])[CH2:10][N:9]1[C:14](=[O:28])[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[C:18]([O:24][CH3:25])=[C:17]([O:26][CH3:27])[CH:16]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:27][O:26][C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([CH2:21][CH2:22][CH3:23])[C:18]=1[O:24][CH3:25])[C:14]([N:9]1[CH2:10][C@@H:11]([CH2:12][CH3:13])[C@@H:8]1[C:6]([OH:7])=[O:5])=[O:28]
Reactant: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)OC(C)(C)C)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid tert-butyl ester (160 mg, 0.41 mmol, 1 eq.) in dry DCM (3.5 mL) at room temperature was added TFA (1.5 mL). The resulting reaction mixture stirred at room temperature for 2 h. The solvent was removed in vacuo and dried under high vacuum. The residue was dissolved in ether and washed with 2% NaOH solution. The aqueous layer was acidified with 1 M HCl and extracted with EtOAc. The organic layer dried over Na2SO4, filtered, and concentrated in vacuo to afford (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid in 80% yield, which was used without further purification. ESMS: m/z 336.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=[O:31])OC3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:33]1([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:42]3[CH2:43][CH2:44][N:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:40][CH2:41]3)=[O:31])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
In a 25 mL round-bottomed flask, 4-nitrophenyl (7-chloro-4-oxo-1-phenyl-1,4-dihydroquinolin-3-yl)methylcarbamate (intermediate M) (0.05 g, 0.111 mmol), 1-phenylpiperazine (18.0 mg, 0.111 mmol) and N,N-diisopropylethylamine (43.1 mg, 58.2 μA, 333 mmol) were combined with methylene chloride (5 mL). The reaction mixture was stirred at room temperature. The crude product was purified using preparative reverse-phase HPLC, giving 4-phenyl-piperazine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide MS calcd. for C27H26ClN4O2 [(M+H)+] 473.2, obsd. 473.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1)[N:37]1[CH2:36][CH2:35][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38]1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 15 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of tert-butyl piperazine-1-carboxylate as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5])=[N+]=[N-].[H][H]>CO.[Pd]>[F:22][C:18]1[CH:17]=[C:16]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[CH:15][C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(N=[N+]=[N-])c1ccc2ccccc2c1-c1cccc(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(N)c1ccc2ccccc2c1-c1cccc(F)c1

Procedure:
A mixture of 2-(1-azidoethyl)-1-(3-fluorophenyl)naphthalene (0.035 g, 0.12 mmol) in 1 mL of methanol was hydrogenated in the presence of 5% Pd/C, under balloon pressure of hydrogen, for 1 hour. After filtering off the catalyst, the filtrate was concentrated under reduced pressure and the resulting residue was used directly in next step. LCMS calculated for C18H14F(M−NH2)+: m/z=249.1; found: 249.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][S:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C(=O)C2C=CC=CC=2N=N1.[CH2:64]([NH2:72])[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(Cl)(Cl)Cl>[CH2:64]([NH:72][C:17](=[O:19])[C@H:12]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:20][S:21][C:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: O=c1c2ccccc2nnn1O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NC[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
The product of Step C (0.108 g, 0.2 mmol), 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide (EDC) (0.042 g, 0.22 mmol), and 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBT) (0.036g, 0.22 mmol) were dissolved in 4 mL of 1:1 EtOAc/CHCl3 and stirred at ambient temperature for 0.5 hr. To this yellow solution was added phenethylamine (0.028 mL, 0.22 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) and stirring was continued for 48 h. The solution was concentrated and the residue was partitioned between EtOAc and H2O. The organic layer was washed with water, aqueous saturated NaHCO3, brine, and dried (Na2SO4). Filtration and concentration followed by chromatography (SiO2, EtOAc: hexane, 1:3) gave 0.09 g (69%) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1.CN.C1COCC1.[CH2:28]([N:30](CC)CC)C>CN(C=O)C.ClCCl>[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:30][CH3:28])=[O:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=1
Reactant: O=C(O)c1ccc(F)cc1C(F)(F)F
Reactant: CCN(CC)CC
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DMF (3 drops) and oxalyl chloride (2.55 ml) were added to a mixture of 4-fluoro-2-(trifluoromethyl)benzoic acid (5.50 g) and dichloromethane (50 ml), followed by stirring at room temperature for 3 hours. The reaction solution was added dropwise to a 2M methylamine-THF solution (17.3 ml) and a solution of triethylamine (5.55 ml) in dichloromethane (50 ml) under ice cooling, followed by stirring for 30 minutes and concentration under reduced pressure, addition of water and extraction with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropylether to obtain 4-fluoro-N-methyl-2-(trifluoromethyl)benzamide (4.37 g) as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 1.5 g of ethyl 3-aminopropionate monohydrochloride and 1.7 g of 2-{(tert-butoxycarbonyl)amino}acetic acid in 50 ml of chloroform, 1.6 g of 1-hydroxybenzotriazole monohydrate, 2.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 1.4 ml of triethylamine were added at room temperature by the order stated, and stirred for 2 hours at the same temperature. The reaction liquid was diluted with chloroform, and washed successively with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and saturated saline solution, by the order stated, and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by means of silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/4) to provide 2.0 g of the title compound.