Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:20]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:17][CH:16]([O:18][C:20]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:21]=2[CH:22]=[O:23])[CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: O=Cc1ccc(F)cc1F
Agent: CC(C)(C)O[K]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(F)ccc2C=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.9 %

Procedure:
tBuOK (948 mg; 8.44 mmol; 1.2 eq.) was added to a solution of 3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (1.46 g; 8.44 mmol; 1.2 eq.) in 1,4-dioxane (5 mL) and the solution was stirred at room temperature for 15 minutes whereupon a solution of 2,4-difluoro-benzaldehyde (1 g; 7.04 mmol; 1 eq.) in 1,4-dioxane (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 minutes then diluted with water. The solution was extracted with DCM (2×) and the combined organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (705 mg, 34%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.41 (d, J=0.8 Hz, 1H), 7.93 (dd, J=8.7, 6.8 Hz, 1H), 6.99-6.72 (m, 1H), 6.33 (dd, J=10.2, 2.2 Hz, 1H), 5.07-4.85 (m, 1H), 4.40 (ddd, J=9.9, 6.4, 1.1 Hz, 2H), 4.10 (ddd, J=9.9, 4.0, 1.1 Hz, 2H), 1.48 (s, 9H). HPLC (max plot) 96.4%; Rt 4.22 min.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[CH:14][CH:15]=1>ClCCl.O>[Br:1][C:19]1[S:18][C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=2)=[N:21][CH:20]=1
Reactant: Clc1cccc(Nc2nccs2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: Clc1cccc(Nc2ncc(Br)s2)c1
Temperature: 25 °C
Reaction time: 0.16 h
Yield: 20.5 %

Procedure:
N-Bromosuccinimide (7.60 g, 42.7 mmol) was added to a solution of 26B (10 g, 47.5 mmol) in dichloromethane (150 mL), and the mixture was stirred at room temperature for 0.16 h. The reaction mixture was diluted with dichloromethane and water, separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 15% ethyl acetate in hexane to afford the title compound (2.54 g, 18%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 7.87 (t, J=2.0 Hz, 1H), 7.41-7.26 (m, 3H), 7.01 (dt, J1=7.3 Hz, J2=1.8 Hz, 1H). ESI-MS m/z: 291 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][C:7](=[O:10])[O:8][CH2:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:16]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[N:6]([CH3:16])[C:7](=[O:10])[O:8][CH2:9][C:4]=2[CH:3]=1
Reactant: O=C1Nc2ncc(Br)cc2CO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)OCc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-1,4-dihydro-pyrido[2,3-d][1,3]oxazin-2-one (Stage 170.1.3, 0.707 mmol) in DMF (1.4 ml) was added 55% sodium hydride in oil (0.778 mmol). The RM was stirred for 5 min at rt then was added iodomethane (0.778 mmol) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc, washed with saturated NaHCO3, with brine (3×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and separated by flash chromatography (heptane/EtOAc 0% to 70%). The fractions containing product were evaporated together to give the title compound as a yellow solid. (HPLC: tR 2.64 min (Method A).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][CH2:14][C:15]([CH3:17])=O>CO.C1CCCCC1>[C-:1]1([C:15]([C-:6]2[CH:10]=[CH:9][CH:8]=[CH:7]2)([CH3:17])[CH2:14][CH2:13][C:12]([O:19][CH3:20])=[O:18])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:11].[CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Fe+2:11]
Reactant: COC(=O)CCC(C)=O
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CO
Solvent: C1CCCCC1
Product: COC(=O)CCC(C)([c-]1cccc1)[c-]1cccc1

Procedure:
REACTING FERROCENE AND METHYL LEVULINATE IN THE PRESENCE OF AN ACID SUCH AS POLYPHOSPHORIC ACID AND A METHANOL-CYCLOHEXANE SOLVENT AT A TEMPERATURE OF FROM 76° TO 78°C to produce methyl 4, 4-diferrocenylpentanoate; and
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(Cl)Cl.[CH3:40][C:41]1[O:45][C:44](=[O:46])[O:43][C:42]=1[CH2:47][O:48][C:49](=[O:77])[C@@:50]([CH2:75]O)([CH3:74])[CH2:51][C@H:52]([NH:66][C:67]([C:69]1[NH:70][N:71]=[N:72][CH:73]=1)=[O:68])[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:56][CH:55]=1.CN1CCOCC1>>[CH3:40][C:41]1[O:45][C:44](=[O:46])[O:43][C:42]=1[CH2:47][O:48][C:49](=[O:77])[C@@:50]([CH2:75][O:15][C:13](=[O:14])[C@@H:9]([NH2:8])[CH:10]([CH3:11])[CH3:12])([CH3:74])[CH2:51][C@H:52]([NH:66][C:67]([C:69]1[NH:70][N:71]=[N:72][CH:73]=1)=[O:68])[CH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[CH:58][CH:59]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1oc(=O)oc1COC(=O)[C@](C)(CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1oc(=O)oc1COC(=O)[C@](C)(COC(=O)[C@@H](N)C(C)C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
N-(t-Butoxycarbonyl)-L-valine (75 mg, 340 μmol), HOBt (47 mg, 0.34 mmol), EDCI (0.061 mL, 0.34 mmol), and DCM (1.8 mL, 29 mmol) were combined and stirred for 15 minutes. (2S,4R)-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester (150 mg, 290 μmol) and 4-methylmorpholine (38 μL, 340 μmol) were added, and the resulting mixture was stirred at room temperature for 3 hours, then evaporated. The crude material was purified by reverse phase column ((Interchim reverse phase chromatography column) to yield the title compound (60.8 mg; purity 98%) as a white solid. MS m/z [M+H]+ calc'd for C32H37N5O8, 620.26. found 620.3.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]3=[O:36])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:39][N:38]=[N:37][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:25]=[C:26]([N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]3=[O:36])[CH:27]=[C:28]([CH3:29])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C)cc(N3CCCCC3=O)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-butyl-4-methyl-6-(2-oxo-piperidin-1-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethyl-formamide.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[C:30]([CH3:32])[CH:31]=1>C(O)CCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([S:33][C:28]4[CH:29]=[C:30]([CH3:32])[CH:31]=[C:26]([CH3:25])[CH:27]=4)[CH:11]=3)[CH:6]=[CH:7][N:8]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc(C)cc(S)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCO
Product: Cc1cc(C)cc(Sc2ccc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c3c2)c1
Temperature: 110 °C
Yield: 65 %

Procedure:
A mixture of 4-(7-bromo-isoquinoline-1-yl)-piperazine-1-carboxylic acid, tert-butyl ester (0.5 g, 1.3 mmol), 3,5-dimethyl-thiophenol (180 mg, 1.3 mmol), NatBuO (0.44 g, 4.5 mmol), Pd(PPh3)4 (74 mg, 0.065 mmol) in nBuOH (10 mL) was heated at 110° C., 3 h. The reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in ethyl acetate. The organic phase was washed with water (50 mL×3), separated and dried (MgSO4), filtered. The volatiles were evaporated and the residue was purified by flash column chromatography (SiO2, n-pentane:ethyl acetate 9.8:0.2→8:2) to give 380 mg of the title compound as colourless oil (yield 65%). 1H NMR (CDCl3) δ 8.05-8.10 (m, 1H), 7.80-7.85 (m. 1H), 7.60-7.75 (m, 1H), 7.17-7.25 (m, 1H), 7.10 (bs, 2H), 7.00 (bs, 1H), 3.40-3.50 (m, 4H), 3.10-3.20 (m, 4H), 2.25 (bs, 6H), 1.50 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH2:18]([Mg]Br)[CH2:19][CH:20]=[CH2:21]>C1COCC1.CCOCC>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH2:21][CH2:20][CH:19]=[CH2:18])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C=CCC[Mg]Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (595 mg) in THF (3 mL) at −78° C. was added 3-butenyl magnesium bromide (7.8 mL of 0.5 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 4 hr. The reaction was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow solid. The yellow solid was dissolved in a minimal amount of Et2O and triturated with hexanes to yield the title compound as a tan solid.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C1(C)C=CC(S([NH:28][NH2:29])(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH:28]1[C:2]2[C:10]3[C:5]([CH2:4][C:3]=2[C:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:29]1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: O=C1C(=Cc2ccc(O)cc2)Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Oc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1

Procedure:
A mixture of 4-(1-oxoindan-2-ylidenemethyl)phenol (1.67 g, Chem. Ber. 1901, 34, 413), p-toluenesulphonyl hydrazine (1.95 g), p-toluenesulphonic acid (0.27 g) and ethanol (15 ml) was boiled under reflux for 72 hours. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica using petroleum ether, b.p. 60-80° C./ethyl acetate (1:1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a residue which was triturated with petroleum ether, b.p. 60-80° C., to give a solid which was crystallized from ethanol to give 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol, m.p. 266-268° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(NS(C)(=O)=O)cc3)cc2)CC1
Yield: 12.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.245 g, 0.58 mmol) was reacted with N-{4-[(2S)oxiranylmethoxy]phenyl}methanesulfonamide (0.13 g, 0.53 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.04 g, 0.064 mmol).
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[CH2:13][C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH:6][C:5]=1[CH:19]=[O:20].O>C(O)C>[OH:20][CH2:19][C:5]1[CH:6]=[C:7]2[C:11]([CH:10]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:9][CH2:8]2)=[CH:12][C:4]=1[OH:3]
Reactant: O=Cc1cc2c(cc1O)C(Cc1c[nH]cn1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cc2c(cc1O)C(Cc1c[nH]cn1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (8 mg) is added into a solution of 6-hydroxy-1-(1H-imidazol-4-ylmethyl)-indan-5-carbaldehyde (44 mg) in ethanol (6 ml). The mixture is stirred at room temperature for one hour and then poured into water. The product is extracted into ethyl acetate which is washed with water, dried with sodium sulfate and evaporated to dryness. The crude product is purified by flash chromatography using methylene chloride-methanol as eluent and crystallized from ethyl acetate.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH3:3].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=O)[S:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.ClC(Cl)C>>[Br:17][C:18]1[CH:19]=[C:20]([CH2:23][N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH:2]([CH3:1])[CH3:3])[CH2:16][CH2:15]2)[S:21][CH:22]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CC(C)Oc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Oc1ccccc1N1CCN(Cc2cc(Br)cs2)CC1
Yield: 98.8 %

Procedure:
A mixture of 1-[2-(methylethoxy)phenyl]piperazine (6.30 g, 0.029 mol), prepared as described by Martin and Scott, et al., J. Med. Chem., 1989, 32, 1052-1056, 4-bromo-2-thiophenecarboxaldehyde (5.50 g, 0.029 mol), NaBH(OAc)3 (8.00 g, 0.038 mol), acetic acid (1.70 g, 0.029 mol), and dichloroethane was stirred for several hours at room temperature. The reaction was then partitioned between diethyl ether/aqueous 10% Na2CO3 and the ether layer was separated, washed with saturated NaCl solution, dried over anhydrous K2CO3, filtered, and evaporated to give 1-[(4-bromo-2-thienyl) methyl]-4-[2-(1-methylethoxy)phenyl]piperazine (11.33 g) as a crude oil. Treatment of this material with HCl diethyl ether-isopropanol gave a crystalline solid which was recrystallized from methanol to give 1-[(4-bromo-2-thienyl)methyl]-4-[2-(1-methylethoxy) phenyl]piperazine monohydrochloride (10 g, 77%). A 2.0 g sample of this was recrystallized twice from methanol, and chromatographed on flash silica (99:1/CHCl3 :MeOH with 1% NH4OH as eluant). The resulting oil was converted to the hydrochloride salt, as described previously, and was recrystallized from methanol , and dried to give 1-[(4-bromo-2-thienyl) methyl]-4-[2-(1-methylethoxy) phenyl]piperazine monohydrochloride, m.p. (darkens 240° C.) 243°-249.5° C. 1H NMR and CI MS support the structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][N:19]([CH3:27])[CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CC(C)([O-])C.[Na+]>O1CCOCC1>[CH3:18][N:19]([CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)[CH2:23][CH2:22]1)[CH3:27]
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: CN(C)CC1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cn(C(C)C)c2cc(N3CCC(CN(C)C)CC3)cc(C(=O)O)c12
Temperature: 98 °C
Yield: 53.8 %

Procedure:
To a 10-mL microwave tube were added 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (100 mg, 0.338 mmol), 1,4-dioxane (2 mL), N,N-dimethyl-1-(4-piperidinyl)methanamine (52.8 mg, 0.371 mmol) and sodium tert-butoxide (71.4 mg, 0.743 mmol), and the mixture was degassed for 5 min. Chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]Pd(11)Me-t-butylether adduct (13.96 mg, 0.017 mmol) was added and the tube was sealed. The mixture was stirred at 98° C. with stirring for 20 h. The mixture was then concentrated and the residue was purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; (30 mL/min, 7% ACN/H2O, 0.1% formic acid to 37% ACN/H2O, 0.1% formic acid) to give the title compound (65 mg, 54%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.34 (m, 2H), 1.39 (d, J=6.57 Hz, 6H), 1.58-1.71 (m, 1H), 1.82 (d, J=11.87 Hz, 2H), 2.23-2.31 (m, 10H), 2.66 (td, J=11.94, 1.89 Hz, 2H), 3.57-3.71 (m, 2H), 4.70 (quin, J=6.63 Hz, 1H), 7.09 (d, J=2.02 Hz, 1H), 7.15 (dd, J=9.60, 1.52 Hz, 2H). MS: (M+H)+=358.2.
Reaction SMILES: [C:1]1([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH2:17](O)[CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:17]([O:10][C:9]([CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][C:1]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)=[O:11])[CH2:18][CH3:19]
Reactant: CCCO
Reactant: O=C(O)CCc1ccc(CCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CCCOC(=O)CCc1ccc(CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,3′-(1,4-phenylene)dipropanoic acid (250 mg, 1.125 mmol) DCM (15 ml) is added 4-dimethylaminopyridine (137 mg, 1.125 mmol) and propanol (3 ml, 40.1 mmol). The solution is cooled to 0° C. and dicyclohexylcarbodiimide (232 mg, 1.125 mmol) is added and the resulting solution is stirred at 0° C. for 30 minutes and 2 hours, at room temperature. Concentration in vacuo affords a white solid which is suspended in Et2O (50 ml) and filtered to remove any insoluble material. The filtrate is concentrated in vacuo and purification by chromatography (SiO2, EtOAc/iso-hexane) affords the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][C@H:25]3[C:36]([O:38]C(C)(C)C)=[O:37])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C@H:24]3[CH2:28][NH:27][CH2:26][C@H:25]3[C:36]([OH:38])=[O:37])(=[O:21])=[O:22])=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)OC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CNC[C@H]3C(=O)O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirred solution of 299 mg of di-tert-butyl cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1,3-dicarboxylate (Example 17, Step 1) in 4 mL of dichloromethane was slowly added 3 mL of trifluoroacetic acid. The solution was stirred at room temperature for 3 hr. After removal of the volatile material, cis-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid was obtained in quantitative yield without further purification. MS: 442.3 (M+H)+
Reaction SMILES: [N:1]#[N:2].S(S(O)=O)(O)=O.C([O:13][C:14](=[O:52])[CH2:15][N:16]([C:24](=[O:51])[C@H:25]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:50])[NH2:49])[NH:26][S:27]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][C:34]([O:42][CH3:43])=[C:35]([O:40][CH3:41])[CH:36]=2)[CH:31]=1)(=[O:29])=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:1]#[N:2].[CH3:41][O:40][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][C:34]=1[O:42][CH3:43])[CH:31]=[C:30]([S:27]([NH:26][C@H:25]([C:24]([N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][C:14]([OH:52])=[O:13])=[O:51])[CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:49])[NH2:50])(=[O:29])=[O:28])[CH:39]=[CH:38]2
Reactant: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OC(C)(C)C)Cc3ccccc3)cc2cc1OC
Agent: Cl
Agent: N#N
Agent: O=S(O)S(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)O)Cc3ccccc3)cc2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
To a solution of 2.00 g of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylglycine tert-butyl ester hydrosulfite in 20 ml of chloroform was added 50 ml of 15% HCl-ethyl acetate. The reaction mixture was stirred for 5 hours at room temperature. At the end of this period, the reaction mixture was evaporated to dryness. The residue was washed several times with dry diethyl ether and chromatographed on 80 ml of Daiaion® SK 102 ion exchange resin (200-300 mesh, H+ form, manufactured by Mitsubishi Chemical Industries Limited) packed in water, washed with water and eluted with 3% ammonium hydroxide solution. The fraction eluted from 3% ammonium hydroxide solution was evaporated to dryness to give 1.20 g (70 percent) of N2 -(6,7-dimethoxy-2-naphthalenesulfonyl)-L-arginyl-N-benzylglycine as an amorphous solid, I.R. (KBr): 3,370, 3,200, 1.615 cm-1.