Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH:53]=[CH2:54])[N:44]2[C:43]1=[O:55]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([CH:53]=[CH2:54])[N:44]2[C:43]1=[O:55])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: C=C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Product: C=C[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(c4ccccc4OC)C3=O)Cc3ccccc3)C(=O)N12

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7S,10aS)-5-oxo-7-vinyloctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (36 mg, 0.067 mmol) and Intermediate 73 (23 mg, 0.067 mmol) to give a white solid (30 mg, 59% yield). Anal. Calcd. for C44H54N4O5S m/z 750.7. found: 751.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.07 (m, 11H), 7.07-6.89 (m, 3H), 6.36-6.18 (m, 1H), 5.33 (s, 1H), 5.23 (d, J=17.1 Hz, 1H), 5.12 (d, J=10.3 Hz, 1H), 5.06-4.90 (m, 2H), 4.84-4.70 (m, 1H), 4.02-3.84 (m, 1H), 3.79 (s, 3H), 3.47-3.29 (m, 1H), 3.04-2.89 (m, 1H), 2.89-2.75 (m, 2H), 2.75-2.64 (m, 1H), 2.61-2.47 (m, 1H), 2.46-2.23 (m, 8H), 2.10-1.55 (m, 11H), 1.54-1.42 (m, 2H), 1.39-1.15 (m, 2H).
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:1]1([CH:7]([NH:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[C:8]2[S:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)=[CH:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc(-c3ccc(C(F)(F)F)cc3)cc2C)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)sc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
A mixture of 2-[chloro(cyclohexyl)methyl]-3-methyl-5-[4-(trifluoromethyl)phenyl]thiophene (1.3 g) obtained by the above-mentioned reaction, methyl 4-aminobenzoate (1.1 g), sodium carbonate (0.8 g) and sodium iodide (2.2 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 100° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 40% ethyl acetate/hexane) to give methyl 4-[(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methyl)amino]benzoate as an amorphous compound. The obtained methyl 4-[(cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-2-yl}methyl)amino]benzoate was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (1.5 mL) was added, and the mixture was stirred at 70° C. for 3 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.7 g, 43%) as an amorphous compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][C:27](=[O:28])[CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
A stirred solution of 2-methoxy-5-nitroaniline (4.86 g, 0.029 mole) and triethylamine (5.2 ml, 0.037 mole) in dichloromethane (150 ml) at 0° C. was treated with phenylacetyl chloride (5.0 ml, 0.037 mole). The mixture was stirred for 0.5 h, then treated with water (20 ml), stirred for a further 20 mins., then basified with Na2CO3 and extracted with dichloromethane. The extract was washed with dil. HCl acid/brine, then dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown solid (9.0 g, 100%).
Reaction SMILES: [NH2:1][C@H:2]([C:12]1[O:13][C:14]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][N:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10].[S:29]1[C:33]([C:34](O)=[O:35])=[CH:32][N:31]=[CH:30]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([C:14]2[O:13][C:12]([C@@H:2]([NH:1][C:34]([C:33]3[S:29][CH:30]=[N:31][CH:32]=3)=[O:35])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH3:10])=[N:16][CH:15]=2)[C:18]1=[O:28]
Reactant: O=C(O)c1cncs1
Reactant: CCC(=O)CCCCC[C@H](N)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)c1cncs1)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-(2-(1-amino-7-oxononyl)oxazol-5-yl)-1-methylquinolin-2(1 H)-one (1 eq), prepared as described in steps 1 to 5 of Example 7, was treated with a solution of thiazole-5-carboxylic acid (1.3 eq), HOBT (1.3 eq) and EDC.HCl (1.3 eq) in DMF (premixed for 3 min), followed by DIPEA (1.3 eq). The mixture was stirred at room temperature for 2 h and the desired product was isolated by preparative RP-HPLC, using water (+0.01% TFA) and MeCN (+0.01% TFA) as eluents (column C18). The pooled product fractions were lyophilized and the product was obtained as a white solid. MS (ES) C26H28N4O4S requires: 492.59, found: 493. 1H-NMR (400 MHz, DMSO-d6) δ: 9.28 (1 H, d, J=8 Hz), 9.26 (1 H, s), 8.62 (1 H, s), 8.29 (1 H, s), 7.91 (1 H, d, J=7.6 Hz), 7.84 (1 H, s), 7.68 (1 H, t, J=7.2 Hz), 7.61 (1 H, d, J=8.2 Hz), 7.34 (1 H, t, J=7.6 Hz), 5.27-5.22 (1 H, m), 3.75 (3 H, s), 2.39-2.36 (4 H, m), 2.09-2.06 (1 H, m), 2.00-1.96 (1H, m), 1.50-1.27 (6 H, m), 0.89 (3 H, t, J=7.2 Hz).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>CCCCCC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCCCCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxoacetic acid (Example 5b) and 3-(trifluoromethyl)-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 87-89° C. (hexane)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]N1C(=O)CCC1=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10][Br:43])=[CH:4][CH:3]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(C(=C(CBr)n2cnnn2)c2ccc(F)cc2)cc1

Procedure:
A solution of 3,3-bis(4-fluorophenyl)-2-(tetrazol-1-yl)2-propenol (108 mg, 0.34 mmol), triphenylphosphine (118 mg, 0.45 mmol) and N-bromosuccinimide (74 mg, 0.42 mmol) in tetrahydrofuran (5 mL) was stirred in an inert atmosphere for a period of 1.5 hours. The suspension (triphenylphosphine oxide precipitate) was diluted with hexanes (25 mL) and the suspension was filtered. The filtrate was concentrated under reduced pressure and the semi-crystalline solid was filtered through a short silica gel column eluted with 5-10% ethyl acetate in hexanes. The title compound, 108 mg (84%), was obtained after removal of solvents under reduced pressure.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:18][C:11]=3[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2].[CH2:24](Cl)Cl.CCCCCC>>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]([CH3:24])[C:11]=3[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2]
Reactant: ClCCl
Reactant: CCOC(=O)c1cc2ccc3c(c4ccccc4n3CC)c2[nH]1
Solvent: CCCCCC
Product: CCOC(=O)c1cc2ccc3c(c4ccccc4n3CC)c2n1C
Yield: 90.5 %

Procedure:
Using the procedure outlined in Example 34A, ethyl 6-ethyl-1,6-dihydropyrrolo[3,2-c]carbazole-2-carboxylate (H.G. Pars Pharmaceutical Laboratories, Inc.) gave a 90.5% yield of ethyl 6-ethyl-1,6-dihydro-1-methylpyrrolo[3,2-c]carbazole-2-carboxylate, mp 115.5°-116°, (CH2Cl2 /hexane), (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[C:38]([O:42][C:43](=[O:47])[CH2:44][CH2:45][NH2:46])([CH3:41])([CH3:40])[CH3:39].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=4)[CH:15]=3)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:46][CH2:45][CH2:44][C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:47])=[O:33])=[CH:35][CH:36]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)O)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)OC(C)(C)C)cc3)ccc2c1
Reaction time: 3 h

Procedure:
4-{(1S)-1-[3-(3,5-Dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoic acid (3.5 g, 6.76 mmol), beta-alanine t-butyl ester hydrochloride (3.7 g, 20 mmol), DIEA (3.53 ml, 20 mmol), and DMAP (40 mg, 5%) were dissolved in DCM (50 ml), followed by addition of solid EDC HCl (1.6 g, 8.1 mmol). More EDC HCl (1.8 g) was added after one hour. The reaction was completed in about 3 hr as monitored by LC-MS. Ethyl acetate was added to the reaction mixture, and this was washed with 1N HCl 3× and brine 2×. The crude product was then purified by column chromatography (SiO2, 0-6% ethyl acetate in DCM) to give tert-butyl N-(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoyl)-β-alaninate as a dry foam. NMR (500 MHz, DMSO-d6) δ: 1.36 (s, 9H); 1.90 (d, J=6.9 Hz, 3H); 2.44 (t, J=6.8 Hz, 2H); 3.41 (q, J=6.8 Hz, 2H); 3.89 (s, 3H); 5.76 (q, J=6.9 Hz, 1H); 7.15 (s, 1H); 7.21 (d, J=8.4 Hz, 2H); 7.22 (dd, J=2.6, 9.0 Hz, 1H); 7.38 (d, J=2.6 Hz, 1H); 7.43 (dd, J=1.9, 8.5 Hz, 1H); 7.55 (t, J=1.9 Hz, 1H); 7.71 (d, J=8.4 Hz, 2H); 7.81 (d, J=9.0 Hz, H); 7.85 (d, J=1.9 Hz, 1H); 7.90 (d, J=8.5 Hz, 1H); 7.92 (d, J=1.9 Hz, 2H); 8.44 (t, J=5.2 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[I:17].C(N(CC)CC)C.[N+:25]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)([O-:27])=[O:26]>O1CCCC1>[N+:25]([C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:7]2[C:2]([I:1])=[C:3]([CH2:8][CH2:9][NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[I:17])[CH:4]=[CH:5][CH:6]=2)=[O:33])=[CH:35][CH:36]=1)([O-:27])=[O:26]
Reactant: Ic1ccccc1CCNc1ccccc1I
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1cccc(CCNc2ccccc2I)c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of 0.90 g of 2-iodo-N-(2-iodophenyl)benzeneethanamine in 4 ml of tetrahydrofuran is added 0.41 g of triethylamine, and 0.57 g of 4-nitrobenzoyl chloride. The mixture is stirred at room temperature for 2 hours and the solvent removed under vacuum. The residue is dissolved in ethyl acetate-dichloromethane (5:1) and the solution washed with 1N HCl, saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate. The filtrate is evaporated and the residual solid triturated with diethyl ether and hexane to give 1.10 g of product as a white solid.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:29])[CH2:8][C:9](=[O:28])[N:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:12][CH2:11]1)C>CO.C1COCC1.O>[O:28]=[C:9]([N:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:14][CH2:15]1)[CH2:8][C:7]([OH:29])=[O:6]
Reactant: CCOC(=O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
LiOH.H2O (400 mg, 9.5 mmol) was added to a solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid ethyl ester (1.4 g, 3.8 mmol) in methanol (10 mL), THF (4 mL) and H2O (10 mL) and the resulting mixture was stirred for 2 hours at room temperature. The mixture was and the residue was diluted with water, washed with diethyl ether, acidified with concentrated HCl, extracted with ethyl acetate and evaporated to dryness. The residue was recrystallized from hexane to afford 1.2 g (92%) of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid. LCMS: 345.1 (M+1)+, 96%
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][C:3]=1Br.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+].CCOC(C)=O>COCCOC.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.O>[NH2:1][C:2]1[C:3]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:4][C:5]([CH:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(OCC(F)(F)F)c(N)c(-c2ccc(C(F)(F)F)cc2)c1
Yield: 85.1 %

Procedure:
A mixture of ethyl 2-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (0.70 g, 1.6 mmol), 4-trifluoromethylphenylboronic acid (0.642 g, 3.39 mmol), CsF (0.641 g, 4.2 mmol) and Pd (PPh3)4 (0.196 g, 0.16 mmol) in 40 mL anhydrous 1,2-dimethoxy ethane was refluxed for 8 h under argon. The reaction mixture was cooled, and 35 mL of EtOAc and 35 mL of water were added. The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yellow oil. The oil was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(6-amino-5-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate (650 mg) as a colorless liquid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:11][C:12]1[CH:13]=[C:14]([NH:18][CH:19]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:20]([O:22][C@@H:23]2[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:21])[CH:15]=[CH:16][CH:17]=1.CC#N.O>CCOC(C)=O>[Cl-:1].[F:11][C:12]1[CH:13]=[C:14]([NH:18][CH:19]([C:31]2[CH:32]=[N:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[C:20]([O:22][C@@H:23]2[CH:28]3[CH2:27][CH2:26][N+:25]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:30][CH2:29]3)[CH2:24]2)=[O:21])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(C(Nc2cccc(F)c2)C(=O)O[C@H]2CN3CCC2CC3)cn1
Reactant: O=C(CCl)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(C(Nc2cccc(F)c2)C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)cn1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
2-Chloro-1-phenylethanone (26.9 mg, 0.17 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(3-fluorophenylamino)-2-(6-methoxypyridin-3-yl)acetate (C77) (67.1 mg, 0.17 mmol) in EtOAc (3 mL), and the resulting reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the crude product was purified by flash chromatography (DCM/MeOH=97/3 to 9/1) and then by preparative HPLC (Eluent: CH3CN/H2O) to obtain (3R)-3-(2-(3-fluorophenylamino)-2-(6-methoxypyridin-3-yl)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane chloride (19.5 mg, 20.7% yield).
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5](=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[S:4][CH:3]=1.[I:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[I-:14].[CH2:15]([N+:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]2[C:2]([CH3:1])=[CH:3][S:4][C:5]=12)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCI
Reactant: Cc1csc2nc3ccccc3n12
Product: CCCCCCC[n+]1c2ccccc2n2c(C)csc21
Product: [I-]
Reaction time: 18 h

Procedure:
198 mg of 3-methyl[1,3]thiazolo[3,2-a]benzimidazole were added to 1-iodoheptane (3 mL). Then the mixture was stirred under reflux. After 18 h, 9-heptyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide was recovered as a pale green powder (421 mg, 97%) by filtration. Mp 137° C.; 1H NMR (300 MHz, MeOD) δ=0.8-0.91 (3H, m, CH3), 1.22-1.54 (8H, m, 4-CH2), 2.05 (2H, quint, J=7.4, CH2), 2.95 (3H, d, J=1.3, CH3), 4.60 (2H, t, J=7.2, CH2), 7.36 (1H, q, J=1.3, H5), 7.64-7.82 (2H, m, Ar), 7.99-8.05 (1H, m, Ar), 8.26-8.32 (1H, m, Ar); 13C NMR (75 MHz, MeOD) δ=14.26, 14.35, 23.57, 27.71, 28.92, 29.89, 32.75, 48.48, 112.18, 113.78, 114.97, 126.30, 128.36, 129.01, 135.35, 137.63, 155.92; HRMS m/z C17H23N2S [M−I]+ calcd: 287.1576, found: 287.1576.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=O)[CH3:22].CC(=O)OCC>C1COCC1>[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=[S:2])[CH3:22]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(OCC)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(OCC)C(N)=S
Yield: 90.2 %

Procedure:
To a stirred mixture of P2S5 (45 g) in THF (300 ml) at 23°, sodium carbonate (21.5 g) was added. At the mixture, vigorously stirred, 2,2-diethoxyacetamide (10 g) was added. After 24 h a 10% aqueous solution of Na3PO4 (200 ml), EA (300 ml) and CH (300 ml) were respectively added. The aqueous layer was washed with EA and united to the organic layer. This was washed with water until clarification, dried and the solvent evaporated under reduce pressure. The crude residue was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white solid (10 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:21])[N:6]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1.[ClH:22].[CH2:23](OCC)C>O1CCOCC1>[ClH:22].[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:23])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:21])[N:6]2[CH2:15][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCOCC
Reactant: CCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCOC3)c2n1

Procedure:
To 6-Amino-2-(propyloxy)-9-(tetrahydro-3-furanylmethyl)-7,9-dihydro-8H-purin-8-one (52.6 mg) was added an excess of 4N hydrogen chloride in 1,4-dioxane (1 mL). The resultant solution was evaporated under reduced pressure (after 5 minutes) to give a colourless gum containing some crystals. To this material was added diethyl ether to triturate out the 1,4-dioxane, giving a free flowing solid on scratching. After evaporation to dryness under reduced pressure for 2 hours (water bath at 50° C., minimum vacuo ˜38 mbar) gave the title compound (61 mg) an off-white free flowing solid.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[C:6]1([C:12]2[N:13]=[CH:14][S:15][C:16]=2[N:17]2C(=O)C3=CC=CC=C3C2=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:28].NN>ClCCl.CO>[NH2:17][C:16]1[S:15][C:14]([S:1]([NH2:28])(=[O:3])=[O:2])=[N:13][C:12]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:17][C:16]1[S:15][CH:14]=[N:13][C:12]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1c1scnc1-c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: NN
Solvent: ClCCl
Solvent: CO
Product: Nc1sc(S(N)(=O)=O)nc1-c1ccccc1
Product: Nc1scnc1-c1ccccc1
Reaction time: 15 h
Yield: 16 %
Yield: 36 %

Procedure:
The crude mixture of sulfonyl chloride with 4-phenyl-5-phthalimido-thiazole (231 mg) in dichloromethane (10 ml) was treated with ammonia in methanol (900 μl, 2.0 M) dropwise at ambient temperature. After 10 min the mixture was concentrated in vacuo. The residue was suspended in ethanol (10 ml), treated with ethanolic hydrazine (660 μl, 1.0 M, 660 μmol) and heated to reflux. After 1.5 hr a further portion of ethanolic hydrazine was added (660 μl, 1.0 M, 660 mol) and reflux continued for 15 hr. The cooled mixture was filtered and concentrated in vacuo. Flash chromatography on silica gel (ethyl acetate/hexanes) yielded pure 5-amino-2-(aminosulfonyl)-4-phenylthiazole (56 mg, 36% for 3 steps) and 5-amino-4-phenylthiazole (17 mg, 16% for 3 steps).
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:20][CH:21]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:20][CH:21]([O:23][C:24]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:25])[CH3:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)c1ccccc1
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)c1ccccc1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.1 g, 7.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl benzoate (800 mg, 2.6 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 23 (160 mg, 18% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.87-0.96 (m, 2H), 1.21-1.38 (br. m, 3H), 1.57 (d, J=5.6 Hz, 3H), 1.71-1.74 (m, 2H), 1.88-1.91 (m, 2H), 2.1-2.2 (m, 1H), 2.84-2.88 (m, 2H), 6.92 (q, J 5.6 Hz, 1H), 7.54-7.58 (m, 3H), 7.70 (m, 1H), 7.94-7.96 (m, 2H), 12.05 (br. s, 1H). MS (ESI) m/z 372.10 (M+Na)+; 348.05 (M−H)−.