Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([C:62]2[CH:63]=[C:64]([OH:68])[CH:65]=[CH:66][CH:67]=2)[CH2:58][CH2:57]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:68][C:64]3[CH:65]=[CH:66][CH:67]=[C:62]([N:59]4[CH2:58][CH2:57][N:56]([CH3:55])[CH2:61][CH2:60]4)[CH:63]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CN1CCN(c2cccc(O)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2cccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)CC1

Procedure:
The title compound 87 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 87A: 1H NMR (DMSO-d6): δ 12.85 (s, 1H), 9.65 (s, 1H), 8.03 (d, J=7.67 Hz, 1H), 7.79 (d, J=7.98 Hz, 2H), 7.67 (d, J=7.67 Hz, 1H), 7.34-7.50 (m, 4H), 7.12 (t, J=8.13 Hz, 1H), 6.54 (dd, J=8.13, 2.3 Hz, 1H), 6.50 (t, J=2.15 Hz, 1H), 6.42 (dd, J=8.29, 2.15 Hz, 1H), 4.83 (s, 2H), 3.96 (t, J=6.29 Hz, 2H), 3.73 (t, J=5.83 Hz, 2H), 3.10-3.18 (m, 5H), 3.03 (t, J=5.98 Hz, 2H), 2.90-2.98 (m, 2H), 2.85 (s, 3H), 1.95-2.02 (m, 2H). ESI (+)/MS: 669 M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:8]2[C:24](O)=[O:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].ClC1C=CC=C[NH+]=1.C(N(CC)CC)C.[NH2:42][CH2:43][CH:44]([OH:51])[CH2:45][N:46]([CH2:49][CH3:50])[CH2:47][CH3:48]>C(Cl)Cl>[CH2:47]([N:46]([CH2:45][CH:44]([OH:51])[CH2:43][NH:42][C:24]([C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10]([C:9]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:25])[CH2:49][CH3:50])[CH3:48]
Reactant: O=C(O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1
Reactant: CCN(CC)CC(O)CN
Agent: Clc1cccc[nH+]1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CC(O)CNC(=O)c1c(OCc2ccccc2)c2ccccc2n1-c1ccccc1

Procedure:
10.5 g of N-phenyl-3-benzyloxyindole-2-carboxylic acid are reacted with 4.5 g of 2-chloro-N-pyridinium iodide, 4.2 ml of triethylamine and 2.5 g of 1-amino-2-hydroxy-3-diethylaminopropane in 45 ml of methylene chloride at room temperature, After 14 h, the reaction mixture is washed with a saturated solution of sodium chloride and with a 10% sodium carbonate solution, dried over sodium sulfate, filtered and evaporated. The residue is dissolved in dilute hydrochloric acid/ether and the ether phase separated. The aqueous phase is made alkaline and extracted with ether. The ether extract is washed with water, dried over sodium sulfate and evporated. The raw 2-[3-N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-benzyloxy-1-phenylindole is recrystallized from isopropanol/ether. Melting point: 80°-81° C.
Reaction SMILES: CS(O[CH:6]([CH2:13][CH3:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=O)=O.[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O>[N:15]([CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:13][CH3:14])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCC(CC)OS(C)(=O)=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCC(CC)N=[N+]=[N-]
Temperature: 50 °C
Reaction time: 16 h

Procedure:
15.0 g (67.46 mmol) of 1-ethyl-heptyl methanesulphonate are dissolved in 300 ml of DMSO and, after addition of 17.54 g (269.8 mmol) of sodium azide, the mixture is stirred at 50° C. for 16 hours. The reaction mixture is poured into ice-water and extracted three times with ether. The extract is dried over sodium sulphate giving 11.4 g (96%) of a yellow liquid.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:3])[CH3:2].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:20])[C@@H:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCCCCCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Product: CCCCCCCC[C@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@@H]1C(C)C

Procedure:
Following the procedure described in Referential Example 4, but using 4-(S)-isopropyl-3-(1-oxodecyl)-2-oxazolidinone (9.85 g), prepared in Referential Example 49, and tert-butyl bromoacetate (25.4 ml) as starting materials, the desired compound (9.17 g) having a m.p. of 58°-59° C. was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]([CH3:32])=[C:21]([C:33]([OH:35])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[NH2:36][C@@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[C:46]([O:45][C:44](=[O:50])[NH:43][C@H:40]1[CH2:39][CH2:38][C@@H:37]([NH:36][C:33]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([F:14])[C:10]([O:12][CH3:13])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]=2[CH3:32])=[O:35])[CH2:42][CH2:41]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c12) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(N(CC(C)C)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and isobutyraldehyde (1.09 g, 15.24 mmol) in methanol (15 mL), acetic acid (0.456 g, 7.6 mmol) was added. The reaction mixture was stirred at room temperature for 8 h. Sodium cyanoborohydride (0.522 g, 7.56 mmol) was then added at 0° C. and the reaction mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and crude product purified by column chromatography to afford methyl 5-bromo-3-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.52 g, 54.33%).
Reaction SMILES: C[Mg]I.[CH2:4]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[CH2:5][CH2:6][CH:7]=[CH2:8].C1(C)C=CC=CC=1.C([O:32][CH2:33][CH3:34])C>>[CH2:4]([C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:33](=[O:32])[CH3:34])=[CH:21][CH:22]=2)[CH2:13][CH2:14]1)[CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: CCOCC
Reactant: C=CCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Agent: C[Mg]I
Solvent: Cc1ccccc1
Product: C=CCCC[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1

Procedure:
A solution of methylmagnesium iodide in diethyl ether (prepared from 195 mg of magnesium shavings and 0.495 ml of methyl iodide in 15 ml of diethyl ether) was treated dropwise at room temperature with a solution of 1.0 g of p-[trans-4-(4-pentenyl)cyclohexyl]benzonitrile. The mixture was heated to reflux for 15 minutes. Subsequently, 15 ml of toluene were added to the reaction mixture, the diethyl ether was distilled off and the mixture was heated to reflux for a further 1.5 hours. Thereafter, the reaction mixture was treated cautiously at 0° C. with saturated ammonium chloride solution and partitioned three times in diethyl ether/water. The organic extracts were washed twice with water, dried over magnesium sulphate, filtered and evaporated. Chromatographic separation of the yellow crystalline residue (1.1 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 0.96 g (90%) of p-[trans-4-(4-pentenyl)cyclohexyl]acetophenone as light yellow crystals; m.p. 47.6° C.
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][CH:5]=1)[C:2]#N.[BH4-].[Na+].Br[CH2:13][C:14](C)([CH3:18])[C:15]([OH:17])=[O:16].C(N(C(C)C)CC)(C)C>CO.O>[NH2:9][C:7]1[S:8][C:4]([S:1][CH2:2][C:14]([CH3:18])([CH3:13])[C:15]([OH:17])=[O:16])=[CH:5][N:6]=1
Reactant: N#CSc1cnc(N)s1
Reactant: CC(C)(CBr)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CSc1cnc(N)s1)C(=O)O
Reaction time: 0.5 h

Procedure:
5-thiocyanato-thiazol-2-ylamine (15.7 g) was dissolved in degassed methanol and sodium borohydride (4.5 g) in MeOH was added in one portion. The reaction was stirred for 30 min and 3-bromo-2,2-dimethyl-propionic acid (27 g) (prepared in the same manner as described by Greene at al, J Am Chem Soc 1955, 77, 3016) and diisopropylethylamine (17 mL) was added and the reaction stirred overnight at room temperature. The reaction was diluted with water, partially concentrated in vacuo and 5% citric acid was added until pH 4. The brown precipitate was filtered, washed with water and acetonitrile, and dried over night at room temperature to give 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid as light brown crystals.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1CCc2ccccc21
Reactant: O=C(Cl)c1ccccc1
Product: O=C(NC1CCc2ccccc21)c1ccccc1

Procedure:
The title compound was prepared in 77% from (rac)-1-aminoindan (1.0 g, 7.5 mmole) and benzoyl chloride (2.1 g, 15 mmole), under the Schotten-Bauman conditions, according to J. Chem. Soc. 71, 251 (1897) and J. Org. Chem. 27, 4465 (1962), m.p.: 140°-2° C.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH:3]([C:8]([OH:10])=[O:9])[CH2:2]1.[H-].[Na+].I[CH2:14][CH2:15][CH3:16]>CN(C)C=O.O>[CH2:14]([C:3]1([C:8]([OH:10])=[O:9])[C:4](=[O:7])[CH2:5][CH2:6][S:1][CH2:2]1)[CH2:15][CH3:16]
Reactant: O=C(O)C1CSCCC1=O
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1(C(=O)O)CSCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester (1.0 g, 5 mmol) in 1 mL of dimethylformamide was added to a stirred mixture of sodium hydride (60% in oil, 0.2.2 g, 5.5 mmol) and 1-iodopropane (0.934 g, 5.5 mmol) in 2.5 mL of dimethylformarnmide at 0° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with ether. The etheral layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluted with hexane:ether (19:1) to give 0.277 g of 3-propyl-tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.O>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[CH2:15]([O:14][C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:8]2[CH:18]=[CH:17][CH:11]=[CH:10][C:9]=2[C:1]([OH:2])=[O:4])=[CH:18][CH:17]=1)=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)c1ccc(Oc2ccccc2C(=O)O)cc1
Yield: 145.5 %

Procedure:
Potassium carbonate (14 g) was added to a solution of 2-indobenzoic acid (50 g) in nitrobenzene (50 ml) at 140°-150° C. with stirring. The mixture was stirred for an additional 10 minutes after the addition. Then, ethyl 4-hydroxybenzoate (33.5 g), potassium carbonate (28 g) and copper (3 g) were added. The mixture was stirred at 150°-160° C. for 30 minutes and allowed to cool. After the addition of water, the mixture was filtered and the filtrate was acidified with concentrated hydrochloric acid. The precipitate was collected and recrystallized from dilute ethanol to give the title compound (42 g, 72%), m.p. 152°-153° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=3)[NH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc2[nH]cc(Cn3ccnc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc2[nH]cc(Cn3ccnc3)c2c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 35.5 %

Procedure:
To a well-stirred solution consisting of 3-(imidazol-1-ylmethyl)-5-methoxyindole (0.30 g.) dissolved in dry methylene chloride (30 ml.) at -70° C., there was added boron tribromide (0.38 ml.) in a dropwise manner. The resulting mixture was allowed to warm up and was then stirred at 20° C. for a period of five hours. Water (50 ml.) was then added to the spent reaction mixture, and the resulting aqueous layer was subsequently separated and washed with methylene chloride (using two-20 ml. portions). The washed aqueous layer was then made basic with solid sodium bicarbonate and evaporated to dryness. The residue obtained in this manner was next treated with boiling ethyl acetate (200 ml.), and the resulting organic solution was separated from the mixture by decantation and then evaporated to give a solid. Crystallization of the latter material from isopropanol/petroleum ether (b.p. 80°-100° C.) then gave pure 5-hydroxy-3-(imidazol-1-ylmethyl)-indole (yield, 0.10 g.), m.p. 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]([C:24]3C=NN(C(C)C)[CH:28]=3)=[O:23])[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C(N1C=C(C([Cl:43])=O)C=N1)(C)C.[CH3:44][N:45]1[C:49]2[S:50][C:51]([C:53](O)=[O:54])=[CH:52][C:48]=2[C:47]([CH3:56])=[N:46]1.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22]([C:24]3[S:50][C:49]4[N:45]([CH3:44])[N:46]=[C:47]([CH3:56])[C:48]=4[CH:28]=3)=[O:23])[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1.[CH3:44][N:45]1[C:49]2[S:50][C:51]([C:53]([Cl:43])=[O:54])=[CH:52][C:48]=2[C:47]([CH3:56])=[N:46]1
Reactant: CC(C)n1cc(C(=O)Cl)cn1
Reactant: Cc1nn(C)c2sc(C(=O)O)cc12
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cnn(C(C)C)c2)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2cc3c(C)nn(C)c3s2)c2ccccc21
Product: Cc1nn(C)c2sc(C(=O)Cl)cc12

Procedure:
N-(4-Chlorophenyl)-N-{(2S,4R)-1-[(1,3-dimethyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide was prepared following the procedure for N-(4-chlorophenyl)-N-{(2S,4R)-1-[(1-isopropyl-1H-pyrazol-4-yl)carbonyl]-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl}acetamide substituting 1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carbonyl chloride for 1-isopropyl-1H-pyrazole-4-carbonyl chloride. (1,3-Dimethyl-1H-thieno[2,3-c]pyrazole-5-carbonyl chloride was prepared from commercially available 1,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid by treatment with oxalyl chloride and catalytic DMF in dichloromethane).
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:39]([OH:41])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37].Cl>CN(C=O)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:32][C@H:33]([C:39]([OH:41])=[O:40])[CH2:34][CH2:35][C:36](=[O:38])[NH2:37])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
Boc-Phe-Gly-Leu-Gln-NA was prepared by coupling Boc-Phe-Gly-Leu-OH (1.42 g, 3.25 mmol) to H-Gln-NA HCl (1.00 g, 3.25 mmol) by a mixed anhydride coupling procedure. A total of 10 mL DMF was used to dissolve H-Gln-NA HCl. During workup of the organic phase resulting from the mixed anhydride coupling procedure, some product crystallized and was separated, washed with water, and dried to yield 0.91 g of Boc-Phe-Gly-Leu-Gln-NA, mp 238°-239°. The remaining organic phase was washed with a saturated salt solution, and a second crop of crystalline product (0.62 g) was obtained, mp 238°-239°. A sample of the first crop was analyzed.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=1)=[O:28]>C(#N)C>[Br-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(NC(=O)CBr)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: Cc1cccc(NC(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)C2(c4ccccc4)CCCCCC2)C3)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 26 h
Yield: 43.6 %

Procedure:
To 1-phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 14e) (50 mg) in acetonitrile (1 mL) was added 2-bromo-N-m-tolyl-acetamide (Example 47a) (38 mg). The reaction was stirred at room temperature for 26 hours and the acetonitrile was removed under reduced pressure. The material was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to afford the title compound (37 mg) as a colourless foam.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].O/[N:17]=[C:18](/[C:20]1[CH:34]=[CH:33][C:23]([CH2:24][N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]2)=[CH:22][CH:21]=1)\[NH2:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]/[N:17]=[C:18](/[C:20]1[CH:34]=[CH:33][C:23]([CH2:24][N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]2)=[CH:22][CH:21]=1)\[NH2:19])=[O:14]
Reactant: COC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cnn(-c4ccccc4)c3N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A mixture of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (90 mg, 0.441 mmol), (Z)-methyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (116 mg, 0.441 mmol), EDC (84 mg, 0.441 mmol) and HOBT (67.5 mg, 0.441 mmol) in DMF (1 mL) was stirred at RT for 1 hr. At this time, Et3N (0.061 mL, 0.441 mmol) was added and stirring was continued at RT for 3 days. The mixture was then heated to 50° C. for 10 minutes. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with saturated sodium bicarbonate solution (30 mL), water (30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to afford (Z)-methyl 1-(4-(N′-(5-amino-1-phenyl-1H-pyrazole-4-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (103 mg, 0.230 mmol) as a white solid. HPLC retention time=1.05 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS:(M+H)=449.3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])=[CH:10][C:9]=1[NH:25][C:26](OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.COC(=N)[C:44]([Cl:47])([Cl:46])[Cl:45]>C(Cl)Cl>[Cl:45][C:44]([Cl:47])([Cl:46])[C:26]1[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][C:21]([F:23])([F:24])[F:22])=[CH:10][C:9]=2[N:25]=1
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2OC(F)(F)F)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)Oc1ccccc1-c1ccc2[nH]c(C(Cl)(Cl)Cl)nc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85 %

Procedure:
(3-tert-Butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-yl)-carbamic acid tert-butyl ester (573 mg, 1.22 mmol, as prepared in the previous step) was placed in a mL vial equipped with a magnetic stir bar. DCM (10 mL) and TFA (5 mL) were added, and the mixture stirred at rt for 12 h. The solvent was removed under reduced pressure, and the residue was dissolved in DCM and washed with 2M aq NaOH. The organic extract was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in AcOH (5 mL) and placed in an 8 mL vial equipped with a magnetic stir bar. The mixture was cooled to 0° C., treated with methyl-2,2,2-trichloroacetimidate (0.167 mL, 1.35 mmol) via syringe, and stirred at rt for 3 days. The solvent was removed under reduced pressure. The crude product was purified by column chromatography using a 12-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 2:5, v/v over 30 min, yielding 409 mg (85%) of the desired compound. 1H-NMR (400 MHz, d4-MeOH) δ: 7.71-7.77 (m, 2H), 7.52-7.57 (m, 1H), 7.39-7.51 (m, 4H).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([NH:19][C@H:20]([C:24]([N:26]([CH3:42])[C@H:27]([C:31]([N:33]1[CH2:41][CH2:40][CH2:39][C@H:34]1[C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH:28]([CH3:30])[CH3:29])=[O:25])[CH:21]([CH3:22])[CH3:23])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
15.29 g (61 mmol) Z-Val-OH and 21.96 g (61 mmol) H-Val-MeVal-Pro-OMe were dissolved in 610 ml dichloromethane and cooled to 0° C. After addition of 8.16 ml (73.2 mmol) N-Methylmoropholine, 2.77 g (20.3 mmol) HOBt and 11.74 g (61 mmol) EDCI, the reaction mixture was stirred overnight at room temperature, diluted with dichloromethane and thoroughly washed with saturated aqueous NaHCO3 solution (3×), water (1×), 5% citric acid (3×) and saturated NaCl solution. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness to yield 31.96 g of the product.