Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:13]=2[NH2:26])=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[O:5])[CH3:2].[CH:34](OCC)(OCC)OCC>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:12]3[CH:17]=[C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:15]=[CH:14][C:13]=3[N:26]=[CH:34]2)=[N:8][C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Nc2cc(OCc3ccccc3)ccc2N)nc1-c1cccc(Cl)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(-n2cnc3ccc(OCc4ccccc4)cc32)nc1-c1cccc(Cl)c1

Procedure:
A mixture of the 2-(2-amino-5-benzyloxy-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (VII.25) from previous step, 50 mL of acetic acid, 5 mL of triethyl orthoformate was heated to 50 degrees for 1 hour. The mixture was concentrated under reduced pressure and the residue taken up in 200 mL of dichloromethane. The mixture was washed with 100 mL saturated sodium bicarbonate. The aqueous layer was extracted twice with 100 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with diethyl ether to afford 3.5 g of 2-(6-benzyloxy-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid ethyl ester (I.25a) as an off-white solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH2:12][O:13]C(C)=O.[CH:17]([C:19]1[C:20]([NH:27][C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=2)=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=O>CC1OCCC1>[CH3:26][S:25][C:22]1[N:23]=[CH:24][C:19]2[CH:17]=[CH:11][C:12](=[O:13])[N:27]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH:31]=[CH:32][CH:33]=3)[C:20]=2[N:21]=1
Reactant: CCOC(C)=O
Reactant: CSc1ncc(C=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC1CCCO1
Product: CSc1ncc2ccc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
LiHMDS (41.6 mL of 1.0 M in THF solution, 41.6 mmol) was added to 2-MeTHF (70 mL) at −78° C. and treated with EtOAc (4.34 mL, 44.4 mmol). The solution was stirred at −78° C. for 10 min, then solid tert-butyl (3-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (50) (5.00 g, 13.87 mmol) was added in one portion and the solution was stirred at −78° C. for 10 min then removed from the cooling bath warmed to RT for 3 h. The reaction was cooled in an ice bath and quenched with a saturated solution of NH4Cl and extracted with EtOAc (2×100 mL), dried over MgSO4, filtered and concentrated. The crude solid was suspended in Et2O (50 mL) and collected by filtration, washed with Et2O (2×15 mL) and dried under vacuum affording tert-butyl (3-(2-(methylthio)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)carbamate (51) (4.24 g, 11.03 mmol, 80% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.60-8.65 (1H, m), 7.64-7.71 (1H, m), 7.52 (1H, s), 7.39-7.47 (1H, m), 7.29 (2H, dd, J=8.3, 1.3 Hz), 6.89-6.95 (1H, m), 6.71 (1H, d, J=9.6 Hz), 6.56 (1H, s), 2.19 (3H, s), 1.50 (9H, s). m/z (ESI, +ve ion) 385.0 (M+1)+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:15][C:14]([N:10]1[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:13])[NH:9]1)=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH][nH]c(=O)n1-c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(=O)n1[nH]c(=O)n(-c2ccccc2)c1=O
Yield: 54 %

Procedure:
To a suspension of 5.3 g (30 mmol) of 4-phenyl-1,2,4-triazolidine-3,5-dione in 175 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride with stirring. The reaction mixture was stirred at room temperature for five days. The reaction mixture was filtered to remove a white precipitate which was washed with 30 ml of chloroform to give 3.55 g (54.0%) of 1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione as white solid, m.p. 215°-218.5° C. The filtrate was washed with three 100 ml portions of water and three 80 portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was formed. The chloroform solution was dried (Na2SO4) and evaporated under reduced pressure to give a liquid residue containing acetic anhydride. The filtered solid was recrystallized from 95% to ethanol to yield pure 1 -methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione; m.p. 216.5°-218.5° C.; IR (Nujol) 1726, 1710, 1688 cm-1 (CO); 1H NMR (60 MHz, CDCl3)δ7.90 (s, 5H) 2.55(s, 3H). Found C, 54.5; H, 4.2: N, 19.4. C10H9N3O3 requires C, 54.8; H, 4.2; N, 19.4
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.CN(C=O)C.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([OH:31])=O.[NH2:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:38])[CH:34]([CH3:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:28])=[C:20]1[C:29]([NH:32][C@H:33]([C:37]([NH:39][CH:40]([CH:49]([OH:52])[CH2:50][F:51])[CH2:41][C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])=[O:38])[CH:34]([CH3:35])[CH3:36])=[O:31]
Reactant: Cc1c(C(=O)O)n(C)c2ccccc12
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)C(C)C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
4-Dimethylaminopyridine (DMAP) (67 mg, 0.55 mmol) and 1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (125 mg, 0.65 mmol) were added as solids to a DMF solution of 1,3-dimethylindole-2-carboxylic acid (95 mg, 0.5 mmol in 1 mL of DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. A methylene chloride solution of N-(valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (153 mg, 0.5 mmol in 1 mL of methylene chloride) was added and the resultant reaction mixture was first stirred for 1 hour at 0° C. and then for 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×), and brine, dried over sodium sulfate, and concentrated to give a solid. The solid was triturated with ether/hexane to yield the title product as a white solid (134 mg, 56%). TLC: (ethyl acetate/hexanes, 2:1): Rf =0.42. 1H NMR (CDCl3): δ 7.59 (d, J=8.8, 1H) , 7.37 (d, J=7.7, 1H), 7.29-7.24 (m, 1H), 7.12-7.07 (m, 1H), 4.49-4.26 (m, 5H), 3.81-3.79 (m, 3H), 2.66-2.47 (m, 5H), 2.22-2.10 (m, 1H), 1.45-1.41 (m, 9H), 1.09-1.03 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[C:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)(=[O:34])[CH3:33].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[C:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=3)[C@H:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=3)[CH2:10]2)=[O:40])=[CH:37][CH:36]=1)(=[O:34])[CH3:33]
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(C(=O)N2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(C)c3)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.7 %

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.25 g) and 4-acetylbenzoic acid (0.09 g) in dichloromethane (8 ml) was added triethylamine (0.2 ml) at room temperature. 2-Chloro-1-methylpyridinium iodide (0.17 g) was added, and the mixture was stirred at room temperature for 2.5 hours. The resulting mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography using ethyl acetate--n-hexane (1:1) as an eluent to afford (2R)-4-(4-acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.31 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH2:15])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38](O)=[O:39])[CH:36]=2)[CH:31]=[CH:30]1>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16][C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:12]([NH:15][C:38]([C:35]2[CH:36]=[C:37]3[C:32]([CH:31]=[CH:30][NH:29]3)=[CH:33][CH:34]=2)=[O:39])=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2N)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2ccc3cc[nH]c3c2)cc1
Yield: 49.6 %

Procedure:
Using the procedure described in Example 9, Part C, 4-t-butyldimethylsilyloxy-N2-(4-t-butylbenzoyl)-1,2-benzenediamine (1.15 g, 2.9 mmol) and indole-6-carboxylic acid (0.46 g, 2.9 mmol) yielded 780 mg (50%) of the title compound.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[O:18][CH3:19].[Li+].[OH-]>O1CCOCC1.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[O:18][CH3:19]
Reactant: COC(=O)c1ccc(O[C@@H]2CCC[C@H]2O)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1O[C@@H]1CCC[C@H]1O

Procedure:
A solution of methyl 4-[(1R,2R)-2-hydroxycyclopentoxy]-3-methoxy-benzoate (2.8 g, 11 mmol) and LiOH (21 mL of 2.0 M, 42 mmol) in dioxane (20 mL) was stirred at 50° C. overnight. The mixture was diluted with ethyl acetate and was washed with water. The aqueous layer was acidified with 1N HCl and the product was extracted into ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated to give 4-((1R,2R)-2-hydroxycyclopentyloxy)-3-methoxybenzoic acid. ESI-MS m/z talc. 252.1, found 253.5 (M+1)+; Retention time: 1.07 minutes (3 min run).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23])[CH3:4]>CCO>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23])[CH3:4]
Reactant: CCOc1cc(C(=O)OC)ccc1-c1ccccc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1-c1ccccc1CC
Temperature: 60 °C

Procedure:
A 5N aqueous solution of NaOH (3 mL, 15 mmol) was added into a solution of methyl 2-ethoxy-2′-ethylbiphenyl-4-carboxylate (2.72 g, 9.6 mmol) in EtOH (30 mL). The resulting mixture was heated at 60° C. for 1 hour. The reaction mixture was concentrated under vacuum. The residue was taken up with water (50 mL) and a 5N aqueous solution of HCl (5 mL), and then extracted twice with MTBE (100 mL+50 mL). The organic layers were washed with brine (50 mL), combined, dried (MgSO4) and concentrated under vacuum. After purification by crystallization from MTBE and heptane, the title compound was obtained as a white powder (2.04 g, 79%). HPLC (Method A) Rt 4.5 min (Purity: 100%). LC/MS (Method B): 269.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.00 (s, 1H), 7.58 (m, 2H), 7.30 (m, 2H), 7.22 (m, 2H), 7.06 (d, J=7.4 Hz, 1H), 4.05 (q, J=7.0 Hz, 2H), 2.45-2.32 (m, 2H), 1.17 (t, J=7.0 Hz, 3H), 0.97 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.N1(O)C2C=CC=CC=2N=N1.[N:51]12[CH2:58][CH2:57][CH:54]([CH2:55][CH2:56]1)[C@@H:53](O)[CH2:52]2>C1COCC1>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]([O:18][C@@H:53]2[CH:54]3[CH2:57][CH2:58][N:51]([CH2:56][CH2:55]3)[CH2:52]2)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccccc1)c1ccc(OCc2ccccc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 12 %

Procedure:
To a solution of 2-(6-(benzyloxy)pyridin-3-yl)-2-(phenylamino)acetic acid (I52) (460 mg, 1.38 mmol) in THF (20 ml), were added DCC (341 mg, 1.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (223 mg, 1.65 mmol), and (R)-quinuclidin-3-ol (210 mg, 1.65 mmol). The resulting reaction mixture was stirred at room temperature for 15 hours, and then the solvent was evaporated. DCM is added, the insoluble was filtered off and the organic phase was washed twice with Na2CO3 and brine, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography (DCM/MeOH=95/5 to 97/3), recovering first diastereomer 1 of C53 (71 mg, 12% yield), then a mixture of diastereomers of C53 (84 mg, 14% yield) and finally diastereomer 2 of C53 (21 mg, 4% yield).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:44])([CH3:43])[CH2:6][NH:7][C:8](=[O:42])[C@H:9]([N:17]([C:19](=[O:41])[C@H:20]([N:32](C(OC(C)(C)C)=O)[CH3:33])[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][C:5]([CH3:44])([CH3:43])[CH2:6][NH:7][C:8](=[O:42])[C@H:9]([N:17]([CH3:18])[C:19](=[O:41])[C@H:20]([NH:32][CH3:33])[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(C)(C)OC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.4 %

Procedure:
2-((2R)-2-(N-((2R)-2-(N-tert-Butoxycarbonyl-N-methylamino)-3-(2-naphthyl)-propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate (511 mg, 0.85 mmol) was dissolved in dichloromethane (2 ml) and cooled to 0° C. Trifluoroacetic acid (2 ml) was added, and the solution was stirred for 15 min at 0° C. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (50 ml), and the solvent was removed in vacuo. The latter is procedure was repeated two times. The crude product was purified by flash chromatogrpahy on silica (30 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 160 mg of 1,1-dimethyl-2-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropionylamino)ethyl acetate.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH2:14]([NH2:16])[CH3:15]>>[CH:9]1([C:6]2[S:7][CH:8]=[C:4]([CH2:3][NH:16][CH2:14][CH3:15])[N:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN
Reactant: ClCc1csc(C2CCCC2)n1
Agent: Cl
Product: CCNCc1csc(C2CCCC2)n1

Procedure:
Using the procedure of Example 1 Q, but replacing 4-(chloromethyl)-2-isopropylthiazole hydrochloride with 4-(chloromethyl)-2-cyclopentylthiazole hydrochloride and replacing 40% aqueous methylamine with 70% aqueous ethylamine provided, after purification of the residue by silica gel chromatography using 5% methanol in chloroform, 1.08 g (50%) of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([CH3:34])[CH:33]=1)[C:28](O)=[O:29]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:28](=[O:29])[C:27]3[CH:31]=[C:32]([CH3:34])[CH:33]=[C:25]([CH3:24])[CH:26]=3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cc(C)cc(C)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3,5-dimethyl-benzoic acid to yield (3aR,4S,7aR)-4-(3,5-dimethyl-benzoyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=8.590 min; LC/MS Method III
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH:11]([Br:13])[Br:12].CN(C=O)C.C(Cl)(=O)C([Cl:22])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:22])=[O:7])=[CH:4][C:3]=1[CH:11]([Br:13])[Br:12]
Reactant: O=C(O)c1ccc(Br)c(C(Br)Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)c(C(Br)Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 250 mL round bottom flask was charged with the 4-Bromo-3-(dibromomethyl)benzoic acid prepared as described above (114.6 g, 307 mmol) in anhydrous toluene (1.14 L) and anhydrous DMF (6.3 mL). The resulting suspension was stirred at RT under an argon atmosphere. Oxalyl chloride (29.5 mL, 338 mmol) was added dropwise. The reaction mixture became a clear yellow solution at the end of the reaction. HPLC indicated the reaction was complete in 2 hours. The solution was decanted away from a gummy oil deposited at the bottom of the reaction flask and the solution was concentrated on a rotary evaporator and then on a high vacuum pump overnight to dryness. The 4-Bromo-3-(dibromomethyl)benzoyl chloride was obtained as a light brown solid 115.02 g, 95.7% yield and area percent=93.5%. The 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][C@@H:17]2[CH2:19][O:18]2)=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]2)=[CH:4][CH:3]=1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: Clc1ccc(OC[C@@H]2CO2)c2c1[nH]c1ccccc12
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1ccc(Cl)c2[nH]c3ccccc3c12
Yield: 53.3 %

Procedure:
Prepared from 1-chloro-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.085 g, 0.31 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.10 g, 0.48 mmol) according to the procedure used for Example 2 without heating to give 0.080 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=O.[NH2:13][C:14]([CH:18]([F:20])[F:19])=[CH:15][C:16]#[N:17]>C(O)(=O)C.C1COCC1>[F:19][CH:18]([F:20])[C:14]1[NH:13][C:14]([CH:18]([F:20])[F:19])=[C:15]([C:16]#[N:17])[CH:11]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[CH:6]3)[C:15]=1[C:16]#[N:17]
Reactant: N#CC=C(N)C(F)F
Reactant: O=Cc1cc2cn[nH]c2cc1F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CC1=C(C(F)F)NC(C(F)F)=C(C#N)C1c1cc2cn[nH]c2cc1F

Procedure:
A solution of 150 mg (0.55 mmol) 6-fluoro-1H-indazole-5-carbaldehyde (Example 5A) and 142 mg (1.21 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in acetic acid (0.5 ml) containing powdered 4 Å molecular sieve was heated to reflux temperature for 5 h. After cooling, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 147 mg (72% of th.) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([O:18][CH2:19][C:20]1[N:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1)(=[O:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([O:18][CH2:19][C:20]1[N:25]=[CH:24][C:23]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:22][CH:21]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OCc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cn1
Yield: 86.2 %

Procedure:
A sample of (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (1.64 g, 8.18 mmol, prepared as in Example 15a above) and 1.05 g (6.29 mmol) of 6-acetyloxymethyl-3-hydroxypyridine, prepared as described by Deady and Dayhe, Aust. J. Chem., 2565:36 (1983), were reacted with triphenylphosphine and DEAD (8.18 mmol each) in 25 mL of THF according to the procedure of Example 14a. Workup gave 1.90 g of title compound. MS (DCI/NH3) m/e: 309 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.32-8.28 (m, 1H), 7.33-7.25 (m,.2H), 5.15 (s, 2H), 4.30-3.90 (m, 2H), 3.65-3.25 (m, 3H), 2.13 (s, 3H), 2.10-1.80 (m, 3H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([CH3:19])[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11](/[CH:19]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][C:9]1=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: CC1=Nc2ccccc2N(Cc2ccccc2)C(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(/C=C/c2ccccc2)=Nc2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.3 %

Procedure:
To a solution of 1-benzyl-4-methyl-1,3-dihydro-1,5-benzodiazepin-2(2H)-one (3.0 g, 11.4 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (content 60%, 0.51 g, 12.8 mmol), and the mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added benzaldehyde (1.45 g, 13.7 mmol), which was stirred for further 30 minutes at the same temperature. The reaction mixture was diluted with water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water and dried, followed by concentration. The concentrate was crystallized from ethylacetate-hexane to give 1.9 g of the titled compound. Yield 75%. m.p. 150°-151° C.