Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]2[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:12]=[CH:13][CH:14]=2)[S:8][CH:9]=1)[CH2:3][OH:4].[Br:22]N1C(=O)CCC1=O.O>O1CCCC1>[Br:22][C:12]1[N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]([C:7]2[S:8][CH:9]=[C:5]([CH:2]([OH:1])[CH2:3][OH:4])[N:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1nc(C(O)CO)cs1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1c(Br)ccc1-c1nc(C(O)CO)cs1
Temperature: 0 °C
Reaction time: 14 h
Yield: 48.4 %

Procedure:
t-Butyl 2-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]-1H-pyrrole-1-carboxylate (868 mg, 2.80 mmol) synthesized in Example (9c) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. N-Bromosuccinimide (498 mg, 2.80 mmol) was added, and stirring was carried out at room temperature for 14 hours under nitrogen atmosphere. Water (20 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (527 mg, yield 48%) as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]([CH2:13][OH:14])[CH2:11][OH:12])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C@H:20]2[O:12][CH2:11][C@H:10]([C@H:7]3[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]3)[CH2:13][O:14]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCCC1CCC(C(CO)CO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CO[C@H](c3ccc(F)cc3)OC2)CC1

Procedure:
In 40 cm3 of dichloromethane, 1.5 g (0.008 mol) of 2-(4'-propylcyclohexyl) propane-1,3-diol, 1.4 g (0.01 mol) of 4-fluorobenzaldehyde (manufactured by Aldrich), and 0.1 g of TsOH were refluxed for 3 hours over a hot water bath fitted with a Dean-Stark trap and the water formed was continuously removed from the reaction system. The reaction solution was washed with water and the dichloromethane was distilled off. The distillation residue was recrystallized from a solvent mixture of acetone and methanol to yield 1.1 g (0.004 mol) of trans-2-(4'-fluorophenyl)-5-(trans-4'-propylcyclohexyl)-1,3-dioxane. The phase transition points of this compound, measured by DSC, were: ##STR25## wherein C is the crystal phase, N is the nematic phase and I is the isotropic liquid phase.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)[C:3]=1[OH:10]
Reactant: Cc1cc(C)c(O)c(Br)c1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(O)c(-c2cccs2)c1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
2-Bromo-4,6-dimethylphenol (500 mg, 2.49 mmol), 2-thiophenyl boronic acid (88 mg, 2.99 mmol), sodium carbonate (791 mg, 7.47 mmol) and Pd2(dppf)2Cl2 (406 mg, 0.49 mmol) were dissolved in dimethoxyethane/water 6 mL/3 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2,4-dimethyl-6-(thiophene-2-yl)phenol (231 mg, 45%).
Reaction SMILES: C([Mg]Br)C.[C:5]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH3:6].[CH2:22]=[O:23].C(N(CC)CC)C>C1COCC1.C1(C)C=CC=CC=1>[C:5]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH:22]=[O:23])[C:15]=1[OH:21])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:7])[CH3:6]
Reactant: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: C=O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
Into a 500 ml reactor thoroughly purged with nitrogen, 21.0 ml of an ether solution containing 63.1 mmol of ethylmagnesium bromide and 40 ml of THF were introduced. To the reactor, a solution containing 13.61 g (60.1 mmol) of 2-cumyl-4-methylphenol diluted with 20 ml of a THF was dropwise added at 0° C. over a period of 1 hour, then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 30 minutes. Then, 220 ml of toluene was added, and the system was heated to 100° C. to distill off about 50 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to 24° C., 4.37 g (145.5 mmol) of paraformaldehyde and 12.0 ml (86.0 mmol) of triethylamine were added, followed by stirring at 90° C. for 1 hour. The reaction solution was allowed to cool to room temperature and then quenched with 42 ml of 18% hydrochloric acid. The organic layer was concentrated, and the resulting liquid was purified by silica gel column chromatography to obtain 14.13 g (yield: 92%) of 3-cumyl-5-methylsalicylaldehyde.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)[CH:2]=1.Cl.Cl.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)=[N:20][C:21]=1[NH2:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:22][C:21]1[C:16]([NH:15][C:10]([C:7]2([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:17][CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([C:29]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])[CH2:24]2)[N:20]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)C1(c2cccnc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cccnc2)CC1
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.5 %

Procedure:
1-(Pyridin-3-yl)cyclopropanecarboxylic acid (30.7 mg, 0.188 mmol), (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (Intermediate 1) (75 mg, 0.19 mmol), and N-methylmorpholine (83 μL, 0.76 mmol) were combined and dissolved in N,N-dimethylformamide (1.0 mL). Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP) (122 mg, 0.207 mmol) was added and the reaction mixture was stirred at 50° C. for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane. A saturated aqueous solution of sodium bicarbonate was added. The organics were collected and the aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-10% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyridin-3-yl)cyclopropanecarboxamide (69 mg, 84%). MS (AP+) (M+H) 435.2; LCMS retention time 1.51 min (Method L).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8](C(OC(C)(C)C)=O)[CH2:7]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]=1[CH2:38][CH2:39][C:40]([OH:42])=[O:41].[ClH:43].[CH3:44]O>>[ClH:43].[F:22][C:23]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][N:1]3[CH2:2][CH2:3][C:4]4([C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[NH:8][CH2:7]4)[CH2:5][CH2:6]3)=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]=1[CH2:38][CH2:39][C:40]([O:42][CH3:44])=[O:41]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: Cc1ccc(COc2ccc(CCC(=O)O)c(F)c2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)CCc1ccc(OCc2ccc(CN3CCC4(CC3)CNc3ccccc34)cc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of tert-butyl spiro[indole-3,4′-piperidine]-1(2H)-carboxylate-3-{2-fluoro-4-[(4-methylbenzyl)oxy]phenyl}propanoic acid (0.12 g, 0.208 mmol) in methanol (5 mL), is added HCl in methanol (4 M, 5 mL) at 0° C. The reaction mixture is allowed to warm to room temperature and stirred for 1 hour. The reaction mixture is evaporated to dryness to give the title compound as a pale yellow solid (0.07 g, 64%). ESI/MS m/z 489.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([C:21]4[S:22][CH:23]=[CH:24][N:25]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>>[O:29]1[CH2:28][CH2:27][N:26]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:13][CH2:14][CH:15]([S:18]([C:21]5[S:22][CH:23]=[CH:24][N:25]=5)(=[O:19])=[O:20])[CH2:16][CH2:17]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:35]=[N:34][C:33]([NH2:32])=[N:38][CH:37]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: O=S(=O)(c1nccs1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(S(=O)(=O)c5nccs5)CC4)cc3n2)cn1

Procedure:
2-Chloro-4-morpholin-4-yl-6-[4(thiazole-2-sulfonyl)-piperidin-1-ylmethyl]-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 310. NMR (CDCl3): 2.03-2.18 (4H, m), 2.18-2.22 (2H, m), 3.12-3.16 (2H, m), 3.39-3.46 (1H, m), 3.84 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 5.20 (2H, br), 7.26 (1H, s), 7.79 (1H, d, J=3.0), 8.11 (1H, d, J=3.0), 9.29 (2H, s). MS (ESI+): MH+ 559.13 (100%)
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18](/[CH:21]=[CH:22]/[C:23]4[C:31]5[O:30][C:29](=[O:32])[NH:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.CN(C=O)C.[Pd]>[CH:1]1([C:7]2[NH:11][C:10](=[O:12])[C:9]3([CH2:17][CH2:16][N:15]([S:18]([CH2:21][CH2:22][C:23]4[C:31]5[O:30][C:29](=[O:32])[NH:28][C:27]=5[CH:26]=[CH:25][CH:24]=4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)/C=C/c1cccc3[nH]c(=O)oc13)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C1NC(C2CCCCC2)=NC12CCN(S(=O)(=O)CCc1cccc3[nH]c(=O)oc13)CC2
Yield: 82.8 %

Procedure:
10% Pd—C (28 mg) was added to a solution of 2-cyclohexyl-8-[(E)-2-(2-oxo-2,3-dihydro-benzoxazol-7-yl)-ethenesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (56.6 mg, 0.123 mmol) in MeOH-DMF (4 ml, 1:1). The mixture was stirred at room temperature overnight in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was then concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate, and the organic layer was then washed with water (×2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, AcOEt-hexane) to give 2-cyclohexyl-8-[2-(2-oxo-2,3-dihydro-benzoxazol-7-yl)-ethanesulfonyl]-1,3,8-triaza-spiro[4.5]dec-1-en-4-one as a colorless foam (46.9 mg, 83%).
Reaction SMILES: C1COCC1.[O:6]=[C:7]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([NH:22][C@H:23]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=4[CH:31]=3)[C:24]([O:26]CC)=[O:25])=[O:21])[CH2:16][CH2:15]2)[CH2:12][CH2:11][C:10]2[CH:40]=[CH:41][CH:42]=[CH:43][C:9]=2[NH:8]1.O.[OH-].[Li+]>O>[O:6]=[C:7]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([NH:22][C@H:23]([CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=4[CH:31]=3)[C:24]([OH:26])=[O:25])=[O:21])[CH2:16][CH2:15]2)[CH2:12][CH2:11][C:10]2[CH:40]=[CH:41][CH:42]=[CH:43][C:9]=2[NH:8]1
Reactant: CCOC(=O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](Cc1ccc2c(c1)CCCC2)NC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 8 h

Procedure:
A mixture of 20 mL THF and 3.4 g (6.5 mmol) ethyl (R)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionate was combined with a solution of 0.58 g (13.5 mmol) lithium hydroxide hydrate in 5 mL water and stirred overnight. The reaction mixture was evaporated down under reduced pressure, the residue was taken up in water and acidified by the addition of 1 M HCl. The precipitate was suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:3]2[C:2]([Cl:1])=[CH:13][C:6]([C:7](=[O:8])[N:9]([O:11][CH3:12])[CH3:10])=[CH:5][N:4]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CON(C)C(=O)c1cnc(Cl)c(Cl)c1
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1

Procedure:
5,6-Dichloro-N-methoxy-N-methyl-nicotinamide from step (a) above (3.2 g, 1.36 mmol) reacted with piperazine-1-carboxylic acid tert-butyl ester (2.53 g, 1.36 mmol, Aldrich) under the conditions of Example 3a to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 385 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4].O.C1(C)C=CC(S(O)(=O)=[O:50])=CC=1.P(=O)(O)(O)O>CS(C)=O.C(OCC)(=O)C>[OH:50][CH2:2][C:3]([C@H:5]1[N:8]([CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:7](=[O:28])[C@@H:6]1[C@H:29]([O:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:30])=[CH2:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C=C(CCl)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Agent: O=P(O)(O)O
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(CO)[C@@H]1[C@@H]([C@@H](C)OC(=O)OCc2ccccc2)C(=O)N1C(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3S,4S)-4-(1-chloromethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-1-di(p-anisyl)methyl-2-azetidinone (20 g) in dimethylsulfoxide (160 ml) were successively added water (40 ml), cuprous oxide (6.76 g) and p-toluenesulfonic acid (7.6 g), and the resultant mixture was warmed to 50° to 55° C. and stirred for 2 hours at the same temperature. After cooling down to room temperature, 1% aqueous phosphoric acid (90 ml) and ethyl acetate (200 ml) were poured into the reaction mixture, followed by stirring for 0.5 hour. An insoluble material was removed by filtration over celite and washed 3 times with ethyl acetate (20 ml). The filtrate and the washings were combined together, and the aqueous layer was separated from the organic layer and the extract were combined together, washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration of the filtrate in vacuo, the concentrate was crystallized from a mixture of toluene and n-hexane (1:1) to give crystals of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)- 1-di(p-anisyl)methyl-2-azetidinone. m.p., 118°-120 ° C. ##STR31##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[I:18]Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH3:17])[C:11]3[N:12]([C:14]([I:18])=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: ClI
Reactant: Cc1cc(-c2ccc(Cl)cc2)cn2ccnc12
Product: Cc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Yield: 79 %

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-methyl-imidazo[1,2-a]pyridine (example C.21 step 1) (6.65 g, 27 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as an off-white solid (8.0 g, 79%). MS (ISP) 369.0 [(M+H)+], 371 [(M+2+H)+].
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11](=[O:24])[CH:12]([OH:23])[C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:27]([O:23][CH:12]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2)[C:11]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:26][CH:25]=1)=[O:24])(=[O:29])[CH3:28]
Reactant: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1cccc2cnccc12
Reaction time: 0.5 h

Procedure:
The product from Example 277B (100 mg, 0.287 mmol) and DMAP (59 mg, 0.480 mmol) in CH2Cl2 (1 mL) was treated with acetic anhydride (38 μL). After stirring for 30 minutes, the mixture was treated with CH2Cl2 (5 mL) and the phases separated. The organic layer was washed with water (10 mL×3), dried (Na2SO4), filtered, and the filtrate was concentrated to provide the title compound. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.25 (s, 9H), 4.27 (dq, J1 14.9, J2 6.1, 2H), 6.56 (s, 1H), 7.09 (d, J 8.5, 2H), 7.28 (d, J 8.5, 2H), 7.72 (t, J 7.1, 1H), 7.90 (d, J 6.1, 1H), 8.07 (d, J 6.1, 1H), 8.17 (d, J 8.1, 1H), 8.53 (d, J 6.1, 1H), 8.86 (t, J 6.1, 1H), 9.35 (s, 1H); Anal. Calcd for C24H26N2O3+0.8 H2O: C, 71.19; H, 6.87; N, 6.92. Found: C, 70.87; H, 6.47; N, 6.92.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.Cl.C[C@@H]1CNCCN1S(C)(=O)=O.[CH2:32]1[C:36]2([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][N:33]1[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C(N(CC)CC)C>C(#N)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]2[C:3]([CH2:2][N:39]3[CH2:40][CH2:41][C:36]4([CH2:32][N:33]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH2:34][CH2:35]4)[CH2:37][CH2:38]3)=[N:4][N:5]=[N:6]2)=[CH:9][C:10]=1[C:16]([F:19])([F:18])[F:17])#[N:13]
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: C[C@@H]1CNCCN1S(C)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3nnnn3-c3ccc(C#N)c(C(F)(F)F)c3)CC2)C1
Temperature: 120 °C

Procedure:
To a mixture of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 34, 300 mg, 1.04 mmol) and 1,1-dimethylethyl 2,8-diazaspiro[4.5]decane-2-carboxylate (commercially available, for example from J&W Pharmlab, Levittown, USA, 301 mg, 1.25 mmol) in acetonitrile (5 mL) was added triethylamine (0.173 mL, 1.25 mmol). The reaction was heated at 120° C. for 20 min in a microwave reactor. Solvent was removed under vacuum to afford 680 mg of the title compound as a pale yellow solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=1[F:48].O.C([O-])([O-])=O.[Na+].[Na+]>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>[F:48][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][C:39]=1[C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:7]3[O:6][C:5]([NH:4][CH:1]([CH3:2])[CH3:3])=[N:9][N:8]=3)[CH:11]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=1)[C:43]([OH:45])=[O:44]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(C(=O)O)cc3F)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C
Yield: 48.8 %

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (2.0 g, 3.831 mmol) and 4-bromo-3-fluorobenzoic acid (1.2 g, 5.74 mmol, Sigma-Aldrich) in DME (38 mL)/water (9 mL) was added Na2CO3 (1.35 g, 11.5 mmol) and Pd(PPh3)4 (439 mg, 0.38 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product (1.0 g), which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 535.1 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].C(N(CC)CC)C.[NH:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:39]([NH:41][CH:42]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=2)[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:34][CH2:33]1.[O:54]1CCC[CH2:55]1>CN(C)C=O>[O:24]=[C:3]1[C@H:2]([NH:1][C:55]([N:32]2[CH2:37][CH2:36][CH:35]([NH:38][C:39]([NH:41][CH:42]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][N:49]=3)[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:40])[CH2:34][CH2:33]2)=[O:54])[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20]([F:21])([F:23])[F:22]
Reactant: CCOC(=O)C(NC(=O)NC1CCNCC1)c1ccccn1
Reactant: C1CCOC1
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)NC1CCN(C(=O)N[C@@H]2N=C(c3ccccc3)c3ccccc3N(CC(F)(F)F)C2=O)CC1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3R)-3-Amino-5-phenyl-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (90 mg, 0.270 mmol) (Y.-J. Shi et al., Tetrahedron, 1999, 55, 909-918) and triethylamine (37 uL, 0.270 mmol) in tetrahydrofuran (3 mL) were added to a solution of p-nitrophenylchloroformate (54 mg, 0.270 mmol) in tetrahydrofuran (15 mL) at 0° C. After 1 h, additional triethylamine (74 uL, 0.540 mmol) and ethyl {[(piperidin-4-ylamino)carbonyl]amino}(pyridin-2-yl)acetate (100 mg, 0.598 mmol) in tetrahydrofuran (5 μL) and dimethyl formamide (1 mL) were added and stirred at 0 oC for 10 min and then warmed to room temperature. After 4 h, the reaction was concentrated and the residue dissolved in ethyl acetate, washed with 1 N sodium hydroxide solution (3×), water, brine, and dried over magnesium sulfate. Purification by silica gel chromatography (100% dichloromethane→12% methanol/dichloromethane) gave 70 mg of the titled compound.