Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].FC(F)(F)C(O[C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=O>N1C=CC=CC=1>[NH:1]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:2]([C:6]([N:8]1[CH2:19][CH2:18][CH2:17][C@H:9]1[C:10]([NH:12][CH2:13][C:14]([O:16][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:15])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)O
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of XIV (4.4 g, 11.8 mmol) in pyridine (30 ml) was added p-nitrophenyl trifluoroacetate (3.22 g, 13.7mmol). After stirring for 24 h at room temperature, the reaction mixture was treated in the same manner as described for the preparation of X. An oil obtained gave a single spot on TLC; yield 5.67 g (98%), Rf1 0.60.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[CH:17][CH:16]=2)[C:10](=[O:26])[CH2:9]1)=O)(C)(C)C.[ClH:27]>CO.C(OCC)(=O)C>[ClH:27].[ClH:27].[N:21]1([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3=[O:26])=[CH:16][CH:17]=2)[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-n3ccnc3)cc2)C(=O)C1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CNCCN1Cc1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-1-[4-(1H-imidazol-1-yl)benzyl]-2-piperazinone (1.5 g) in methanol (10 ml) was added 4N hydrochloric acid in ethyl acetate solution (50 ml), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was powdered with ethyl acetate, filtered and dried to give hygroscopic colorless solid of the title compound (1.12 g).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:8]([NH:10][CH2:11][C:12](=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:34]>C(O)(=O)C>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:34][C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:11][N:10]=2)[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)NCC(=O)c2ccccn2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ncc(-c3ccccn3)[nH]2)cc1
Temperature: 25 °C
Yield: 25.4 %

Procedure:
To a solution (10 mL) of 3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]-N-(2-oxo-2-pyridin-2-ylethyl)propanamide (330 mg) in acetic acid was added ammonium acetate (310 mg), and the mixture was stirred with heating under reflux for 4 hr. After cooling to room temperature, the reaction mixture was concentrated, the residue was diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was concentrated, and the residue was subjected to preparative high performance liquid chromatography to give the title compound (80 mg, yield 25%) as colorless amorphous crystals. MS: 396 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccccc3OC)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2-methoxy-phenylboronic acid (49 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:41]=[O:42]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([C:27]([CH3:32])([CH3:31])[CH:28]([CH3:30])[CH3:29])[O:23][SiH:24]([CH3:26])[CH3:25])=[C:14]([CH:41]=[O:42])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: CC(C)C(C)(C)C(O[SiH](C)C)c1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of 26.5 g (0.049 mol) (4R,9aR)-7-bromo-6-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxymethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 800 ml toluene was added at −78° C. during 10 minutes 50 ml of a 1.5 M solution of tert. butyllithium in pentane. The reaction mixture was stirred at −78° C. for 30 minutes. To the resulting orange solution was added 30 ml dimethylformamide during 3 minutes. The reaction mixture was stirred at −78° C. for 30 minutes and the cooling bath was then removed and the mixture was stirred for 30 min at ambient temperature. The reaction was quenched by addition of 300 ml of a 10% aqueous solution of citric acid and extracted with ethyl acetate. The organic phase was washed with a 10% aqueous solution of sodium bicarbonate and brine, dried over sodium sulfate, evaporated under aspirator vacuum and purified by chromatography on silica gel with heptane:ethyl acetate=4:1 to 3:1. to yield 22.70 g (94.6%) of the title compound as yellow foam (MS: 490 (M+H+)).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([N:11]=1)=[C:9]([CH3:12])[CH:8]=[C:7]([CH3:13])[N:6]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][N:4]1[C:5]2=[N:6][C:7]([CH3:13])=[CH:8][C:9]([CH3:12])=[C:10]2[N:11]=[C:3]1[CH2:2][O:1][C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)c2nc(CO)n(C)c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1
Yield: 71.3 %

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.47 g of 2-hydroxymethyl3,5,7-trimethylimidazo[5,4-b]pyridine (prepared as described in Preparation 86), 3.58 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.87 g of tributylphosphine, 2.33 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of toluene were used. After working up the product as described in Preparation 4, the resulting crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.5 g of the title compound, melting at 96°-99° C. (softening).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([CH2:20][CH2:21][CH:22]=O)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH2:1]([C:3]1[N:4]2[CH2:9][CH2:10][NH:11][CH:22]([CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([F:12])[CH:14]=3)[C:5]2=[C:6]([I:8])[N:7]=1)[CH3:2]
Reactant: CCc1nc(I)cn1CCN
Reactant: Cc1ccc(CCC=O)cc1F
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(C)c(F)c1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (320.7 mg; 1.210 mmol) and 3-(3-fluoro-4-methyl-phenyl)-propionaldehyde (202 mg; 1.210 mmol) afforded 3-ethyl-8-[2-(3-fluoro-4-methyl-phenyl)-ethyl]-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]5[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=5)=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][S:36]([CH2:39][CH2:40][NH2:41])(=[O:38])=[O:37]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]5[O:32][C:31]([CH2:33][NH:41][CH2:40][CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:30][CH:29]=5)=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1

Procedure:
Prepared by an analogous method to Example 10 from 5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde and 2-methanesulphonylethylamine; δH [2H6] DMSO 9.92(1H, bs), 8.60(1H, d), 8.55(1H, s), 8.25(1H, s), 8.17(1H, s), 8.00(2H, m), 7.72(2H, m), 7.30(6H, m), 6.53 (1H, d), 5.72(2H, s) 4.55 (1H, m), 3.87 (2H, m), 3.35 (2H, m), 3.08 (3H, s), 3.04 (2H, m); m/z (M+1+) 553.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br.Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:20]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]=1[C:19](=[O:20])[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Product: CCOC(=O)n1c(C(=O)c2ccncc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 4-(bromoacetyl)pyridine hydrobromide (A. Taurins and A. Blage, J. Heterocycl. Chem., 1970, 7, 1137-1141). 1H-NMR (CDCl3) δ: 8.75-8.73 (2H, m), 8.24 (1H, d, J=1.5 Hz), 7.57-7.54 (3H, m), 7.33 (1H, dd, J=1.8, 8.4 Hz), 6.04 (2H, br s), 3.82 (2H, q, J=7.0 Hz), 0.93 (3H, t, J=7.0 Hz)
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[O:30][CH3:31].C1C([N+]([O-])=O)=CC=C([Cl-][C:42]([O-])=[O:43])C=1.[CH3:45][C:46]([CH3:50])([CH3:49])[CH2:47][NH2:48]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:42]([NH:48][CH2:47][C:46]([CH3:50])([CH3:49])[CH3:45])=[O:43])=[C:3]([O:30][CH3:31])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1N
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1NC(=O)NCC(C)(C)C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a stirred solution of 3-((4-(4-amino-3-methoxybenzoyl)piperazin-1-y)methyl)-N-tert-butylbenzamide (0.155 mmol, 66 mg) in dichloromethane (2 mL) was added 4-nitrophenylchloroformate (0.155 mmol, 31.3 mg). After 1 hour stirring, 2,2-dimethylpropan-1-amine (0.311 mmol, 27.1 mg) was added and stirring continued for 1 hour. The reaction was concentrated under vacuum and the residue dissolved in methanol (1 mL). Purification by basic reverse phase HPLC gave the title compound (35 mg). MS (ESI) m/z 539.0 [M+H]+
Reaction SMILES: [I-].[K+].C(=O)([O-])[O-].[K+].[K+].[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1.Cl[CH2:19][C:20]1[S:35][C:23]2[N:24]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:22]=2[CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[N:9]1([CH2:19][C:20]2[S:35][C:23]3[N:24]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:25](=[O:30])[N:26]([CH3:29])[C:27](=[O:28])[C:22]=3[CH:21]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(CCl)sc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cn3cnc4ccccc43)sc21
Yield: 59.5 %

Procedure:
Potassium iodide (few crystals), potassium carbonate (140 mg) and benzimidazole (100 mg) were added to a solution of 6-chloromethyl-3-methyl-1-(2-methylpropyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (170 mg) in dimethylformamide (5 ml). After 2 h the reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogen carbonate solution thrice and with brine, then dried over magnesium sulfate and evaporated. Column chromatography of the residue eluting with isohexane:ethyl acetate (1:1 to 0:1) containing 1% Et3N gave the title compound (130 mg).
Reaction SMILES: [OH:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1.[CH3:12][C:13](O)([CH3:15])[CH3:14].[O-]S([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[C:13]([O:1][CH:2]1[O:6][C@H:5]2[CH2:7][C:8]([CH:10]=[O:11])=[CH:9][C@H:4]2[CH2:3]1)([CH3:15])([CH3:14])[CH3:12]
Reactant: O=CC1=C[C@H]2CC(O)O[C@H]2C1
Reactant: CC(C)(C)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC1C[C@@H]2C=C(C=O)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Partially purified residue containing lactol 7, was dissolved in CH2Cl2 (40 ml) and stirred at r.t. t-BuOH (2.58 g, 3.33 ml, 34.8 mmol, 2.0 eq. based on ˜14% of 7 detected by internal standard in the previous reaction) was added via syringe. Amberlyst 15 (249 mg) and MgSO4 (5.15 g) were added as solids in one portion and the reaction mixture was stirred at r.t. for 14 h. The reaction was charged with further portions of t-BuOH (2.58 g, 3.33 ml, 34.8 mmol, 2.0 eq.), Amberlyst 15 (249 mg) and MgSO4 (5.15 g) and stirred for a further 24 h. The reaction mixture was filtered through a sinter funnel and the solids washed with CH2Cl2 (2×15 ml). The filtrate was concentrated under reduced pressure and purified by column chromatography (˜50 g silica), eluting with petrol/EtOAc (4:1), to give the t-butyl acetal 52, (as an approximately 2:1 mixture of diasteroisomers (635 mg, 2% (over 2 steps from succinaldehyde, 17% from lactol 7))) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58]([C:60]1[NH:64][C:63]2[CH:65]=[CH:66][C:67]([NH2:69])=[CH:68][C:62]=2[N:61]=1)=[O:59]>ClCCl>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:69][C:67]2[CH:66]=[CH:65][C:63]3[NH:64][C:60]([C:58]([O:57][CH3:56])=[O:59])=[N:61][C:62]=3[CH:68]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1nc2cc(N)ccc2[nH]1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1nc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@](C#N)(c4ccc(Cl)cc4F)[C@H]3c3cccc(Cl)c3F)ccc2[nH]1
Reaction time: 0.33 h

Procedure:
A solution of chiral (2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (60.3 mg, 0.129 mmol) in dichloromethane (3 ml) was reacted with DIPEA (66.8 mg, 0.514 mmol) and DIPHENYLPHOSPHINIC CHLORIDE (75.7 mg, 0.320 mmol) and stirred for 20 min under argon. 5-AMINO-1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID METHYL ESTER (25.7 mg, 0.134 mmol, Biofine) was added and stirred 2.5 hrs. The reaction mixture was diluted with dichloromethane and extracted with water then with sat'd NaHCO3, water, and brine. After drying over Na2SO4 the crude material was purified by silica gel chromatography with ethyl acetate and n-hexanes giving a white lyophilized solid, chiral methyl 542R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-1H-benzo[d]imidazole-2-carboxylate (43 mg, 52%). MS (ES+) m/z Calcd: [(M+H)+]: 640.16. found: 640.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:17])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.Cl[CH2:19][CH2:20][N:21]=[C:22]=[S:23]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([N:17]=[C:22]1[NH:21][CH2:20][CH2:19][S:23]1)[CH2:10][C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: NC(Cc1ccncc1)c1cccc(Cl)c1Cl
Reactant: S=C=NCCCl
Solvent: ClCCl
Product: Clc1cccc(C(Cc2ccncc2)N=C2NCCS2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)ethanamine (0.30 g, 1.13 mmol) in dichloromethane (6 mL) was added chloroethylisothiocyanate (0.097 mL, 0.988 mmol). The solution was stirred at room temperature for 1.5 hour, and quenched with water. The aqueous layer was extracted with dichloromethane (3×). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The filtrate was added silica gel, and the solvents were removed under vacuum. Purification by chromatography on silica gel (2 to 10% methanol in dichloromethane) gave a crude material, which was recrystallized in methanol/water to give 1-(2,3-dichlorophenyl)-2-(pyridin-4-yl)-N-(thiazolidin-2-ylidene)ethanamine Compound 18 as a solid (15.9 mg, 0.045 mmol, 4% yield).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].[NH:19]([C:26]1[O:27][C:28]2[CH:34]=[C:33]([O:35][CH2:36][C:37](O)=[O:38])[CH:32]=[C:31](OC)[C:29]=2[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[NH:19]([C:26]1[O:27][C:28]2[CH:34]=[C:33]([O:35][CH2:36][C:37]([NH:16][C:14]3[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([O:9][CH2:8][CH:2]([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[CH:15]=3)=[O:38])[CH:32]=[CH:31][C:29]=2[N:30]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CC(C)COc1cc(N)ccc1OC
Reactant: COc1cc(OCC(=O)O)cc2oc(Nc3ccccc3)nc12
Product: COc1ccc(NC(=O)COc2ccc3nc(Nc4ccccc4)oc3c2)cc1OCC(C)CC(=O)O

Procedure:
Methyl 3-methyl-4-(2-methoxy-5-aminophenoxy)butyrate and 2-anilino-4-methoxy-6-carboxymethoxybenzoxazole were coupled together using the method described in example 1 g above.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:10][NH2:11])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)(=O)[CH3:15].C(O)C>CN(C)C=O>[N:20]1[CH:21]=[CH:22][C:17]([C:14](=[N:11][NH:10][C:8](=[O:9])[C:7]2[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH3:15])=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)c1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=NNC(=O)c1ccc([N+](=O)[O-])cc1)c1ccncc1
Yield: 78.4 %

Procedure:
A mixture of 3.62 gm (0.02 mole) of p-nitrobenzhydrazide, 2.42 gm (0.02 mole) of 4-acetylpyridine and 100 ml of absolute ethanol is refluxed 3 hours. Sufficient dimethylformamide is added to the mixture at boiling to give a solution. The hot solution is filtered. The filtrate is diluted with water to the cloud point. The mixture is chilled in the refrigerator. The product is collected, washed with ether and dried to yield 4.46 gm (79%) of the title compound; mp 251.1°.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:8]1[C:13]([Cl:14])=[CH:12][C:11]([Cl:15])=[CH:10][N:9]=1)[CH2:6]Br)[CH3:2].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O>[Cl:14][C:13]1[C:8]([C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[N:9][CH:10]=[C:11]([Cl:15])[CH:12]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCON=C(CBr)c1ncc(Cl)cc1Cl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
To 3.00 g of 2-bromo-1-(3,5-dichloropyridin-2-yl)ethanone-O-ethyloxime in 20 ml of N,N-dimethylformamide, 2.32 g of potassium phthalimide was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 50 ml of water and extracted with ethyl acetate (100 ml×1), the resulting organic layer was washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was washed with 10 ml of diisopropyl ether to obtain 3.08 g of the desired product as white crystals. m.p.: 99.0 to 101.0° C.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=1>>[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:12]=2[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:34][CH:35]=1
Reactant: CCCc1nc(-c2ccccc2)oc1C(=O)ON1C(=O)CCC1=O
Reactant: COCCN(C)c1ccc(N)cn1
Product: CCCc1nc(-c2ccccc2)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-phenyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H26N4O3 (m/e) 394, obsd 395 (M+H).