Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[CH:30]2)#[N:13]
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ccnc4cc(OCCCN5CCS(=O)(=O)CC5)c(C#N)cc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol), (prepared as described for the starting material in Example 1), 5-hydroxy-2-methylindole (46 mg, 0.32 mmol) and cesium carbonate (129 mg, 0.39 mmol) in DMF (1 ml) was stirred for 10 minutes at ambient temperature followed by 1.5 hours at 70° C. After cooling, water (5 ml) was added. The mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with methanol/methylene chloride/ethyl acetate (5/45/50) to give 6cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)-4-(2-methylindol-5-yloxy)quinoline (30 mg, 23%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC([C:29]([NH2:31])=[NH:30])=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:29]([NH2:31])=[NH:30])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N=C(N)c1cc[nH]n1
Reactant: Cc1cccnc1CN(CCCCN)Cc1ncccc1C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(CCCCNC(=N)N)Cc1ncccc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a solution of N1,N1-bis-(3-methyl-pyridin-2-ylmethyl)-butane-1,4-diamine (0.1970 g, 0.46 mmol) in DMF (5 mL) was added 1H-pyrazole-carboxamidine hydrochloride (0.0681 g, 0.46 mmol) and DIPEA (0.48 mL, 2.76 mmol) and stirred at room temperature for 16 hours. The reaction mixture was concentrated, and purification of the crude material by column chromatography on silica gel (20:1:1, then 10:1:1, then 1:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (20:4:1 CH2Cl2-MeOH—NH4OH) provided 0.1380 g (64%) of COMPOUND 196 as a white solid. 1H NMR (CDCl3) δ 1.49-1.53 (m, 2H), 1.65-1.69 (m, 2H), 2.17 (s, 6H), 2.70-2.75 (m, 4H), 3.12-3.14 (m, 2H), 3.87 (s, 4H), 7.10-7.14 (m, 2H), 7.41-7.44 (m, 2H), 8.34-8.39 (m, 2H). 13C NMR (CDCl3) δ 18.53, 23.14, 26.99, 41.30, 54.57, 58.09, 123.15, 133.48, 138.87, 146.21, 155.66, 158.02. ES-MS m/z 341.3 (M+H). Anal. Calcd. for C19H28N6.1.1CH2Cl2.1.8H2O: C, 51.77; H, 7.31; N, 18.02. Found: C, 51.50; H, 7.04; N, 18.31.
Reaction SMILES: [CH3:1][C:2]1[C:12]2[CH:11]([C:13](O)=[O:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[CH2:8][O:7][C:6]=2[C:5]([CH3:20])=[CH:4][CH:3]=1.[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[C:24]=1[NH2:25])[CH3:22]>>[CH2:21]([C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH3:31])[C:24]=1[NH:25][C:13]([CH:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[CH2:8][O:7][C:6]2[C:5]([CH3:20])=[CH:4][CH:3]=[C:2]([CH3:1])[C:12]1=2)=[O:14])[CH3:22]
Reactant: CCc1cccc(CC)c1N
Reactant: Cc1ccc(C)c2c1OCc1ccccc1C2C(=O)O
Product: CCc1cccc(CC)c1NC(=O)C1c2ccccc2COc2c(C)ccc(C)c21
Yield: 41 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.0 g of 6,11-dihydro-1,4-dimethyldibenz[b,e]oxepin-11-carboxylic acid obtained in Example 64 (Compound AC) in place of Compound A and 0.62 g of 2,6-diethylaniline in place of aniline to obtain 0.61 g of Compound 50.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Br:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>CO>[Br:10][C:11]1[N:16]=[CH:15][C:14]([CH:17]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[OH:18])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC(c1ccc(Br)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
A mixture of 1H-Pyrrolo[2,3-b]pyridine (1, 1.2 g, 0.010 mol), 6-bromo-pyridine-3-carbaldehyde (88, 1.8 g, 0.0097 mol), and potassium hydroxide (1.8 g, 0.032 mol) in methanol (25 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a white solid (89, 1.4 g, 45%), or may be used as mixture of 89 and 90 in Step 2.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>CC#N.O>[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[C:31]([C:2]2[N:7]=[CH:6][C:5]([C@@H:8]3[CH2:10][C@H:9]3[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(Br)nc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)nc1
Yield: 57.8 %

Procedure:
A solution of tert-butyl (trans)-2-(6-bromopyridin-3-yl)cyclopropylcarbamate (Intermediate J[a2]) (100 mg, 0.32 mmol), potassium carbonate (132 mg, 0.96 mmol) and 3-trifluoromethylbenzeneboronic acid (72 mg, 0.38 mmol) in CH3CN:H2O (4:1) (10 mL) was degassed for 30 mins, added tetrakis triphenylphosphine palladium (37 mg, 0.032 mmol), degassed for 10 mins and heated the reaction mixture at reflux temperature for 2 h. After completion, the reaction mixture was poured in ice water (100 mL), extracted with ethyl acetate (5×40 mL). The combined extract were washed with water (70 mL), brine (70 mL), dried over anhydrous Na2SO4, filtered and evaporated. The crude residue was purified by column chromatography (SiO2), by using EtOAc:Petroleum ether (1:9) to get tert-butyl (trans)-2-(6-(3-(trifluoromethyl)phenyl)pyridin-3-yl)cyclopropylcarbamate (70 mg, 58.3%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:30]4[CH2:31][CH2:32][N:33]([CH2:36][C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[CH2:34][CH2:35]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(Cc4ccccc4)CC3)cc2)cc1
Yield: 78.6 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.17 g, 3.00 mmol), 4-hydroxy-1-benzylpiperidine (1.15 g, 6.00 mmol), triphenylphosphine (1.57 g, 6.00 mmol), and DEAD (6.00 mmol) were converted to product by the procedure of Example 1 to give 1.33 g of the title compound. Yield: 79%. MS(FD) 563(M+). IR (CHCl3) ν max 3030, 3011, 2955, 2846, 1645, 1597, 1476, 1254, 1166.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:31][CH:32]([CH3:36])[CH2:33][CH2:34][NH2:35].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[CH2:34]([NH:35][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=1)[CH2:33][CH:32]([CH3:36])[CH3:31]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Nitrobenzoic acid (0.8 g, 4.79 mmol) and 1-hydroxybenzotriazole hydrate (1.1 g, 7.18 mmol) in dimethylformamide (20 mL) was treated with N-methylmorpholine (1.8 mL, 16.75 mmol) and 3-methylbutan-1-amine (0.724 mL, 6.22 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.38 g, 7.18 mmol). The reaction mixture was stirred at room temperature for 17 hours. Water was added and the resulting suspension was stirred for 2 hours. The suspension was filtered and the solid collected was washed with water and dried to provide the title compound.
Reaction SMILES: [OH:1][CH:2]=[C:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[CH3:15]I.O>C1COCC1>[CH3:15][O:1][CH:2]=[C:3]1[CH2:4][O:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][CH2:8]1
Reactant: OC=C1COC(c2ccccc2)OC1
Reactant: CI
Solvent: O
Solvent: C1CCOC1
Product: COC=C1COC(c2ccccc2)OC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a mixture of HNa (50%, 1.06 gr) in 40 ml of dry THF, stirred at 0° C., a solution of 5.12 gr of 4 in 40 ml THF was added dropwise. After 30 min, CH3I (6.6 ml) was added and the mixture was stirred at 0° C. for 6 hours, then overnight at room temperature. Water was added and the mixture was extracted with diethyl-ether, the organic layer was washed with water until neutral, then with brine, dried and evaporated. The residue was purified on alumina column (eluent CH2Cl2) to yield 4.8 gr of 5 (86%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([OH:16])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([NH2:14])=[C:9]([Cl:15])[CH:8]=1)[CH:2]=[CH2:3].[C:17](Cl)(Cl)=[O:18]>>[NH2:14][C:10]1[C:11]([Cl:13])=[CH:12][C:7]([CH:6]2[O:16][C:17](=[O:18])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]2)=[CH:8][C:9]=1[Cl:15]
Reactant: O=C(Cl)Cl
Reactant: C=CCNCC(O)c1cc(Cl)c(N)c(Cl)c1
Product: C=CCN1CC(c2cc(Cl)c(N)c(Cl)c2)OC1=O

Procedure:
In the same manner, α-[(allylamino)methyl]-4-amino-3,5-dichlorobenzyl alcohol is allowed to react with phosgene to afford 5-(4-amino-3,5-dichlorophenyl)-3-allyl-2-oxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:28][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CN1CCN(CCN)CC1
Product: COc1ccc2nc3cc(Cl)ccc3c(NCCN3CCN(C)CC3)c2c1

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 2-(4-methylpiperazin-1-yl)ethanamine, the title compound was obtained; MS (Found M+1=385).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1O
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C#N)ccc1OC1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2.04 g 4-Hydroxy-3-methoxy-benzonitrile, 1.57 g 1-methyl-piperidine-4-ol and 7.17 g triphenylphosphine were placed in 125 mL tetrahydrofuran at 0° C. before 6.30 g di-tert-butylazodicarboxylate (DBAD) as a solution in 125 mL tetrahydrofuran was added over 15 min. The reaction was stirred for 5 min at 0° C. and then warmed to ambient temperature where it was maintained overnight. After this time additional 0.31 g 1-methyl-piperidine-4-ol, 1.79 g triphenylphosphine and 1.58 g di-tert-butylazodicarboxylate (DBAD) were added and the reaction was stirred for a further 3 h at ambient temperature. The mixture was then diluted with ethyl acetate and water and the organic phase was separated, washed with 1N sodium hydroxide (×2), water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The material that remained was dissolved in tert-butyl dimethyl ether and washed with 3N hydrochloric acid. The aqueous phase was then made basic with 5N sodium hydroxide and extracted with ethyl acetate (×3). The combined organic fractions were washed water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel chromatography (SiO2: dichloromethane/methanol 5% then dichloromethane/7N ammonia in methanol 5%) provided the title compound.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[S:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:12][NH:13][C:9]([C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:10]
Reactant: NNc1nc2ccccc2s1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Product: O=C(NNc1nc2ccccc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4a was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and 2-hydrazino-benzothiazole (300 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 245 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1)=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(O)c(C(=O)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1

Procedure:
A solution of 5.0 g. (0.03 mole) of 2-hydroxy-5-methoxybenzoic acid in 50 ml. of dimethylformamide is treated with 2.5 g. (0.06 mole) of sodium hydride in a 56.6% oil suspension, followed by the addition of 7.6 g. (0.06 mole) of benzyl chloride. The resulting mixture is heated at 98°-103° C. for one hour, after which the insolubles are filtered, the filtrate diluted with 100 ml. of water and the aqueous solution extracted with ether. The aqueous phase is discarded and the ether phase dried over sodium sulfate and evaporated to provide the intermediate, benzyl 2-benzyloxy-5-methoxybenzoate, as an oil, 5.0 g.
Reaction SMILES: [OH:1][C@@:2]([C@H:9]1[CH2:13][N:12]([C@H](C2C=CC(OC)=CC=2)C)[C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]>C(O)(C(F)(F)F)=O.CC(O)C>[OH:1][C@@:2]([C@H:9]1[CH2:13][NH:12][C:11](=[O:24])[CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3]
Reactant: COc1ccc([C@H](C)N2C[C@H]([C@](C)(O)c3nccs3)CC2=O)cc1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@](O)(c1nccs1)[C@H]1CNC(=O)C1
Temperature: 25 °C

Procedure:
A solution of (4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one (3.6 g, 10.4 mmol) in TFA (10 mL) was heated to 70° C. for 5 hours. The reaction mixture was cooled to room temperature, diluted with IPA (30 mL), and stirred until the color dissipated. The reaction mixture was then absorbed on silica gel and purified by silica gel chromatography to afford (4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]pyrrolidin-2-one. MS ESI calc'd. for C9H13N2O2S [M+H]+ 213. found 213. 1H NMR (600 MHz, DMSO-d6) δ 7.68 (d, J=3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 7.39 (s, 1H), 6.10 (s, 1H), 3.25 (t, J=9.2 Hz, 1H), 3.19 (dd, J=9.6, 7.4 Hz, 1H), 2.91-2.81 (m, 1H), 2.20 (dd, J=16.7, 8.6 Hz, 1H), 1.77 (dd, J=16.7, 9.6 Hz, 1H), 1.43 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:43]=[CH:42][CH:41]=[CH:40][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:39]=[CH:38][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)[N:10]=1.O.[OH-].[Li+:47]>C1COCC1.O>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:23]2[CH:38]=[CH:39][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:40]=[CH:41][CH:42]=[CH:43][C:5]=4[CH2:4][C:3]([O-:44])=[O:2])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=3)=[CH:21][CH:22]=2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36].[Li+:47]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I96) (120 mg, 0.196 mmol) was dissolved in THF (4 mL), and a solution of lithium hydroxide hydrate (25 mg, 0.59 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 18 hours then concentrated and the residue evaporated twice from toluene to give the title compound (I97) as a tan solid which was used without purification. LCMS Method C: rt 5.17 min; m/z 600.2 [M−Li+2H]+; 544.1 [M−tBu−Li+3H]+; m/z 598.2 [M−Li]−.
Reaction SMILES: [C:1](Cl)(=O)C.[NH:5]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][NH2:8]>CO>[NH2:8][CH2:7][CH:6]([NH:5][C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[C:9]([O:11][CH3:1])=[O:10]
Reactant: CC(=O)Cl
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)C(CN)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Acetyl chloride (0.627 ml, 8.81 mmol) was added dropwise to a suspension of commercially available Z-Dap-OH ((S)-3-amino-2-(((benzyloxy)carbonyl)amino)propanoic acid) (1 g, 4.20 mmol) in methanol (20 ml) at 0° C. The mixture was stirred at 0° C. for 4 hours and at room temperature for 16 hours. The solvent was evaporated under vacuum to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:16]([OH:18])=[O:17])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1>>[CH:19]1([C:2]2[CH:3]=[CH:4][C:5]([C:16]([OH:18])=[O:17])=[N:6][C:7]=2[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(Br)c(OCc2ccccn2)n1
Reactant: OB(O)C1CC1
Product: O=C(O)c1ccc(C2CC2)c(OCc2ccccn2)n1

Procedure:
The title compound was synthesized in analogy to Example 42 a, using 5-bromo-6-(pyridin-2-ylmethoxy)-pyridine-2-carboxylic acid and cyclopropylboronic acid (CAN 411235-57-9) as starting materials, LC-MS (UV peak area/ESI) 100%, 271.1081 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@H:23]([N:28]5[CH2:32][CH2:31][C@@:30]([NH:34]C(=O)OC(C)(C)C)([CH3:33])[CH2:29]5)[C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@H:23]([N:28]5[CH2:32][CH2:31][C@:30]([CH3:33])([NH2:34])[CH2:29]5)[C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:42])[CH3:2]
Reactant: CCOc1cc2nc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOc1cc2nc(-c3nnc4ccc([C@H](N5CC[C@](C)(N)C5)C(F)(F)F)cn34)ccc2cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of tert-butyl (S)-1-((S)-1-(3-(7-ethoxy-6-fluoro quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-ylcarbamate (5.406 g, 9.185 mmol) in DCM (40 mL) was added 4M HCl in dioxane (22.96 mL, 91.85 mmol) and stirred at ambient temperature for 1.5 h. The filtered precipitate was dissolved in water and basified (1N NaOH), extracted with ethyl acetate (3×200 mL), washed with brine (200 mL), dried (MgSO4), filtered concentrated under reduced pressure and the residue purified by flash chromatography (1 column volume DCM, increasing to 10% methanol/DCM over 2 column volumes, holding for 3 column volumes, then switching to 10% [10% NH4OH/Methanol]/DCM for 7 column volumes) to give (S)-1-((S)-1-(3-(7-ethoxy-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)-3-methylpyrrolidin-3-amine (4.13 g, 8.45 mmol, 92.05% yield). MS APCI (+) m/z 489 (M+1) detected. Specific rotation: [α]20D=−0.87° (c=1.02, MeOH).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][N:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].Cl>O.CS(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:3][C:4]2[N:5]([CH2:9][C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)=[CH:21][C:20]=1[O:26][CH3:27]
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: COc1cc(O)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a mixture of 2-chloromethyl-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (see Example 1) (150 mg, 0.5 mmol), 4-chloro-3-methoxyphenol (158 mg, 1 mmol) and DMSO (1 mL) was added K2CO3 (415 mg, 3 mmol). The reaction was stirred at ambient temperature for 8 h before diluting with water (10 mL). A solution of 1N HCl was added until the mixture was only slightly basic (pH 8) before extracting with EtOAc (30 mL). The EtOAc phase was washed with water (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2, hexanes/EtOAc) to afford the title compound (194 mg, 97%) as a white solid: ESI MS m/z 397 [C18H15Cl3N2O2+H]+.