Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:10](=[O:11])[NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:20]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1nccs1)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Yield: 49.8 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 36, 147.8 mg, 0.38 mmol) and acetic anhydride (72 μL, 0.77 mmol) in pyridine (2 mL) and methylene chloride (1 mL) was stirred at 25° C. for 20 h. The resulting reaction mixture was concentrated in vacuo. Since the reaction did not go to completion, the residue was re-dissolved in pyridine (1.8 mL) and acetic anhydride (1.4 mL, 14.84 mmol) and then stirred at 25° C. for an additional 7 h. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (3×50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 35% ethyl acetate/hexanes) afforded acetic acid 3-[2-(3,4-dichloro-phenyl)-2-(thiazol-2-ylcarbamoyl)-ethyl]-cyclopentyl ester (80.8 mg, 49%) as a white solid: mp 49–52° C.; (ES)+-HRMS m/e calcd for C19H20Cl2N2O3S (M+H)+ 427.0645 found 427.0648.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=12.[CH3:22][O:23][C:24]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[CH:26][C:25]=1[NH:39][C:40](=[O:47])[O:41][C@H:42]([CH2:44][CH2:45][CH3:46])[CH3:43]>>[CH3:20][N:19]([CH2:18][C@H:15]1[CH2:16][CH2:17][C@H:12]([C:4]2[N:5]3[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]3=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:39][C:40](=[O:47])[O:41][C@H:42]([CH2:44][CH2:45][CH3:46])[CH3:43])=[C:24]([O:23][CH3:22])[CH:29]=3)[N:3]=2)[CH2:13][CH2:14]1)[CH3:21]
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CCC[C@H](C)OC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Product: CCC[C@H](C)OC(=O)Nc1ccc(-c2nc([C@H]3CC[C@H](CN(C)C)CC3)n3ccnc(C)c23)cc1OC

Procedure:
1-((Trans)-4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl)-N,N-dimethylmethanamine (26 mg) and (S)-pentan-2-yl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (27 mg) were used according to the procedure described in example 4 step 4c and the crude product was purified by prep-HPLC (column Luna C18(2); gradient acetonitrile/water with constant 0.003M trifluoroacetic acid). Proper fractions were collected and made basic with aqueous sodium hydrogencarbonate, extracted with dichloromethane, organic layer dried (Na2SO4) and concentrated in vacuo to give (S)-pentan-2-yl 4-(3-((trans)-4-((dimethylamino)methyl)cyclohexyl)-8-methylimidazo[1,5-a]pyrazin-1-yl)-2-methoxyphenylcarbamate (9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5](Cl)[N:4]=1.[C:11]([CH2:13][C:14]([O:16][CH3:17])=[O:15])#[N:12].[H-].[Na+]>>[C:14]([CH:13]([C:11]#[N:12])[C:5]1[N:6]=[C:7]([CH:13]([C:14]([O:16][CH3:17])=[O:15])[C:11]#[N:12])[N:8]=[C:3]([O:2][CH3:1])[N:4]=1)([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC#N
Reactant: COc1nc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C(C#N)c1nc(OC)nc(C(C#N)C(=O)OC)n1
Yield: 82 %

Procedure:
The preparation was carried out in the same way as indicated in Example II. 2.70 g (0.015 moles) of 2-methoxy-4,6-dichloro-s-triazine were converted with the reaction product of 5.95 g (0.06 moles) of methyl cyanoacetate and 1.44 g (0.06 moles) of sodium hydride. After extraction with methanol and petroleum ether (boiling point 40°-60° C.) 3.74 g of 2,4-di-(carbomethoxycyanomethyl)-6-methoxy-s-triazine were obtained in 82% yield. The UV absorption maxima were at' ##EQU18##
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][NH2:11])[CH:3]=1.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=O>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][N:11]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH3:12])[CH:3]=1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Reactant: COc1nc(Cl)cc(NN)n1
Solvent: CCO
Product: COc1nc(Cl)cc(NN=C(C)c2ccc(N(C)C)cc2)n1

Procedure:
The title compound was prepared from (6-chloro-2-methoxy-pyrimidin-4-yl)hydrazine (414 mg, 2.4 mmol) and 4-dimethylaminoacetophenone (387 mg, 2.4 mmol) in ethanol (10 mL) by a procedure similar to Example 1, step 4 yielding 305 mg (40%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8]C(=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:11]([O:16][CH3:17])([O:14][CH3:15])OC>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][C:11]([O:14][CH3:15])([O:16][CH3:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: COC(OC)OC
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1(OC)CCN(C(C)=O)CC1
Yield: 89.2 %

Procedure:
A solution of 1-acetyl-4-piperidone (17.0 g, 121 mmol), trimethyl orthoformate (26.4 mL, 241 mmol) and para-toluenesulfonic acid monohydrate (80 mg, 0.42 mmol) in dry methanol (34 mL) was refluxed for one hour. Then 1.0 M methanolic NaOMe (0.42 mL, 0.42 mmol) and excess of methanol and trimethyl orthoformate were removed by distillation (atmospheric pressure). Further distillation under reduced pressure afforded 1-acetyl-4,4-dimethoxy-piperidine (20.2 g, 89%) 1H NMR (DMSO) δ 3.45-3.32 (m, 4H), 3.10 (s, 6H), 1.99 (s, 3H), 1.72-1.62 (m, 2H), 1.61-1.52 (m, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: BrCCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3ccccc3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.692 g of (3-bromopropoxy)benzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.24 (1:2 EtOAc-heptane); Rt=5.13.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:15]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=O>C(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([N:1]=[CH:15][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=Cc1ccncc1
Solvent: CCO
Product: C(=NC1CCN(Cc2ccccc2)CC1)c1ccncc1
Yield: 100.4 %

Procedure:
8.57 ml (42.01 mmol) of 4-amino-1-benzylpiperidine were added to a solution of 3.95 ml (42.01 mmol) of 4-formylpyridine in 5 ml of ethanol, and the resulting mixture was then heated under reflux for 1 hour. At the end of this time, the solvent was distilled off from the reaction mixture by evaporation under reduced pressure to afford 11.78 g (quantitative yield) of the title compound as a pale brown powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].Cl[C:19]([O:21][CH2:22][CH2:23][Cl:24])=[O:20]>COCCOCCOC.O>[Cl:24][CH2:23][CH2:22][O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=C(Cl)OCCCl
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc(NC(=O)OCCCl)cc1[N+](=O)[O-]
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
420.5 g of 4-amino-2-nitroanisole are dissolved in 1275 ml of diethylene glycol dimethyl ether and 150 ml of water, 135 g of calcium carbonate are added and the mixture is heated to 78° C. 375 g of 2-chloroethyl chloroformate are allowed to run into this mixture in the course of 3 hours such that the reaction temperature remains at 78°-80° C. The mixture is subsequently stirred for 1.5 hours to bring the reaction to completion and is cooled to 35° C. and water and ice are added. The product which has precipitated is filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][N:15]=2)=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][N:15]=2)=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3nsc4ccccc34)[C@H]2C1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2nsc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isothiazole-3-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:9]3[N:44]=[C:42]([NH:41][C:31]4[CH:32]=[CH:33][C:34]([N:35]5[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]5)=[C:29]([O:28][CH3:27])[CH:30]=4)[N:43]=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: CN(C)C=C1CCCC(c2ccc(Cl)cc2)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2ccc(Cl)cc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(4-chloro-phenyl)-cyclohexanone (134 mg, 0.50 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (186 mg, 0.50 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (69 mg, 31%). MS ISP (m/e): 446.1 [(M+H)+]. mp 210-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:24]([C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[O:21][C:20]([F:19])([F:31])[F:32])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc2nc(-c3ccccc3OC(F)(F)F)oc(=O)c2c1
Temperature: 25 °C

Procedure:
2-Amino-5-methylbenzoic acid (0.5 g) and triethyl amine (10 ml) were mixed in dry toluene (20 ml). 2-Trifluoromethoxybenzoyl chloride (1.64 g) was added dropwise under cooling and stirring. The mixture was subsequently heated to RT for 2 days.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH2:20])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[Cl:19].[F:22][C:23]([F:34])([F:33])[C:24]([F:32])([F:31])[C:25](F)(F)C(O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:10]=2[Cl:19])=[CH:6][C:5]2[NH:20][C:25]([C:24]([F:32])([F:31])[C:23]([F:34])([F:33])[F:22])=[N:21][C:4]=2[CH:3]=1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2Cl)cc1N
Product: FC(F)(F)c1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (50 mg, 0.15 mmol) was added heptafluorobutanoic acid (3 ml). The resulting solution was stirred overnight at 80° C. and quenched with the addition of water (100 ml). The pH value of the solution was adjusted to 8 with potassium carbonate, extracted with ethyl acetate (3×50 ml), organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue which was purified by Prep-HPLC to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenoxy]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a light yellow solid (41.2 mg, 54%).
Reaction SMILES: C(C1C=CC(OCC2ON=C(CC3C=C(C=CC=3)[C:19]([OH:21])=[O:20])N=2)=C(C)C=1O)(=O)C.[OH:29][C:30]1[C:35]([CH3:36])=[C:34]([O:37][CH2:38][C:39]2[O:43][N:42]=[C:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=3)[N:40]=2)[CH:33]=[CH:32][C:31]=1[C:52](=[O:54])[CH3:53]>>[C:52]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[O:43][N:42]=[C:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([C:19]([OH:21])=[O:20])=[CH:47][CH:46]=3)[N:40]=2)=[C:35]([CH3:36])[C:30]=1[OH:29])(=[O:54])[CH3:53]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(C)c1O
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(C(=O)O)c3)no2)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(C(=O)O)cc3)no2)c(C)c1O

Procedure:
The title compound is prepared essentially as described for 3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoic acid of Example 146, employing 1-{2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone. 1H NMR (DMSO-d6) δ 12.84 (s, 1H), 12.80 (s, 1H), 7.86 (m. 2H), 7.78 (d, 1H), 7.38 (d, 2H), 6.67 (d, 1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s, 3H), 1.99 (s, 3H). LC-MS (m/e): 381 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].Cl>CO.C(Cl)Cl.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Cc1c(N)cc(F)cc1Br
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a solution of crude 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96 g) in MeOH (90 mL) was added concentrated hydrochloric acid (11.7 mL) and iron (6.1 g) and the reaction mixture was heated to reflux. After 16 h, the mixture was cooled, diluted with DCM, washed with sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 3-bromo-5-fluoro-2-methyl-phenylamine (1.46 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Br[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-n2nccn2)nc1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-methylpyridine. MS (ESI) 409.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2C(=O)C3=CC=CC=C3C2=O)=[CH:6][C:5]=1[CH:22](C(OCC)=O)[C:23]([O:25][CH2:26]C)=[O:24])([O-:3])=[O:2].[ClH:33]>O1CCOCC1>[ClH:33].[NH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(CN2C(=O)c3ccccc3C2=O)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1cc(CN)ccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A solution of diethyl 2-nitro-5-phthalimidomethylphenylmalonate in a mixture of concentrated hydrochloric acid (150 mL) and 1,4-dioxane (150 mL) was heated at 120° C. for 24 h. The solvents was removed in vacuo and the residual solid was dissolved in methanol (100 mL). To the solution was added thionyl chloride (11.8 g) at 0° C. The mixture was stirred for 2 h at 40° C. and the solvent and the excess reagent were removed in vacuo. The residue was washed with diethyl ether and dried to give 6.5 g of the title compound (quant): 1H NMR (CD3OD) δ8.18 (d, 1H, J=8.6 Hz), 7.63 (dd, 1H, J=8.6, 1.6 Hz), 7.56 (d, 1H, J=1.6 Hz), 4.23 (s, 2H), 4.09 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.CC1C=C(C)N=C(S[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[O:29])N=1>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)=[O:29]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.8 %

Procedure:
To a clear solution of L-hydroxyproline methyl ester hydrochloride (27.2 g, 0.15 mol) and triethylamine (50 ml, 0.36 mol) in chloroform (500 ml) was added 4,6-dimethyl-2-(4-nitrobenzyloxycarbonylthio)pyrimidine (40.7 g, 0.13 mol) and then the resulting solution was stirred at room temperature for 12 hours, sequentially washed with H2O (200 ml), 0.5N NaOH (400 ml) and brine (200 ml) and dried (MgSO4). Concentration followed by silicagel column chromatography (Wakogel® C-300, ethyl acetate) afforded (2S, 4R)-4-hydroxy-N-(4-nitrobenzyloxycarbonyl)proline methyl ester (34.5 g, 70.9% yield) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH:29][C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:25]=2)[CH2:23][CH2:22]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (1.76 g, 11.1 mmol) and DIEA (1.93 ml, 11.1 mmol) in THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (0.91 g, 7.39 mmol) in THF (5 ml) at 25° C. After addition, the reaction mixture was stirred at 80° C. for 48 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:DCM:EtOAc=2:1:1) to give the title compound as a yellow solid (0.62 g, 32%). NMR (400 MHz) 12.37 (s, 1H), 9.83 (s, 1H), 8.25 (m, 1H), 7.98 (d, J=11.2 Hz, 1H), 6.75 (m, 1H), 5.95 (s, 1H), 1.90 (m, 1H), 0.96 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=3)=[CH:11][C:10]([NH2:27])=[N:9]2)=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C@H:21]([CH3:26])[C:22]([F:24])([F:23])[F:25])[CH:14]=3)=[CH:11][C:10]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cccc(-c2cc(N)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@@H](OCc1cccc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccc(F)cc2)c1)C(F)(F)F
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-[3-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1H-pyrazol-3-ylamine (52 mg) in N,N-dimethylacetamide (0.5 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (20 mg) prepared according to the same procedures as Preparation 5 and WSC.HCl (40 mg) at room temperature, and the mixture was stirred for 0.5 hours. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected by filtration from this suspension, and dried under reduced pressure to give the titled compound (37 mg).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[S:19][C:20]([CH2:24][C:25]([O:27][CH2:28]C)=[O:26])=[C:21]([CH3:23])[N:22]=1>N1C=CC=CC=1>[CH3:28][O:27][C:25]([CH2:24][C:20]1[S:19][C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)=[N:22][C:21]=1[CH3:23])=[O:26]
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: CCOC(=O)Cc1sc(N)nc1C
Agent: [I-]
Solvent: c1ccncc1
Product: COC(=O)Cc1sc(N=C2SC[C@@H]3Cc4ccccc4CN23)nc1C
Temperature: 0 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (10 g) is added to a solution of ethyl (2-amino-4-methylthiazol-5-yl)acetate (5.5 g) in pyridine (150 cc). After 48 hours at a temperature of the order of 20° C., the solution is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 60° C. The residue is dissolved in a mixture of methylene chloride (200 cc) and N sodium hydroxide solution (100 cc). The organic phase is washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C. The residue is crystallised by dissolving it in boiling ethanol (120 cc) and cooling to 0° C. The resulting crystals are filtered off, washed with ethanol (30 cc) and diethyl ether (20 cc) and dried at 20° C. under reduced pressure (0.1 mm Hg; 0.013 kPa) to yield (S)-3-[(5-methoxycarbonylmethyl-4-methylthiazol-2-yl)imino]-1,5,10,10a-tetrahydrothiazolo[3,4-b]-isoquinoline (8.1 g), as a white solid, m.p.=66° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=O.[CH3:13][C:14]([CH3:16])=[O:15]>O>[Cl:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: O=Cc1cc(F)ccc1Cl
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (0.78 g) was dissolved in water (55 ml) and treated dropwise with acetone (55 ml) followed by a solution of 2-chloro-5-fluorobenzaldehyde (2.8 g) in acetone (10 ml). The reaction mixture was stirred at room temperature for 2 hours. Acetone was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and concentrated under reduced 5 pressure to obtain 4-(2-chloro-5-fluorophenyl)-3-buten-2-one (0.24 g).