Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:21]3[N:22]=[C:23]([CH3:25])[N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)n1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(N2CCC3(CC2)OC(=O)Nc2ncccc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
77 mg (0.30 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 88 mg (0.28 mmol) 6-(6-chloro-2-methyl-pyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.17 mL (1.0 mmol) DIPEA were combined in 2 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N1C=CC=CC=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: COC(=O)c1ccccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-aminobenzoate (10 g, 66.2 mmol) was dissolved in DCM (100 ml), and pyridine (8.1 ml, 99.2 mmol, 1.5 eq.) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride (24.4 g, 99.2 mmol, 1.5 eq.) in DCM (150 ml) was then added dropwise at 0° C., and the reaction mixture was stirred overnight at room temperature. TLC monitoring (silica gel, DCM) showed complete conversion. When the reaction was complete, the reaction solution was diluted with DCM (250 ml) and washed with 0.5 M KHSO4 (500 ml), saturated NaHCO3 (500 ml) and saturated NaCl solution (500 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. For purification, filtration over a thin layer of silica gel was carried out (gradient: heptane/DCM (3:1) to DCM).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]3[CH2:35][CH2:34][C:24]4([CH2:28][NH:27][C@H:26]([C:29]([O:31]CC)=[O:30])[CH2:25]4)[CH2:23][CH2:22]3)[CH:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[CH:3]=1.[Li+].[OH-]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]3[CH2:22][CH2:23][C:24]4([CH2:28][NH:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25]4)[CH2:34][CH2:35]3)[CH:15]=2)[C:9]([F:10])([F:11])[F:12])=[C:4]([N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(C)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(C)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)-2-methylpyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[NH:13]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C([O-])=O.CCN(CC)CC.[N:34]([C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:39]([C:46]([NH2:48])=[O:47])[CH:38]=1)=[C:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[N:13]2[C:35](=[O:36])[NH:34][C:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([C:46](=[O:47])[NH2:48])[CH:38]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC[C@@H]1C[C@H]2C[C@H]2N1)Oc1cccc(Cl)c1F
Reactant: NC(=O)n1cc(N=C=O)c2ccccc21
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)n1cc(NC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of [(1R,3S,5R)-1-(2-aza-bicyclo[3.1.0]hex-3-yl)methyl]-carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate (60.0 mg, 0.211 mmol) and Et3N (88 μl, 0.62 mmol) in THF (5 mL) was added 3-isocyanato-indole-1-carboxylic acid amide (43.0 mg, 0.211 mmol; prepared as described in Scheme A1). The solution was stirred at RT under a nitrogen atmosphere for 3 days. Purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) afforded after lyophilization of the purified HPLC fractions the title compound. MS (LC/MS): 486.0 [M+H]+; tR (HPLC conditions k): 3.57 min.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[CH:7]([CH3:9])[CH3:8].CN(C)[CH:23]=[O:24]>>[CH2:6]([C:10]1[NH:11][C:12]2[C:17]([C:18]=1[CH:23]=[O:24])=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2)[CH:7]([CH3:9])[CH3:8]
Reactant: COc1ccc2[nH]c(CC(C)C)cc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(CC(C)C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Dimethylformamide (1 mL) was cooled to 0° C. Phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 2-isobutyl-5-methoxyindole (375 mg, 1.8 mmol) in dimethylformamide (2 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (35 mL) and stirred for 10 minutes. The precipitate was collected, washed with cold water (30 mL) and dried overnight in a vacuum desiccator set at 40° C. equipped to an oil driven vacuum pump yielding a tan solid (393 mg, 94%): TLC Rf 0.45 in 1:1 ethyl acetate/hexanes. Melting point=146-147° C. 1H NMR (600 MHz, CDCl3) δ 10.13 (s, 1H), 8.74 (s, 1H), 7.81 (d, 1H, J=2.5 Hz), 7.24-7.23 (d, 1H, J=8.7 Hz), 6.89-6.87 (dd, 1H, J1=8.7 Hz, J2=2.5 Hz), 3.87 (s, 3H), 2.93-2.92 (d, 2H, J=7.3 Hz), 2.11-2.05 (m, 1H), 1.02-1.01 (d, 6H, J=6.7 Hz); 13C NMR (150 MHz, CDCl3) δ 184.62, 156.48, 150.72, 129.69, 126.68, 115.22, 113.59, 111.55, 102.99, 55.80, 35.46, 30.08, 22.51. Elemental analysis calculated for C14H17NO2: C, 72.70; H, 7.41; N, 6.06. Found: C, 72.62; H, 7.52; N, 5.98.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[F:19])[CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:10][CH:9]=1
Reactant: CC(=O)Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of 4-(3,4-difluorobenzyloxy)phenyl acetate (6.77 g, 24.4 mmol) in methanol (100 ml) was added potassium carbonate (3.36 g, 24.3 mmol), followed by reflux for 3 hours. After allowing to stand overnight, the reaction solution was poured into water, made acidic with hydrochloric acid and extracted with chloroform. The solvent was evaporated under reduced pressure to give the title compound (5.68 g), which was used for the following reaction without purification.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][C:19]2[S:23][CH:22]=[N:21][CH:20]=2)[CH:5]=1.Cl.O>O1CCOCC1>[CH2:12]([CH:11]([N:10]1[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:25])=[CH:5][C:6]=2[N:16]=[C:17]1[CH2:18][C:19]1[S:23][CH:22]=[N:21][CH:20]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1cncs1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)n1c(Cc2cncs2)nc2cc(C(=O)O)ccc21
Temperature: 130 °C
Yield: 76.2 %

Procedure:
To 2.16 g of 4-(1-Ethyl-propylamino)-3-(2-thiazol-5-yl-acetylamino)-benzoic acid methyl ester were added 15 ml of 4M hydrochloric acid in dioxane. The reaction was divided in three portions and each was heated at 130° C. in a microwave reactor for 15 min. 2 ml of water were added to each vial and the reaction mixtures were heated to 140° C. for 15 min. The combined reaction mixtures were concentrated and the residue purified by chromatography (silica, ethyl acetate/heptane) to yield 1.50 g (77%) of 1-(1-Ethyl-propyl)-2-thiazol-5-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=[CH:5][N:4]=1.Cl[C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: FC(F)(F)c1ncc(Cl)cn1
Product: COc1cc(-c2cnc(C(F)(F)F)nc2)ccn1
Yield: 46.1 %

Procedure:
2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 13 mmol) were reacted according to the procedure of Example 3 (step a) to provide the title compound (1.0 g, 46%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 2H), 8.35 (d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6 Hz, 1H), 6.98 (d, J=1.6 Hz, 1H), 4.02 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:34])[O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si](C(C)(C)C)(C)C)=[CH:14][C:13]=2[O:26][Si](C(C)(C)C)(C)C)[CH2:8][CH2:7]1)[CH3:2].[F-]>CO>[CH2:1]([NH:3][C:4](=[O:34])[O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[OH:26])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCNC(=O)O[C@H]1CC[C@H](c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Agent: [F-]
Solvent: CO
Product: CCNC(=O)O[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl ethylcarbamate (18 mg), methanol (10 ml) and Amberlyst fluoride resin (0.3 g) were stirred at room temperature for 24 hr. The reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:3 v/v) to give the title compound as a white solid (24 mg, 87%). δH(CD3OD) 1.10 (3H, t), 1.40-1.60 (4H, m), 1.80-1.90 (2H, m), 2.00-2.10 (2H, m), 2.72-2.80 (1H, m), 3.10 (2H, t), 4.50-4.60 (1H, m), 6.20-6.26 (2H, m), 6.88 (1H, d); m/z (ES+) 280 (M+H)+.
Reaction SMILES: [CH:1]([N:3]([O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[C@@H:4]([CH3:33])[C@@H:5]([CH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)[C:6](OC1C(F)=C(F)C(F)=C(F)C=1F)=[O:7])=[O:2].[S:41]1[CH:45]=[CH:44][N:43]=[C:42]1[NH:46][C:47](=[O:54])[C@@H:48]([NH2:53])[C:49]([CH3:52])([CH3:51])[CH3:50].C1C=CC2N(O)N=NC=2C=1.CCOC(C)=O>CN(C=O)C>[CH3:52][C:49]([CH3:51])([CH3:50])[C@H:48]([NH:53][C:6](=[O:7])[C@H:5]([CH2:20][CH:21]1[CH2:22][CH2:23][CH:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][CH2:26]1)[C@@H:4]([N:3]([CH:1]=[O:2])[O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[CH3:33])[C:47](=[O:54])[NH:46][C:42]1[S:41][CH:45]=[CH:44][N:43]=1
Reactant: CC(C)(C)[C@H](N)C(=O)Nc1nccs1
Reactant: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)Oc1c(F)c(F)c(F)c(F)c1F)N(C=O)OC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]([C@@H](CC1CCC(c2ccccc2)CC1)C(=O)N[C@H](C(=O)Nc1nccs1)C(C)(C)C)N(C=O)OC1CCCCO1
Temperature: 41 °C
Yield: 45.5 %

Procedure:
A mixture of pentafluorophenyl (2R,3S)-3-(formyl-2-tetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoate (0.25 g, 0.44 mmol), (2S)-2-amino-3,3-dimethylbutanoic acid 1,3-thiazol-2-ylamide (0.10 g, 0.49 mmol), HOBt (6.1 mg, 0.040 mmol) and TEA (0.07 g, 0.67 mmol) in DMF (3 mL) is heated at 41° C. for 18 h. The reaction mixture is poured into a mixture of hexanes (100 mL) and EtOAc (100 mL) and the resulting mixture is washed with water, 1 M aqueous sodium carbonate and water. The organic phase is dried (sodium sulfate) and concentrated in vacuo and the residue is purified by column chromatography on silica gel with EtOAc-hexanes (1:1) as eluent to give 0.12 g (46%) of (2R,3S)-3-(formyltetrahydropyranyloxyamino)-2-(4-phenylcyclohexylmethyl)butanoic acid [(1S)-2,2-dimethyl-1-(1,3-thiazol-2-ylcarbamoyl)-1-propyl]amide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Li]CCCC.O1CCCC1.[CH:21]([N:24]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[C:25](=[O:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[O:31])=[CH:28][CH:27]=1)([CH3:23])[CH3:22]>C(OCC)C.C1COCC1.C(OCC)C>[CH:35]1([N:24]([CH:21]([CH3:23])[CH3:22])[C:25](=[O:34])[C:26]2[CH:27]=[CH:28][C:29]([CH:30]([OH:31])[C:2]3[CH:7]=[CH:6][C:5]4[O:8][CH2:9][O:10][C:4]=4[CH:3]=3)=[CH:32][CH:33]=2)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)N(C(=O)c1ccc(C=O)cc1)C1CCCCC1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)N(C(=O)c1ccc(C(O)c2ccc3c(c2)OCO3)cc1)C1CCCCC1
Temperature: -20 °C

Procedure:
To a stirred solution of 4-bromo-1,2-(methylenedioxy)benzene (1.00 g, 6.0 mmol) in ethyl ether (30 mL) at 0° under an argon atmosphere is added n-BuLi (3.75 mL of 1.6 M solution in hexane). Tetrahydrofuran (10 mL) is added. The reaction mixture is cooled to -20° C. and a solution of terephthalaldehydic acid N-isopropyl-N-cyclohexyl amide (0.82 g, 3.0 mmol) in THF: ethyl ether (4:3, 35 mL) is added rapidly. The reaction is followed by thin layer chromatography until complete. The reaction is quenched at -15° C. by adding water (50 mL) and 1N HCl(20 mL). The reaction is further diluted with water (300 mL) and extracted three times with EtOAc (50 mL portions). The combined extracts are washed twice with saturated NaCl solution and dried (MgSO4). The drying agent is filtered and the filtrate concentrated in vacuo to give the crude product. The crude product is chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:37])=[O:36]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H]1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
To a solution of 1,1-dimethylethyl(2S)-2-methyl-1-piperazinecarboxylate (1.18 g, 4.98 mmol) in dichloromethane (40 ml) was added DIPEA (2.70 ml, 15.45 mmol) and then 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (1.613 g, 4.98 mmol). The reaction mixture was stirred for 1 h 20 min at room temperature, and then washed with water (50 ml), dried on a phase separation cartridge and concentrated under vacuum to give the crude title compound (2.5 g) used directly in the next step.
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:13]=[N-:14]>>[ClH:1].[C:18]1([CH:17]=[CH:16][CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [N-]=[N+]=NCC=Cc1ccccc1
Reactant: C#CCCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(CCc2cn(CC=Cc3ccccc3)nn2)c[nH]1
Yield: 39 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g, 0.383 mmol) was reacted with (3-azido-propenyl)-benzene, which was synthesized using previously reported methods (Rad et al., Tetrahedron Letters 2007, 48, 3445-3449), (0.079 g, 0.460 mmol) following the general procedure for click reactions outlined above to produce 4-{2-[1-(3-Phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-ethyl}-1H-imidazol-2-ylamine hydrochloride (0.049 g, 39%) of a pale yellow oil. 1H NMR (300 MHz, CD3OD) δ 8.19 (s, 1H), δ 7.44 (d, 2H), δ 7.29 (m, 3H), δ 6.73 (d, 1H), δ 6.53 (s, 1H), δ 6.42 (m, 2H), δ 5.24 (d, 2H), δ 3.07 (t, 2H), δ 2.88 (t, 2H) ppm; 13C 148.6, 145.3, 139.4, 139.2, 129.8, 129.7, 129.6, 128.5, 128.4, 127.6, 54.6, 47.3, 45.9, 26.3, 22.6 ppm; HRMS (ESI) calcd for C16H19N6 (M+) 295.1665. Found 295.1670.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28]N(C)P(=O)(N(C)C)N(C)C.[H-].[Na+].IC>CC1C=CC=CC=1>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][C:11]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)([C:14]([O:16][CH3:28])=[O:15])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: O=C(O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: Cc1ccccc1
Product: COC(=O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 78 parts of 1-(phenylmethyl)-4-[3-(trifluoromethyl)phenylamino]-4-piperidinecarboxylic acid in 470 parts of dry hexamethylphosphoric triamide are added portionwise 6.3 parts of sodium hydride dispersion 78% (slightly exothermic reaction). After stirring for one hour at room temperature, 29.3 parts of iodomethane are added dropwise. Upon completion, stirring is continued overnight at room temperature. Methylbenzene is added and the whole is washed with water. The organic phase is separated, washed with a sodium hydroxide solution 10% and with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 3% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the hydrochloride salt in 1,1'-oxybisethane and 2-propanol. After stirring vigorously, the salt is filtered off and crystallized twice from 4-methyl-2-pentanone, yielding methyl 1-(phenylmethyl)-4-[3-(trifluoromethyl)phenylamino]-4-piperidinecarboxylate; mp. 120.4° C.
Reaction SMILES: [CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[CH2:25]([C@H]1N(C(=O)C2C=CC(OC)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:25])[C:4]1=[O:24])[CH3:2]
Reactant: CC[C@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(OC)cc1
Product: CC[C@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Yield: 83 %

Procedure:
(3S)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 6) was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3S)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (83%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCC(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(CCC(=O)OCc2ccccc2)cc1

Procedure:
3-(4-tert-Butoxycarbonylmethoxy-phenyl)-propionic acid benzyl ester (step 1) (10 g, 27 mmol) in DCM (100 ml) was treated with TFA (20 ml) and heated at reflux for 4 h. The resulting mixture was concentrated in vacuo. The residue was dissolved in DCM and concentrated in vacuo a further four times until a viscous oil of the title compound was obtained.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:21]([C:25]1[CH:49]=[CH:48][C:28]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:33]=2[CH3:47])=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:21]([C:25]1[CH:49]=[CH:48][C:28]([C:29]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([F:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:33]=2[CH3:47])=[O:30])=[CH:27][CH:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cn1cc(Br)nc(Nc2ccc(F)c([N+](=O)[O-])c2)c1=O
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1B1OC(C)(C)C(C)(C)O1
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
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(F)c([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A mixture of 5-bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one (1) (8.8 g; 25.7 mmol), 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (11.1 g; 28.3 mmol), tetrakis(triphenylphosphine)palladium (1.48 g; 1.28 mmol), 1N sodium carbonate (77 mL; 77 mmol), and 1,2-dimethoxyethane (100 mL) was heated at 100 degrees in a sealed pressure vessel for 16 hr. The mixture was cooled to room temperature, filtered, and the residue washed with water (3×60 mL). The solid was slurried with ethyl acetate for 1 hr, filtered, and washed with diethyl ether to give 4-tert-butyl-N-{3-[6-(4-fluoro-3-nitro-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (2) as a dull yellow solid (13 g).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1F)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][Cl:2])([O-:11])=[O:10]
Reactant: ClCc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2ccnc2CCl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Chloromethyl)imidazole hydrochloride (920 mg) was dissolved in 5 ml of acetonitrile. To this solution was added 830 μL of 2,4-dinitrofluorobenzene and 2.5 g of potassium carbonate. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried (sodium sulfate) and concentrated. The crude reaction product was purified by flash silica gel chromatography (1:1 ethyl acetate-hexane elution) to give 710 mg of the title compound as a yellow solid.