Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C:23]3([C:29]([OH:31])=[O:30])[CH2:28][O:27][CH2:26][CH2:25][O:24]3)=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]([Cl:57])([Cl:56])[CH2:34][O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44](=[O:55])[C@@H:45]([NH:47][C:48](=[O:54])[C@@H:49](O)[CH:50]([CH3:52])[CH3:51])[CH3:46])[NH:39]1)=[O:37].C(N(CC)C(C)C)(C)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O>CN(C)C1C=CN=CC=1.ClCCl>[Cl:56][C:33]([Cl:32])([Cl:57])[CH2:34][O:35][C:36]([C@@H:38]1[CH2:43][CH2:42][CH2:41][N:40]([C:44](=[O:55])[C@@H:45]([NH:47][C:48](=[O:54])[C@@H:49]([O:30][C:29]([C:23]2(/[CH:22]=[CH:21]/[C:15]3[CH:14]=[C:13]4[C:18]([CH:19]=[CH:20][C:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:10])=[N:12]4)=[CH:17][CH:16]=3)[CH2:28][O:27][CH2:26][CH2:25][O:24]2)=[O:31])[CH:50]([CH3:51])[CH3:52])[CH3:46])[NH:39]1)=[O:37]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C3(C(=O)O)COCCO3)cc2n1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](OC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Yield: 55.7 %

Procedure:
A solution of 2-{(E)-2-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-vinyl}-[1,4]dioxane-2-carboxylic acid (50 mg, 0.1 mmol), [(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (44 mg, 0.1 mmol), N,N-diisopropylethylamine (32 mg, 0.043 mL, 0.25 mmol), 4-dimethylaminopyridine (6 mg, 0.05 mmol) and 2-methyl-6-nitrobenzoic anhydride (58 mg, 0.17 mmol) in dichloromethane (5 mL) was stirred at room temperature under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated ammonium chloride solution, ice-cold saturated sodium hydrogen carbonate solution and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 1:3 to afford the title compound (47 mg, 55%) as a white solid and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 842.2/844.0 [M+H], Tr=3.25 and 3.31 min.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]([N:12]1[CH2:18][CH2:17][CH2:16][CH:15]([N:19]([C:35](=[O:37])[CH3:36])[CH2:20][C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=2)[C:14]2[CH:38]=[C:39]([NH2:42])[CH:40]=[CH:41][C:13]1=2)=[O:11])([CH3:8])[CH3:7].N1C=CC=CC=1>ClCCl>[C:35]([N:19]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH:15]1[CH2:16][CH2:17][CH2:18][N:12]([C:10]([O:9][CH:6]([CH3:8])[CH3:7])=[O:11])[C:13]2[CH:41]=[CH:40][C:39]([NH:42][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][C:14]1=2)(=[O:37])[CH3:36]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(N)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
Add methanesulfonyl chloride (8 μl, 0.103 mmol) dropwise to a suspension of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-amino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.050 g, 0.094 mmol) and pyridine (8 μl, 0.103 mmol) in dichloromethane (2 mL) at 0° C. under atmosphere of nitrogen. Stir the suspension for 30 min, then remove the cooling bath and warm to room temperature while stirring overnight. Dilute the mixture with dichloromethane (30 mL) and wash with 2 N hydrochloric acid, water, and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Chromatograph the residue over silica gel, eluting with ethyl acetate/hexanes (10:1 to 1:2), to provide the title compound as a white solid (0.037 g, 65%): ESI MS 610 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].[O:50]1[CH2:54][CH2:53]OC1=O.O>CN(C=O)C>[OH:50][CH2:54][CH2:53][O:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.416 g, 0.686 mmol) obtained in Step 2 in DMF (6 mL) was added with potassium carbonate (1.42 g, 10.3 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with 1,3-dioxolan-2-one (0.725 g, 8.23 mmol), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and then added with water (60 mL), and the mixture was vigorously stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-{[6-(2-hydroxyethoxy)-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.331 g, 74%).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:40])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20](=[O:31])[CH2:21][C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:23])[N:11]=[N:10]1.O>C(Cl)Cl>[F:40][C:4]([F:3])([F:39])[C:5]1[CH:6]=[C:7]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:8][N:9]1[C:13]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([C:20](=[O:31])[CH:21]([Br:1])[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[O:23])[N:11]=[N:10]1
Reactant: O=C(CC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1ccccc1Cl
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)C(Br)C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Add bromine (28 μL, 0.54 mmol) to a mixture of 1-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-3-(2-chloro-phenyl)-propane-1,3-dione (256 mg, 0.463 mmol) in 1:1 CH2Cl2:H2O (4 mL). Stir mixture at RT for 30 min, then dilute with additional CH2Cl2 (20 mL) and wash with NaHCO3 (20 mL). Dry, filter, and concentrate the organic layer to give the title compound (287 mg, 98%). MS (IS) 553.2 (M+1), MS (ES−) 551.2 (M−1). 1HNMR (400 MHz, CDCl3): δ 7.80 (m, 1H), 8.53 (m, 1H), 7.85 (m, 2H), 7.63 (m, 1H), 7.46 (m, 7H), 7.04 (s, 1H), 5.60 (m, 2H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[C:27]#[N:28])=[C:10]([CH3:31])[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:27]([C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][C:11]1[CH:29]=[CH:30][C:8]([C:6]([OH:7])=[O:5])=[CH:9][C:10]=1[CH3:31])[O:20][CH2:19][CH2:18][CH:17]2[C:23]([O:25][CH3:26])=[O:24])#[N:28]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3C)c(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3C)c(C#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Methyl 7-(4-(tert-butoxycarbonyl)-2-methylphenoxy)-6-cyanochroman-4-carboxylate was taken up in dichloromethane (10 mL). To the solution was added 2 ml TFA and the solution was stirred at ambient temperature for 2 hours. The reaction was concentrated and the crude material was purified over silica gel, eluting with 2-3% methanol/dichloromethane, to provide the desired product (0.103 g, 89%).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH:26][C:36]([N:35]([CH3:39])[CH3:34])=[O:37])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.39 g (3 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine trihydrochloride was suspended in dichloromethane (100 ml), triethylamine (2.1 ml, 15 mmol) was added followed by 0.30 ml (3.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature, filtered. The filtrate was washed with water (2×20 ml), dried and evaporated in vacuo. Recrystallizing from methanol gave the title compound (0.83 g, 65%), melting at 212-4° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:20])[NH:10][O:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[CH:3][CH:2]=1.Cl.O1CCOCC1>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:20])[NH:10][O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CONC(=O)NCc1ccncc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O)CONC(=O)NCc1ccncc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetate (Compound V-5) (42.2 mg, 0.15 mmol) in tetrahydrofuran (1 ml) was added 4N HCl/dioxane (2 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo to obtain the title compound (34 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>C(O)C>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH2:13]2)=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CC1(C)CC(c2ccc(O)cc2)CC(C)(C)N1
Reactant: CCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOc1ccc(C2CC(C)(C)NC(C)(C)C2)cc1

Procedure:
1 Part of 4-(4-hydroxyphenyl)-2,2,6,6-tetramethylpiperidine was dissolved in warm ethanol and treated with 0.172 parts of sodium hydroxide dissolved in ethanol. The solution was stirred and heated to reflux whilst 0.65 parts of n-butyl bromide dissolved in ethanol was added. The solution was heated at reflux overnight and then evaporated under reduced pressure. The residue was dissolved in ether and washed with water, sodium hydroxide solution (3%) and further water. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was distilled to yield the desired product having b.p. 160°/0.2 mm. and the following elemental analysis:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[Cl:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in acetonitrile (15 ml) were added 4-fluoronaphthalenecarboxylic acid (144 mg, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (218 mg, 1.14 mmol) and 1-hydroxy-1H-benzotriazole (116 mg, 0.76 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (324 mg, 85%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([CH3:15])[CH2:11][C:12](O)=[O:13])=[CH:5][CH:4]=1.O.[NH2:18][NH2:19]>C(O)(C)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([CH3:15])[CH2:11][C:12](=[O:13])[NH:18][N:19]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C(=O)C(C)CC(=O)O)cc1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: CSc1ccc(C2=NNC(=O)CC2C)cc1

Procedure:
2.3 g (0.01 mole) of 4-(4-methylthio-phenyl)-4-oxo-3-methyl-butyric acid and 1 ml of hydrazine hydrate are heated under reflux in 20 ml of isopropanol for 2 hour. After the mixture has been cooled, the product is filtered off with suction and dried.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][C:10]([C@@H:19]([NH2:21])[CH3:20])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34]([NH:21][C@H:19]([C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8][N:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])[CH2:12][CH2:11]1)[CH3:20])=[O:35]
Reactant: CCCS(=O)(=O)N1CCC(c2ccccn2)([C@H](C)N)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCC(c2ccccn2)([C@H](C)NC(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {(1S)-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine (80 mg, 0.26 mmol) in DMF (0.7 mL) was treated with i-Pr2NEt (0.2 mL, 1.15 mmol) and 2,6-dichloro-benzoyl chloride (0.15 mL, 0.8 mmol) and stirred at room temperature for 30 min. The reaction mixture was purified directly by reverse phase HPLC to afford the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][N:54]1[NH:58][CH:57]=[CH:56][S:55]1>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:53][N:54]2[NH:58][CH:57]=[CH:56][S:55]2)=[O:7])=[CH:4][C:3]=1[B:11]1[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:17])([CH3:16])[O:15]1
Reactant: NN1NC=CS1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NN2NC=CS2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (2.0 g, 7.63 mmol), DIPEA (4 ml, 22.89 mmol) and HATU (3.05 g, 8.02 mmol) were dissolved in DMF (20 ml) and stirred at room temperature for 15 mins. 2-Aminothiadiazole (810 mg, 8.01 mmol) was added and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the reaction partitioned between ethyl acetate (250 ml) and hydrochloric acid (2N, 150 ml). The aqueous was extracted with ethylacetate (2×250 ml). The combined organic extracts were dried (magnesium sulphate) and the solvent evaporated under vacuum. The residue was absorbed onto silica and purified by flash column chromatography eluting with cyclohexane/ethyl acetate (4:1 then 1:1). The solvent was evaporated from the product fractions under vacuum to 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiadiazol-2-yl)-benzamide (0.95 g). LCMS: retention time 3.34 min, MH− 346. NMR: δH [2H6]-DMSO 13.08, (1H, b), 9.22, (1H, s), 8.35, (1H, d), 8.11, (1H, dd), 7.38, (1H, d), 2.55, (3H, s), 1.34, (12H, s).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](C)(C)Cl.[CH3:25][CH:26]([CH:28]([Cl:33])[O:29][C:30](Cl)=[O:31])[CH3:27]>ClCCl>[Cl:33][CH:28]([O:29][C:30]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:31])[CH:26]([CH3:27])[CH3:25]
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: CC(C)C(Cl)OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.33 h
Yield: 77.5 %

Procedure:
To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol) and the resulting mixture was stirred until clear (about 20 min). A solution containing 1-chloro-2-methylpropylchloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was then added at 0° C. and stirred at room temperature for 60 min. The reaction mixture was washed with 10% citric acid (30 mL) and the organic layer separated. The aqueous layer was further extracted with ether (3×20 mL) and the combined organic phases were dried over MgSO4 and then concentrated in vacuo. Chromatography of the residue on silica gel, eluting with hexane:ethyl acetate (1:4) gave 2.37 g (77%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.04 (d, J=6.4 Hz, 3H), 1.06 (d, J=6.4 Hz, 3H), 1.36-1.53 (m, 10H), 2.15 (m, 1H), 2.34 (s, 2H), 3.24 (m, 2H), 5.39 (t, 1H), 6.32 (d, J=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:18][C:17]1[CH:12]=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=1)=[O:5]
Reactant: Cc1ccc(O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(OC(=O)c2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
2,6-Dichlorobenzoyl chloride (2.14 g) was added to a solution of p-cresol (1.08 g) and triethylamine (1.11 g) in dichloromethane (30 ml) dropwise at 4° C. The mixture was stirred at ambient temperature overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo to give 4-methylphenyl 2,6-dichlorobenzoate (2.73 g) as an oil. NMR (CDCl3, δ): 2.38 (3H, s), 7.17 (2H, d, J=8 Hz), 7.25 (2H, d, J=7 Hz), 7.30-7.45 (3H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[CH2:12][CH3:13].C(N(CC)C(C)C)(C)C.[NH2:27][C@@H:28]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[C:48]([F:51])([F:50])[F:49])[CH2:29][N:30]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]1=[O:40].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:27][C@@H:28]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]([F:51])([F:49])[F:50])[CH2:29][N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])=[O:16])[S:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (200 mg, 0.74 mmol), N,N-diisopropylethylamine (0.64 ml, 3.69 mmol) and 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (284 mg, 0.74 mmol) [prepared according to Preparation 6] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (414 mg, 0.886 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-thiophenecarboxamide (316 mg, 0.526 mmol, 71% yield) as a white foam: LCMS (ES) m/e 601, 603 (M, M+2)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]([CH3:12])[OH:11])=[C:4]([F:13])[CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10](=[O:11])[CH3:12])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(C)O)c(F)cc1Cl
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)c(F)cc1Cl
Reaction time: 2 h
Yield: 90.3 %

Procedure:
A stirred solution of 10.4 g of 4-chloro-2-fluoro-5-methoxybenzaldehYde in 150 mL of anhydrous THF was cooled in a dry ice-acetone bath and treated with 35 mL of a 3M solution of methyl magnesium chloride in THF over a period of one minute. The ice bath was removed and the mixture allowed to warm to room temperature. After warming, the solution was slowly poured into ice water. The water slurry was extracted three times with diethyl ether, the ether extracts dried and concd to afford a crude oil. Crystallization from hexanes yielded 10.8 g (95.6%) of 4-chloro-2-fluoro-5-methoxy-α-methylbenzenemethanol: mp 68.5°-69.5° C. This benzenemethanol intermediate was dissolved in 100 mL of acetone, cooled in an ice water bath and treated dropwise with 50 mL of freshly prepared Jones' reagent (prepared from 6.7 g of CrO3, 6 mL of H2SO4 and 50 mL of water), keeping the temperature below 10° C. After stirring for 2 hrs, the solution was diluted with water and extracted three times with methylene chloride. The organic extracts were dried and concd to give a crude product. Recrystallization from methanol yielded 9.66 g (90.3%) of 1-(4-chloro-2-fluoro-5-methoxyphenyl)ethanone as a white solid: mp 96.5°-98.5° C.; 1HNMR (CDCl3) δ2.50 (d, 3H, 5.4 Hz), 3.80 (s, 3H), 7.10 (d, 1H, 10.1 Hz), 7.30 (d, 1H, 6.3 Hz).