Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:20][C:21](=[O:23])[CH3:22].O>CN(C)C=O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:20][C:21](=[O:23])[CH3:22])[C:10]3[C:11]([N:16]=2)=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (2.29 g, 0.01 mole), was added to a suspension of sodium hydride (0.44 g of 60% of sodium hydride/oil, 0.01 mole, washed one with hexanes) in 50 ml of dimethylformamide. The mixture was heated to 70° C. for 1 hr before the addition of chloroacetone (0.93 g, 0.01 mole) at room temperature. The reaction mixture was stirred at room temperature overnight, then poured into 300 ml of water. The precipitate was collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight. The solid was recrystallized from methanol-water and dried under high vacuum at 50° C. overnight. The solid was dissolved in methanol, treated with charcoal, and filtered through Celite to give a pale yellow filtrate. The filtrate was concentrated and diluted with water to initiate crystallization. The precipitate was collected by filtration, washed with water, and dried under high vacuum overnight. The solid was dissolved in isopropyl alcohol, acidified with ethereal hydrogen chloride, diluted with isopropyl ether, and seeded to initiate crystallization. The crystalline solid was collected by filtration, washed with isopropyl ether, and dried under high vacuum overnight to give 1.6 g, (50%), m.p. 220°-22° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:11]1)=[O:4].Cl[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[C:26]([CH3:34])[CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:17][CH:16]=2)[CH2:11]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1C1CC(c2ccc(O)cc2)=NO1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: COC(=O)[C@@H]1CCC[C@@H]1C1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1
Temperature: 50 °C
Yield: 42.7 %

Procedure:
The product from step 28a (0.31 g, 1.1 mmol) was combined with 4-chloromethyl-2-methylquinoline (0.20 g, 1.0 mmol), potassium carbonate (0.22 g, 1.6 mmol) and potassium iodide (0.05 g, 0.3 mmol) in acetontrile (5 mL) under a nitrogen atmosphere and heated to 50° C. for 18 h. The reaction was filtered, concentrated, and purified by FCC on silica gel eluting ethyl an acetate:hexanes gradient to give cis-2-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-cyclopentanecarboxylic acid methyl ester (0.19 g, 47%) as an oil. MS found: (M+H)+=445.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([CH3:12])[CH:6]=[CH:5][N:4]=1.CO[C:15](OC)(N(C)C)[CH3:16]>>[CH3:15][C:16]1[NH:9][C:8]2[C:7]([CH:12]=1)=[CH:6][CH:5]=[N:4][C:3]=2[O:2][CH3:1]
Reactant: COC(C)(OC)N(C)C
Reactant: COc1nccc(C)c1[N+](=O)[O-]
Product: COc1nccc2cc(C)[nH]c12
Reaction time: 18 h
Yield: 57 %

Procedure:
2-Methoxy-3-nitro-4-methyl pyridine (200 mg, 1.2 mmol) and dimethylacetamide dimethylacetal (0.5 mL) were heated at 130° C. for 18 h. The reaction mixture was cooled and concentrated in vacuo to a deep purple-red oil. Benzene (4 mL) and 10% Pd/C (25 mg) were added and the solution hydrogenated at 45 psi for 18 h (Parr apparatus). The red coloration disappeared. The crude reaction mixture was purified directly by silica gel chromatography (20% EtOAc/hex) to furnish 2-methyl-7-methoxy-6-azaindole (112 mg, 57% yield). LC-MS 163.1, M+H.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:19]4[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=4[N:13]([CH3:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH2:29][C:30](O)=[O:31])[CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH2:29][C:30]([N:2]2[C:10]3[C:5](=[CH:6][C:7]([C:11]4[C:19]5[C:18]([NH2:20])=[N:17][CH:16]=[N:15][C:14]=5[N:13]([CH3:21])[CH:12]=4)=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:31])[CH:28]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(Cl)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(Cl)ccc2F)c2c(N)ncnc21
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine HCl (70 mg, 0.232 mmol), (5-chloro-2-fluorophenyl)acetic acid (44.2 mg, 0.234 mmol), and HATU (89 mg, 0.234 mmol) in DMF (2 mL) was added Hunig's base (0.162 mL, 0.928 mmol). The mixture was stirred overnight. The reaction was poured into water (100 mL), and an off-white solid was formed. The solid was filtered, washed with water (10 mL), and dried to afford the title compound as an off-white solid. LC-MS (ES) m/z=436.4 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.22-3.30 (m, 2H), 3.74 (s, 3H), 3.96 (s, 2H), 4.25-4.32 (m, 2H), 7.21-7.28 (m, 2H), 7.30 (s, 1H), 7.33 (s, 1H), 7.39-7.44 (m, 1H), 7.47 (dd, J=6.32, 2.78 Hz, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7]([OH:14])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[Pd]>[CH2:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:2][CH2:3][O:14][CH2:7][CH3:8]
Reactant: OCC(O)CO
Reactant: CCCCCC(=O)O
Agent: [Pd]
Product: CCCCCCOCC(O)CO
Product: CCOCC
Temperature: 120 °C
Yield: 70 %

Procedure:
A stirred autoclave was charged, at room temperature, with 66.75 g (725 mmol) of glycerol, 2.05 g (17.6 mmol) of caproic acid, 0.20 g (10 wt %) of AMBERLYST® (a polymer based catalyst) 35 resin and 0.39 g (1.0 mol %) of Pd/C at 5%. The autoclave was then pressurized at 50 bar of dihydrogen gas H2, and then it was heated at 120° C. for 16 h, stirring vigorously. After 16 h of reaction, the reaction mixture was brought back to room temperature. The catalyst was then filtered on a MILLIPORE® filter (a membrane filter) (0.45 μm) and was rinsed with absolute ethanol. The solvents were then evaporated and the organic products were extracted from the glycerol phase by extraction with CH2Cl2 (3×50 ml). The organic phase was washed with water (2×20 ml) and the CH2Cl2 was then evaporated at reduced pressure. The crude reaction product was purified on a flash silica column (eluent:cyclohexane/ethyl acetate=4:1˜1:1). 1-O-hexyl-glycerol ether was obtained at an isolated yield of 70%.
Reaction SMILES: C1(C)C=CC=CC=1[C:7]1[CH:8]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3C=CC=CC=3C)[CH:15]=2)[CH:10]=[CH:11][CH:12]=1.O(C1C=C(C=CC=1)C[Br:39])C1C=CC=CC=1.[CH2:43]([N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])[CH3:44]>C1(C)C=CC=CC=1>[Br-:39].[O:13]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][N+:45]([CH2:48][CH3:49])([CH2:46][CH3:47])[CH2:43][CH3:44])[C:9]1[CH:8]=[CH:7][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1-c1cccc(Oc2cccc(-c3ccccc3C)c2)c1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC[N+](CC)(CC)Cc1cccc(Oc2ccccc2)c1
Product: [Br-]

Procedure:
37.5 g of the brominated product of m-tolylphenyl ether containing 26.3 g of 3-phenoxybenzyl bromide was mixed with 100 ml of toluene, and then a solution of 15.1 g of triethylamine in 30 ml of toluene was added dropwise thereto. After the additon, the mixture was maintained at 90° to 100°C for 1 hour while stirring and then cooled. The separated crystals were filtered out, washed with toluene and then dried under a reduced pressure to obtain 35.8 g of 3-phenoxybenzyl triethyl ammonium bromide (m.p. 160° - 163°C).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([OH:11])[C:5]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[C:4]([O:24][CH2:25][CH2:26][Cl:27])[C:3]=1[C:28](=[O:30])[CH3:29].O.O.Cl[Sn]Cl.[CH3:36][CH2:37]O>>[C:28]([C:3]1[C:4]([O:24][CH2:25][CH2:26][Cl:27])=[C:5]([O:12][CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])[C:6]2[O:11][C:36]([CH3:37])=[N:8][C:7]=2[C:2]=1[Cl:1])(=[O:30])[CH3:29]
Reactant: CCO
Reactant: CC(=O)c1c(Cl)c([N+](=O)[O-])c(O)c(OCCC(C)c2ccc(F)cc2)c1OCCCl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(=O)c1c(OCCCl)c(OCCC(C)c2ccc(F)cc2)c2oc(C)nc2c1Cl
Temperature: 50 °C
Yield: 64 %

Procedure:
To a stirred solution 38f) (242 mg, 0.52 mmol) in dry EtOH (10 mL) under nitrogen was added SnCl2.2H2O (1.11 g, 4.92 mmol). The solution was heated at reflux for 4 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc (10 mL) and treated with sodium potassium tartrate (1M, 10 mL). The mixture was warmed at 50° C. until the layers visibly separated. The organic layer was separated and the aqueous further extracted with EtOAc (2×5 mL). The organics were pooled, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was taken up in dry DMF (5 mL) and to this was added triethyl orthoacetate (5 mL, excess). The solution was stirred at reflux for 1 h. The solution was concentrated in vacuo and the residue was taken in CH2Cl2 (5 mL) and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate/petroleum spirit 2:8) to give the title compound (151 mg, 64%). 1H NMR (300 MHz, CDCl3) δ 7.21-7.16 (m, 2H), 7.02-6.96 (m, 2H), 4.36-4.19 (m, 4H), 3.74-3.71 (m, 2H), 3.30-3.11 (m, 1H), 2.62 (s, 3H), 2.58 (s, 3H) 2.16-1.97 (m, 2H), 1.34-1.31 (d, J=7.0 Hz, 3H), ESIMS m/z [M+H]+ 454.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[CH:4][CH:3]=1.[I:16]N1C(=O)CCC1=O>C(O)(=O)C.ClCCl.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][C:5]([OH:15])=[C:4]([I:16])[CH:3]=1
Reactant: Oc1ccc(Cl)c(-c2ccc(F)cc2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1cc(-c2ccc(F)cc2)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
To a solution of 6-chloro-4′-fluorobiphenyl-3-ol (Preparation 104, 280 mg, 1.26 mmol) in acetic acid (2.5 mL), dichloromethane (2.5 mL) and concentrated sulfuric acid (25 μL) was added N-iodosuccinimide (272 mg, 1.21 mmol) at room temperature. The reaction mixture was stirred for 18 hours at room temperature. Dichloromethane (60 mL) was added and the organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated. The residue was purified by silica gel chromatography eluting 33% dichloromethane in heptane to afford the title compound (306 mg, 70%) as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[Cl-].[CH3:21][O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH2:5][N:6]([C:25](=[O:26])[CH2:24][C:23]([O:22][CH3:21])=[O:28])[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)O
Reactant: COC(=O)CCNCC(=O)OC
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCN(CC(=O)OC)C(=O)CC(=O)OC

Procedure:
Analogously to the procedure described in Example 1(a), from 35.0 g (0.2 mol) of N-(methoxycarbonylmethyl)-β-aminopropionic acid methyl ester, 33 ml (0.24 mol) of triethylamine and 36.2 g (0.24 mol) of malonic acid monomethyl ester chloride in 60 ml of methylene chloride there is obtained N-methoxycarbonylacetyl-N-methoxycarbonylmethyl-β-aminopropionic acid methyl ester in the form of a yellowish oil.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:34][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([C:30](OC)=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2.[NH2:35][NH2:36]>CO>[O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:34][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([C:30]([NH:35][NH2:36])=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2
Reactant: COC(=O)c1ccc2nc3c(cc2c1)C[C@@]1(C3)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Reactant: NN
Solvent: CO
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4cc(C(=O)NN)ccc4nc3C2)c2cccnc21
Temperature: 70 °C

Procedure:
To a solution of methyl (2S)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′, 3-tetrahydrospiro[cyclopenta[b]quinoline-2,3′-pyrrolo[2,3-b]pyridine]-7-carboxylate from Step G (317 mg, 0.667 mmol) in MeOH (1 mL) was added hydrazine (1.0 mL, 32 mmol). The reaction was sealed and then heated to 70° C. for 18 hours. After cooling to ambient temperature, the bulk of the solvent was removed in vacuo. The residue was diluted with DCM (50 mL) and water (20 mL). The organics were then successively washed with water, half-saturated brine and brine before being dried over sodium sulfate. The organics were then filtered, concentrated in vacuo to give the title compound. MS: m/z=476 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12].[I:19][CH2:20]I.O>O1CCCC1>[CH3:9][O:10][C:11]([C:13]1([CH2:20][I:19])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[O:12]
Reactant: COC(=O)C1CCOCC1
Reactant: ICI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CI)CCOCC1
Temperature: 25 °C
Yield: 53 %

Procedure:
Lithium diisopropylamide (10.9 ml of 2.0M solution in heptane/tetrahydrofuran/ethylbenzene) was added to a stirred solution of tetrahydro-pyran-4-carboxylic acid methyl ester (3.00 g) in tetrahydrofuran (50 ml) at 0° C. under an atmosphere of nitrogen. The mixture was stirred for 30 minutes before dropwise addition of diiodomethane (2.51 ml). Stirring was continued for a further hour during which it warmed to room temperature. The reaction was poured into water (50 ml) and then extracted with diethyl ether (3×40 ml). The combined organics were washed with water (2×20 ml), 2M hydrochloric acid (20 ml), water (20 ml) and brine (20 ml). After drying (MgSO4), filtering and evaporating under reduced pressure a yellow oil was obtained which was purified by column chromatography eluting with 3:1 hexane/diethyl ether to give the title compound as a colourless oil (3.11 g, 53%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][C:10](/[CH:13]=[C:14]2\[CH2:15][N:16]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18][CH:19]\2O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C(N(CC)CC)C.[C:52]([O-:55])(=[S:54])[CH3:53].[K+]>ClCCl.O>[C:52]([S:54][CH:19]1[CH2:18][CH2:17][N:16]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:15]/[C:14]/1=[CH:13]\[C:10]1[CH:11]=[CH:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[N:9]=1)(=[O:55])[CH3:53]
Reactant: CC(C)(C)OC(=O)n1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)n1
Reactant: CC([O-])=S
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccn(C(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (15.0 g) in dichloromethane (300 ml) were added successively methanesulfonyl chloride (2.5 ml) and triethylamine (4.5 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour and then evaporated in vacuo. Subsequently, to a solution of the residue thus obtained in dimethyl sulfoxide (200 ml) was added potassium thioacetate (16.5 g) at room temperature, and the resulting mixture was stirred at 50° C. for 30 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane and dichloromethane (1:8:1) as the eluent to afford (E)-4-(acetylsulfanyl)-3-{[1-(t-butoxycarbonyl)-1H-pyrazol-3-yl]methylidene}-1-(triphenylmethyl) piperidine (including impurities) as a yellow amorphous solid.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)O)C(=O)CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of (3RS)-3-[N-((1-naphthyloxy)acetyl)valinyl]amino-5-fluoro-4-oxopentanoic acid, tert-butyl ester (0.113 g, 0.23 mmol) in CH2Cl2(2.0 mL)-anisole(0.5 mL) at room temperature under nitrogen was added trifluoroacetic acid (1.0 mL). The resulting clear solution was stirred at room temperature for 1 hr, evaporated to dryness and chased with toluene-CH2Cl2 (1:1). The residue was purified by flash chromatography on silica gel eluting with AcOH-MeOH-CH2Cl2 (0.5:2:100) to give the title compound (0.069 g, 69%) as a white solid. TLC(AcOH-MeOH-CH2Cl2; 1:1:20) Rf=0.38. MS(ES) for C22H25FN2O6 (MW 432.45): positive 433(M+NH); negative 431(M−H). 1H NMR (CD3OD): δ 8.32–8.29 (m, 1H), 7.82–7.79 (m, 1H), 7.49–7.46 (m, 3H), 7.38–7.32 (m, 1H), 6.88 (d, 1H, J=7.7 Hz), 4.78–4.73 (m, 2H), 4.55–4.26 (m, 2H), 2.82–2.76 (m, 2H), 2.16–2.03 (m, 1H), 0.94–0.85 (m, 6H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].S(Cl)([Cl:21])(=O)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:21][C:10]1[CH:11]=[C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:7]=[CH:8][C:9]=1[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCc1ccc(CNC(C)=O)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)CCc1ccc(CNC(C)=O)cc1Cl

Procedure:
Methyl 3-(4-acetylaminomethylphenyl)propionate (5.00 g, 21.25 mmol) was added to a sulfuryl chloride (85 ml) solution of anhydrous aluminum chloride (14.2 g, 106 mmol) at -25° C. Thereafter, the temperature of the mixture was gradually elevated to 5° C., at which temperature the mixture was subjected to reaction under agitation for 24 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=N1.[I:19]I>>[I:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: c1ccc2[nH]ccc2c1
Agent: c1ccc2[nH]ncc2c1
Product: Ic1c[nH]c2ccccc12

Procedure:
Compounds of formula VIII may also be prepared directly from an indole or indazole of formula XVII by reacting the formula XVII substrate with iodine to give the 3-iodoindole or -indazole of formula XVIII; coupling the formula XVIII compound with an appropriate thiol of formula XIX to give the 3-thioindole or -indazole of formula XX and oxidizing said formula XX compound with a conventional oxidizing agent such as H2O2, m-chloroperbenzoic acid, or the like to afford the desired formula VIII intermediate. The reaction is shown in flow diagram IV.
Reaction SMILES: [OH:1][C@@H:2]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])/[CH:3]=[CH:4]/[C@H:5]1[C@H:12]([O:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:11][C@H:10]2[C@@H:6]1[CH2:7][C:8](=[O:28])[O:9]2.[O:36]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[C:21]1([C:18]2[CH:17]=[CH:16][C:15]([C:14]([O:13][C@@H:12]3[CH2:11][C@H:10]4[C@H:6]([CH2:7][C:8](=[O:28])[O:9]4)[C@H:5]3/[CH:4]=[CH:3]/[C@@H:2]([O:1][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:27])=[CH:20][CH:19]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1
Reactant: C1=COCCC1
Solvent: ClCCl
Product: CCCCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccc(-c2ccccc2)cc1)OC1CCCCO1

Procedure:
The 3S-hydroxy compound (4a) (4.58 g) was dissolved into methylene chloride (100 ml), and reacted with dihydropyran in the presence of a catalytic amount of p-toluenesulfonic acid-1H2O. After a usual work-up, the reaction mixture was column-chromatographed to give the title compound (5). Yield: 5.03 g.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[NH:35]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2].[CH:45]1([CH:48]=O)[CH2:47][CH2:46]1>>[C:1]([NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[N:20]=[CH:19][N:18]=[C:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=4[NH:31][C:32]([C@@H:34]4[CH2:38][CH2:37][C@H:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[N:35]4[CH2:48][CH:45]4[CH2:47][CH2:46]4)=[O:33])[CH:16]=3)[C:8]=2[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4)ncn3)cccc2s1
Reactant: O=CC1CC1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NC(=O)[C@@H]4CC[C@H](c5ccccc5)N4CC4CC4)ncn3)cccc2s1

Procedure:
(2S,5R)-N-(2-(6-(2-Acetamidobenzo[d]thiazol-4-yloxy)pyrimidin-4-yl)-5-(trifluoromethyl)phenyl)-5-phenylpyrrolidine-2-carboxamide, Example 60, (62 mg, 0.1 mmol) was reacted with cyclopropanecarboxaldehyde (0.009 mL, 0.12 mmol, Aldrich) under the conditions of Example 3(d) to give the title compound as a white solid. MS (ESI, pos. ion.) m/z: 673 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:13]Br>C(O)(=O)C.Br>[Br:13][CH:10]([CH3:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:12]
Reactant: CCC(=O)c1ccc(OC)cc1
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)Br)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
0.30 mol of 4′-methoxypropiophenone is dissolved in 230 ml of glacial acetic acid and mixed with 3 drops of 48% HBr solution. In the stirred mixture, 0.30 mol of bromine is now slowly added in drops while being cooled in an ice bath such that the temperature in the flask does not exceed 15° C. The ice bath is removed, and it is stirred for about another 45 minutes in a continuous nitrogen stream to remove the HBR that is produced in the reaction. Then, it is carefully poured onto 300 ml of ice water. The settled precipitate is suctioned off, washed with several portions of water to remove all bromine and dried in a desiccator overnight. The crude product is recrystallized from 96% ethanol.