Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5]([O:8]C)[O:4]1.Cl.Cl[C:12]1[CH:17]=[CH:16][N:15]=[CH:14]C=1.NC1[CH:27]=[C:26]([Cl:28])[CH:25]=CC=1C(O)=O>O1CCOCC1>[Cl:28][C:26]1[CH:25]=[CH:3][C:7]([N:15]2[CH:14]=[CH:12][CH:17]=[CH:16]2)=[C:6]([CH:27]=1)[C:5]([OH:8])=[O:4]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: COC1CCC(OC)O1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)ccc1-n1cccc1
Yield: 95 %

Procedure:
18.6 ml (0.143 mol) of 2,5-dimethoxytetrahydrofuran are stirred for 10 minutes with 21.5 g (0.143 mol) of 4-chloropyridine hydrochloride in 600 ml of 1,4-dioxane. 24.6 g (0.143 mol) of 2-amino-4-chlorobenzoic acid are added, and the mixture is heated at reflux for 4 hours. After removal of the dioxane under reduced pressure, the residue is taken up with 1 liter of water and extracted with 800 ml of diethyl ether. The ethereal phase is washed with water and then extracted with 500 ml of a saturated aqueous sodium hydrogen carbonate solution. The aqueous phase is acidified with 10N hydrochloric acid and then extracted with 800 ml of diethyl ether. The ethereal phase is washed with water, decanted off, dried over magnesium sulfate, rendered colourless with animal charcoal and concentrated under reduced pressure to yield the title compound in the form of a grey powder.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](OC=C)(=O)[CH3:11]>[Pd]>[C:1]([O:9][CH:10]=[CH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C=COC(C)=O
Agent: [Pd]
Product: C=COC(=O)c1ccccc1

Procedure:
Analogously to the procedure described in Example I, 0.28 g of the polymer prepared according to Example 15 and having a palladium content of 19.7% by weight are warmed with 12.2 g of benzoic acid and 55.4 ml of vinyl acetate. In the first reaction run, 76% of theory of vinyl benzoate are isolated after 22 hours. In a further reaction batch with the same polymer, 76% of theory of vinyl benzoate are obtained after 20 hours.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](O)=[CH:16][CH:15]=1>>[ClH:13].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:16][CH:15]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: Cc1cc2c(o1)CN(C)CC2O
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(Cl)c2ccccc12
Product: Cl

Procedure:
The same method as in Example 47 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 4-chloro-1-naphthol instead of 4-chloro-3-methylphenol to give the objective compound.
Reaction SMILES: S([Cl:11])(C1C=CC(C)=CC=1)(=O)=O.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:25]O)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)([O-:14])=[O:13].C(N(CC)CC)C>ClCCl>[Cl:11][CH2:25][C:17]1[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.8 %

Procedure:
Add slowly tosyl chloride (1.1 g, 6.02 mmol) to the mixture of (3-nitro-5-(trifluoromethyl)phenyl)methanol (1.1 g, 5.18 mmol) and triethylamine (1.62 mL) in dichloromethane (20 mL) at 0° C., stir the resulting mixture for 15 hrs at room temperature. Concentrate the mixture to obtain the crude product, purify by flash chromatography (silica gel, EtOAc:PE=1:15) to afford the title compound (655 mg, 55%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]3[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]3)[N:11]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Nc1cccc(Cl)c1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(Nc3cccc(Cl)c3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 3-chloroaniline and 3,5-dimethylpyrazole. Mp. 259.1-262.4° C.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:34]4[CH:35]=[C:36]([C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])[CH:37]=[CH:38][C:33]=4[O:32][CH3:31])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: COc1ccc(C(C)(C)CO)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(C)(C)CO)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 9) (107.0 mg, 0.207 mmol) and 2-[4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-methylpropan-1-ol (64 mg, 0.207 mmol) in THF (2.3 mL) was added aqueous potassium carbonate (1.6 mL of a 1M solution, 1.6 mmol). The mixture was degassed with nitrogen. While stirring the reaction vigorously at room temperature, 1,1-bis(di-t-butylphosphino)ferrocene palladium chloride (6.7 mg, 0.01 mmol) was added. The reaction was stirred vigorously at room temperature for 15 min, and then diluted with EtOAc (50 mL). The organics were washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (5 to 50% EtOAc/hexanes) afforded impure product, which was repurified with 1:1:1 CH2Cl2:hexanes:Et2O on silica gel to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({6-chloro-3-[5-(2-hydroxy-1,1-dimethylethyl)-2-methoxyphenyl]pyridin-2-yl}methyl)-4-methyl-1,3-oxazolidin-2-one. Rf=0.29 (40% EtOAc/hexanes). LCMS=616.9 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 6.94-7.85 (m, 8H), 5.40-5.55 (m, 1H), 4.81-5.08 (m, 1H), 3.54-4.36 (m, 7H), 1.95-2.59 (m, 1H), 1.30-1.34 (m, 6H), 0.62-0.74 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14].O.[NH2:16]N>>[Cl:1][C:2]1[C:7]([NH:8][NH2:16])=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14]
Reactant: NN
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Solvent: O
Product: NNc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
Process of claim 1 wherein pentachlorophenylhydrazine is prepared by reacting pentachloronitrobenzene with hydrazine hydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9](B(O)O)=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].C([O-])(=O)C.[Pb+4:34].CCCCCC.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[C:18]([O-:21])(=[O:20])[CH3:19].[C:22]([O-:25])(=[O:24])[CH3:23].[C:26]([O-:29])(=[O:28])[CH3:27].[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([Pb+3:34])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Temperature: 25 °C
Yield: 55.5 %

Procedure:
4′-Chloro-3-methylbiphen-4-ylboronic acid (6.0 g, 0.024 mol) is added in one portion to a mixture of lead tetraacetate (13.0 g, 0.029 mol) and mercuric acetate (0.38 g, 5 mol %) in chloroform (50 ml) under an atmosphere of nitrogen. The reaction mixture is stirred at ambient temperature until dissolution is complete, and then heated at 40° C. for 4 hours. The reaction mixture is cooled to ambient temperature, filtered through a plug of diatomaceous earth and the filtrate is concentrated under reduced pressure to give an orange solid. Trituration with hexane (50 ml) affords a yellow solid which is dried under high vacuum. This solid is then dissolved in chloroform (100 ml), anhydrous potassium carbonate (42.5 g, 0.3 mol) is added and the suspension is stirred rapidly for 10 minutes. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 4′-chloro-3-methylbiphen-4-yllead triacetate (7.8 g) as a cream solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1>>[CH3:10][O:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)=[CH:4][CH:5]=1
Reactant: COc1ccc(CBr)cn1
Reactant: Cc1cc(O)nc(S)n1
Product: COc1ccc(CSc2nc(C)cc(O)n2)cn1
Yield: 75 %

Procedure:
The title compound was prepared by following the procedure described for Example 55 using 6-methoxypyridine-3-carbaldehyde to provide (6-methoxypyridin-3-yl)methanol, which was converted to 5-(bromomethyl)-2-methoxypyridine. The reaction of 5-(bromomethyl)-2-methoxypyridine and 6-methyl-2-sulfanylpyrimidin-4-ol provided 2-{[(6-methoxypyridin-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as a white solid (0.975 g, 75% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.79 (s, 3H), 4.29 (s, 2H), 5.99 (bs, 1H), 6.74 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H), 8.19 (s, 1H); M+263.87.
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[NH:28][C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:39](=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>O.C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:26])[F:27])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[N:28]([CH3:39])[C:29](=[O:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:35][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Nc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CI
Product: COC(=O)C(=O)N(C)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
A mixture of methyl N-{4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-yl}oxamate (compound of Example 6 (4); 3.0 g, 5.982 mmol), methyl iodide (9.387 g, 66.180 mmol), potassium carbonate (2.480 g, 17.946 mmol), 18-crown-6 (158 mg, 0.598 mmol) and acetonitrile (50 ml) was stirred at 85° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (3.066 g, 99.4%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[C:8]([CH2:10]O)[CH:7]=[N:6]1.[Cl:13]CCCl>S(Cl)(Cl)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][Cl:13])[CH:7]=[N:6]1
Reactant: COC(=O)Cn1cc(CO)cn1
Reactant: ClCCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)Cn1cc(CCl)cn1
Yield: 36 %

Procedure:
(4-Hydroxymethyl-pyrazol-1-yl)-acetic acid methyl ester (194 mg) was dissolved in 1,2-dichloroethane (2 mL) and thionylchloride (0.7 mL). The solution was refluxed for 2.5 hours. The reaction was cooled and concentrated in vacuo. The residue was poured into ice/water and basified with sat. Na2CO3 to pH 11. The aqueous phase was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=100:0 to 50:50) to give the title compound as a colorless oil (81 mg, 36%). MS (EI)=188.0 [M+].
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[CH2:3][C@H:4]([NH:13][C:14]([C@@H:16]1[O:20][S:19](=[O:21])[O:18][C@H:17]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])[C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[OH:28][C@H]([C@@H](O)C(=O)N[C@H](C(=O)NCCC(C)C)CC(C)C)C(OCC)=O>>[CH3:1][CH:2]([CH3:27])[CH2:3][C@H:4]([NH:13][C:14]([C@@H:16]1[O:20][S:19](=[O:28])(=[O:21])[O:18][C@H:17]1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])[C:5](=[O:12])[NH:6][CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Reactant: CCOC(=O)[C@@H]1OS(=O)O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Product: CCOC(=O)[C@@H]1OS(=O)(=O)O[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C

Procedure:
Following the same procedures as in Example 3, ethyl (4R,5R)-5-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]-1,3,2-dioxathiolane-4-carboxylate-2-oxide was prepared from ethyl (2R,3R)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionate (40 mg). Subsequently, 30 mg of a target compound were obtained following the same procedures as in Example 4. NMR data of the compound were as follows.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]([CH3:20])[CH2:17][CH2:18]O>C(Cl)Cl>[ClH:2].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:16]([CH2:17][CH2:18][Cl:2])[CH3:20]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CN(CCO)CCc1ccccc1Cl
Solvent: ClCCl
Product: CN(CCCl)CCc1ccccc1Cl
Product: Cl

Procedure:
A suspension of 36 g. (0.173 mol) of phosphorous pentachloride in 300 ml. of methylene chloride was treated dropwise with a solution of 37 g. (0.173 mol) of the 2-[[2-(2-chlorophenyl)ethyl]methylamino]ethanol in 150 ml. of methylene chloride. After addition was complete, the mixture was refluxed overnight, evaporated to dryness and partitioned between dilute hydrochloric acid and ether. The aqueous layer was made basic with 10% sodium hydroxide and extracted well with ether. The ether extracts were washed with water and saturated sodium chloride, dried over magnesium sulfate and filtered. Addition of a saturated solution of ethereal hydrochloric acid gave a solid precipitate which was removed by filtration, washed with ether and dried to give 2-chloro-N-(2-chloroethyl)-N-methylbenzene ethanamine hydrochloride, m.p. 110°.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([NH:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:22]([CH2:24][C:25](OCC)=[O:26])#[N:23].C([O-])(=O)C.[NH4+].C(O)C>O>[C:22]([C:24]1[C:25](=[O:26])[N:10]([C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=2)[CH2:11][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:23]
Reactant: CCOC(=O)CC#N
Reactant: CS(=O)(=O)Nc1ccc(NCC(=O)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(N2CC(c3ccccc3)=C(C#N)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Methanesulfonamidoanilino)acetophenone (5.0 g, 16.4 mmol), ethyl cyanoacetate (4.5 g, 39.4 mmol) and ammonium acetate (1.5 g, 19.5 mmol) were combined in a 100 mL round-bottomed flask equipped with a magnetic stir bar. The mixture was lowered into a pre-heated 140° C. oil bath, and became a stirrable melt within several minutes. Heating continued for 35 min during which time ethanol and water byproducts were observed boiling off, and a bright yellow solid formed amidst the dark supernatant. The reaction was removed from the heat and allowed to cool to 25° C. under vacuum. The crude material was stirred in ethanol (20 mL) for 30 min, then the product was collected by filtration, washed with more ethanol, and dried to yield 3.0 g (52%) as a bright yellow powder, m.p. 280° C. (dec). NMR and mass spectral data were consistent with the assigned structure. Elemental analysis: Calculated: C=61.18, H=4.28, N=11.89, S=9.07; Found: C=60.77, H=4.33, N=11.66, S=9.14.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][CH:8]([CH2:13][O:14][Si](C(C)C)(C(C)C)C(C)C)[O:7]2)([O-:3])=[O:2].Cl.C(=O)=O.CC(C)=O.N>CCO.CO>[N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][CH:8]([CH2:13][OH:14])[O:7]2)([O-:3])=[O:2]
Reactant: CC(C)[Si](OCC1CCn2cc([N+](=O)[O-])nc2O1)(C(C)C)C(C)C
Agent: Cl
Agent: N
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])c1cn2c(n1)OC(CO)CC2
Temperature: 25 °C
Reaction time: 35 h
Yield: 96.1 %

Procedure:
A suspension of silyl ether 133 (1.627 g, 4.58 mmol) in a solution of 1% HCl in 95% EtOH (desilylation conditions described by Cunico et al., 1980) (58 mL) was stirred at room temperature for 35 h. The resulting solution was cooled (CO2/acetone), neutralised by dropwise addition of 7 M NH3 in MeOH (7 mL) with stirring, and then concentrated to dryness and the residue was chromatographed on silica gel. Elution with 0-2% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 2% MeOH/CH2Cl2 gave (2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl)methanol (134) (877 mg, 96%) as a pale yellow solid: mp (THF/MeOH/CH2Cl2/hexane) 179-181° C.; 1H NMR [(CD3)2SO] δ 8.04 (s, 1H), 5.12 (t, J=5.8 Hz, 1H), 4.48 (dtd, J=10.2, 4.7, 2.5 Hz, 1H), 4.13 (ddd, J=12.5, 5.8, 3.0 Hz, 1H), 4.04 (ddd, J=12.4, 11.0, 5.1 Hz, 1H), 3.64 (m, 2H), 2.18 (dtd, J=14.4, 5.0, 2.8 Hz, 1H), 2.03 (dtd, J=14.4, 10.6, 5.7 Hz, 1H). Anal. (C7H9N3O4) C, H, N.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][C:22]#[N:23])[C@@H:17]([O:24][CH3:25])[CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:25][O:24][C@H:17]1[CH2:16][C@@H:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][CH2:19][C@@H:18]1[CH2:21][C:22]#[N:23]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CO[C@H]1C[C@@H](N)CC[C@@H]1CC#N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1C[C@@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC[C@@H]1CC#N
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (381 mg, 1.78 mmol), [(1R,2S,4S)-4-amino-2-methoxycyclohexyl]acetonitrile (racemic) (310 mg, 1.8 mmol) and N,N-diisopropylethylamine (1.2 mL, 7.1 mmol) in isopropyl alcohol (4.2 mL) was heated at 90° C. for 2 h. The crude was concentrated and purified with flash chromatography to give the desired product (469 mg, 76%). LCMS calculated for C15H19N4O3S (M+H)+: m/z=347.1. Found: 347.0.
Reaction SMILES: CN(C)[CH2:3][CH2:4][OH:5].C([Li])CCC.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1.C(=O)C>CCCCCC.O>[CH3:18][C:14]1[C:13]([CH:4]([OH:5])[CH3:3])=[N:12][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)CCO
Reactant: Cc1cccnc1
Agent: CC=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: Cc1cccnc1C(C)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dissolve N,N-dimethylethanolamine (70.45 mmol) in hexane (90 mL) at 0° C., add 2.5M n-butyl lithium in hexane (140.9 mmol,) and stir for 30 min at this temperature. Add a solution of 3-picoline (35.23 mmol) in hexane (10 mL) and continue stirring at 0° C. for 1 h. Cool the resulting mixture to −78° C., add acetaldehyde (70.45 mmol) and continue stirring at −78° C. for 1 h. Dilute with water, warm to ambient temperature, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography eluting with hexane/EtOAc (85:15) to give the desired intermediate as a light yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>O1CCCC1.C1(C=CC(O)=CC=1)O>[C:13]([O:1][CH2:2][C:3](=[O:5])[CH3:4])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: CC(=O)CO
Reactant: C=C(C)C(=O)Cl
Agent: Oc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(C)=O
Temperature: 5 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
In a 2 L four-necked flask subjected to replacement with nitrogen, 50 g of 1-hydroxy-2-propanone was put, and dissolved in 700 g of tetrahydrofuran, and a stirrer, a thermometer and a Dimroth cooling tube were connected thereto. After the resulting solution was stirred and cooled to about 5° C., 76.8 g of triethylamine and 25 mg of hydroquinone were added thereto. While the resulting mixture was cooled to about 5° C. under stirring, 71.9 g of methacryloyl chloride (made by Wako Pure Chemical Industries Ltd., purity: 97.0% or more) was slowly added dropwise thereto, and stirring was further continued for 3 hours to carry out an esterification reaction. While the reaction mixture was held at about 5° C., the mixture was acid-washed with 2N-hydrochloric acid, and an extraction operation was performed twice using 300 mL of ethyl acetate to obtain an organic layer. The organic layer was washed with a 10% sodium hydrogen carbonate aqueous solution and saturated brine, dried over anhydrous magnesium sulfate, and separated by filtration to obtain a reaction crude liquid. The solvent was distilled off from the reaction crude liquid using an evaporator to obtain 85.5 g of crude 2-oxopropyl methacrylate. A yield of 2-oxopropyl methacrylate determined from a proton ratio by NMR was 67.1 g (yield: 69.9% based on 1-hydroxy-2-propanone).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([CH:34]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][CH:38]=1)[CH3:35])([F:33])[C:29]([F:32])([F:31])[F:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:34]([C:28]([F:27])([F:33])[C:29]([F:30])([F:31])[F:32])[CH3:35])=[CH:44][CH:43]=1
Reactant: CC(Oc1ccc(CN)cc1)C(F)(F)C(F)(F)F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)C(F)(F)F
Yield: 100.9 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (751 mg, 1.8 mmol) with (±)-4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamine (950 mg, 3.5 mmol) in anhydrous toluene (20 mL). Purify the crude mixture by chromatography on silica gel eluting sequentially with hexane/EtOAc (10:1, 5:1, 3:1) to obtain (±)-7-chloro-6-{4-[1-(1,1,2,2,2-pentafluoroethyl)-ethoxy]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (990 mg, 99%).