Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(OCC)C>[O:4]=[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccccc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of diethyl oxalate (11.15 mL, 82.1 mmol) in diethyl ether (50 mL) at −78° C. was treated dropwise with 1 M benzylmagnesium chloride in diethyl ether (82 mL, 82 mmol) while maintaining an internal temperature of −60° C. The mixture was stirred for 30 minutes and poured into a mixture of concentrated HCl (8 mL), ice (40 mL), and diethyl ether (50 mL). The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 15.5 g (98%) of the desired product of sufficient purity for subsequent use.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Temperature: 60 °C

Procedure:
To a 3-neck, 1 L flask equipped with mechanical stirring, a nitrogen inlet, and temperature probe, 3-fluoro-4-nitrophenol (30 g, 191 mmol) was added to a suspension of 2-(chloromethyl)-5-methylpyridine hydrochloride (33.4 g, 187 mmol), potassium carbonate (57.5 g, 412 mmol), potassium iodide (31.1 g, 187 mmol), and acetonitrile (400 mL) and the mixture was then heated to 60° Celsius. After 3 hours the solvent was evaporated to dryness and the residue was partitioned between EtOAc and water and the organic layer was separated, dried, filtered and concentrated to dryness. To the resulting residue was added IPA (200 mL) and the mixture was heated to 70° Celsius where the suspension became homogeneous. The solution was allowed to cool to RT over 2 hours and placed in the freezer overnight. The solids were collected by filtration and were rinsed with IPA (100 mL) followed by heptanes (2×100 mL) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.16 (t, J=9.2, 1H), 7.76-7.62 (m, 1H), 7.45 (d, J=7.9, 1H), 7.30 (dd, J=13.7, 2.5, 1H), 7.07 (dd, J=9.3, 1.9, 1H), 5.30 (s, 2H), 2.31 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].P(Br)(Br)[Br:18].O>CCOCC>[Br:18][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)Cc1ccccc1CCCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)Cc1ccccc1CCCBr

Procedure:
To a solution of ethyl [2-(3-hydroxypropyl)phenyl]acetate (44.4 g., 0.20 mole) in ether (300 ml.) is added dropwise during 40 minutes a solution of phosphorus tribromide (20.7 g., 0.075 mole) in ether (100 ml.). The temperature is maintained at 25°-28° C. during this time by means of a cold water bath. The reaction solution is then heated at reflux for 4 hours. It is cooled and poured into iced-water. The ether layer is separated, washed with water, dried over magnesium sulfate, and evaporated in vacuo to yield ethyl [2-(3-Bromopropyl)phenyl]acetate.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[NH:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[N:18]=2)[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:16]2[NH:15][C:14]([CH:10]3[CH2:11][CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]3)=[N:18][C:17]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)C1

Procedure:
To a stirring solution of 3-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (200 mg) in THF (2.0 mL) was added lithium aluminum hydride (1.14 mmol, 1.14 mL of a 1M solution in THF) and the mixture heated to reflux for 6 h. The reaction was quenched with water (2.0 mL), diluted with ethyl acetate (25 mL) and filtered. The filtrates were washed with saturated sodium bicarbonate (50 mL) and the aqueous layer extracted with CH2Cl2 (2×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure and the residue crystallized from diethyl ether to give 60 mg. of the title compound as an off white powder.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCC[C@H]1CO>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:23][CH2:24][CH2:28][C@H:27]2[CH2:26][OH:25])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: OC[C@@H]1CCCN1
Product: CC(C)(C)c1nc(N2CCC[C@H]2CO)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-2-ylmethanol and isolated as light-yellow gum (14.6 mg, 77%). MS (m/e): 401.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CN(C=O)C.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[C:20]([F:27])=[CH:19][C:18]=1[OH:28].C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[C:20]([F:27])=[CH:19][C:18]=1[OH:28])=[O:5]
Reactant: O=C(Cl)c1ccncc1Cl
Reactant: Nc1cc(C(F)(F)F)c(F)cc1O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(C(F)(F)F)c(F)cc1O)c1ccncc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 0.69 g of 3-chloroisonicotinic acid, 5 ml of thionyl chloride and 30 mg of DMF was heated to reflux for 3.5 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-chloroisonicotinic acid chloride. A mixture of the resultant 3-chloroisonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.85 g of 2-amino-5-fluoro-4-trifluoromethylphenol, 0.88 g of triethylamine and 4 ml of DMF while ice-cooling. Thereafter, the reaction mixture was stirred at room temperature for one hour and at 50° C. for one hour. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers wee washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resultant solid was washed with diethyl ether to give 0.77 g of 3-chloro-N-[4-fluoro-2-hydroxy-5-(trifluoromethyl)phenyl]-isonicotinamide.
Reaction SMILES: C(O)(C)(C)C.N.C([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1([CH3:30])[CH2:25][CH2:24][CH2:23][C:22]2([O:29][CH2:28][CH2:27][O:26]2)[CH2:21][O:20]1)C1C=CC=CC=1.[Na]>O1CCCC1>[CH2:28]1[CH2:27][O:26][C:22]2([CH2:21][O:20][C:19]([CH2:18][CH2:17][CH2:16][CH2:15][OH:14])([CH3:30])[CH2:25][CH2:24][CH2:23]2)[O:29]1
Reactant: CC1(CCCCOCc2ccccc2)CCCC2(CO1)OCCO2
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CC1(CCCCO)CCCC2(CO1)OCCO2
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
t-Butyl alcohol (8.88 g, 0.12 mol) is added to freshly distilled ammonia (360 ml) cooled to 78° C. in an argon atmosphere. The cooling bath is removed and 2-(4'-benzyloxybutyl)-6,6-ethylenedioxy-2-methyloxepane (6.7 g, 0.02 mol) in tetrahydrofuran (90 ml) is added. Freshly cut sodium metal (1.0 g, 0.04 mol) is added in small pieces and the resulting blue solution is stirred for 30 minutes. The reaction is quenched by adding ether (350 ml) followed by water (5 ml). The ammonia is evaporated at room temperature and the ether phase is washed with satd. NaCl (300 ml). The aqueous phase is extracted with ether (5×100 ml). The ether phases are combined, dried (MgSO4) and the solvents are removed under reduced pressure to give 6,6-ethylenedioxy-2-(4'-hydroxybutyl)-2-methyloxepane (13) (4.88 g, 99%): nmr (CDCl3) δ1.18 (s, 3H, CH3), 1.30 (s, 1H, OH), 3.42 (s, 2H, --O--CH2), 3.60 (m, 2H, HO--CH2 --CH2) 3.98 (s, 4H, ketal).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[C:21]([NH:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26])(=[O:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[C:21]([NH:24][S:25]([C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([S:25]([NH:24][C:21](=[O:23])[CH3:22])(=[O:27])=[O:26])=[CH:29][CH:30]=2)=[O:13])=[CH:30][CH:29]=1)(=[O:27])=[O:26])(=[O:23])[CH3:22]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CC(=O)NS(=O)(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NS(=O)(=O)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(S(=O)(=O)NC(C)=O)cc2)cc1
Yield: 8.9 %

Procedure:
The compound was prepared according to the general method of Preparation 9 using 2,2'-dithiobisbenzoyl chloride (3.0 g, 8.0 mmol) in 30 mL of dichloromethane and 4-[(acetylamino)sulfonyl]aniline (5.6 g, 26.0 mmol) in 100 mL of pyridine. The crude product was purified on a silica gel column using chloroform/methanol (1:1 v/v) as the mobile phase. The pure fractions were pooled, concentrated in vacuo, and the solid was crystallized from ethanol/water (1:1 v/v) to yield 0.5 g of the title compound, mp 180°-182° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24](F)[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36].O.CCOC(C)=O>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[NH:12][C:13]([C:21]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:22]=2[N:23]=[C:24]([NH:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[C:25]([CH3:31])=[N:26]3)=[CH:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(N)CO
Reactant: CCOC(=O)c1cc(-c2cccc3nc(C)c(F)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)CO)nc23)[nH]c1C(C)NC(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A mixture of ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(3-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (302b) (250 mg, 0.57 mmol) and 2-amino-2-methyl-1-propanol (Sigma-Aldrich) (0.11 mL, 1.13 mmol) in DMSO (2 mL) was heated at 70° C. for 18 h. The reaction mixture was cooled to RT and water and EtOAc was added. The layers were separated and the aq. layer was extracted with EtOAc (2×). The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by chromatography (0-100% EtOAc in hexanes) to provide ethyl 2-(1-((tert-butoxycarbonyl)amino)ethyl)-5-(34(1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (302c) (208 mg, 0.41 mmol, 72% yield) as a yellow oil. m/z (ESI, +ve) 512.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:1])=[O:18])[CH3:21]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCSc1ccccc1N
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To an ice bath cooled solution of 2-aminothiophenol (1.80 g) in N,N-dimethylformamide (35 ml) was added sodium hydride (60% in oil, 575 mg). After being stirred in an ice bath for 30 minutes, ethyl 6-bromohexanoate (3.21 g) was added and the mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with ethyl acetate (100 ml) and the solution was washed with water and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo to give an oil. The oil was purified by silica gel column (1% methanol in chloroform) to give 2-(5-ethoxycarbonylpent-1-yl)thioaniline (3.20 g) as a pale yellow amorphous.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 83 %

Procedure:
2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.300 g, 0.7723 mmol) and ethyl formate (0.185 mL, 2.30 mmol) were dissolved in anhydrous ethanol (8 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.44 mL, 3.86 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.267 g, 0.641 mmol, 83%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[O:19])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>CN(C=O)C.O>[CH2:29]([N:23]1[CH:24]=[CH:25][C:20]([C:18]([NH:17][C:8]2[S:9][C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:7]=2)=[O:19])=[CH:21][C:22]1=[O:26])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1cc[nH]c(=O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccn(Cc2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.8 %

Procedure:
Compound 112 (146 mg, 0.400 mmol) was dissolved in DMF (2 mL), 60% sodium hydride (35.2 mg, 0.880 mmol) was added thereto, followed by stirring at room temperature for 30 minutes. Benzyl bromide (0.0523 mL, 0.440 mmol) was added dropwise to the reaction mixture, followed by stirring overnight at room temperature. The reaction mixture was poured into water, and 1 mol/L hydrochloric acid was added thereto to adjust the pH to 7, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=99:1) to afford the entitled Compound 113 (25.0 mg, 14%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.[CH:9]([O:11][CH2:12][CH3:13])=[CH2:10].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:9]([O:11][CH:12]([O:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1)[CH3:13])[CH3:10]
Reactant: O=C1CC[C@H](CO)N1
Reactant: C=COCC
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)OC[C@H]1CCC(=O)N1
Reaction time: 3 h
Yield: 102 %

Procedure:
To a solution of (5R)-5-(hydroxymethyl)pyrrolidin-2-one (Aldrich, 8.86 g, 77 mmol) in 70 mL of chloroform at room temperature under an argon atmosphere was added ethyl vinyl ether (10.4 mL, 108 mmol) and catalytic anhydrous trifluoroacetic acid (0.2 mL). After stirring for 3 hours, the reaction was partitioned between methylene chloride (150 mL) and aqueous sodium bicarbonate solution (150 mL) and the phases were separated. The organic phase was dried (K2CO3) and filtered. The filtrate was evaporated under reduced pressure to give 14.7 g of the (5R)-5-(1-ethoxyethoxymethyl)pyrrolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:22](O)=[O:23])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C@@H:62]([OH:64])[CH3:63]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[NH:60][CH2:61][C@@H:62]([OH:64])[CH3:63])[CH:25]=[CH:26][C:27]=4[Cl:28])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: C[C@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)CNC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To the mixture of 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (2.5 g, 5.07 mmol) in THF (50 mL) was added EDCI (1.94 g, 10.14 mmol), HOBt (1.03 g, 7.61 mmol), DIPEA (5 mL) and (S)-1-amino-propan-2-ol (0.57 g, 7.61 mmol) by sequence under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water. The resulting precipitate was washed with water and EtOAc to give 8-bromo-N-(2-chloro-5-((S)-2-hydroxypropylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (2.0 g, yield 72%). 1H NMR (DMSO-d6, 400 MHz): δ8.62-6.60 (m, 8H, NH, ArH), 4.77 (d, J=4.8 Hz, 1H, OH), 4.18 (br s, 2H, CH2), 3.79-3.75 (m, 1H, CH), 3.31 (s, 3H, NCH3), 3.19 (br s, 2H, CH2), 2.94 (br s, 2H, CH2), 1.05 (d, J=6.0 Hz, 3H, CH3). LC-MS: (ESI, m/z)=549 [M+H]+
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([CH:10]=O)=[C:4]2[N:3]=[CH:2]1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][NH2:17])[CH3:13].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([CH2:10][NH:17][CH2:16][CH:15]([O:18][CH2:19][CH3:20])[O:14][CH2:12][CH3:13])[C:4]=2[N:3]=[CH:2]1
Reactant: O=Cc1cccc2scnc12
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(CNCc1cccc2scnc12)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzothiazole-4-carbaldehyde (1.96 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.74 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (816 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](O)([CH3:9])[CH:7]=[CH:6][C:5]1=[O:11])[CH:2]=[CH2:3].[CH:12](/[OH:17])=[CH:13]/[CH2:14][CH2:15][CH3:16].[H-].[Na+].Cl>>[CH2:1]([C:4]1[C:5](=[O:11])[CH2:6][CH:7]([O:17]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH3:16])[C:8]=1[CH3:9])[CH:2]=[CH2:3]
Reactant: C=CCC1C(=O)C=CC1(C)O
Reactant: CCC/C=C\O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: C=CCC1=C(C)C(O/C=C\CCC)CC1=O
Reaction time: 1 h

Procedure:
Into the same flask as used in Example 1, 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (0.1 mol; 1 part), 2-cis-pentenol (5 parts) and sodium hydride (1/30 part) were charged, and the mixture was stirred at a temperature of 10° to 15° C. for 1 hour. After completion of the reaction, the mixture was neutralized with 1N HCl and extracted with toluene. Toluene was evaporated off from the organic layer to obtain 2-allyl-3-methyl-4-(2-cis-pentenyloxy)-2-cyclopentenone, which was purified by chromatography. Yield, 97%. nD20 1.4946.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Cl)[O:7][CH2:8][CH3:9])(=[O:3])[CH3:2].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12].C(OCC(P(OCC)(OCC)=O)OCC)(=O)C>>[C:1]([O:4][CH:5]([P:14]([O:15][CH2:16][CH3:17])([O:13][CH2:11][CH3:12])=[O:18])[CH2:6][O:7][CH2:8][CH3:9])(=[O:3])[CH3:2]
Reactant: CCOC(Cl)COC(C)=O
Reactant: CCOP(OCC)OCC
Agent: CCOC(COC(C)=O)P(=O)(OCC)OCC
Product: CCOCC(OC(C)=O)P(=O)(OCC)OCC
Temperature: 150 °C

Procedure:
18.5 g (112 mmol) of chloro-ethoxy-ethyl acetate and 19.2 ml (112 mmol) of triethylphosphite are put in a flask and heated at 150° C. for 5 hours. The progress of the reaction is monitored with NMR. 34 g (100%) of (diethoxy-phosphoryl)-ethoxy-ethyl acetate is obtained directly in the form of a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].I[CH2:26][CH3:27]>>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:26][CH3:27])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: CCI
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Product: CCN(c1c(C)cc(C)cc1C(=O)OC)S(=O)(=O)c1ccc(OC)cc1
Yield: 99.8 %

Procedure:
In the same manner as described in Example 9, 0.30 g (0.860 mmol) of the product of Example 62 and 0.103 mL (1.289 mmol) of iodoethane provided 0.324 g (100%) of the desired product as a white solid. Electrospray Mass Spec 378.2(M+H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[S:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cccc2c(N3CCSCC3)nc(Cl)cc12
Reactant: C1CNCCN1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: O
Product: COc1cccc2c(N3CCSCC3)nc(N3CCNCC3)cc12
Yield: 41 %

Procedure:
1-Thiomorpholino-3-piperazino-5-methoxy-isoquinoline was prepared analogous to Example 3 from 1-thiomorpholino-3-chloro-5-methoxy-isoquinoline by heating for 50 hours with piperazine at 190°C in diphenyl ether. M.p. of the hemisulfate: 282°-284°C (decomp., from water). Yield: 41% of theory.