Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C[Mg]Br.[C:15]1([C:25](Cl)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:25]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:26]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1ccc2[nH]cc(C(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a cooled solution at 0° C. of 5-methoxy-1H-indole 3 (7.4 g, 50 mmol) in diethyl ether (150 ml) under nitrogen was added dropwise a solution of methylmagnesium bromide (3M) in diethyl ether (17.5 ml) and the mixture was stirred for 2 h at room temperature. The solution was then cooled at 0° C. and to this solution was added a solution of 1-naphthoylchloride (9.5 g, 50 mmol) in diethyl ether (100 ml) dropwise over a period of 15 min. After the addition was completed the solution was warmed up at room temperature and stirred for 2 h followed by slow addition of saturated ammonium chloride solution (375 ml) and stirred overnight. The white solid formed was filtered, washed by ether and dried under high vacuum to give 5-methoxy-3-(1-naphthoyl)-1H-indole 4 (11.3 g, 75%).
Reaction SMILES: C[S-].[Li+].CCOCC.CCCCCC.[C:15]([C:19]1[CH:20]=[C:21]([C:26]([CH3:37])=[CH:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[C:15]([C:19]1[CH:20]=[C:21](/[C:26](/[CH3:37])=[CH:27]/[C:28]2[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=2)[CH:22]=[CH:23][C:24]=1[OH:25])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=Cc1ccc(C(=O)O)cc1)c1ccc(O)c(C(C)(C)C)c1
Agent: C[S-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCCC
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc(O)c(C(C)(C)C)c1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
1.84 g of lithium methanethiolate are added to 2 g (5.67 mmol) of the E ester obtained in Example 33(b) in 40 ml of DMF. The reaction mixture is stirred under nitrogen at 120° C. for 4 h. After the same treatment as in Example 8, followed by a chromatography in the ether/hexane eluent (80/20), 1.69 g of a mixture of E and Z isomers of 4-[-2-(3-tert-butyl-4-hydroxyphenyl)propenyl]benzoic acid are isolated in the respective proportions (83:17). A recrystallization from the hexane/ether mixture gives 225 mg of the expected derivative which melts at 209° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)(=O)C>[CH2:7]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH:12]([CH2:13][C:14]([C:1]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([CH2:4][CH2:5][CH3:6])[C:2]=2[CH3:10])=[O:15])[C:11]([OH:16])=[O:17])=[C:2]1[CH3:1])[CH2:8][CH3:9]
Reactant: O=C1C=CC(=O)O1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: c1ccccc1
Solvent: CC(=O)O
Product: CCCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CCC)c3ccccc23)c2ccccc21
Temperature: 60 °C

Procedure:
A stirred solution of 90.0 g (0.686 mole) of 2-methylindole, 30.0 g (0.306 mole) of maleic anhydride, 350 ml of benzene and 5.0 ml of glacial acetic acid was heated at reflux under a nitrogen atmosphere for a period of approximately sixty-five hours. The resulting slurry was cooled to approximately 60° C. and the solid was collected by filtration, washed with approximately 100 ml of benzene that had been heated to approximately 60° C. After drying to a constant weight of 29.7 g in vacuo at 60° C. there was obtained 2,4-bis(2-methyl-3-indolyl)-4-oxobutanoic acid (Formula VII: R=Y=H; R1 =CH3) as a pale yellow solid which melted at 217°-218° C. with decomposition.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][C:9]1([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[C:17]([F:23])[CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(O)=O.O.[CH2:28]([CH:31](CO)CO)[CH2:29]C>C1(C)C=CC=CC=1>[CH2:29]([CH:5]1[CH2:4][O:3][CH:2]([CH2:7][CH2:8][C:9]2([C:15]3[CH:16]=[C:17]([F:23])[C:18]([F:22])=[C:19]([F:21])[CH:20]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[O:1][CH2:6]1)[CH2:28][CH3:31]
Reactant: CCCC(CO)CO
Reactant: Fc1cc(C2(CCC3OCCCO3)CCCCC2)cc(F)c1F
Solvent: O=CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1COC(CCC2(c3cc(F)c(F)c(F)c3)CCCCC2)OC1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
1-(2-(1,3-Dioxane-2-yl)ethyl)cyclohexyl-3,4,5-trifluorobenzene 3.7 g (11 mmol) obtained in Example 8 and formic acid 25.0 g (540 mmol) were added to toluene 20 ml, and the mixture was refluxed with heating for 3 hours. The reactant was cooled to room temperature, water 100 ml was added, and the product was extracted with toluene. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain crude 3-(4-(3,4,5-trifluorophenyl)cyclohexyl)propanal 3.5 g. The product and 2-propyl-1,3-propanediol 2.3 g (20 mmol) were dissolved in toluene 20 ml, PTS 0.5 g was added. The mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene) and recrystallized twice from ethanol to obtain 1-(2-(5-propyl-1,3-dioxane-2-yl)ethyl)cyclohexyl-3,4,5-trifluorobenzene 1.4 g (3.8 mmol). The yield was 34.5% from 1-(2-(1,3-dioxane-2-yl)ethyl)cyclohexyl-3,4,5-trifluorobenzene.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])O[C:2]1=O.C([O-])([O-])OCC.[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH3:20]>>[CH2:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:36]2[C:4](=[O:11])[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:1]=[CH:2]2)[CH2:32][CH2:33]1)[CH3:20]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCOc1ccccc1N1CCN(CCN)CC1
Agent: CCOC([O-])[O-]
Product: CCOc1ccccc1N1CCN(CCn2cnc3ccccc3c2=O)CC1
Yield: 99.2 %

Procedure:
A mixture comprising of 1.63 g 2H-3,1-benzoxazine-2,4-(1H)-dione, 1.78 g of ethyl orthoformate and 2.49 g of 4-(2-ethoxyphenyl)-1-(2-aminoethyl)piperazine was heated on a boiling water bath for about 10 minutes and further heated on an oil bath of 120° to 130° C. for about 2 hours. After the completion of the reaction, the reaction mixture was concentrated under a reduced pressure. The obtained residue was columnchromatographed over silica gel column and eluted with an ethyl acetate-triethylamine solvent (30:1) to give 3.75 g of 3-[2-[4-(2-ethoxyphenyl)-1-piperazinyl]-ethyl]-4(3H)-quinazolone as an oil (yield: 99.2%).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].[NH2:26][C@H:27]1[C@H:33]([OH:34])[CH2:32][CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]1>ClCCl.CN(C)C1C=CN=CC=1.CCCCCCC>[C:12]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:26][C@H:27]2[C@H:33]([OH:34])[CH2:32][CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]2)=[O:23])=[CH:24][CH:25]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](N)C1
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Reaction time: 2 h

Procedure:
12.91 g of p-toluenesulphonyl chloride dissolved in 15 ml of dichloromethane were added at room temperature in the course of 15 minutes to 1.94 g of 4-(tert-butoxy)-benzoic acid and 2.63 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred for 2 hours and added in the course of 1 hour to 2.30 g of tert-butyl (3R,4R)-3-amino-4-hydroxy-azepan-1-carboxylate dissolved in 10 ml of dichloromethane. After stirring for 1 hour the reaction mixture was washed with 20 ml of 1N NaOH, 20 ml of 1N HCl and 20 ml of water. All aqueous phases were washed in succession with 10 ml of dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and the solvent was evaporated. The foam-like residue obtained was dissolved in 80 ml of hot heptane and crystallized at room temperature overnight. The crystals were washed with 10 ml of heptane and dried to yield 3.23 g of tert-butyl (3R,4R)-3-(4-tert-butoxy-benzoylamino)-4-hydroxy-azepan-1-carboxylate, m.p. 134-135° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:21])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]>N1C=CC=CC=1>[S:7]([O:21][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: OCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
p-Toluenesulfonyl chloride (17.1 g) was added portionwise to triethylene glycol (15 g) in pyridine (600 ml) at 0° C. The solution was allowed to warm to room temperature and stirring continued for 16 h. The solvent was removed under reduced pressure to approximately 50 ml and the residue diluted with hydrochloric acid (100 ml, 3M), extracted with dichloromethane (3×100 ml), washed with brine (150 ml), dried (Na2SO4), and the solvent removed under reduced pressure. The resulting pale orange oil was purified by flash chromatography (ethyl acetate) to give triethylene glycol mono tosylate from the most polar fractions as a clear oil (6.94 g, 23%). 1H nmr (CDCl3) δ2.44 (s, 3H), 2.56 (br s, 1H OH), 3.56-3.73 (m, 10H), 4.16 (m, 2H), 7.38 and 7.78 (AB quartet, 2H each); 13C nmr (CDCl3) δ21.33, 42.52, 61.25, 68.31, 69.00, 69.86, 70.36, 72.25, 127.64, 129.63, 144.71; m/z (CI) 305 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C@@H:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.6 %

Procedure:
To a solution of 1,1-dimethylethyl (3R)-3-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (may be prepared as described in Description 6) (3.39 g, 8.30 mmol) in 1,4-dioxane (20 ml) was added HCl (4M in 1,4-dioxane) (10.37 ml, 41.5 mmol) and the resultant mixture stirred under an atmosphere of Ar for 16 hours. A further 5 ml of 4M HCl in dioxane was added and the mixture stirred at room temperature for 72 hours. The mixture was concentrated to dryness and the residue triturated with diethyl ether and the solid collected by filtration giving the title compound (2.507 g) as a white powder.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]([OH:12])([CH3:11])([CH3:10])[CH3:9].[CH3:13][O:14][C:15](=[O:39])[CH2:16][NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:24][C:23](=[O:36])[C:22]([O:37][CH3:38])=[CH:21]2.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:13][O:14][C:15](=[O:39])[CH2:16][N:17]([S:2](=[O:4])(=[O:3])[NH:5][C:6]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:7])[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:24][C:23](=[O:36])[C:22]([O:37][CH3:38])=[CH:21]2
Reactant: COC(=O)CNc1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1
Reactant: CC(C)(C)O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CN(c1cc2cc(OC)c(=O)oc2cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of chlorosulfonyl isocyanate (0.15 mL, 1.75 mmol) in 4 mL of CH2Cl2, cooled in a ice bath, is added t-butanol (0.17 mL, 1.75 mmol). The mixture is warmed to ambient temperature and stirred for 15 min. The solution is cooled in an ice bath and a solution of (7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-ylamino)-acetic acid methyl ester (0.430 g, 1.17 mmol) and triethylamine (0.35 mL, 2 mmol) is added dropwise. After addition is complete, the mixture is warmed to ambient temperature and stirred for 1.5 h. To this is added water (1 mL) and the mixture is extracted with EtOAc. The organic layer is washed with water, sat. NaCl and dried over sodium sulfate. The solvent is removed under reduced pressure to afford N-(t-butoxycarbonylsulfamoyl)-N-(7-benzyloxy-3-methoxy-2-oxo-2H-chromen-6-yl)glycine methyl ester as a white solid: 1H NMR (CDCl3) δ 7.78 (s, 1H), 7.71 (s, 1H), 7.38-7.30 (m, 5H), 6.82, (s, 1H), 6.78 (s, 1H), 5.18 (s, 2H), 4.55 (s, 2H), 3.83 (s, 3H); 3.66 (s, 3H), 1.41 (s, 9H); (M+H)+=549.
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[C:13]1([CH:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[O:11]=[C:4]1[CH:5]([C:8]([OH:9])=[O:10])[CH2:7][CH2:6][N:21]1[CH:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:20]
Reactant: CC(N)c1ccccc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: CC(c1ccccc1)N1CCC(C(=O)O)C1=O
Yield: 89.2 %

Procedure:
This compound was prepared according to general method 1 starting from 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.250 g, 1.47 mmol) and 1-phenylethanamine (0.568 mL; 4.41 mmol) in ethanol (3 mL). 2-oxo-1-(1-phenylethyl)pyrrolidine-3-carboxylic acid 0.306 g (89%) was obtained as a white solid.
Reaction SMILES: [C:1]1(=[O:26])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8]([NH2:10])=O)[C:4](=[O:21])[C:3]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:2]12.CN1CCOCC1.S(Cl)(Cl)=O>CN(C)C=O>[C:4]1(=[O:21])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[CH2:7][C:8]#[N:10])[C:1](=[O:26])[C:2]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:3]12
Reactant: COc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC
Solvent: CN1CCOCC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(CC#N)N2C(=O)c3ccccc3C2=O)cc1OC
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To an ice bath cooled stirred suspension of 3-phthalimido-3-(3,4-dimethoxyphenyl)propionamide (1.77 g, 5.00 mmol) and 4-methylmorpholine (1.3 mL, 12 mmol) in dimethylformamide (17 mL) under nitrogen, was added thionyl chloride (0.7 mL, 9.6 mmol) dropwise via a syringe. There was a slight exotherm and after 30 minutes, the cooling bath was removed and the reaction nlixture was stirred for 2 hours at room temperature. The reaction mixture was poured into a mixture of sodium bicarbonate (17 g) and 75 mL of ice water and stirred until the ice had melted. The slurry was filtered and the solid was washed with copious amounts of water. The wet solid was dissolved in methylene chloride (50 mL) and the organic layer was separated, dried over sodium sulfate, and concentrated in vacuo to afford an orange solid. The solid was purified by flash column chromatography (silica gel, 5/95 ethyl acetate/methylene chloride, 50 mm id column) to afford 1.32 g (79%) of the product as a white solid: 1H NMR (CDCl3) δ 7.9-7.6 (m, 4H), 7.10 (m, 2H), 6.83 (m, 1 H), 5.64 (dd, J=6.5, 10.2 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.82 (dd, 1H), 3.30 (dd, J=6.5, 16.8 Hz, 1 H); 13C NMR (CDCl3) δ 167.7, 149.5, 149.2, 134.4, 131.5, 129.1, 123.6, 120.1, 116.9, 111.1, 110.7, 56.0, 55.9, 51.1, 21.1. Anal. Calcd for C19H16N2O4 0.18 H2O. Theoretical: C, 76.2. H, 4.85; N, 8.25. Found: C, 67.23; H, 4.79; N, 8.27.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22](OC)=[CH:21]C=2)=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27](N1C=CN=C1)(N1C=CN=C1)=[O:28].[BH4-].[Na+].[CH3:41]COC(C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:13])[CH2:14][C:15]([N:17]([CH3:41])[C:18]2[CH:19]=[CH:24][C:23]([O:28][CH3:27])=[CH:22][CH:21]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc(CNC(=O)CC(CC(=O)O)c2ccc(Cl)c(Cl)c2)cc1
Reactant: CCOC(C)=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(N(C)C(=O)CC(CCO)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,4-Dichloro-beta-[2-[(4-methoxyphenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (7.2 g) in EtOAc (125 mL) was treated with carbonyldiimidazole (4.4 g) and N,N-dimethylaminopyridine (0.22 g). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for one hour. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (4.46 g) in H2O (75 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O (100 mL), 1N HCl (100 mL), and H2O (100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 60-100% EtOAc/hexane gave the title compound (5.43 g).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH3:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH3:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:6]([CH:12]([OH:14])[CH3:13])[O:7]2.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:14][C@@H:12]([C:6]1[O:7][C:8]2[C:3]([C:4](=[O:22])[C:5]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[CH3:13])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](OS(C)(=O)=O)c1oc2cccc(F)c2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of (+)-5-fluoro-3-(3-fluorophenyl)-2-(1-hydroxyethyl)-4H-chromen-4-one (0.800 g, 2.63 mmol) in dichloromethane (16 ml) and triethylamine (1.10 ml, 7.91 mmol), methanesulphonyl chloride (0.400 ml, 5.27 mmol) is added stirred at room temperature for 2 h. The reaction mass is quenched with water, extracted with dichloromethane, dried over sodium sulphate and concentrated to afford the title compound as brown solid which is used as such in next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH2:38]([NH:41][C:42]([N:44]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[NH2:45])=[O:43])[CH2:39][CH3:40].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:45][N:44]([CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:42]([NH:41][CH2:38][CH2:39][CH3:40])=[O:43])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Reactant: CCCNC(=O)N(N)Cc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCNC(=O)N(Cc1ccccc1)NC(=O)CCCc1ccc(OC(C)(C)C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl] butyric acid (1.50 g, 5.04 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl chloride (524 μL, 6.01 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (30.1 μL, 0.41 mmol). Completion of acid chloride formation was verified by HPLC. This solution was then concentrated to remove residual oxalyl chloride and the resulting oil was redissolved in ethyl acetate (10 mL). This solution was then added dropwise to a suspension of N-propyl-1-phenylmethylhydrazine carboxamide methanesulfonate (1.52 g, 5.01 mmol) and pyridine (970 μL, 12.6 mmol) in ethyl acetate (15 mL) at 0° C. After stirring at 0° C. for 1 h, the solution was warmed to rt and washed with 1N HCl (2×20 mL) and 5% aq. NaHCO3 (2×20 mL) followed by sat'd aq. NaCl (20 mL). The organic layer was dried (MgSO4), filtered and concentrated to a yellow oil. The oil was purified by column chromatography (SiO2, 1:1 ethyl acetate:hexanes) to afford the title compound as a clear oil (1.42 g, 59%): 1H NMR (DMSO-d6, 60° C.) δ 9.51 (s, 1H), 7.20 (m, 5H), 7.01 (d, 2H, J=8 Hz), 6.71 (t, 1H, J=7 Hz), 4.55 (s, 2H), 4.17 (q, J=7 Hz), 3.00 (q, 2H, J=7 Hz ), 2.45 (t, 2H, J=2Hz ), 2.07 (t, 2H, J=2 Hz), 1.73 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.40 (q, 2H, J=7 Hz ), 1.17 (t, 3H, J=7 Hz), 0.81 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174. 0, 172.0, 158.2, 153.8, 139.0, 135.8, 129.7, 128.84, 128.79, 127.6, 119.4, 79.2, 61.6, 51.3, 42.3, 34.3, 33.4, 27.1, 25.7, 23.7, 14.6, 11.9 ; IR (CHCl3) 3009, 1726, 1672, 1143 cm−1; Anal. Calcd. For C27H37N3O5: C, 67.05; H, 7.71; N, 8.69. Found: C, 66.65.; H, 7.63; N, 8.57.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3cnccn3)nc3sc(Cl)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:21][C:22]1[CH:23]=[C:24]([CH:29]([NH2:31])[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[F:21][C:22]1[CH:23]=[C:24]([CH:29]([NH:31][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH3:30])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CC(N)c1cc(F)cc(F)c1
Reactant: CCOc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Yield: 92.7 %

Procedure:
Following a similar procedure to that described in Example (1a), 1.0 g of 4-ethoxyphenyl 3-nitrophenyl ketone, 1.16 g of 1-(3,5-difluorophenyl)ethylamine, 2.01 ml of triethylamine, 0.49 ml of titanium tetrachloride, 975 mg of sodium cyanoborohydride and 0.32 ml of acetic acid were reacted, to obtain 1.41 g of the title compound as a yellow oil.