Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].O1CCOCC1.O.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(C(F)(F)F)cc4)C3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(Oc4ccc(C(F)(F)F)cc4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.4 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-(4-(trifluoromethyl)phenoxy)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoate (D199) (24 mg, 0.428 mmol) in a mixture 1,4-dioxane and water (3 ml/1 ml) lithium hydroxide monohydrate (2.7 mg, 0.064 mmol) was added and the mixture was stirred 2 days at room temperature. After solvent evaporation the residue was diluted with water (5 ml) and HCl 1M (15 ml) and extracted with ethylacetate (3×20 ml). Collected organics after solvent evaporation gave the title compound (E73) (15 mg) as racemic mixture.
Reaction SMILES: [CH3:1][N-:2][CH3:3].[C:4]1([S:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:12](O)=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=P(Cl)(Cl)Cl>C1C=CC=CC=1.ClC1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[C:12]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:10][C:11]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1
Reactant: C[N-]C
Reactant: O=C(O)C(Sc1ccccc1)c1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: CN(C)c1c(-c2ccc(Cl)cc2)sc2ccccc12

Procedure:
A solution of 15.3 g (50 mmol) of the dimethylamide of α-phenylthio-p-chloro-phenylacetic acid (colourless rods in a mixture of petroleum ether and benzene, mp 81°-83°) and of 23.0 g (150 mmol) of POCl3 in 160 milliliters of chlorobenzene is refluxed for 6 hours. By treatment similar to that of Example 29 the 3-dimethylamino-2-(4-chloro-phenyl)-benzo(b)thiophene is obtained in the form of a crude oily product which crystallises after trituration with ethanol: 11.1 g (77% of theory), yellow rods, mp 114°-116° (ethanol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][CH2:26][O-:27].[Na+].CCO>O>[CH2:26]([O:27][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:25]
Reactant: CC[O-]
Reactant: CCc1cccc(NC(=O)Nc2csc(-c3ccnc(Cl)c3)n2)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(-c2nc(NC(=O)Nc3cccc(CC)n3)cs2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 10 mL round bottom flask containing 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-ethylpyridin-2-yl)urea (40 mg, 0.11 mmol) (prepared similar to that described for Example 95) was charged a 21 wt % NaOEt/EtOH solution (5 mL). The reaction mixture was heated to reflux. After 2 h, the reaction mixture was cooled to RT and diluted with H2O then concentrated in vacuo. The solid residue was washed with CH2Cl2 and EtOAc then the solid was diluted with MeOH and concentrated in vacuo. The residue was diluted with EtOAc; washed with saturated NH4Cl and H2O, dried (MgSO4) and concentrated in vacuo to afford the title compound as a light-orange solid. MS m/z: 370.2 (M+H). Calc'd for C18H19N5O2S: 369.13.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH3:12])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].O>O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=[O:13])[CH2:12][C:18](=[O:19])[C:17]([F:24])([F:23])[F:16])=[CH:10][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc2c(c1)CCCO2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, 1-(3,4-dihydro-2H-1-benzopyran-6-yl)ethan-1-one (49a) (1.55 g, 8.8 mmol) was dissolved in anhydrous tetrahydrofuran (48 mL) and sodium hydride (60% in mineral oil, 0.42 g, 10.6 mmol) was added portionwise, maintaining the temperature between −5 and 0° C. After 30 minutes stirring at the same temperature, ethyl trifluoroacetate (1.5 mL, 10.6 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. Water (10 mL) was added and tetrahydrofuran was removed in vacuo. The resulting aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo to provide 1-(3,4-dihydro-2H-1-benzopyran-6-yl)-4,4,4-trifluorobutane-1,3-dione (49b) (2.39 g, 8.8 mmol, 100%) which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:22]#[N:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([O:20]C)[CH:14]=3)[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:22]#[N:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([OH:20])[CH:14]=3)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc2cc(-c3ccc(OC)c(F)c3)cc(C#N)c2c1
Agent: BrB(Br)Br
Product: N#Cc1cc(-c2ccc(O)c(F)c2)cc2ccc(O)cc12
Yield: 73 %

Procedure:
In a highly preferred process of this invention, 3-Bromo-7-methoxy-1-naphthonitrile (6) is coupled with 3-fluoro-4-methoxyphenylboronic acid, which is commercially available, under the well-known Suzuki condition using sodium bicarbonate and catalytic amount of dichloro-bis(triphenylphosphine) palladium (II) in a mixture of water and 1,2-dimethoxyethane to give 3-(3-fluoro-4-methoxyphenyl)-7-meythoxy-1-naphthonitrile (8); typically the yield is approximately 98% with about 95%+HPLC purity. Finally, in this highly preferred process 3-(3-fluoro-4-methoxyphenyl)-7-methoxy-1-naphthonitrile (8) is demethylated using boron tribromide at about 83° C. and recrystallized from a mixture of water and ethanol to give 3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile (1), typically in about 73% yield with 99%+HPLC purity.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]([CH3:11])[CH3:10])[S:7][CH:8]=1.[CH3:12][NH2:13]>O>[CH:9]([C:6]1[S:7][CH:8]=[C:4]([CH2:3][NH:13][CH3:12])[N:5]=1)([CH3:11])[CH3:10]
Reactant: CN
Reactant: CC(C)c1nc(CCl)cs1
Agent: Cl
Solvent: O
Product: CNCc1csc(C(C)C)n1
Reaction time: 1 h
Yield: 55 %

Procedure:
A solution of 40 g of 4-(chloromethyl)-2-isopropylthiazole hydrochloride in 100 ml of water was added dropwise with stirring to 400 ml of 40% aqueous methylamine. The resulting solution was stirred for 1 h, then concentrated in vacuo. The residue was taken up in chloroform, dried over Na2SO4, and concentrated in vacuo. Purification of the residue by silica gel chromatography using 10% methanol in chloroform provided 21.35 g (55%) of the desired compound. 1H NMR (DMSO-d6) δ1.34 (d, J=7 Hz, 6H), 2.56 (s, 3H), 3.30 (heptet, J=7 Hz, 1H), 4.16 (s, 2H), 7.63 (s, 1H). Mass spectrum: (M+H)+ =171.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]2)=[N:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.[OH-].[Na+].Cl>C(O)C.[Cl-].[Na+].O>[CH3:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]2)=[N:4][C:3]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)c(C)s2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1sc(Cn2cc(C(=O)O)cn2)nc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 47.6 %

Procedure:
To a solution (3 mL) of the compound (112 mg, 0.28 mmol) obtained in Example 34a in ethanol was added 2N aqueous sodium hydroxide solution (0.56 mL, 1.08 mmol), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was neutralized with 1N aqueous hydrochloric acid solution, saturated brine was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (ethyl acetate-hexane) to give the title compound (49 mg, 48%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N.CCOC(C)=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCc3ccccc3)cc21
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (0.15 mol, 50 mg) obtained in Step 1 in CH3CN was added K2CO3(1.5 eq). 1-(2-bromoethyl)benzene (1.5 eq) was added dropwise and the resulting mixture was heated to reflux for 3 d. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo to obtain the title compound (30%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[Cl:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: COc1cc(Cl)cc(C=O)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: COc1cc(Cl)cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(5-Chloro-2-hydroxy-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-chloro-2-hydroxy-3-methoxybenzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.50-2.55 (m, 4H), 3.60-3.66 (m, 4H), 3.70 (s, 2H), 3.88 (s, 3H), 5.39 (s, 1H), 6.61-6.62 (m, 1H), 6.80-6.81 (m, 1H), 7.84 (s, 1H), 12.40 (br s, 1H). Mass spectrum (ES) MH+=351.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[NH:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=1)[C:6]#N.O=[CH:24][C:25](=C)[CH3:26]>>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[N:4]1[CH:24]=[C:25]([CH3:26])[CH:6]=[C:5]1[C:8]1[CH:13]=[CH:12][C:11]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:10][CH:9]=1
Reactant: N#CC(Nc1ccc(F)cc1F)c1ccc(S(N)(=O)=O)cc1
Reactant: C=C(C)C=O
Product: Cc1cc(-c2ccc(S(N)(=O)=O)cc2)n(-c2ccc(F)cc2F)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(2,4-difluoroanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a white powder (yield 63%), melting at 140-141° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[C:29]([F:31])[C:28]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[C:27]([F:39])[CH:26]=4)=[CH:21][C:20]=3[O:42][CH:43]([CH3:45])[CH3:44])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C.O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[C:29]([F:31])[C:28]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:27]([F:39])[CH:26]=4)=[CH:21][C:20]=3[O:42][CH:43]([CH3:45])[CH3:44])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1c(F)cc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(CNc2cc(F)c(CCC(=O)O)c(F)c2)ccc1Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To a solution of ethyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzyl}amino)-2,6-difluorophenyl]propanoate (0.431 g, 0.710 mmol) in a mixture of ethanol (5 mL) and tetrahydrofuran (8 mL) was added 1 N sodium hydroxide (2.12 mL, 2.12 mmol) and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from diethyl ether-hexane to give the title compound (0.310 g, yield 75%) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][CH:8]=2)[NH:3]1>C(OC(=O)C)(=O)C>[CH2:10]1[C:9]2=[CH:8][CH:7]=[CH:6][C:5]3=[C:4]2[N:3]([C:14](=[O:16])[CH2:13][CH2:12]3)[C:2](=[O:1])[CH2:11]1
Reactant: O=C(O)CCc1cccc2c1NC(=O)CC2
Solvent: CC(=O)OC(C)=O
Product: O=C1CCc2cccc3c2N1C(=O)CC3
Temperature: 100 °C

Procedure:
The 1,2,3,4-tetrahydro-2-oxo-8-quinolinepropanoic acid (2.1 g, 0.0096 mole) is dissolved in acetic anhydride (10 ml) and the solution is heated to 100° C. for one hour. Excess acetic anhydride is removed at reduced pressure and the residual anhydride is removed by addition of toluene and repeated concentration. The solid is recrystallized from ethyl acetate to yield pure 1,2,6,7-tetrahydro-3H,5H-benzo[ij]quinolizine-3,5-dione, mp 136°-140° C.
Reaction SMILES: [OH:1][CH:2]([C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:3].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:1][CH:2]([C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6])[CH3:3])(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: C=C(C(=O)OC)C(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C(=O)OC)C(C)OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.6 %

Procedure:
To a solution of methyl 2-(1-hydroxyethyl)acrylate (50 g) and pyridine (32.6 ml) in dichloromethane (200 ml) was added dropwise acetyl chloride (34.8 g) at 0° C. After the reaction mixture was stirred for 1 hour, the mixture was allowed to warm to room temperature, and quenched with water (500 ml). The aqueous layer was separated and extracted twice with dichloromethane. The combined organic layer were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated, and the residue was distilled in vacuo to give methyl 2-(1-acetoxyethyl)acrylate (28.2 g).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH2:7])[CH2:2]1.[Cl-].[Na+].[OH-].[Na+].[CH3:12][NH:13][C:14](=[N:17][N+:18]([O-:20])=[O:19])OC.Cl>O.C(#N)C>[CH3:12][NH:13][C:14]([NH:7][CH2:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[N:17][N+:18]([O-:20])=[O:19]
Reactant: NCC1CCOC1
Reactant: CNC(=N[N+](=O)[O-])OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCC1CCOC1
Reaction time: 4 h

Procedure:
[(3-tetrahydrofuryl)methyl]amine (38.0 g, 0.38 mole), 27.4 g of sodium chloride and 107.0 g of water were mixed, and the resulting mixture was cooled to −10 degree centigrade. Furthermore, 2.3 g (0.06 mole) of 96% NaOH was added to the solution and dissolved. Sodium chloride was dissolved in water with 78% of the saturated solubility at a water temperature of −10 degree centigrade. N,O-dimethyl-N′-nitroisourea (49.2 g, 0.37 mole) was introduced into the above solution, stirred at −10 degree centigrade for 4 hours, and then heated to 10 degree centigrade and further stirred for 19 hours. 35% hydrochloric acid (6.7 g, 0.07 mole) was added to the suspension so that the pH became not more than 4. Water and acetonitrile were added to the above suspension for complete dissolution. The resulting solution was analyzed by HPLC and as a result, the reaction yield of the titled compound was 95%.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].Cl.[C:33]([O:37][C:38](=[O:42])[C@H:39]([CH3:41])[NH2:40])([CH3:36])([CH3:35])[CH3:34].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([NH:40][C@H:39]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:42])[CH3:41])=[O:23])=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(OCC(=O)N[C@@H](C)C(=O)OC(C)(C)C)cc3)[nH]c2n(CCC)c1=O
Temperature: 25 °C

Procedure:
Mix (-)-2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenoxy]acetic acid (4.28 g, 10 mmol), L-alanine t-butylester hydrochloride (965 mg, 5.3 mmol), hydroxybenztriazole (1.65 g, 11 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 11 mmol). Add a solution of diisopropylethylamine (3.8 mL) in methylene chloride (20 mL) and stir at room temperature for several hours. Dilute with ethyl acetate (150 mL), wash with cold 0.5N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine. Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1.[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cc(Cl)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1ccnc(C(=O)OCC)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of ethyl 4-chloropyridin-2-carboxylate (0.37 g) and allyltributyltin (IV) (0.86 mL) in toluene (5.0 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.12 g). The reaction mixture was stirred under nitrogen atmosphere at 120° C. for 12 hr. The solvent of the reaction mixture was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=3/2) to give the title compound (0.28 g, 73%).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:17]([CH2:25][CH2:26][N:27]=4)[C:18]([NH2:24])=[N:19][C:20]=3[C:21]=2[O:22][CH3:23])[CH2:4][CH2:3]1.[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36](O)=[O:37])=[CH:32][N:31]=1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33]([C:36]([NH:24][C:18]2[N:17]3[CH2:25][CH2:26][N:27]=[C:16]3[C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][S:2](=[O:1])(=[O:28])[CH2:3][CH2:4]4)=[C:21]([O:22][CH3:23])[C:20]=3[N:19]=2)=[O:37])=[CH:32][N:31]=1
Reactant: Nc1ncc(C(=O)O)cn1
Reactant: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 8-[3-(1,1-dioxidothiomorpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Example 19, Step 1) and 2-aminopyrimidine-5-carboxylic acid. High vacuum drying at 60° C. gave the title compound (272 mg, 79%): HPLC MS RT=1.45 min, MH+=529.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.25-2.30 (2H, m), 3.44-3.49 (2H, m), 3.61-3.63 (4H, m), 3.83 (4H, bs), 3.99 (3H, s), 4.18-4.25 (2H, m), 4.33 (2H, t), 4.48-4.55 (2H, m), 7.43 (1H, d), 8.02 (1H, d), 9.04 (2H, s).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:36][C:37]([F:42])([F:41])[C:38](O)=O>ClCCl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]([CH3:35])[CH2:28][C:19]4[CH:20]=[CH:15][CH:16]=[CH:17][C:38]=4[C:37]([F:42])([F:41])[F:36])[CH2:25][CH2:26]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1C(F)(F)F)C1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.4 %

Procedure:
0.80 g of (R)-2-methyl-2-(4-(4-(N-methyl-N-tert-butoxycarbonylamino)piperidin-1-yl)phenoxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole was dissolved in 2 ml of trifluoroacetic acid and 2 ml of dichloromethane, followed by stirring at room temperature for 15 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and then, 2 ml of dichloromethane and 2 ml of triethylamine were added thereto. The mixture was stirred at room temperature for 5 minutes, and it was then concentrated under a reduced pressure. The residue was dissolved in 8 ml of dichloroethane, and then, 0.57 g of 2-trifluoromethylbenzaldehyde and 0.70 g of triacetoxy sodium borohydride were added thereto while cooled by ice. The mixture was warmed to room temperature, and the mixture was then stirred for 24 hours. Thereafter, an aqueous solution of potassium carbonate and dichloromethane were added to the reaction solution. The mixture was stirred, and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and then filtered. The obtained filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=9:1). The resultant product was then crystallized from ethyl acetate to obtain 0.47 g (yield: 52.4%) of light yellow powders, (R)-2-methyl-2-(4-(4-(N-methyl-N-(2-trifluoromethylbenzyl)amino)piperidin-1-yl)phenoxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)[C:3]=1[C:4](O)=[O:5].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[Cl:1][C:2]1[C:3]2[C:4](=[O:5])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=3)[NH:14][C:7]=2[C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Nc1ccc(OCc2ccccc2)cc1
Solvent: CN(C)c1ccccc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cc(OCc3ccccc3)ccc2[nH]c2c([N+](=O)[O-])ccc(Cl)c12

Procedure:
Four grams of 2-chloro-5-nitro-6-[[4-(phenylmethoxy)phenyl]amino]benzoic acid was suspended in 80 ml of boiling 1,2-dichloroethane to which 0.2 ml of N,N-dimethylaniline was added followed by 8.0 ml of phosphorus oxychloride. The mixture was stirred under reflux for 30 minutes and cooled overnight. The resulting suspension was filtered providing the title compound as a red solid, mp 216°-217° C.