Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](Cl)=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].[I:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH:28]=[C:27](N3CCOCC3)[C:26]2=[O:37])=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>CCOC(C)=O.O>[CH2:1]([O:3][C:4]([C:5]1[C:28]2[CH2:29][CH2:30][N:25]([C:22]3[CH:23]=[CH:24][C:19]([I:18])=[CH:20][CH:21]=3)[C:26](=[O:37])[C:27]=2[N:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[N:6]=1)=[O:17])[CH3:2]
Reactant: O=C1C(N2CCOCC2)=CCCN1c1ccc(I)cc1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A solution of chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 100 g, 0.39 mol) in EtOAc (800 mL) was treated with 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (10, 150 g, 0.39 mol, 1.0 equiv) at 0–5° C. under N2, and the resulting reaction mixture was treated with triethylamine (TEA, 78.8 g, 109 mL, 0.78 mol, 2.0 equiv) at 0–5° C. under N2. The reaction mixture was then warmed up to room temperature for 30 min before being warmed up to reflux for an additional 6 h. When HPLC and TLC showed that the reaction was complete, the reaction mixture was cooled down to 5–10° C. before being treated dropwise with 4.0 N aqueous HCl solution (488 mL, 1.95 mol, 5.0 equiv) at 0–5° C. The resulting mixture was stirred at 5–20° C. for 4 h. The resulting slurry was then treated with water (400 mL) before being stirred at 5–20° C. for an additional 30 min. The solids were collected by filtration, washed with water (2×200 mL) and 50% of isopropyl acetate/hexane (2×200 mL), dried in vacuo at 40–45° C. for 12 h. The crude desired 1-(4-methoxy-phenyl)-6-(4-iodo-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (55, 175.5 g, 201.8 g theoretical, 87% for two steps) was obtained as pale-yellow solids, which was found to be essentially pure to do the following reaction without further purification. For 55, CIMS m/z 518 (M++H, C22H20IN3O4).
Reaction SMILES: C([Mg]Cl)CCC.[Li]CCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1.C[O:28][B:29](OC)[O:30]C>C1(C)C=CC=CC=1.CCCCCCC.C1COCC1>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([B:29]([OH:30])[OH:28])=[CH:14][CH:15]=1)#[N:26]
Reactant: COB(OC)OC
Reactant: N#Cc1ccccc1-c1ccc(Br)cc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 54.7 %

Procedure:
Dry THF (4 mL) is cooled to at −3° C. under nitrogen. BuMgCl (0.6 mL, 1.2 mmol, 2M in THF) is added. n-BuLi (1.5 mL, 2.4 mmol, 1.6 M in hexanes) is then added dropwise over 20 min at −3° C. to 0° C. After the addition, the solution is stirred at 0° C. for 45 min. The solution is cooled to −45° C. and treated dropwise over 20 min at −45 to −40° C. with a solution of 2-(4-bromophenyl)benzenecarbonitrile (0.5 g, 1.9 mmol) in a total of 4 mL THF. The resulting yellowish-orange solution is allowed to warm to −25° C. over 1 h. After 1 h, the solution is cooled to −73° C. Trimethylborate (0.43 mL, 3.87 mmol) is added dropwise over 15 min at −73° C. The solution is stirred 1 h at −73° C. The reaction is allowed to warm to −63° C. The reaction is quenched with 5 mL of 1N HCl and allowed to warm to 0° C. with stirring. The mixture is extracted with 10 mL ethyl acetate. The organic solution is shaken with brine, dried (Na2SO4).and concentrated to obtain 0.435 g of crude product. This in 5 mL of 1:1 toluene/heptane is heated to 95° C. with stirring for 10 min. Upon cooling to rt and then to 10° C., the solid is collected by filtration and rinsed three times 1:1 toluene/heptane. The solid is vacuum-dried to provide title compound (0.232 g, 95.65% HPLC, Hitachi 7000 series, SB phenyl column, 218 nm, 65% MeCN/35% water with 0.05% TFA, 1 mL/min).
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][C@H:6]([NH:21][C:22](=[O:39])[CH:23]([N:25](C(OC(C)(C)C)=O)[CH2:26][C:27]([O:29]CC)=[O:28])[CH3:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:10][CH:9]=1)C.[OH-].[Na+].C(O)(C(F)(F)F)=O>C1COCC1.CO>[C:27]([CH2:26][NH:25][C@@H:23]([CH3:24])[C:22]([NH:21][C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:12][CH:13]=1)[CH2:5][C:4]([OH:40])=[O:3])=[O:39])([OH:29])=[O:28].[C:27]([CH2:26][NH:25][C@H:23]([CH3:24])[C:22]([NH:21][C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)=[CH:12][CH:13]=1)[CH2:5][C:4]([OH:40])=[O:3])=[O:39])([OH:29])=[O:28]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)C(C)N(CC(=O)OCC)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C[C@@H](NCC(=O)O)C(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Product: C[C@H](NCC(=O)O)C(=O)N[C@@H](CC(=O)O)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 25 °C

Procedure:
To a solution of (R)-3-[2-(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-propionylamino]-4-(3′-chloro-biphenyl-4-yl)-butyric acid ethyl ester (290 mg, 0.504 mmol) in THF (3 ml) and MeOH (0.5 ml) at room temperature is added 2M NaOH (1.009 ml, 2.017 mmol). The reaction is stirred at room temperature over night. The mixture is concentrated to dryness and the crude i taken up in DCM (3.00 ml), to which is added TFA (3.89 ml, 50.4 mmol) and the mixture is stirred at room temperature for 2 hr. The reaction is concentrated for HPLC purification. Reverse phase HPLC [25 to 50% ACN—H2O (0.1% TFA) over 10 min by Sunfire C18 column] give (R)-3-[(S)-2-(Carboxymethyl-amino)-propionylamino]-4-(3′-chloro-biphenyl-4-yl)-butyric acid and (R)-3-[(R)-2-(Carboxymethyl-amino)-propionylamino]-4-(3′-chloro-biphenyl-4-yl)-butyric acid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:20]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([NH:40][CH:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[O:39])=[CH:36][CH:35]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:38]([NH:40][CH:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[O:39])=[CH:47][CH:48]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Cl)ncc21
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN1C(=O)C(F)(F)CN(C2CCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 64.7 %

Procedure:
A mixture of 0.0636 g (0.21 mmole) 2-chloro-9-cyclobutyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1), 0.0609 g (0.32 mmole) of toluenesulfonic acid monohydrate, 0.0463 g (0.21 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 19.5 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile-methanol to give 0.0661 g of 4-(9-cyclobutyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-17) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6]1.[Cl-].[NH4+]>C(O)C.C1COCC1.O.[Fe]>[Cl:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([Cl:22])[C:3]=1[O:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6]1
Reactant: O=[N+]([O-])c1cc(Cl)c(OC2C=Nc3ccccc3C2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(OC2C=Nc3ccccc3C2)c(Cl)c1
Yield: 89.1 %

Procedure:
To a solution of compound II (6.9 g) in ethanol/THF/water (ratio 40:20:10) was added ammonium chloride (3.3 g) and powdered iron (3.4 g). This mixture was heated to reflux for 5 h. The hot mixture was then filtered through Celite and concentrated. The residue was dissolved in ethyl acetate and washed with saturated NaHCO3 solution followed by water and then brine. The solution was dried over magnesium sulfate and concentrated to afford compound III as an off-white solid (5.6 g).
Reaction SMILES: FC1C=C([N+]([O-])=O)C(OC)=CC=1CO.[F:15][C:16]1[C:24]([O:25][CH3:26])=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[F:15][C:16]1[C:24]([O:25][CH3:26])=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=[CH:21][C:17]=1[CH2:18][OH:19]
Reactant: COc1c([N+](=O)[O-])ccc(C(=O)O)c1F
Agent: COc1cc(CO)c(F)cc1[N+](=O)[O-]
Product: COc1c([N+](=O)[O-])ccc(CO)c1F

Procedure:
The title compound was prepared using the procedure from Compound 130D ((2-fluoro-5-methoxy-4-nitrophenyl)methanol) with 2-fluoro-3-methoxy-4-nitrobenzoic acid (Compound 147E). 1H NMR (CDCl3, 400 MHz): δ=4.08 (d, J=1.77 Hz, 3H), 4.85 (s, 2H), 7.29-7.35 (m, 1H), 7.64 (dd, J=8.46, 1.89 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[C:10]([NH:13][C:14]1[C:22]([Cl:23])=[CH:21][C:17]([C:18]([Cl:20])=[O:19])=[C:16]([O:24][CH3:25])[CH:15]=1)(=[O:12])[CH3:11]>[OH-].[Na+].O1CCOCC1>[ClH:20].[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[CH:2]([NH:1][C:18](=[O:19])[C:17]1[CH:21]=[C:22]([Cl:23])[C:14]([NH:13][C:10](=[O:12])[CH3:11])=[CH:15][C:16]=1[O:24][CH3:25])[CH2:3]2
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Reactant: N[C@@H]1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Product: Cl
Reaction time: 0.25 h

Procedure:
(S)-(-)-3-Aminoquinuclidine (1.9 g) is dissolved in 33.5 ml of 1N aqueous sodium hydroxide solution. 4-Acetamido-5-chloro-2-methoxybenzoyl chloride (3.75 g) dissolved in 70 ml of dioxane is added dropwise to this solution. After 15 minutes' stirring, the medium is acidified, washed with chloroform and alkalinized with concentrated aqueous sodium hydroxide solution, and the product extracted with chloroform. The organic phase is dried (over Na2SO4) and then evaporated. The oily residue is dissolved in ethanol and ethanolic hydrogen chloride is added until an acid pH is obtained. The N-(3-quinuclidinyl)-4-acetamido-5-chloro-2-methoxybenzamide hydrochloride thereby formed precipitates (quantitative yield), and the latter is collected by filtration.
Reaction SMILES: [CH2:1]([O:8][C@:9]1([CH:33]=C)[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:10]1[OH:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:36].[Na+].[BH4-].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O.C(O)(C)(C)C>[CH2:1]([O:8][C@:9]1([CH2:33][OH:36])[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[C@H:10]1[OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@]1(OCc2ccccc2)[C@H](O)[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1COCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CO)(OCc3ccccc3)[C@@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.3 %

Procedure:
To a solution of nucleoside 26 (2.00 g, 4.31 mmol) in a mixture of THF (15 cm3) and water (15 cm3) was added sodium periodate (2.76 g, 12.9 mmol) and a 2.5% solution of osmium tetraoxide in t-butanol (w/w, 0.54 cm3, 43 μmol). The reaction was stirred at room temperature for 18 h, quenched with water (50 cm3), and the mixture was extracted with dichloromethane (2×100 cm3). The combined extract was washed with saturated aqueous sodium hydrogen carbonate (3×75 cm3), dried (Na2SO4) and evaporated under reduced pressure. The residue was redissolved in a mixture of THF (15 cm3) and water (15 cm3), and sodium borohydride (488 mg, 12.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 h, water (50 cm3) was added, and the mixture was extracted with dichloromethane (2×100 cm3). The combined organic phase was washed with saturated aqueous sodium hydrogencarbonate (3×75 cm3) and dried (Na2SO4). The solvent was removed and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 27 as a white foam (732 mg, 36%). δH (CDCl3) 11.09 (1H, br s, NH), 7.41 (1H, d, J 1.0, 6-H), 7.38-7.26 (Bn), 6.16 (1H, d, J 2.6, 1′-H), 5.12 (1H, d, J 5.4, 2′-OH), 4.66-4.29 (6H, m, 2′-H, 4′-H, Bn), 4.02-3.96 (2H, m, 1″-Ha, 1″-Hb), 3.90 (1H, dd, J 7.2, 9.7, 5′-Ha), 3.79 (1H, dd, J 5.6, 9.7, 5′-Hb), 2.49 (1H, t, J 6.4, 1″-OH), 1.68 (3H, d, J 0.6, CH3); δC (CDCl3) 166.1 (C-4), 150.6 (C-2), 139.0, 137.9, 137.0 (C-6, Bn), 128.7, 128.6, 128.4, 128.3, 128.0 (Bn), 107.5 (C-5), 88.2 (C-1′), 88.1 (C-3′), 84.2 (C-4′), 73.7 (C-5′), 72.1 (C-2′), 69.3, 65.4 (Bn), 58.6 (C-1″), 12.3 (CH3).
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:19][C@H:18]2[C:28]([O:30][CH3:31])=[O:29])[C:13]1=[O:32]
Reactant: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 97 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate (2.42 g, 5.43 mmol) in methanol was treated with 600 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 1.64 g of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)-cyclohexanecarboxylate as a white solid. This was used without further purification. MS found: (M+H)+=312.32.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([C:12](=O)[C:13]([O-:15])=[O:14])[CH3:11].[CH3:17][C:18]1[CH:25]=[CH:24][C:21](C=C)=[CH:20][CH:19]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(#N)C.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[CH:11]([C:21]1[CH:24]=[CH:25][C:18]([CH3:17])=[CH:19][CH:20]=1)[CH2:10][CH:12]([C:13]([OH:15])=[O:14])[NH:5]2
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: C=Cc1ccc(C)cc1
Reactant: CCC(=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCO
Product: Cc1ccc(C2CC(C(=O)O)Nc3cc(Cl)cc(Cl)c32)cc1

Procedure:
Compound 20 was prepared by the basic process from 5.0 mmol 3,5-dichloroaniline, 5.5 mmol ethylglyoxalate solution (50% toluene), 15.0 mmol 4-methylstyrene and 5.0 mmol trifluoroacetic acid in 30.0 ml acetonitrile. Subsequent saponification was carried out using 1.0 ml of sodium hydroxide solution (6N water) in 20.0 ml of ethanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>>[CH2:19]([NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: CC(C)CCN
Product: CC(C)CCNc1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 75 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and isopentylamine in 75% yield using the procedure described for example 37, and was characterized by its mass spectrum as follows: MS (m/z): 310 ([M+H]+, 100).
Reaction SMILES: CS(O)(=O)=O.[CH2:6]([N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:9][CH3:10])[CH3:7].[C:18]([OH:29])(=[O:28])[CH2:19][CH2:20][S:21][S:22][CH2:23][CH2:24][C:25]([OH:27])=O>C(C(C)=O)C(C)C>[CH2:9]([N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:25](=[O:27])[CH2:24][CH2:23][S:22][S:21][CH2:20][CH2:19][C:18]([O:29][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:28])[CH2:6][CH3:7])[CH3:10]
Reactant: CCN(CC)CCCCCCO
Reactant: O=C(O)CCSSCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: CCN(CC)CCCCCCOC(=O)CCSSCCC(=O)OCCCCCCN(CC)CC
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
1.3 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 2.3 g of the obtained 6-(N,N-diethyl)amino-1-hexanol. After stifling for 10 minutes, 1.4 g of 3,3′-dithiodipropionic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. and then stirred at 110° C. for 4 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 50 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stirring for 2 hours, the precipitated crystals were collected by filtration and washed with acetone, yielding the methanesulfonate salt of di[6-(N,N-diethyl)aminohexyl]3,3′-dithiodipropionate.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:7][CH:6]=1.O.Cl>O1CCCC1.CO>[F:4][C:5]1[CH:6]=[CH:7][C:8](/[C:11](=[N:22]\[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[N:34]=[C:35]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[O:36][C:37]=3[CH3:38])=[CH:27][CH:26]=2)/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:9][CH:10]=1
Reactant: COC(=O)CCCCCC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCCCCCC(=O)O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
Lithium hydroxide monohydrate (42.8 mg) was added to a solution of methyl Z-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoate (190 mg) in tetrahydrofuran (10 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 3 hours. 1N hydrochloric acid (1.1 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain Z-8-(4-fluorophenyl)-8-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]octanoic acid (59 mg, yield 32%) as colorless crystals. m.p. 56-57° C.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([N:6]1[CH2:10][CH2:9][N:8]=[C:7]1SC)=[O:5].[CH3:17][N:18]([CH3:20])[NH2:19]>COCCOCCOC.O>[CH3:17][N:18]([CH3:20])[N:19]1[C:2]2[C:3](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:4](=[O:5])[N:6]2[CH2:10][CH2:9][N:8]=[C:7]12
Reactant: CSC1=NCCN1C(=O)c1ccccc1F
Reactant: CN(C)N
Solvent: COCCOCCOC
Solvent: O
Product: CN(C)N1C2=NCCN2C(=O)c2ccccc21
Yield: 77 %

Procedure:
A solution of 2.40 g (10.1 mmoles) of the product of Example 1 and 3 ml of 1,1-dimethylhydrazine in 6 ml of diglyme was heated at 165° C. for 3 hours in a sealed glass tube. Upon cooling, the solution was diluted with water and the resulting solid was collected and air-dried to give 1.80 g of 2,10-dihydro-10-(dimethylamino)imidazo[2,1-b]quinazolin-5(3H)-one. Melting point 197°-198° C. Total yield 77%.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:8])[C:5]([OH:7])=O.[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17].N1C=CC=CC=1>C(Cl)Cl>[Br:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:5](=[O:7])[C:4]([O:3][CH3:2])=[O:8])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C(=O)O
Reactant: Nc1cccc(OCCCBr)c1
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(=O)Nc1cccc(OCCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 ml of oxalic acid monomethyl ester chloride in 10 ml of methylene chloride is added dropwise to a solution of 3.5 g of 3-(3-bromopropoxy)-aniline and 1.3 ml of pyridine in 40 ml of methylene chloride in the course of 10 minutes. After stirring at room temperature for 2 hours, the mixture is poured onto water and extracted with methylene chloride. The combined extracts are evaporated and the residue is chromatographed on silica gel with methylene chloride/ethyl acetate (10:1). The eluate is evaporated and the residue is crystallised from ether/hexane. Methyl N-[3-(3-bromopropoxy)-phenyl]-oxamate of melting point 90°-91° is obtained.
Reaction SMILES: [C:1]1([C:7]([CH:9]=[CH2:10])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:12]([C@@H:19]1NC(C)(C)N(C)[C:20]1=[O:27])C1C=CC=CC=1.C(C=C)=O>C[N+]([O-])=O.O>[C:1]1([C:7]2[CH2:8][CH2:12][C@@H:19]([CH:20]=[O:27])[CH2:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC(=C)c1ccccc1
Reactant: CN1C(=O)[C@H](Cc2ccccc2)NC1(C)C
Agent: C=CC=O
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: O
Product: O=C[C@H]1CC=C(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 90 %

Procedure:
To a 0° C. solution of 2-phenyl-1,3-butadiene (89 mg, 0.68 mmol) in CH3NO2/H2O (95/5 v/v, 1.0 M) was added 5 (29.8 mg, 0.14 mmol) and acrolein (135 μL, 2.1 mmol). The solution was stirred at 0° C. for 7 hr, then directly placed onto a silica gel column and eluted with 5% EtOAc/hex affording the title compound as a cololess oil in 90% yield (114 mg, 0.61 mmol, 83% ee). Product ratios were determined, after reduction to the corresponding alcohol (4 eq NaBH4, MeOH (0.1 M)), by HPLC (Chiralcel OD-H column, 6% isopropanol in hexanes, 1 mL/min) tr=16.2 and 20.4, min. (1R)-4-phenyl-3-cyclohexene-1-carboxaldehyde: IR (CH2Cl2) 2926, 2837, 2714, 1722, 1494, 1444 cm−1; 1H NMR (400 MHZ, CDCl3) δ 9.78 (s, 1H, CHO), 7.40-7.23 (m, 5H, ArH), 6.16-6.12 (m, 1H, PhC═CH), 2.64-2.50 (m, 5H), 2.23-2.15 (m, 1H), 1.90-1.79 (m, 1H). 13C NMR (100 MHZ, CDCl3) δ 204.2, 141.6, 136.8, 128.2, 126.9, 125.0, 122.0, 45.7, 26.0, 25.0, 22.6; HRMS (CI) exact mass calcd for (C13H19N2OCl) requires m/z 186.1045, found m/z 186.1041. (1R)-4-phenyl-3-cyclohexene-1-ol: IR (CH2Cl2) 3374, 3289, 2918, 2860, 1444, 1034 cm−1; 1H NMR (500 MHZ, CDCl3) δ 7.41-7.39 (d, J=7.6 Hz, 2H, o-PhH), 7.34-7.31 (t, J=7.7 Hz, 2H, m-PhH), 7.26-7.22 (m, 1H, p-PhH), 6.13 (br, 1H, PhC═CH), 3.66-3.58 (m, 2H, CH2OH), 2.58-2.41 (m, 2H), 2.40-2.31 (m, 1H), 2.05-1.83 (m, 3H), 1.72-1.68 (s, 1H), 1.50-1.41 (m, 1H); 13C NMR (125 MHZ, CDCl3) δ 142.1, 136.5, 128,2, 126.6, 124.9, 123.3, 67.6, 35.9, 28.8, 26.8, 25.7; HRMS (CI) exact mass calcd for (C13H19N2OCl) requires m/z 188.1201, found m/z 188.1203.