Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[CH3:12][O:13][CH:14](OC)[CH2:15][CH:16](OC)OC.FC(F)(F)C(O)=O>>[CH3:12][O:13][CH:14]=[CH:15][CH:16]=[C:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7]
Reactant: COC(CC(OC)OC)OC
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC=CC=C1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
1,3-Dimethylbarbituric acid (20 g, 0.1 mol; Aldrich) was placed in 100 mL round-bottom one-necked flask equipped with magnetic stir bar and reflux condenser, 1,1,3,3-tetramethoxy-propane, (40 mL, 0.2 mol; Aldrich) and 1 mL of Trifluoroacetic Acid (2 mL, 0.03 mol; Sigma) were added to the reaction mixture. The flask was heated at 100° C. with stirring for 5 hours and then cooled to room temperature. The crystallized product was filtered, washed with methanol and dried. The yield was 23 g (80% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:32])[C:20]=1[O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH2:5][CH:6]([CH2:16][OH:17])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:32][C:19]1[CH:18]=[C:4]([CH2:5][CH:6]([CH:16]=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[C:20]=1[O:21][Si:22]([CH:26]([CH3:27])[CH3:28])([CH:29]([CH3:31])[CH3:30])[CH:23]([CH3:24])[CH3:25]
Reactant: CCOC(=O)CCCCC(CO)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CCCCC(C=O)Cc1cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1
Temperature: 25 °C

Procedure:
1.19 g (2.52 mmol) of ethyl 6-(3,5-difluoro-4-triisopropylsilanyloxybenzyl)-7-hydroxyheptanoate are stirred with 5 g of 4 Å molecular sieves and 442 mg (3.78 mmol) of N-methylmorpholine N-oxide in 50 ml of dichloromethane at room temperature for 10 minutes. 44 mg (0.13 mmol) of tetrapropylammonium perruthenate are added, and the mixture is stirred at room temperature until reaction is complete. The mixture is filtered and the filtrate is washed with water and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1). 1.0 g (84% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:7]=1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]2[C:7]=1[C:11](=[O:13])[CH2:10][CH2:9][CH2:8]2
Reactant: COc1ccc(Cl)cc1CCCC(=O)O
Solvent: CCOCC
Product: COc1ccc(Cl)c2c1CCCC2=O
Temperature: 0 °C
Yield: 44 %

Procedure:
A flask containing 1600 g. of polyphosphoric acid and 160 g. (0.70 mole) 4-(5-chloro-2-methoxyphenyl)butyric acid was heated on a steam bath (internal temperature 90°-95° C.) for 1.5 hours. The hot reaction mixture was then poured onto 2 liters of crushed ice with stirring. The quenched mixture was stirred for 30 minutes, then extracted 3 times with 500 ml. portions of chloroform, the extract carbon treated, dried with MgSO4 and filtered. The filtrate was concentrated in vacuo to afford 146 g. of dark oil. This was dissolved in ether, washed with aqueous NaHCO3, then water, carbon treated, dried over MgSO4 and evaporated to dryness. The oil thus produced was distilled under high vacuum to obtain 65.4 g. of product (44% yield). Upon cooling the distillate it crystallized, m.p. 46°-48° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C[O:20][C:21]1[CH:41]=[CH:40][C:24]2N=C(NC(=O)CC(=O)C3C=CC=CC=3)[S:27][C:23]=2[CH:22]=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH2:22][C:21](=[O:20])[C:41]1[S:27][CH:23]=[CH:24][CH:40]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Product: CCOP(=O)(OCC)C(CCC(=O)c1cccs1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and 2-acetylthiophene (II, 0.76 ml); MS (m/e) 426, 381, 315, 289, 261, 152 and 111; IR (neat) 1663, 1518, 1478, 1443, 1416, 1392, 1368, 1355, 1250, 1164 and 1142 cm-1 ; NMR (CDCl3) 7.77, 7.62, 7.12, 4.2, 3.32, 2.58, 2.36 and 1.33 δ; CMR (CDCl3) 192, 144, 133.5, 135.5, 128, 62, 38, 32.5 (t), 20.5 and 16 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14]C(=O)OC)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.O>[OH-].[Na+].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: COC(=O)Nc1ccc(OCc2ccc(Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 1 h

Procedure:
A slurry of methyl 5-(4-chlorobenzyloxy)-2-pyridylcarbamate (0.75 g, 2.6 mmol) in 10% sodium hydroxide (20 ml) and methanol (40 ml) is heated to 90° under nitrogen gas. After 1 hour, 10 ml of 10% sodium hydroxide and 10 ml of methanol are added. Heating is continued, and after 2 hours, 10 ml of methanol is added. The reaction is heated under reflux overnight. The reaction is then rotoevaporated, and chloroform and water are added. The residue is extracted with chloroform (4×). The combined chloroform extracts are washed with water until neutral and with brine, dried over calcium sulfate, filtered and rotoevaporated to yield 2-amino-5-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22]>C(O)(C)C>[Br:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][NH:19][C:18]3=[O:22])[N:8]=2)=[CH:4][CH:3]=1
Reactant: Clc1nccc(-c2ccc(Br)s2)n1
Reactant: NCCN1CCNC1=O
Solvent: CC(C)O
Product: O=C1NCCN1CCNc1nccc(-c2ccc(Br)s2)n1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
A mixture of 4-(5-bromothiophen-2-yl)-2-chloropyrimidine (1.0 g, 3.63 mmol), 1-(2-aminoethyl)imidazolidin-2-one (0.47 g, 3.63 mmol) and triethylame (0.44 g, 4.36 mmol) in isopropanol (25 mL) was refluxed for 30 h. After cooling down to rt the precipitate was filtered and washed with methanol (5 mL) and dried to give the title compound as a yellow solid (0.9 g, 68%). MS (M+H)+ 368/370.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([S:19]([CH3:18])(=[O:21])=[O:20])[CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a solution of 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.12 g, 4.66 mol) in CH2Cl2 (10 ml), triethylamine (3.88 ml) and methanesulfonyl chloride (1.08 ml, 14 mmol) are added at 0° C. The reaction mixture is stirred for overnight, quenched with ice-water and extracted with dichloromethane. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give crude 8-methane sulfonyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.32 g).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][C@@H:38]([CH3:42])[C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:39](=[O:40])[C@@H:38]([OH:37])[CH3:42])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2>[Cu]I.O1CCOCC1>[I:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Brc1ccc2ncccc2c1
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1ccc2ncccc2c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 95.3 %

Procedure:
Sodium iodide (4.32 g, 28.8 mmol), copper (I) iodide (137 mg, 0.72 mmol), 6-bromo-quinoline (3 g, 14.4 mmol), N,N′-dimethyl-cyclohexane (0.227 ml, 1.44 mmol) and dioxane were charged in microwave tube (25 mL). The tube was flushed with nitrogen for 10 min and sealed with a Teflon septum. The reaction mixture was stirred at 110° C. for 15 hours. Then the suspension was allowed to cooled to rt, poured into ice-water and extracted with DCM. The crude was purified by silica gel column to give 6-iodo-quinoline as a little green solid (3.5 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[C:14](=O)[C:13](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10]2)=[CH:4][CH:3]=1.[CH2:26]([NH:29][NH2:30])[CH2:27][CH3:28]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:29]([CH2:26][CH2:27][CH3:28])[N:30]=[C:14]3[C:13](=[CH:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)[CH2:12][S:11](=[O:25])(=[O:24])[CH2:10][CH:9]23)=[CH:4][CH:3]=1
Reactant: CCCNN
Reactant: O=C1C(=Cc2ccc(Cl)cc2)CS(=O)(=O)CC1=Cc1ccc(Cl)cc1
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccc(Cl)cc3)CS(=O)(=O)CC2C1c1ccc(Cl)cc1
Yield: 43 %

Procedure:
A mixture of 5.1g of tetrahydro-3,5-bis[(4-chlorophenyl)methylene]-4H-thiopyran-4-one-1,1-dioxide and 0.96g of n-propyl hydrazine in 250ml of methanol is heated at reflux temperature for 45 minutes. The solids which precipitate out are collected by filtration. The crude product is recrystallized twice from acetone/hexane to give 2.5g of the title compound, melting point 208°-210°C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH2:23]4)=[O:21])=[N:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][N:38]=2)[CH2:6][C@@H:5]1[CH3:45])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.[ClH:53]>C(Cl)Cl.CO.C(OCC)C>[ClH:53].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[N:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]4)=[O:21])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][N:38]=2)[CH2:6][C@@H:5]1[CH3:45])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCC(NC(=O)OC(C)(C)C)CC4)nc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCC(N)CC4)nc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.59 %

Procedure:
tert-Butyl (1-(5-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)picolinoyl)piperidin-4-yl)carbamate (for a preparation see Intermediate 43) (0.258 ml, 0.313 mmol) was dissolved in anhydrous DCM (4 ml). TFA (1 ml, 12.98 mmol) was added and the reaction mixture which was stirred under nitrogen at r.t. for 8 h. The reaction mixture was concentrated in vacuo and loaded onto a SCX cartridge (5 g, pre-conditioned with MeOH). The cartridge was washed with MeOH (40 ml) and eluted with ammonia in MeOH (2M). The methanolic ammonia fractions were concentrated to give an orange oil. The oil was further purified by chromatography on a silica cartridge (10 g), eluting with a MeOH/DCM gradient (2-12%, over 120 mls) followed by 10% of 2M NH3 in MeOH/DCM for 120 mls to give a pale orange solid. The solid was re-dissolved in MeOH (1 ml) and 1.1 equivalents of 1M hydrogen chloride in diethyl ether were added. The mixture was triturated with diethyl ether to give 6-(((2S,4R)-1-acetyl-6-(6-(4-aminopiperidine-1-carbonyl)pyridin-3-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile, hydrochloride (19 mg, 0.030 mmol, 8.59% yield) as an orange solid. LCMS (Formate, 2 min), Rt=0.60 min, MH+=510.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][C:20](=[O:28])[CH:19]=1.Cl>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[F:27][C:24]([F:25])([F:26])[C:22]1[O:21][C:20](=[O:28])[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)[CH:23]=1
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: O=c1cc(Br)cc(C(F)(F)F)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)o1
Reaction time: 1 h
Yield: 100.6 %

Procedure:
To a solution of commercially available 4-iodobenzotrifluoride (1.36 g, 5.00 mmol) in THF (13 mL) at −78° C. was added isopropylmagnesium chloride (2 M in THF, 2.63 mL, 5.25 mmol) within 2 min keeping the internal temperature below −65° C., stirring was continued at −78 to −20° C. for 60 min. ZnCl2 (1 M in THF, 5.50 mL, 5.50 mmol) was added, the cooling bath was removed, the mixture was allowed to reach 23° C. and stirred at 23° C. for 35 min. Pd(PPh3)4 (58 mg, 1 mol %) and 4-bromo-6-trifluoromethyl-pyran-2-one (example C.22 step 3) (1.22 g, 5.00 mmol) were added at 23° C. and stirring was continued at 23° C. for 30 min [slightly exothermic reaction; internal temperature rose to 45° C.]. Poured into icecold 0.5 M HCl, extracted with EtOAc, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4, evaporated and dried at HV to give an orange solid (1.55 g), which was purified by MPLC to give the title compound as a yellow solid (1.27 g, 82%). MS (EI) [(M)t]; mp 52° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[Cl:24].[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:24][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[N:27]1[C@H:26]([CH3:25])[CH2:30][O:29][C:28]1=[O:31]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(Cl)c3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)c(Cl)c3)CC2)c(C)c1
Yield: 16.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-3-chlorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.7 g) described in Preparation Example 70 and (R)-4-methyloxazolidin-2-one (607 mg) described in Preparation Example 25, the title compound (288 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.N[C:20]1C=CC(N2CCC(N(C)C)C2)=C[CH:21]=1>>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH2:20][CH3:21])=[O:10])=[CH:12][CH:13]=1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(Oc2ccc(F)cc2F)cc1
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2F)cc1

Procedure:
4-(2,4-Difluorophenoxy)benzoic acid was reacted with [1-(4-aminophenyl)pyrrolidin-3-yl]-dimethylamine by method E-b. This resulted in the product with the molecular weight of 437.19 (C25H25F2N3O2); MS (ESI): 438 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1.C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
2-({4-[2-(Heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (0.40 g) synthesized in Example 303-2 and 1-fluoro-4-nitrobenzene (0.14 g) were dissolved in N,N-dimethylformamide (10 mL), N,N-diisopropylethylamine (0.52 mL) was added thereto, and the mixture was stirred at 80° C. for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:3) to give the title compound (0.20 g) as a yellow oil.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCOC(=O)NC(=N)c1ccc(CCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 72 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 72% of theory, C35H42N6O5 (626.8); Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=627; (M+Na)+=649.
Reaction SMILES: [CH:1]([N:3]1CCC[C:4]1=O)=C.[CH:9]([CH:11]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:12]1=[O:13])=C.CN(CCCC=C(C)C(N)=O)C.[C:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])(=[O:35])[C:32]([CH3:34])=[CH2:33]>C(O)C>[CH3:9][C:11]([C:12]([NH:14][CH2:15][CH2:16][CH2:17][N:3]([CH3:4])[CH3:1])=[O:13])=[CH2:18].[C:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])(=[O:35])[C:32]([CH3:34])=[CH2:33]
Reactant: C=CN1CCCC1=O
Reactant: C=CC1CCCCNC1=O
Agent: C=C(C)C(=O)OCCCCCCCCCCCCCCCCCC
Agent: CC(=CCCCN(C)C)C(N)=O
Solvent: CCO
Product: C=C(C)C(=O)NCCCN(C)C
Temperature: 68 °C
Reaction time: 5 h

Procedure:
Vinyl pyrrolidone (55.6 g), vinyl caprolactam (577.5 g), dimethylaminopropyl methacrylamide (DMAPMA) (42.6 g), n-octadecyl methacrylate (33.9 g) and ethanol (867.2 g) were charged into a 2-liter water-jacketed resin flask. The reaction flask was equipped with a condenser, a thermometer, a septum (for catalyst addition), an anchor-type metal stirrer, and a nitrogen sparge tube. Nitrogen was bubbled through the solution while the resin flask was heated to 68° C. using hot water circulating through the jacketed flask. After an additional half-hour of degassing at reflexing, a first shot of Lupersol 11 (0.25 ml) was injected into the flask. Subsequently, Lupersol 11 additions were made at 10, 40, 70, 100, 140, 180 and 240 minutes after the first addition. The reaction temperature was then brought up to 75° C. and held for an additional 5 hours, then cooled to room temperature and discharged.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23].COCCO.Cl>C(O)C>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([CH:18]3[CH2:19][CH2:20][CH2:21][O:17]3)=[O:23])[CH2:25][CH2:26]2)[N:3]=1
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Agent: Cl
Solvent: COCCO
Solvent: CCO
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 70 °C
Yield: 93.1 %

Procedure:
A slurry of 60 grams (0.25 mol) of 4-amino-2-chloro-6,7-dimethoxy-quinazoline, 55.3 g (0.3 tool) of 1-(2-tetrahydrofuroyl)piperazine and 175 grams of 2-methoxyethanol was heated, under a nitrogen atmosphere with mechanical stirring, to 120°-123° C. for eight hours. The slurry was then cooled to 70° C. and 140 ml of 3A 200 proof ethanol was added. The resulting mixture was heated to 60°-70° C. for one hour and then cooled to 0°-5° C. To the cooled solution was added 2.5 g of concentrated aqueous hydrochloric acid in 12 ml of 3A 200 proof ethanol. This mixture was kept at -5°-5° C. for one and one-half hours after which the precipitated solid was collected by filtration and washed with 50 ml of cold 3A 200 proof ethanol to yield 98.7 g (0.233 tool, 93%) of anhydrous 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-tetrahydrofuroyl)piperazine hydrochloride of a previously unknown crystalline modification.