Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:13]([F:16])([F:15])[F:14])=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](=O)[CH3:5].C[S:18][CH2:19][C:20]([O-:22])=[O:21].[CH2:23]1CCN2C(=NCCC2)CC1.[NH4+].[Cl-]>CC#N>[CH3:5][C:4]1[C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([C:13]([F:16])([F:15])[F:14])[S:18][C:19]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)C(=C(Cl)C(F)(F)F)c1ccccc1
Reactant: CSCC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Product: COC(=O)c1sc(C(F)(F)F)c(-c2ccccc2)c1C
Reaction time: 15 h

Procedure:
To a solution of 4-chloro-5,5,5-trifluoro-3-phenylpent-3-en-2-one (950 mg) and methylsulfanylacetate (446 mg) in MeCN (23.8 mL) was added dropwise DBU (0.63 mL) at 25° C., followed by stirring at the same temperature for 15 hours. To the reaction liquid was added a saturated aqueous NH4Cl solution (50 mL), followed by extraction with diethylether (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=98:2 to 90:0) to obtain methyl 3-methyl-4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylate (1.08 g) as a colorless liquid.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27].O>CN(C)C=O>[F:27][C:26]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]2)=[N:11]1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Reactant: Fc1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC(c2nn(-c3ccccc3C(F)(F)F)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a stirred suspension of 1.0 g of a 50% oil dispersion of sodium hydride in 20 ml of dimethylformamide was added, dropwise, 3.2 g of 3-(1-methyl-4-piperidinyl)-1H-indazole dissolved in 25 ml of hot dimethylformamide. After stirring for one hr at ambient temperature, 3.75 ml of 2-fluorobenzotrifluoride was added. The reaction mixture was heated to 90° C. and stirred for 17 hrs. The mixture was then poured into water, extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue was purified using flash chromatography (silica gel, diethylamine-ethyl acetate, 1:9). The appropriate fractions were g evaporated The residue was recrystallized once from hexane, then combined with a previously prepared sample (1.1 g), and recrystallized from hexane to yield 2.17 g (24%) of product, mp 110°-111° C.
Reaction SMILES: [OH:1]C[C:3]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:18])[C:5]=2[CH:4]=1.C(CC[O:23][P:24]([N:32](C(C)C)C(C)C)N(C(C)C)C(C)C)#N.N1C=NN=N1>>[P:24]([NH2:32])([OH:23])[OH:1].[CH:8]1[C:7]2[C:6](=[O:18])[C:5]3[C:14](=[CH:15][CH:16]=[CH:3][CH:4]=3)[C:13](=[O:17])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)N(C(C)C)P(OCCC#N)N(C(C)C)C(C)C
Reactant: O=C1c2ccccc2C(=O)c2cc(CO)ccc21
Agent: c1nnn[nH]1
Product: NP(O)O
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Alternatively, reaction of 2-(hydroxymethyl)anthraquinone (4) with 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphorodiamidite and tetrazole afforded the phosphoramidite 5 as a bright yellow solid material after filtration and aqueous workup.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([OH:32])[CH:30]([CH3:31])[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][NH:25][CH2:26]2>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([OH:32])[CH:30]([CH3:31])[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][N:25]([C:11](=[O:13])[CH2:10][C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=1)[CH2:26]2
Reactant: COc1ccccc1C1(O)C(C)CCC2CNCC21
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Product: COc1ccccc1C1(O)C(C)CCC2CN(C(=O)Cc3c[nH]c4ccccc34)CC21
Yield: 39.5 %

Procedure:
By working according to the experimental procedure of Example 16, from 1.21 g of 3-indoleacetic acid and 1.39 g of (3aRS,4RS,5RS,7aSR)-4-(2 -methoxyphenyl)-5-methyl-4-perhydroisoindolol, and after purification on a column of silica gel (particle size 0.04-0.06 mm, diameter 2.8 cm, height 25 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (40/60 by volume), 0.88 g of (3aRS,4RS,5RS,7aSR)-4-(2-methoxyphenyl)-2-(3-indolylacetyl)-5-methyl-4-perhydroisoindolol is obtained in the form of a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[C:7](Br)[C:8]([NH2:15])=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5](=[O:17])[NH:4][C:3]1=[O:18]>[Pd].CO>[CH3:1][C:2]1([CH3:19])[C:11]2[CH:10]=[C:9]3[NH:12][C:10]([C:11]4[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=4)=[N:15][C:8]3=[CH:7][C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18]
Reactant: CC1(C)C(=O)NC(=O)c2c1cc([N+](=O)[O-])c(N)c2Br
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)NC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21
Reaction time: 4 h

Procedure:
27 g. (82 mmole) 4,4-dimethyl-6-nitro-7-amino-8- bromo-1,2,3,4-tetrahydroisoquinoline-1,3-dione were hydrogenated in 300 ml. methanol in the presence of 2 g. 10% palladium on charcoal. After separating off the catalyst, the filtrate was evaporated, the residue was mixed with 500 ml. methylene chloride and 50 ml. triethylamine and, while cooling, 24 g. isonicotinic acid chloride hydrochloride slowly introduced. After 4 hours, the methylene chloride was evaporated off, the residue was worked up with water, filtered off with suction and the moist residue heated under reflux for 20 hours in 500 ml. ethanol and 200 ml. concentrated hydrochloric acid. The evaporation residue was subsequently mixed with water, neutralised and purified by column chromatography (silica gel, elution agent: methylene chloride/ methanol saturated with ammonia; 10:1 v/v). After recrystallisation from ethanol/water, there were obtained 12.2 g. (51% of theory) of the title compound; m.p. above 300° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[NH:19][C:18](=S)[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:22]>>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[N:19]=[C:18]([NH2:22])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCOCC1
Reactant: N
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCOCC1
Temperature: 120 °C
Yield: 74.3 %

Procedure:
6′-Bromo-5-methyl-2″,3″,5″,6″-tetrahydro-3′H-dispiro[imidazole-2,1′-indene-2′,4″-pyran]-4(3 H)-thione (Example 25 Step 3, 415 mg, 1.14 mmol) was taken up in NH3 (7M in MeOH, 13 mL, 91 mmol) and the resulting mixture was heated in a microwave reactor at 120° C. for 2×1 h. The mixture was concentrated and the resulting residue was taken up in NH3 (7M in MeOH, 13 mL, 91 mmol) and then heated again for 1 h at 120° C. The mixture was concentrated and the resulting residue was taken up in DCM (10 mL) and sat. aq. NaHCO3 (5 mL) and poured into a phase separator. The organic layer was collected, concentrated and purified on a silica gel column eluted with 0-10% (0.1M NH3 in MeOH) in DCM to give 295 mg (75% yield) of the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (dd, 1 H), 7.27 (d, 1 H), 6.68 (d, 1 H), 6.65 (br. s, 1 H), 3.65 (m, 2 H), 3.46 (m, 1 H), 3.38 (m, 1 H), 3.15 (m, 1 H), 3.00 (m, 1 H), 2.18 (s, 3 H), 1.66 (td, 1 H), 1.19 (m, 3 H); MS (ES+) m/z 348[M+H]+.
Reaction SMILES: [N:1]([CH:4]([C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[F:12][C:11]([F:13])([F:14])[C@H:10]([CH3:15])[C@@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH2:1]
Reactant: CCOC(=O)C(N=[N+]=[N-])[C@@H](C)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](N)[C@@H](C)C(F)(F)F
Reaction time: 8 h

Procedure:
32.8 g of crude ethyl (3R)-2-azido-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in 110 ml of ethanol and, after inertizing with argon, 6.98 g of palladium on carbon (5%) were added. The mixture was stirred overnight at standard pressure under an atmosphere of hydrogen, with the reaction vessel repeatedly being vented and filled with fresh hydrogen. The reaction mixture was then filtered off through Celite, the filter residue was washed with 50 ml of ethanol and the filtrate was concentrated under reduced pressure (up to about 20 mmHg). The slightly yellowish liquid that remained was briefly freed from residual solvent under high vacuum. This gave 23.5 g of the target compound as an about 70% pure crude product which was not purified any further (yield over three steps about 38% of theory).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26](O)=[N:27][CH:28]=1>COCCOC>[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)=[N:27][CH:28]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Cc1ccc(O)nc1
Solvent: COCCOC
Product: Cc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)nc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and 5-methyl-2-pyridinol, using dry DME as reaction solvent: MS (APCI) m/z 404 (M+1).
Reaction SMILES: [CH2:1]([N:8]([CH2:15][Si](C)(C)C)[CH2:9]OCCCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][C:25]([NH:27][C:28]1([C:31]#[C:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:30][CH2:29]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:9][C:31]([C:28]2([NH:27][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:30][CH2:29]2)=[C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)C#CC1(NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(C2(NC(=O)OC(C)(C)C)CC2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
N-Benzyl-N-(n-butoxymethyl)trimethylsilylmethylamine (2.006 g, 7.176 mmol) and ethyl 3-(1-tert-butoxycarbonylaminocyclopropyl)propiolate (1.136 g, 4.485 mmol) were dissolved in dry dichloromethane (9 ml) and, while stirring at room temperature, the solution was mixed with dichloromethane solution of 1.0 M trifluoroacetic acid (0.72 ml, 0.72 mmol). After 3 hours of stirring, the reaction solution was mixed with a saturated sodium bicarbonate aqueous solution (20 ml) and extracted with dichloromethane (20 ml×3). The organic layers were combined, washed with saturated brine (30 ml) and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was applied to a flash silica gel chromatography column and eluted with chloroform, to thereby obtain 1.449 g (83.6%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.CO.[C:17]([O-:26])(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23]>C(O)CO>[C:1]([O-:13])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[C:17]([O-:26])(=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O-:24])=[O:23]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: O=C([O-])CCCCC(=O)[O-]
Solvent: OCCO
Solvent: CO
Product: O=C([O-])c1ccc(C(=O)[O-])cc1
Reaction time: 2 h

Procedure:
In a stainless steel distilling pot having a drain valve in the bottom is placed 11 lbs. (5.0 kilograms) of dimethyl terephthalate, 7 lbs. 6 oz. (3.35 kilograms) of ethylene glycol and 120 milliliters glycol solution of 2.45 grams Mn(C2H3O2)2 . 4H2O and 1.69 grams of Sb2O3. The mixture is heated to 240°C. over a 3 hour period during which time 1,650 grams of methyl alcohol and 750 grams of ethylene glycol are removed sequentially. The resulting monomer is drained to a stainless steel autoclave fitted with stirrer, charging port, vacuum distillation system, and extrusion valve. To the autoclave is added 285 grams of a glycol solution of di(2-hydroxyethyl) adipate (equal to 163.6 grams of adipic acid), 24 milliliters of an ethylene glycol solution of phosphoric acid containing 1.79 grams of phosphoric acid (as 100% H3PO4), and 27 milliliters of 20% TiO2 in ethylene glycol. The pressure is reduced slowly over a period of about 2.5 hours to about 5 torr, then the autoclave is pressurized with inert gas (Kemp gas) and 317 grams of PHP-20EO diluted with 200 milliliters of ethylene glycol is added. The pressure is gradually reduced over a period of 0.5-hour and polymerization is then continued for about 2 hours at 225°C. at 1.3 torr. The melt is extruded, cooled, and cut to 0.25-inch (0.64-centimeter) flake. The flake has a relative viscosity of 11.1 and contains 0.077% nitrogen and 4.5 mole % adipate units.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH3:11])(=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[H][H].Cl[C:15]1[CH:20]=[C:19]([S:21][CH3:22])[N:18]=[CH:17][N:16]=1>CS(C)=O>[CH3:8][O:7][C:5](=[O:6])[CH:4]([C:15]1[CH:20]=[C:19]([S:21][CH3:22])[N:18]=[CH:17][N:16]=1)[C:3]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: CSc1cc(Cl)ncn1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C(=O)OC)c1cc(SC)ncn1
Temperature: 80 °C

Procedure:
To a suspension of NaH (1.98 g, 50 mmol, 60% in oil) in DMSO (20 mL) is added dimethyl malonate (5.67 mL, 50 mmol) at 23° C. (cooled by ice-water if necessary). After the evolution of hydrogen has ceased, 4-chloro-6-methylsulfanyl-pyrimidine 2 (3.22 g, 20 mmol) is added. The reaction is further heated at 80° C. for 5 hours. The reaction mixture is then cooled to room temperature, and quenched with saturated NH4Cl solution (50 mL). The organics are extracted with ethyl acetate (3×60 mL). The combined organic layers are washed with brine (2×) and dried over Na2SO4, filtered and concentrated. 50 mL of hexanes are added to the residue and heated at 60° C. for half hour and then cooled to room temperature. The solid is filtered and washed with hexanes to afford 2-(6-methylsulfanyl-pyrimidin-4-yl)-malonic acid dimethyl ester. (If necessary, the hexanes washing can be concentrated and purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 0% to 40% to afford additional product). 1H NMR 400 MHz (DMSO-d6) Compound A δ 8.92 (s, 1H), 7.53 (s, 1H), 5.20 (s, 1H) 3.70 (s, 6H), 2.56 (s, 3H); Compound B (tautomer of A, the structure is tentatively assigned) 8.37 (s, 1H), 7.34 (s, 1H), 3.66 (s, 6H), 2.48 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](=O)[CH2:20][C:21](OCC)=[O:22])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]2[CH:20]=[C:21]([OH:22])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)Cc1cccc(Cl)c1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(Cc3cccc(Cl)c3)cc2O)c1
Yield: 32 %

Procedure:
The title compound was prepared in 32% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 4-(3-chlorophenyl)-3-oxobutanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:12])[CH:7]=[C:8]([CH3:11])[C:9]=1[Br:10].S(O[CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])(C1C=CC(C)=CC=1)(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([CH3:11])[C:9]=1[Br:10])[O:12][CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28]
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(COc1cc(C)c(Br)c(C)c1)OCC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred suspension of NaH (0.5 g, 22.0 mmol) in anhydrous DMF (20 mL) at 0° C. was added 3,5-dimethyl-4-bromophenol (2.2 g, 11.0 mmol) in DMF (5 mL) followed by diethyl tosyloxymethylphosphonate (3.9 g, 24.2 mmol) in DMF (5.0 mL) 30 min later. The reaction mixture was stirred for 14 h at room temperature and poured into water (30 mL). The aqueous solution was extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (2:3) to afford diethyl (3,5-dimethyl-4-bromophenoxy)methylphosphonate as a syrup. (1.85 g, 48%): 1H NMR (300 MHz, CDCl3): δ 6.88 (s, 2H), 4.15-4.25 (m, 6H), 2.41 (s, 2H), 1.40 (t, J=6.0 Hz, 6H); LC-MS m/z=351[α]3H20BrO4P+H]+; TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (2:3); Rf=0.3.
Reaction SMILES: [CH3:1]O.[OH-].[Na+].Cl.[F:6][CH2:7][CH2:8][N:9](NC)[C:10](=[O:14])[C:11]([OH:13])=[O:12]>O>[F:6][CH2:7][CH2:8][N:9]([CH3:1])[C:10](=[O:14])[C:11]([OH:13])=[O:12]
Reactant: CNN(CCF)C(=O)C(=O)O
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CCF)C(=O)C(=O)O
Reaction time: 1 h
Yield: 66 %

Procedure:
To a mixed solvent comprising 6 ml of methanol and 5 ml of water, there was suspended 1.56 g of N-(2-fluoroethyl)-N-methylmethoxyoxalylamide, then 3.2 g of a 15% aqueous solution of sodium hydroxide was dropwise added, with ice-cooling, to the suspension and then the mixture was stirred for one hour. Concentrated hydrochloric acid was added to the reaction system, the mixture was then extracted with ethyl acetate, the organic phase thus separated was washed with water, dried over magnesium sulfate and then the ethyl acetate was distilled off from the organic phase to thus give, as the target product, 0.94 g (yield: 66%, a solid product) of N-(2-fluoroethyl)-N-methylaminooxamic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=2)[CH2:23][CH2:22]1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-2-nitrophenylamine (1.3 g, 7.0 mmol), 1-(2-methoxyphenyl)-piperazine hydrochloride (5.0 g, 20 mmol), and K2CO3 (4.0 g, 29 mmol) in DMF (20 mL) was stirred at 110° C. for 18 h. The reaction mixture was cooled to room temperature and poured into water (200 mL). The crude solid product was collected by filtration, air dried, and purified by trituration with CHCl3 (1.3 g, 57%).
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([C:40]([O:42]C)=[O:41])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].Cl>O1CCCC1.CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[C:23]3[S:27][CH:26]=[CH:25][CH:24]=3)[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH:34]=3)[C:40]([OH:42])=[O:41])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(NC(=O)NC2CN(C(=O)c3cccs3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)ccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1ccc(C)c(C(=O)O)c1)CN2C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.7 %

Procedure:
1-[1-(2-toluoylmethyl)-2-oxo-5-(2-thenoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-methoxycarbonyl-4-methylphenyl)urea (0.70 g) was dissolved in a mixed solvent of tetrahydrofuran (10 ml) and methanol (10 ml), aqueous lithium hydroxide hydrate (0.23 g) solution (10 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N HCl and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography(chloroform:methanol=30:1), to thereby obtain 224 mg of the title compound as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:19][CH:18]=[CH:17][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=2[F:16])[N:7]=1.C([N:23]([CH:26]([CH3:28])C)[CH2:24][CH3:25])(C)C.[C:29](#N)[CH3:30]>O>[ClH:1].[N:23]1([C:2]2[C:3]3[S:19][CH:18]=[CH:17][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=3[F:16])[N:7]=2)[CH2:24][CH2:25][CH2:30][CH2:29][CH2:28][CH2:26]1
Reactant: Fc1cc(-c2nc(Cl)c3sccc3n2)c(F)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: CC#N
Solvent: O
Product: Cl
Product: Fc1cc(-c2nc(N3CCCCCC3)c3sccc3n2)c(F)cc1Cl
Temperature: 70 °C
Reaction time: 5 h

Procedure:
A mixture of 9.52 g of 4-chloro-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine, 3.13 g of hexamethyleneimine, 10.50 ml of diisopropyl ethylamine and 190 ml of acetonitrile was stirred for 5 hours at 70° C. 600 ml of water was added to the reaction mixture and the precipitate was filtered, washed with water and dried at 50° C. under reduced pressure. The obtained solid was dissolved in 40 ml of THF. The solution was added to 15 ml of 4M HCl-EtOAc solution and concentrated under reduced pressure to give a solid. Through recrystallization of this solid from EtOH-ether, 10.97 g of 4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine hydrochloride was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11](=[O:18])[NH:10][C:9]1=[O:19])(O)=[O:2].[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([C:1]([C:4]2[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=2)[CH2:7][N:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[O:2])[CH2:31][CH2:30]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
A mixture of 1-(3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (0.2 mmol), 1-(pyrimidin-2-yl)piperazine (0.2 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.26 mmol) and N,N-diisopropylethylamine (DIPEA, 0.4 mmol) in DMF (5 mL) was stirred at room temperature overnight. To the mixture was added 50 mL of water and it was extracted with EA (50 mL×3). The organic layer was washed by 1 N hydrochloric acid (50 mL×1) and saturated NaCl aquenous solution (50 mL×1), dried with anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by flash chromatography (DCM: MeOH=20:1) to give the title compound (20.43 mg, 23.3% yield) as white solid. 1H NMR (DMSO-d6): 11.35 (s, 1H), 8.39 (d, J=4.5 Hz, 2H), 7.48-7.41 (m, 1H), 7.36-7.24 (m, 3H), 6.67 (t, J=4.8 Hz, 1H), 5.10 (s, 2H), 3.88-3.20 (m, 8H), 2.46-2.42 (m, 2H), 2.25-2.21 (m, 2H), 1.69-1.43 (m, 4H). MS: m/z 447.4 [M+H]+.