Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:16][CH:15]=2)=[N:11][CH:12]=1.[CH:45](=O)[CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][N:6]([CH2:45][CH3:46])[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:19]=2)=[N:11][CH:12]=1
Reactant: O=C(CNCc1ccc(Oc2ccc(NCc3ccc(Cl)c(Cl)c3)cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(Cc1ccc(Cl)c(Cl)c1)c1ccc(Oc2ccc(CNCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)ethanone (1.59 g, 2.5 mmol) was dissolved in dichloroethane (80 mL). To this solution were added acetoaldehyde (1.40 mL, 25.0 mmol) and sodium triacetyloxy borohydride (1.59 mL, 7.5 mmol) under ice cooling. To the resulting solution was added dropwise acetic acid (0.43 mL, 7.5 mmol), and this solution was stirred at room temperature for 16 hours. The resulting reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=50:1). The obtained solid was recrystallized from ethanol, to thereby yield 0.65 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13](OC)(=[O:18])[C:14]([O:16][CH3:17])=[O:15].[H-].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:13](=[O:18])[C:14]([O:16][CH3:17])=[O:15])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)=O
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.8 %

Procedure:
To dimethylformamide (13 ml), 1-(4-chloro-2-methoxyphenyl)ethanone (3.13 g) and dimethyl oxalate (2.4 g) were added, and 60% sodium hydride suspension in oil (811 mg) was added thereto at 0° C. The mixture was stirred at a room temperature for one hour, and then heated to 50° C. and stirred for 19 hours. The mixture was allowed to cool to a room temperature, 3-N hydrochloric acid was added to the mixture. The resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated saline solution in order, then dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure. In the process of the concentration, the precipitated crystal was separated by filtration to give the title compound (2.47 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]([OH:14])=O)=[CH:5]2.[NH2:15][C@@H:16]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)=[O:18]>>[CH2:24]([C@H:16]([NH:15][C:12]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[F:11])=[O:14])[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][S:21][CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2cc(F)cc(F)c2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCSC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCSC1)c1cc2cc(F)cc(F)c2[nH]1

Procedure:
From 5,7-difluoro-1H-indole-2-carboxylic acid and (S)-2-amino-3-phenyl-1-thiazolidin-3-yl-propan-1-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]=[CH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH3:18][CH:19]([N+:30]#[C-:31])S(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[C:6]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[C:19]([CH3:18])[NH:30][CH:31]=1)=[O:17])[CH3:2]
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C=Cc1cccc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c[nH]c(C)c1-c1cccc2ccccc12
Yield: 66 %

Procedure:
4.3 g(18.9 mmol) of 3-(naphthalen-1-yl)-acrylic acid ethylester prepared in Preparation 6-1) and 3.95 g(18.9 mmol) of α -methyltosylmethylisocyanide disclosed in A. M. van Leusen, et al., Tetrahedron Letter, 1975, 40, 3487 were dissoved in 100 ml of tetrahydrofuran. 2.55 g(22.7 mmol) of potassium t-butoxide dissolved in 100 ml of tetrahydrofuran was slowly added thereto, which was then refluxed for 30 minutes. To the reaction solution was added 100 ml of water to stop the reaction and the solvent was removed under reduced pressure. The residue was extracted with diethylether, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to silica gel column chromatography using a solvent mixture of ethyl acetate/n-hexane(1/3, v/v) as an eluent to give 3.50 g(12.5 mmol, Yield 66%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][OH:7].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.N1C=CC=CC=1>ClCCl>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:7][CH2:6][CH2:5][C:4]#[C:3][Si:2]([CH3:9])([CH3:8])[CH3:1])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[Si](C)(C)C#CCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 77.6 %

Procedure:
A mixture of 4-(trimethylsilyl)but-3-yn-1-ol (1.00 mL; 6.00 mmol), 4-methylbenzene-1-sulfonyl chloride (2.29 g; 12.01 mmol), pyridine (0.970 mL; 12.00 mmol) in dichloromethane (15 mL) was stirred at room temperature for 60 hours. The reaction mixture was washed with an aqueous solution of saturated ammonium chloride, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 2 to 40% ethyl acetate in heptane) to yield 1.38 g (76%) of 4-(trimethylsilyl)but-3-ynyl 4-methylbenzenesulfonate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:28]COCC>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]2[S:11][C:12]3[C:13](=[CH:14][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[CH2:28][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCC
Reactant: CC(C)(C)c1ccc(Sc2ccc(C(C)(C)C)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1S2
Yield: 72 %

Procedure:
The red oil obtained as described above from 12 g of bis-(4-t-butylphenyl)-sulfide was dissolved in 100 mL of dry ether, and the solution added dropwise over 15 min. to a suspension of 2.5 g of lithium aluminum hydride in 100 mL of dry ether while cooling in an ice bath. The mixture was refluxed for 3 hours, cooled and excess hydride destroyed by means of saturated ammonium chloride solution. The ether layer was washed with H2O and saturated NaCl solution, dried over MgSO4, and then evaporated to a white solid which was recrystallized from CH2Cl2 -hexane to give 9.0 g (72%) of the thioxanthene as white crystals, m.p. 152°-154°, 'H NMR (CDCl3) δ 1.28 (s, 18H, CH3), 3.84 (s, 2H, CH2), 7.31 (m, 6H, aryl). Anal. calculated for C21H26S: C, 81.23; H, 8.44; S, 10.33. Found: C, 81.45; H, 8.61; S, 10.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:32](=[O:33])[NH:31][C:26]3[CH:27]=[CH:28][C:29]([Cl:30])=[C:24]([Cl:23])[CH:25]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(Cl)c(Cl)c3)C2=O)cc1
Reaction time: 4 h

Procedure:
The stirred solution of 4.1 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 75 ml of warm benzene and 2.4 g of triethylamine is combined with the solution of 3.8 g of 3,4-dichlorophenylisocyanate in 50 ml of benzene. After standing at ambient temperature for 4 hours, the benzene is evaporated, the residue taken up in methanol and the solution poured into 100 ml of 0.3 N hydrochloric acid. The mixture is allowed to stand overnight at room temperature, the precipitate is collected, washed with water, dried, triturated with benzene-ethyl acetate and recrystallized from methanol to yield the 1-(p-methoxyphenyl)-3-methyl-4-(3,4-dichlorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=OCH3, R'=3--Cl and R"=Cl, melting at 120°-125°, resolidifying and remelting at 228°-232° (dec.).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH3:11].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][Br:12]
Reactant: Cc1c(F)c(F)cc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(F)c(F)c(CBr)c1F
Temperature: 25 °C

Procedure:
A mixture of 2,3,5,6-tetrafluorotoluene (1.7 g), N-bromosuccinimide (1.9 g), dry carbon tetrachloride (10 ml) and benzoyl peroxide (0.01 g) was heated at the reflux temperature for 20 hours, cooled to the ambient temperature (ca.25° C.) filtered and the filtrate diluted with diethyl ether. The ethereal solution was washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvents to yield 2,3,5,6-tetrafluorobenzyl bromide as a mobile colourless oil.
Reaction SMILES: CS(C)=O.CS(O[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([Cl:27])=[C:14]([Cl:28])[CH:13]=1)(=O)=O.[C-:29]#[N:30].[K+]>CCOCC>[Cl:28][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:29]#[N:30])[CH:17]=[C:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]=1[Cl:27]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCOS(C)(=O)=O)cc(Cl)c1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCC#N)cc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a DMSO (0.4 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethyl methanesulfonate (1 eq.) from the previous step was added potassium cyanide (1.3 eq.). The resulting solution was stirred at 80° C. for 4 h. The reaction was then diluted with ether and quenched with water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to give the title compound as a pink oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH3:9][C:10]1[O:14][N:13]=[CH:12][C:11]=1[C:15](Cl)=[O:16]>O>[CH3:9][C:10]1[O:14][N:13]=[CH:12][C:11]=1[C:15]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:16]
Reactant: C1CCNCC1
Reactant: Cc1oncc1C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1oncc1C(=O)N1CCCCC1

Procedure:
0.4 mol (34.1 g) of piperidine and 40 ml of 10N sodium hydroxide solution are added dropwise to 0.4 mol (58.2 g) of 5-methyl-4-isoxazolecarboxylic acid chloride, emulsified in 300 ml of water, such that the temperature of the reaction mixture does not rise above 35° C. 40 ml of 2N sodium hydroxide solution are then added and the mixture is extracted with 300 ml methylene chloride. The aqueous phase is extracted once more by shaking with 200 ml of methylene chloride. The combined methylene chloride phases are washed with water and, after drying over sodium sulfate, evaporated to dryness under reduced pressure. N-(5-Methyl-4-isoxazolylcarbonyl)-piperidine is thus obtained, the product having, after recrystallization from methylcyclohexane, a melting point of 40° to 43° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[C:3]([O:5][C@H:6]([O:10][C:11]([O:13]N1C(=O)[C@@H](OC(=O)C2C=CC=CC=2)[C@H](OC(=O)C2C=CC=CC=2)C1=O)=O)[CH:7]([CH3:9])[CH3:8])=[O:4].[NH2:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH2:48][CH2:49][CH3:50])(=[O:46])[OH:45].C1COCC1>O>[C:3]([O:5][C@H:6]([O:10][C:11]([NH:40][CH2:41][CH2:42][CH2:43][P:44]([CH2:47][CH2:48][CH2:49][CH3:50])(=[O:45])[OH:46])=[O:13])[CH:7]([CH3:8])[CH3:9])(=[O:4])[CH:2]([CH3:1])[CH3:39]
Reactant: CC(C)C(=O)O[C@H](OC(=O)ON1C(=O)[C@@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)C1=O)C(C)C
Reactant: CCCCP(=O)(O)CCCN
Solvent: C1CCOC1
Solvent: O
Product: CCCCP(=O)(O)CCCNC(=O)O[C@@H](OC(=O)C(C)C)C(C)C
Temperature: 19 °C
Reaction time: 4 h

Procedure:
To a 3 L three necked round bottom flask fitted with a mechanical stirrer, temperature probe, and nitrogen inlet was added compound (25) (100 mmol), 3-aminopropyl(n-butyl)phosphinic acid (100 mmol), THF (1 L), and water (100 mL). The suspension was stirred under a nitrogen atmosphere at 18-20° C. for 4 h during which time the reaction mixture became homogeneous. The THF was removed in vacuo and the reaction mixture was diluted with methyl tert-butyl ether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL). The organic phase was separated and concentrated in vacuo to leave a white solid. The solid was purified by flash chromatography to afford the product (39) as a white solid. 1H-NMR (400 MHz, CD3OD): δ 6.74-6.70 (q, J=5.2, 1H), 4.06-3.96 (m, 1H), 3.22-3.21 (m, 2H), 2.547-2.477 (m, 1H), 1.92-1.84 (m, 2H), 1.52-1.48 (s, 3H), 1.142-1.138 (d, J=1.6, 3.0H), 1.124-1.121 (dd, J=1.6, 3.0H). Phosphorus (162 MHz, CD3OD): δ1.04; MS (ESI) m/z 346 (M+H)+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([O:14]CC)=[O:13])[C:7]2=[O:17].[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]([F:21])([F:19])[F:20])=[C:6]2[C:11]=1[NH:10][CH:9]=[C:8]([C:12]([OH:14])=[O:13])[C:7]2=[O:17]
Reactant: CCOC(=O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1c[nH]c2c(Cl)ccc(C(F)(F)F)c2c1=O
Temperature: 25 °C
Yield: 88.5 %

Procedure:
Ethyl 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylate (5A) (1200 g, 3.754 mol) was charged into a reaction vessel followed by the addition of 2-popanol (1.200 L) and water (7.200 L) and stirred. Sodium hydroxide (600.6 g, 7.508 mol) and water (1.200 L) were mixed and allowed to cool to room temperature. The resulting mixture was charged into the reaction vessel and then was heated to 80° C. with stirring for 3.5 h to generate a dark, homogenous mixture. After an additional hour, acetic acid (9.599 L of 20% w/v, 31.97 mol) was added via dropping funnel over 45 min. The reaction mixture was cooled with stirring to 22° C. at a rate of 6° C./h. The resulting solid was filtered and washed with water (3 L) to generate a wet cake (1436 g). The filtrate was dried in a vacuum oven with a nitrogen bleed over Drierite® to generate 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (5B) as a brown solid (1069 g). The 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (5B) was purified by slurrying in 1.5 L methanol and stirring for 6 h. It was then filtered and dried to furnish 968.8 g of purified 8-chloro-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (5B).
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([N+:26]([O-])=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1>[C].[Pd].C(OCC)(=O)C>[NH2:26][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: COc1cccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cccc(CCc2ccc(C(=O)OC(C)(C)C)c(N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a mixed solution of methanol 22 mL and ethyl acetate 22 mL of tert-butyl 4-((E)-2-(3-methoxyphenyl)vinyl)-2-nitrobenzoate 2.2 g was added 10% palladium-carbon 0.66 g, and it was stirred under hydrogen atmosphere at room temperature for 2 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=8:1] to give tert-butyl 2-amino-4-(2-(3-methoxyphenyl)ethyl)benzoate 1.6 g of colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:23][NH2:24].O>CS(C)=O>[F:1][C:2]1[C:3]([NH:24][CH3:23])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=C1c2cc(F)c(F)cc2OCN1c1ccc([N+](=O)[O-])cc1
Reactant: CN
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc([N+](=O)[O-])cc1)CO2
Temperature: 140 °C
Yield: 81 %

Procedure:
To 6,7-difluoro-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.05 g, 0.16 mmol) in dimethyl sulfoxide (0.5 ml) was added methyl amine (0.3 ml, 2M solution in tetrahydrofuran) and the reaction heated to 140° C. for 1 hr. Water was added and product extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to give 0.42 mg (81%) of 6-fluoro-7-(methylamino)-3-(4-nitrophenyl)-2,3-dihydrobenzo[e][1,3]oxazin-4-one. RP-HPLC: 2.38 min; ES-MS (M+H)+=318.0; 1H-NMR (DMSO-d6) δ (ppm): 3.1 (s, 3 H), 5.73 (s, 2 H), 6.2 (d, 1 H), 7.38 (d, 1 H), 7.61 (d, 1 H), 8.2 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13]OS(C)(=O)=O)[C:9]2=[O:19])=[CH:4][CH:3]=1.[CH2:20]([O:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:21]#[CH:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:29]3[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][O:23][CH2:20][C:21]#[CH:22])[CH2:27][CH2:28]3)[C:9]2=[O:19])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCC1CCN(c2ccc(Cl)cc2)C1=O
Reactant: C#CCOCCN1CCNCC1
Product: C#CCOCCN1CCN(CC2CCN(c3ccc(Cl)cc3)C2=O)CC1

Procedure:
The title compound was prepared from 1-(4-chlorophenyl)-3-mesyloxymethyl-2-pyrrolidinone and 1-(2-(2-propynyloxy)ethyl)piperazine, in the same manner as in Preparation Example 1(8).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>ClCCl.C(#N)C>[Br:41][C:22]1[CH:23]=[CH:24][C:19]2[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15][N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C:20]=2[C:21]=1[CH3:25]
Reactant: Cc1cccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(Br)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 5 °C
Reaction time: 12 h

Procedure:
To a solution of the product of Step C (0.95 g, 2 mmol mol) in dichloromethane (5 ml) and acetonitrile (50 ml) was added NBS (0.35 g, 2 mmol mol) in portions at 0° C. After stirring at 5° C. for 12 h, the reaction mixture was concentrated, and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.13 (m, 5H), 6.52 (m, 2H), 5.20 (d, J=16.8 Hz, 1H), 4.34 (d, J=16.8 Hz, 1H), 2.65 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH2:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](Cl)=[O:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:15][N:14]=[C:13]([CH3:16])[C:12]=2[NH:17][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(Cl)c1ccccn1
Reactant: COc1ccc(-c2[nH]nc(C)c2N)cc1OC
Product: COc1ccc(-c2[nH]nc(C)c2NC(=O)c2ccccn2)cc1OC

Procedure:
The preparation took place in analogy with Example 15a), starting with 200 mg of 5-(3,4-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-ylamine (44) and 168 mg of pyridine-2-carbonyl chloride*HCl. The following was obtained: 55 C18H18N4O3 (338.37); MS (ESI) 339 (M+H)
Reaction SMILES: O[NH:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].CO>[Ni].C(O)(=O)C>[C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)(=[NH:2])[NH2:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Agent: [Ni]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
Into a 2-L round-bottom flask purged and maintained with an inert atmosphere of argon, was placed tert-butyl 4-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate (46.5 g, 181.56 mmol, 1.00 equiv, 95%), methanol (1500 mL), acetic acid (20 mL), and Raney-Ni (13 g). The reaction system was bubbled for 5 times with hydrogen. The resulting mixture was stirred for 3 h at 50° C. in an oil bath. The solids were filtered out. The resulting solution was concentrated under vacuum to afford 40 g of tert-butyl 4-carbamimidoylpiperidine-1-carboxylate as yellow green crude oil, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 278.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])O)=[CH:5][CH:4]=1.[NH3:12].CO.[Cl-].[NH4+]>CCO>[ClH:1].[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:12])=[NH:9])=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=N)O)cc1
Reactant: N
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Product: Cc1ccc(C(=N)N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
To a solution of p-methylbenzimidate hydrochloride (8.00 g, 43.09 mmol) in MeCH (100 ml) is added NH3 /MeOH solution (2.68M, 24.12 ml, 64.64 mmol). Upon the addition of the NH3, the mixture has a pH around 8.5. To this solution is added ammonium chloride (2.30 g, 43.09 mmol). The reaction mixture is stirred at room temperature for 20 hours, then cooled in refrigerator and the precipitate is removed by filtration. The mother liquor is concentrated to yield the crude product which is taken up in a limited amount of cold EtOH and the white preciptate is filtered. The beige filtrate is concentrated to yield p-methylbenzamidine hydrochloride as an off-white solid (7.15 g, 97%).