Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH3+:2][C:3]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:17]([O-])=O.[Na+]>C(O)=O>[CH:17]1[N:15]2[C:16]3[C:3](=[CH:4][CH:5]=[CH:6][C:7]=3[O:8][C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:2]=1
Reactant: O=C[O-]
Reactant: [NH3+]c1cccc2c1Nc1ccccc1O2
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Product: c1ccc2c(c1)Oc1cccc3ncn-2c13
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18.45 g (78.6 mmol) of 1-ammoniophenoxazine chloride are suspended in 85 ml of 85% strength formic acid. After addition of 5.38 g (78.6 mmol) of sodium formate, the reaction mixture is refluxed for 3.5 hours. After cooling to room temperature, the reaction mixture is precipitated in 700 g of 10% strength NaOH and stirred for another 30 minutes. The solid is filtered off with suction on a “black band” filter, washed with water and dried at 70° C. under reduced pressure. The crude product (16.35 g) is stirred in 160 ml of methanol for 2 hours, subsequently filtered off with suction, washed with methanol and dried at 70° C. This gives 13.09 g (80% of theory) of gray needles which melt at 177-181° C. (lit.: 177-178° C.).
Reaction SMILES: [OH-].[Na+].[CH3:3][CH:4]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8]CC)=[O:7]>CO.O>[CH3:3][CH:4]([C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CC(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(CC(=O)O)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium hydroxide (0.19 g, 4.8 mmol) was added to a solution of ethyl 3-methyl-3-pyridin-4-ylpropanoate (Method 8; 0.501 g, 2.6 mmol) in MeOH (10 ml) and water (5 ml). The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuc and the residue shaken with 1 M hydrochloric acid (4.8 ml). The solvent was removed in vacuo to leave a colourless solid. M/z′164 (M-H)−.
Reaction SMILES: [CH2:1]([C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].N[CH2:15][CH2:16][OH:17].N>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C.C(O)CCC>[CH2:1]([C:12]1[O:17][CH2:16][CH2:15][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: N
Agent: [Cd+2]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCCC1=NCCO1
Temperature: 125 °C
Yield: 88 %

Procedure:
The reaction was carried out under nitrogen atmosphere in a three neck flask equipped with a magnetic stirring bar, reflux condenser, addition funnel and thermometer. 50 ml of 1-butanol and 667 mg (2.5 mmoles) of cadmium acetate dihydrate was introduced and the catalyst was dissolved by slight warming. 18.13 g (100 mmoles) of undecyl cyanide was added and the solution was heated to 125° C. 7.33 g (120 mmoles) of 2-aminoethanol was then added dropwise controlling the evolution of ammonia. At the end of the reaction (ca. 48 hrs.) the solvent was removed under vacuo. The residue was treated with 100 ml of petroleum ether and filtered after keeping for several hours. The filtrate was washed with water, dried over anhydrous magnesium sulfate, concentrated and the residue was distilled 114° C./0.5 mm to give 19.83 g (88%) of 2-undecyl-2-oxazoline.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:27]=[CH:26][C:25](OS(C(F)(F)F)(=O)=O)=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:38].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:76]([O:78][CH2:79]C)C>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:76][O:78][C:79](=[O:38])[C:25]1[CH:24]=[CH:23][C:22]([C:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)=[CH:27][CH:26]=1
Reactant: CS(C)=O
Reactant: CCOCC
Reactant: COc1cccc(C2(c3ccc(OS(=O)(=O)C(F)(F)F)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of trifluoro-methanesulfonic acid 4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-phenyl ester (10.0 g, 19.8 mmol) in a Parr pressure bottle in MeOH (69 mL) were added DMSO (62 mL) and triethylamine (21.8 mL, 157 mmol). To the reaction mixture were added palladium acetate (2.2 g, 9.1 mmol) and 1,3-bis(diphenylphosphino)propane (3.75 g, 9.1 mmol). The mixture was shaken under 40 psi of CO at 70° C. for 4 hours. The reaction mixture was cooled to room temperature and was diluted with diethyl ether (600 mL). The ether layer was washed with water (5×60 mL), dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with hexanes/EtOAc (1:1) to afford 6.9 g (85% yield) of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methyl ester. 1HNMR (400 MHz, CDCl3) δ 7.91 (d, 2H), 7.32 (d, 2H), 7.28-7.16 (comp, 6H),), 6.82 (d, , 1H), 6.79 (s, 1H), 6.68 (dd, 1H), 3.86 (s, 3H), 3.74 (s, 3H), 3.38 (s, 2H), 2.47-2.44 (comp, 8H); MS (M+1) 416.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([F:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.[Cl:36]CCl.CO>>[ClH:36].[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][C@H:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH:9]4[C:13]5=[C:14]([F:22])[CH:15]=[N:16][C:17]6[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=65)[CH2:10]4)[CH2:4][C@H:3]3[OH:23])[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(F)c2c43)C[C@H]1O
Reactant: ClCCl
Reactant: O=Cc1cc2c(cn1)OCCO2
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(F)c3c2n1CC3CN1CC[C@H](NCc2cc3c(cn2)OCCO3)[C@H](O)C1

Procedure:
The free base of the title compound was prepared from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-fluoro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c)) according to the general method of Example 2(h), chromatographing with dichloromethane/methanol/0.88 ammonia 95:5:0.5 (20 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[N:3](S(C2C=CC=CC=2)(=O)=O)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+]>CO.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:7]=[CH:6][CH:5]=2
Reactant: Cc1cc2c(C(F)(F)F)cccc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cc2c(C(F)(F)F)cccc2[nH]1
Yield: 138.7 %

Procedure:
A mixture of 2-methyl-1-(phenylsulfonyl)-4-(trifluoromethyl)-1H-indole (13.5 g, 39.82 mmol; step C above) and K2CO3 (27.5 g) in MeOH/H2O (2:1, 300 mL) was heated at reflux temperature. After 14 h the mixture was cooled and concentrated in vacuo. The residue was partitioned between Et2O/H2O, the layers were separated and the aqueous layer was extracted with Et2O (×2). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via column chromatography (SiO2, 1:1 EtOAc/hexanes eluent), affording 11.0 g of the deprotected indole as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.46 (s, 1H), 2.48 (s, 3H); MS (ES) m/z 200 (M+1).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]=O.Cl.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH3:12])[CH2:17][CH2:10][C:9](=[O:11])[CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)C=Cc1ccccc1
Agent: Cl
Product: CN(C)CCC(=O)C=Cc1ccccc1

Procedure:
Analogously to Examples 1 and 2, 4-phenyl-3-butene-2-one is reacted with paraformaldehyde, HCl and dimethylamine to produce 5-dimethylamino-1-phenyl-1-penten-3-one. 2.2 g of this amine and 16.1 g of methyl iodide are combined in 40 ml of diethyl ether and the mixture is stirred. After 10 minutes a white precipitate forms, and after 30 minutes, 50 ml of diethyl ether is added to maintain a stirrable slurry. The precipatate is filtered, washed with diethyl ether and dried in a dessicator to produce E-N,N,N-trimethyl-3-ox-5-phenyl-4-penten-1-aminium iodide, m.p. 204°-206° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:25])[CH3:24])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[C:31]=1[F:38].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCCC>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[C:3](=[O:27])[N:4]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([OH:26])([CH3:24])[CH3:25])[N:18]=3)[CH:11]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([CH3:37])[C:31]=1[F:38]
Reactant: Cc1c(F)ccc(CBr)c1F
Reactant: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(O)c(Cl)c1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(OCc2ccc(F)c(C)c2F)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.5 %

Procedure:
To a solution of 3-chloro-4-hydroxy-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (386 mg, 1.0 mmol) in N,N-dimethylformamide (1.7 mL) was added 1-(bromomethyl)-2,4-difluoro-3-methylbenzene (243 mg, 1.1 mmol), potassium carbonate (0.35 g, 2.52 mmol) and 18-crown-6 (7 mg). The slurry was stirred at ambient temperature for 18 hours. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The solution was concentrated in vacuo to provide a brown oil. Normal phase chromatography (ethyl acetate/heptane) provided 319 mg of the alkylated product: MS (M+H) 528.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].[OH2:33]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([O:33][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccccc2O)CC1
Reactant: CCOC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.5 g of [1-(benzyloxycarbonyl)piperidin-4-yl]phenol in 20 ml of N,N-dimethylformamide was added 0.083 g of sodium hydride (60% or more oily) and the resulting mixture was stirred at room temperature for 10 minutes. Next, ethyl iodoacetate was added thereto and the resulting mixture was reacted at 60° C. for 1.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.4 g of the title compound as a colorless oily substance.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[O:9])=[CH:10][CH:11]=1)=[O:2]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Yield: 86.6 %

Procedure:
In an analogous manner to 21, 4-formylbenzoic acid (600 mg, 3.99 mmol) was reacted with tert-butyl piperazine-1-carboxylate (818.8 mg, 4.40 mmol) to afford desired product as off-white solid (1.1 g, 86.6%).
Reaction SMILES: CS(C)=O.[OH-].[Na+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[CH3:33][C:34]1[CH2:35][C:36]([CH:46]([CH3:50])[CH2:47][CH:48]=O)([O:44][CH3:45])[C:37]([CH3:43])=[C:38]([CH3:42])[C:39]=1[O:40][CH3:41]>O.C1COCC1>[CH3:45][O:44][C:36]1([CH:46]([CH3:50])[CH2:47][CH:48]=[CH:13][CH2:12][CH2:11][C:8]([OH:10])=[O:9])[C:37]([CH3:43])=[C:38]([CH3:42])[C:39]([O:40][CH3:41])=[C:34]([CH3:33])[CH2:35]1
Reactant: COC1=C(C)CC(OC)(C(C)CC=O)C(C)=C1C
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC1=C(C)CC(OC)(C(C)CC=CCCC(=O)O)C(C)=C1C
Temperature: 80 °C
Yield: 62 %

Procedure:
DMSO (30 ml) was added to sodium hydroxide (1 g, 24 mmole, 60% oil suspension was washed with hexane and dried under reduced pressure) under an atmosphere of argon, followed heating at 80° C. for 1 hour with stirring. After cooling, 3-carboxypropyltriphenyl phosphonium bromide (4.6 g, 11 mmole) was added to the solution, followed by stirring at room temperature. After stirring for 10 minutes, a THF solution (5 ml) of 3-(3,5,6-trimethyl-1,4-dimethoxyphenyl)butanal (2.7 g, 11 mmole) was added dropwise to the mixed solution. The reaction solution was stirred at room temperature for 2 hours, and water (50 ml) was added to it. The organic layer was washed with toluene (100 ml), and the water layer was adjusted to pH 4 with 2N hydrochloric acid, followed by extraction with IPE. The organic layer was washed with water, dried and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluting solution: IPE) to give 7-(1,4-dimethoxy-3,5,6-trimethylphenyl)-4-octenoic acid (2.2 g, 68%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.CCOCC>C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:8]=[O:9])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1CCC(C=O)(c2ccccc2)CC1

Procedure:
Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate (2.7 g, 10 mmol) was dissolved in dry toluene (30 ml). The stirred solution was cooled to -63° C. under an atmosphere of N2, whereafter a solution of diisobutylaluminiumhydrid (DIBAH, 1 M, 20 ml) was added dropwise. Stirring was continued at -70° C. for 11/2 h, whereafter methanol (5 ml) was added, in order to destroy excess of DIBAH. At ambient temperature water (50 ml) was added, and the mixture was filtered through a pad of filter aid. The organic phase was dried over Na2SO4 and evaporated to leave an oily residue. Treatment with ether afforded precipitation of the side product 4-hydroxymethyl-1-methyl-4-phenylpiperidine as pale crystals. Filtration followed by evaporation of the filtrate left the title compound as an oil, which was processed without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[F:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][C:51]([N:53]=[C:54]=[S:55])=[O:52])=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:54]([NH:53][C:51](=[O:52])[CH2:50][C:47]2[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=2)=[S:55])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH:8]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 0.08 h
Yield: 36.8 %

Procedure:
After dissolving 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (70.3 mg) in ethanol (2 ml) under a nitrogen atmosphere, D-10-camphorsulfonic acid (43.7 mg) was added and the mixture was stirred for 5 minutes. A 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (1.02 ml) was added thereto, and the mixture was stirred for 17.5 hours. Then, a 0.24 M solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.3 ml) was further added to the reaction mixture, and stirring was continued for 30 minutes. Ethyl acetate (30 ml) and saturated aqueous sodium hydrogencarbonate (20 ml) were added to the reaction mixture for partition. The organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:8), and then fractions containing the target compound were concentrated under reduced pressure. Diethyl ether (1 ml) and hexane (2 ml) were added to the resultant residue to produce a suspension. After filtering the solid, it was subjected to aeration drying to provide the title compound (39.4 mg, 36.8%) as pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[B:10]([OH:17])[O:11][CH:12]([CH2:13][N+:14]([O-:16])=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH3:2].C1C(=O)N([Cl:25])C(=O)C1>CN(C=O)C>[Cl:25][C:7]1[C:8]2[CH:12]([CH2:13][N+:14]([O-:16])=[O:15])[O:11][B:10]([OH:17])[C:9]=2[C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cl)c2c1B(O)OC2C[N+](=O)[O-]

Procedure:
To a solution of 7-ethoxy-3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (42 g, 0.18 mol) in DMF (200 mL) at 80° C. was added a solution of NCS (11.8 g, 0.18 mol) in DMF (50 mL) in 30 min. The reaction was quenched with an aqueous solution of LiCl solution (500 mL) and the resulting mixture was extracted by EtOAc (3×250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the compound as white solid. (39.7 g, contaminated with 18% C6-C1 regioisomer). The mixture was then re-crystallized from Ether/PE (1/5) to give the pure compound (28 g, yield 46.3%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 7.50-7.48 (d, 1H), 6.98-6.96 (d, 1H), 5.77-5.74 (d, 1H), 5.35-5.31 (d, 1H), 4.73-4.67 (m, 1H), 4.12-4.07 (m, 2H), 1.34-1.28 (t, 3H).