Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O>O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Product: O=C(O)c1cc(-c2nc(-c3ccccc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 39 %

Procedure:
2′-Nitro-4-(4-phenyl-thiazol-2-yl)-biphenyl-2-carboxylic acid (100 mg, 39%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 2-bromoacetophenone (available from Chem-Impex International, Inc.) using the procedure described for the preparation of Example 18 except that the entire 4 mL of water was added at the beginning of the hydrolysis step rather than being added in two portions. 1H NMR (300 MHz, DMSO-d6) δ 13.16 (br s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.06-8.28 (m, 5H), 7.36-7.82 (m, 7H).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7](O)=[O:8].[CH2:11]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O.[Cu]>[CH2:11]([C:18]1[CH:19]=[CH:20][C:21]2[NH:22][C:2]3[CH:3]=[N:4][N:5]([CH3:10])[C:6]=3[C:7](=[O:8])[C:23]=2[CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1ncc(I)c1C(=O)O
Reactant: Nc1ccc(Cc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4)cc3c(=O)c21
Temperature: 100 °C
Reaction time: 17 h
Yield: 50 %

Procedure:
A mixture of 4-iodo-1-methyl-1H-pyrazole-5-carboxylic acid ((Manaev, Yu. A. et al., J. Gen. Chem. USSR (Engl. Transl.), 1982, 52 (11), 2291), 8.0 g, 31.74 mmol), 4-benzylaniline (21.03 g, 114.76 mmol) and copper powder (3.2 g) in a mixture of 5% aqueous sodium carbonate (160 ml) and dimethylsulfoxide (80 ml) was stirred for 17 h at 100° C. After cooling to room temperature, the mixture was filtered through a pad of Celite, which was washed with water, 2N aqueous sodium hydroxide and diethyl ether. The separated water layer was washed with diethyl ether (100 ml×2). The water layer was acidified with concentrated hydrochloric acid and the formed solid was collected by filtration, dried, to give 4.86 g (50%) of the pure title compound as a pale brown solid.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([Br:26])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.CO.[OH-].[Na+]>O>[Br:26][C:16]1[CH:17]=[C:18]([S:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Br)cc1Sc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NC(=S)Nc1ncc(Br)cc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To 1-Benzoyl-3-(5-bromo-3-(phenylthio)pyridin-2-yl)thiourea (25.7 g, 57.8 mmol) and MeOH (250 mL) was added sodium hydroxide (38.6 mL, 116 mmol) and stirred at ambient temperature for 8 hours. Diluted with water (250 mL) and filtered and washed with water. The precipitate was dried in vacuum oven to afford the title compound (19.0 g, 96.5% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2[CH:29]=[C:30]([N+:33]([O-:35])=[O:34])[CH:31]=[CH:32][C:25]=2[S:24]1(=[O:37])=[O:36]>>[O:37]=[S:24]1(=[O:36])[C:25]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:26]=2[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1CCCCBr
Reactant: O=c1ccc2ccccc2n1C1CCNCC1
Product: O=C1c2cc([N+](=O)[O-])ccc2S(=O)(=O)N1CCCCN1CCC(n2c(=O)ccc3ccccc32)CC1

Procedure:
From the hydrochloride salt of 1-(4-piperidyl)-2(1H)-quinolinone prepared according to H. Ogawa et. al. J. Med. Chem. 1993, 36, 2011-2017, and 2-(4-bromobutyl)-5-nitro-1,1-dioxido-1,2-benzothiazol-3(2H)-one using the procedure described for Example 15, Step 5 there was obtained a white solid: 1H NMR (300 MHz, CDCl3) 8.88 (d, J=1.9 Hz, 1H), 8.73 (dd, J=8.36, 1.71 Hz, 1H), 8.15 (d, J=8.36 Hz, 1H), 7.79 (br m, 1H), 7.62 (d, J=3.47 Hz, 1H), 7.51 (m, 2H), 7.20 (m, 2H), 6.66 (d, J=9.33 Hz, 1H), 3.91 (t, J=7.33 Hz, 2H), 2.85 (br m, 2H), 2.48 (t, J=8.27 Hz, 2H), 2.21 (t, J=10.65 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.C([O:40][C:41](=O)[C:42]1[C:47]([CH2:48]Br)=[CH:46][CH:45]=[CH:44][C:43]=1[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[CH2:48][C:47]4[C:42](=[C:43]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:52])[CH3:53])[CH:44]=[CH:45][CH:46]=4)[C:41]3=[O:40])[N:13]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[CH2:12][C:11]=2[S:10][C:9]=1[NH2:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(CBr)cccc1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CN2Cc3sc(N)c(C(=O)OC(C)(C)C)c3CC2CN2Cc3cccc(O[Si](C)(C)C(C)(C)C)c3C2=O)cc1
Reaction time: 12 h
Yield: 66.1 %

Procedure:
To a solution of 2-amino-5-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (3.00 g, 7.45 mmol) and diisopropyl ethylamine (1.93 ml, 11.2 mmol) in acetonitrile at room temperature was added a solution of 6-bromomethyl-2-(tert-butyl-dimethyl-silanyloxy)-benzoic acid ethyl ester (2.78 g, 7.45 mmol) in acetonitril over 48 hours. The solution was stirred for 12 hours after the addition was complete. The volatiles were evaporated in vacuo and the residue was taken into ethyl acetate (50 ml) and washed with water, 1 N hydrochloric acid, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was chromatographed on silica gel column eluted with a mixture of 20% ethyl acetate/Hexane, which afforded 3.2 g (66%) of 2-amino-5-(7-(tert-butyl-dimethyl-silanyloxy)-1-oxo-1,3-dihydro-isoindol-2-ylmethyl]-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 63.4 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propylamine (348 mg, 1.3 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (310 mg, 1.3 mmol) and DIPEA (1.1 mL, 6.4 mmol) in IPA (4 mL) was heated for 72 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) to afford 247 as a white solid (320 mg, 63%). LCMS (Method K): RT 3.17 min [M+H]+ 389.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.85 (1H, br s), 8.65 (1H, s), 8.15-8.03 (2H, m), 7.99 (1H, s), 7.84-7.76 (2H, m), 7.71 (1H, dd, J=8.75, 4.90 Hz), 7.55-7.48 (1H, m), 7.20-7.08 (2H, m), 5.73 (1H, s), 2.15-2.06 (1H, m), 2.05-1.95 (1H, m), 0.90 (3H, t, J=7.30 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH3:39][C:40](=[CH2:42])[CH3:41].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([O:16][C:40]([CH3:42])([CH3:41])[CH3:39])[CH2:13][N:12]1[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Reactant: C=C(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Tert-Butyletherification: To a solution of (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (14.8 g) in dichloromethane (140 ml) were added boron trifluoride ethyl etherate (3 ml) and isobutylene (cooled and liquefied at −30° C., 170 ml) at −30° C. The turbid reaction mixture was stirred at −20° C. for 2 h, poured onto a saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:4 and 1:2 as eluents to obtain (2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (16.4 g) as a glassy syrup, MS: 467 (M).
Reaction SMILES: F[C:2]1[CH:16]=[C:15](I)[CH:14]=[CH:13][C:3]=1[C:4]([O:6][CH2:7][CH2:8][Si](C)(C)C)=[O:5].[CH:18](C1C=CC(C(O)=O)=CC=1)=[CH2:19]>>[CH:18]([C:15]1[CH:14]=[CH:13][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][CH:16]=1)=[CH2:19]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(I)cc1F
Product: C=Cc1ccc(C(=O)OCC)cc1

Procedure:
Employing the same general procedure as for the preparation of trimethylsilanylethyl 2-fluoro-4-iodobenzoate (Compound D), 323 mg (2.2 mmol) of 4-vinylbenzoic acid was converted into the title compound using 462 mg (2.4 mmol) of 1-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride), 264 mg (2.2 mmol) of 4-dimethylaminopyridine, 0.32 ml (250 mg, 5.45 mmol) of ethanol and 16 mL of dichloromethane. Purification by flash chromatography (silica, 10% ethyl acetate in hexane) gave the title compound as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.[O-]S([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=[CH:18][N+:19]=1[O-:31]
Reactant: CCOC(=O)c1cccnc1-c1ccc(F)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc[n+]([O-])c1-c1ccc(F)cc1F
Temperature: 30 °C

Procedure:
To a nitrogen purged, 12 L, 5-necked flask, fitted with an overhead stirrer, a thermocouple and a condenser, was charged ethyl 2-(2,4-difluorophenyl)nicotinate, 3 (144 g, 548 mmoles, 1.0 eq), and 4 L of CH2Cl2. With stirring, mCPBA was added over 5 minutes, and the temperature was gradually increased from 22 to 38° C. in 45 minutes (completeness of reaction determined by HPLC). The reaction was cooled to room temperature and the contents slowly poured into 3 L of water. Na2SO3 was added slowly (exotherm from 20 to 33° C.) until the peroxide test (starch/I2 paper) indicated no peroxides remained in the mixture. The aqueous layer was separated and the organic layer was washed with saturated NaHCO3 (˜3 L). The organic layer was dried with MgSO4, filtered, and concentrated to a brown thick oil. The oil was then treated with MTBE (2 L) and stirred to give a white precipitate, which was collected by filtration, washed with MTBE and dried under vacuum to give the title Compound 4.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=O)(C)(C)C.[ClH:20].CO>>[ClH:20].[NH2:8][CH2:9][C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CCOC(=O)CCNC(=O)CN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2.0 Grams of ethyl 3-(2-{(tert-butoxycarbonyl)amino}acetylamino)propionate were dissolved in 30 ml of 10% hydrochloric acid-methanol and stirred for 15 hours at room temperature. Upon distilling the reaction liquid off under reduced pressure, 1.52 g of the title compound was obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6](=[O:23])[C:7](=[O:22])[C:8]=1[Sn](CCCC)(CCCC)CCCC)([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1I.CN(C)C=O>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.C(OCC)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:8]1[C:7](=[O:22])[C:6](=[O:23])[C:5]=1[O:4][CH:1]([CH3:2])[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(OC(C)C)c(=O)c1=O
Reactant: Brc1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1c(-c2ccccc2Br)c(=O)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-isopropoxy-4-tributylstannyl-cyclobut-3-ene-1,2-dione (4.68 g; preparable as described in Liebeskind and Fengl, Journal of Organic Chemistry (1990), Vol.55, pp 5359/5364), 1-bromo-2-iodobenzene (3.54 g), dry dimethylformamide (15 ml), tetrakis(triphenylphosphine)palladium(0) (0.606 g) and cuprous iodide (0.196 g) was stirred under a nitrogen atmosphere at ambient temperature for approximately 2.5 hours then kept at ambient temperature for 3 days. Diethyl ether (225 ml) was added, and the mixture obtained was washed with saturated aqueous ammonium chloride (225 ml) and then with 10% aqueous potassium fluoride solution (3×225 ml). The organic phase was filtered through a silica bed (5 cm diameter×1 cm depth), and the collected solids were washed with diethyl ether (50 ml). The resulting orange filtrate and washings were combined and evaporated to give a semi-solid brown oil, which was purified by flash chromatography on silica gel (loading in dichloromethane and eluting with 20% diethyl ether in petroleum ether (b.p. 40°-60° C.)) to give the intermediate compound 3-(2-bromophenyl)-4-isopropoxycyclobut-3-ene-1,2-dione, as a yellow oil (2.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[N+:9]([C:12]1[C:17](Cl)=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:9]([C:12]1[C:17]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([O-:11])=[O:10]
Reactant: Sc1ccccc1Cl
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(Sc2ccccc2Cl)c1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 2-chlorobenzenethiol (8.0 g.), ethyl 2-(2-nitro-3-chlorophenyl)acetate (12.2 g.), anhydrous potassium carbonate (7.5 g.) and dry dimethylformamide (50 ml.) was stirred for an hour at 85° C. The reaction mixture was poured into water (300 ml.) and extracted with diethyl ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. The oily residue was pulverized and recrystallized from methanol (20 ml.) to give the captioned compound (11.6 g.). mp 78° to 80° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[NH:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])=[N:18]1>>[F:16][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[N:7][C:2]([NH:25][C:24]2[CH:26]=[CH:27][CH:28]=[C:22]([C:19]3[CH:20]=[CH:21][NH:17][N:18]=3)[CH:23]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(-c2cc[nH]n2)c1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(Nc3cccc(-c4cc[nH]n4)c3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine with 3-(1H-pyrazol-3-yl)aniline gave 5-fluoro-N4-(3-hydroxyphenyl)-N2-[3-(1H-pyrazol-3-yl)phenyl]-2,4-pyrimidinediamine. LCMS: purity: 84%; MS 363 (MH+)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=2[N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=O)[CH2:4][CH2:3]1>P(Cl)(Cl)(Cl)=O>[Br:17][C:15]1[CH:14]=[CH:13][C:12]2[N:18]3[CH2:19][CH2:20][CH2:21][C:22]4=[CH:23][CH:24]=[CH:25][C:26](=[C:27]34)[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[N:10][C:11]=2[CH:16]=1
Reactant: CN1CCN(C(=O)Nc2cc(Br)ccc2N2CCCc3ccccc32)CC1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3cc(Br)ccc3N3CCCc4cccc2c43)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
A stirred solution of 4-methyl-N-[5-bromo-2-(1,2,3,4-tetrahydro-1-quinolinyl)phenyl]piperazinecarboxamide (8.6 g, 0.020 mole) in phosphorus oxychloride (200 ml) was heated under reflux under nitrogen for 6 hours. The reaction mixture was cooled to room temperature and excess phosphorus oxychloride was removed at aspirator pressure with heating. The residue was chilled in an ice-bath (with exclusion of moisture), and treated with ice-cold 2N sodium hydroxide solution (250 ml) and dichloromethane (250 ml). The mixture was stirred and triturated until the residue dissolved. The organic phase was separated, washed again with 2N sodium hydroxide solution, twice with water, dried over sodium sulfate, and concentrated in vacuo. The residue was taken up in 4N hydrochloric acid (100 ml), filtered, and the filrate was stirred 15 minutes with charcoal. After filtration, the solution was stirred with dichloromethane (100 ml), and the mixture was made alkaline by the addition of cold 2N sodium hydroxide solution. The organic phase was separated, washed twice with water, dried over sodium sulfate, and boiled 15 minutes with charcoal. After filtration, the solution was concentrated to give 4.6 g (56%) of product, as an oil, which crystallized on standing. The product was taken up in boiling methanol (20 ml) and allowed to crystallize first at room temperature, then in the refrigerator. Recrystallization from methanol afforded the analytical sample, mp 153°-156° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][CH3:12])[C:7]=1[CH3:13])=[O:5])[CH3:2].C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][CH3:12])[C:7]=1[CH2:13][Br:21])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(CC)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(CC)c1CBr
Temperature: 25 °C
Yield: 20.6 %

Procedure:
3-Ethyl-4-methyl-isoxazole-5-carboxylic acid ethyl ester (3.5 g, 19.1 mmol), NBS (3.4 g, 19.1 mmol), and benzoyl peroxide (0.46 g mg, 1.91 mmol) were added to 110 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% EtOAc/hexanes) to give 1.03 g of the title compound. MS: (+) m/z 262.17, 264.14 (M+1, 79Br/81Br).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[C:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH:13]([CH3:15])[CH3:14].C([O-])(=O)C.[Na+]>O>[CH2:21]([O:20][C:18]([C:17]1[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:3][NH:2][C:12]=1[CH:13]([CH3:15])[CH3:14])=[O:19])[CH3:22]
Reactant: NCC(=O)c1ccccc1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1C(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
A mixture of 2-aminoacetophenone hydrochloride (1 equiv.), ethyl isobutyrylacetate (1.2 equiv.) and sodium acetate (2.4 equiv.) in H2O was stirred at 100° C. for 18 hours and then cooled to room temperature. The aqueous layer was decanted off and the oil was dissolved in ethyl acetate. It was then washed with water and brine and then dried to give (93%) of 2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester as a red brown oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH2:21])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[S:32](Cl)(=[O:34])=[O:33])[CH:25]=[CH:24][CH:23]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]([NH:21][S:32]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[N:22]=[CH:23][CH:24]=[CH:25]4)(=[O:33])=[O:34])[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15]3)=[O:13])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CC1CCN(C(=O)C(N)Cc2ccc3[nH]cnc3c2)CC1
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cccc3cccnc23)CC1

Procedure:
Prepared from 1-(1H-benzimidazol-5-yl-methyl)-2-(4-methyl-piperidin-1-yl)-2-oxo-ethylamine and quinoline-8-sulphonic acid chloride analogously to Example 2.
Reaction SMILES: [P:1](Cl)([Cl:4])([Cl:3])=[O:2].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:10]2.C(N(CC)CC)C>C(OCC)C>[Cl:3][P:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:10]2)([Cl:4])=[O:2]
Reactant: COC(=O)[C@@H](C)c1ccc2cc(O)ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)Cl)ccc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
Phosphorus oxychloride (0.202 mL, 1 equiv) and (S)-methyl 2-(6-hydroxynaphthalen-2-yl)propanoate (Aldrich, 500 mg, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (0.302 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min, the triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow thick syrup (750 mg, 95%).
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[F:14][C:15]([F:36])([C:20]1[CH:35]=[CH:34][C:23]([CH2:24][NH:25][C:26]([NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[S:27])=[CH:22][CH:21]=1)[C:16]([F:19])([F:18])[F:17]>C1(C)C=CC=CC=1>[F:31][C:30]([F:32])([F:33])[CH2:29][N:28]=[C:26]1[N:25]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:15]([F:14])([F:36])[C:16]([F:17])([F:18])[F:19])=[CH:35][CH:34]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:27]1
Reactant: FC(F)(F)CNC(=S)NCc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(C(F)(F)C(F)(F)F)cc3)C2=O)cc1
Yield: 43.2 %

Procedure:
0.71 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 1.20 g of 1-(4-pentafluoroethylbenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of toluene, and the solution was heated under reflux for 4 hours. After the reaction, toluene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (10:1)]to give 0.72 g of the captioned compound.