Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>CO>[OH:1][CH:2]([CH2:18][NH:22][CH:19]([CH3:21])[CH3:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: O=C1CCC(c2ccc(OCC3CO3)cc2)=NN1
Solvent: CO
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1
Yield: 99.9 %

Procedure:
A mixture of the 6-[4-(2,3-epoxypropoxy)phenyl]-4,5dihydro-3(2H)-pyridazinone (38.37 g, 0.156 mole), isopropylamine (80 ml, 0.94 mole), and methanol (380 ml) was stirred under reflux for one hour, and then evaporated under reduced pressure to give 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (47.59 g, 100%), m.p. 108°-113° C. The hydrochloride, crystallised from a mixture of 2-propanol, ethanol and ether, had m.p. 195°-200° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[CH:5][CH2:4][O:3]1>CO.[Pd]>[CH3:1][C@@H:2]1[CH2:7][C@H:6]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.[CH3:1][C@H:2]1[CH2:7][C@@H:6]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1
Reactant: CC1CC(c2cnc(N)cn2)=CCO1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](c2cnc(N)cn2)CCO1
Product: C[C@H]1C[C@@H](c2cnc(N)cn2)CCO1
Reaction time: 25 h

Procedure:
To a solution of 5-(2-methyl-3,6-dihydro-2H-pyran-4-yl)pyrazin-2-amine (250 mg, 1.307 mmol) in MeOH (13.100 mL) was added Pd/C (278 mg, 0.261 mmol). The solution was degassed by N2 stream for 10 min. After flushed by H2 gas, hydrogen balloon was equipped. The reaction mixture was stirred for 25 h. After filtered through Celite, the volatile material was removed to give the crude product, which was purified with flash chromatography eluting with 0-10% of MeOH in DCM to provide 180 mg of diastereomers. Then chiral separation (ChiralPak 5mic AD column, 4.6×100 (mm), 5 mL/min, EtOH+0.1% DEA=15%) provided 40 mg of 5-((2R,4R)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine (Rt=1.32 min; LCMS (m/z): 194.2 (MH+), 0.44 min) in 22% yield and 30 mg of desired 5-((2S,4S)-2-methyltetrahydro-2H-pyran-4-yl)pyrazin-2-amine (Rt=1.83 min; LCMS (m/z): 194.2 (MH+), 0.44 min) in 16% yield.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li]CCCC.[CH3:21][C:22]([CH:24]([CH3:26])[CH3:25])=O.OS(O)(=O)=O>C1COCC1>[CH:24]([C:22]1([CH3:21])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]2[C:2]1=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:26])[CH3:25]
Reactant: CC(=O)C(C)C
Reactant: CN(c1ccccc1)c1ccccc1Br
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C1(C)c2ccccc2N(C)c2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A flame-dried two-necked flask was charged with 2-bromo-N-methyl-N-phenylaniline (1.0 g, 3.8 mmol) and 100 mL dry THF under argon and cooled to −78° C. in a dry ice-acetone bath. 2.6 mL of a 1.6 M solution of n-BuLi in hexanes (4.16 mmol) was added dropwise over 5 minutes and the reaction stirred at −78° C. under argon for 1 h. Isopropyl methyl ketone (0.361 g, 4.2 mmol) was added in one portion to the reaction mixture at −78° C., the reaction allowed to warm to room temperature and stirred overnight under argon. After quenching with saturated ammonium chloride, the reaction was extracted with Et2O, the organic layers combined, washed with brine and water and dried over anhydrous MgSO4 and the solvent evaporated under reduced pressure. To the neat residue thus obtained was added 2 mL of concentrated H2SO4 under argon and the mixture stirred at room temperature for 1 h under argon. After dilution with 30 mL DI H2O, the reaction was extracted with Et2O (5×50 mL), the organic layers were combined, washed with brine and water and dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography using hexanes as the eluent to yield 0.62 g (60%) of the desired compound as a clear oil. 1H NMR (400 MHz, CHCl3) δ 1.51 (s, 3H), 1.64 (s, 3H), 1.70 (s, 3H), 3.04 (s, 3H), 6.64 (m, 3H), 7.12 (m, 6H). 13C NMR (100 MHz, CHCl3) δ 21.5, 22.2, 23.8, 31.8, 39.0, 114.6, 117.4, 120.6, 121.4, 125.1, 127.4, 127.8, 128.0, 128.7, 129.3, 133.6, 140.0, 141.1, 147.2, 149.5. HRMS (ESI) calc for C18H21N [M+H]+ 252.1747, found 252.1742. IR (KBr plate) 692 (m), 747 (s), 1137 (m), 1342 (m), 1443 (m), 1486 (s), 1499 (s), 1591 (s), 1601 (s), 2911 (m), 2984 (m) cm−1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[C:18]([C:23]([O:25]CC)=O)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11].[OH-].[Na+]>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([C:23]([NH:1][CH2:2][CH2:10][C:12]3[CH:29]=[CH:28][CH:15]=[CH:14][CH:13]=3)=[O:25])=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:28][CH:29]=1)=[O:11]
Reactant: CCOC(=O)c1nccnc1Oc1ccc(C(=O)c2nc3ccccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(c1ccc(Oc2nccnc2C(=O)NCCc2ccccc2)cc1)c1nc2ccccc2[nH]1

Procedure:
To the solution of ethyl 3-(4-(1H-benzo[d]imidazole-2 carbonyl)phenoxy)pyrazine-2-carboxylate (30 g, 77 mmol) in methanol (250 mL) was added aqueous NaOH solution (4.62 g, 115 mmol) in 50 mL of water. The reaction mixture was heated to reflux for 1 h. The reaction mixture was concentrated then diluted with water. The aqueous layer was washed with ethyl acetate and then acidified by addition of 2N HCl to pH 6. The precipitate was collected by filtration, dried to give the title compound as a light brown solid. MS [M+H]=351.2.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:7][OH:8])[CH2:3][CH2:4][C:5]#[N:6].C(N(C(C)C)CC)(C)C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:1][C:2]([CH3:9])([CH2:7][O:8][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:3][CH2:4][C:5]#[N:6]
Reactant: CC(C)(CO)CCC#N
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CO[Si](C)(C)C(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of 16.13 g (0.127 mmol) of 4,4-dimethyl-5-hydroxyvaleronitrile in 250 mL of dry CH2Cl2 was added, at 20° C., in 2 min., 24.2 mL (0.139 mmol; 1.09 eq) of diisopropylethylamine, followed after 5 min. by 25.0 g (0.165 mmol; 1.3 eq) of solid t-butyldimethylsilyl chloride, all at once. Then, 1.55 g (0.0127 mmol; 0.1 eq) of 4-dimethylaminopyridine was added and the whole was stirred at 20° C. during 18h. After removing the solvent under vacuum (aspirator) the brown residue was taken up in H2O, followed by ethyl ether. The layers were separated and the aqueous one extracted three times with 200 mL of ether. The combined organic layers were back extracted with water (100 mL), HCl 1.2N (100 mL), 5% KHCO3 (2×100 mL), dried over Na2SO4 and concentrated under vacuum to give a faint yellow oil. Distillation at 94°-97° C. (0.7 mm) gave 21 g (69%) of the title compound. TLC:(Silica),Rf 0.59(CH2Cl2), detection with molybdophosphoric acid blue on yellow.
Reaction SMILES: O[CH:2]([C:8]1[N:15]2[C:11]([N:12]([CH3:21])[C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=32)=[N:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].S(Cl)(Cl)=O>ClCCl>[CH3:7][N:5]([CH3:6])[C:3](=[O:4])[CH2:2][C:8]1[N:15]2[C:11]([N:12]([CH3:21])[C:13]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:14]=32)=[N:10][C:9]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc2c(c1)n1c(C(O)C(=O)N(C)C)c(-c3ccccc3)nc1n2C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1ccc2c(c1)n1c(CC(=O)N(C)C)c(-c3ccccc3)nc1n2C
Reaction time: 48 h
Yield: 85.4 %

Procedure:
12.73 g (0.035 mol) of α-Hydroxy-N,N,6,9-tetramethyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetamide are treated with 75 ml of thionyl chloride in 250 ml of dichloromethane for 24 h. The solvent is evaporated and the excess thionyl chloride is evaporated under reduced pressure. The residue is taken up in toluene and the mixture is again evaporated. The residue is taken up in 600 ml of dichloromethane, 22 g of Rongalite® are added and the mixture is stirred for 48 h. Insoluble matter is removed by filtration. The filtrate is washed with water, with an aqueous sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulphate, and the solvent is evaporated under reduced pressure. 10.36 g of solid are isolated which are purified by silica gel column chromatography, eluting with a chloroform/methanol 90/10 mixture. 7.86 g of product are isolated of which 1.3 g are removed and dissolved in dichloromethane. The solution is filtered and the filtrate is evaporated under reduced pressure. The residue is treated with carbon black in methanol, the suspension is filtered, the methanol is evaporated under reduced pressure, and the residue is dried under vacuum. 0.9 g of white solid are obtained. Melting point: 222°-223° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[CH:2]1.CCN(CC)CC.[Si:15](OS(C(F)(F)F)(=O)=O)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl.CCOC(C)=O>[Si:15]([O:7][CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCc1cscn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cscn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-thiazol-4-ylmethanol (311.4 mg, 2.7 mmol) in CH2Cl2 (15 mL) was added Et3N (1.9 mL, 13.6 mmol). The solution was cooled to −78° C. and TBSOTf (776 μL, 3.38 mmol) was added. The reaction was warmed to room temperature and stirred for 1 hour. Next, the reaction was diluted with EtOAc (75 mL) and washed with saturated NaHCO3, brine, 1N HCl, and brine (20 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) to afford 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole. Rf=0.28 (15% EtOAc/hexanes). LCMS=230.1 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 8.77 (d, J=2.0 Hz, 1H), 7.25 (m, 1H), 4.93 (d, J=1.1 Hz, 2H), 0.95 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4](Cl)[N:3]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=CC=1.C(N(CC)CC)C>C(O)CC>[NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([C:14]2[S:17][CH:11]=[CH:16][CH:15]=2)[N:3]=1
Reactant: Nc1cc(Cl)nc(N)[n+]1[O-]
Reactant: Sc1ccccc1
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Nc1cc(-c2cccs2)nc(N)[n+]1[O-]
Yield: 51.7 %

Procedure:
5 g of 2,4-diamino-6-chloropyrimidine 3-oxide, 6.85 g of thiophenol and 11.5 g of triethylamine are placed in 110 ml of n-propanol. The reaction mixture is heated at reflux for 24 hours. It is evaporated to dryness. The residue is taken up in 25 ml of ethyl ether, stirred for 1/2 an hour, filtered on sintered glass and rinsed with 2×25 ml of ethyl ether. The precipitate is taken up in 75 ml of water. The pH is adjusted to 1 with concentrated hydrochloric acid. After stirring for 1/2 an hour, the pH is returned to 8 by addition of concentrated sodium hydroxide solution. The precipitate is filtered, rinsed with 10 ml of water and then recrystallized twice from a 75/25 ethanol/water mixture. 3.35 g of 2,4-diamino-6-thiophenylpyrimidine 3-oxide are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[Br:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Br:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:25]
Reactant: CCOC(=O)C1(NC(=O)c2ccc(C)cc2Br)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
2-(2-bromo-4-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (445 mg, 1.11 mmol) is dissolved in EtOH (15 mL), and solid KOH (1.42 g, 24.7 mmol) and water (1.5 mL) are added. The mixture is stirred at RT for 30 min then concentrated in vacuo. The residue is dissolved in water (10 mL) and acidified with conc. HCl until no more white solid precipitated. The solid is collected by vacuum filtration to give product (277) as white solid (415 mg, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH:9]1[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])=O)(C)(C)C.[ClH:30]>ClCCl.C(OCC)C>[ClH:30].[O:12]1[C:11]2([CH2:16][CH2:17][NH:8][CH:9]([CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH2:10]2)[O:15][CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1CN1C(=O)c3ccccc3C1=O)OCCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1CC1CC2(CCN1)OCCO2
Reaction time: 62 h
Yield: 90 %

Procedure:
To the above 7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.1 g, 2.7 mmol) dissolved in dichloromethane (6 ml) was added 1.0 N hydrogen chloride in diethyl ether (50 ml) and the solution kept at ambient temperature for 62 h. The precipitate was filtered off and washed with diethyl ether and dried with nitrogen which afforded 0.83 g (90%) of 2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione hydrochloride as a solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:18]=[C:17]([CH3:19])[C:15]([NH2:16])=[C:14]([CH3:20])[CH:13]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:5]1([O:4][C:2](=[O:3])[NH:16][C:15]2[C:17]([CH3:19])=[CH:18][C:12]([Cl:11])=[CH:13][C:14]=2[CH3:20])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(Cl)cc(C)c1N
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Cl)cc(C)c1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.56 g of phenyl chloroformate in 20 ml of toluene was added to a cold solution of 2.47 g of 4-chloro-2,6-dimethylaniline and 2.4 ml of N,N-dimethylaniline in 80 ml of toluene. The resulting mixture was stirred at room temperature for 11/2 hours and then diluted with water The organic layer was washed with 3N hydrochloric acid, brine, dried, and evaporated. The residual solid was crystallized from ethylacetate:hexane to yield phenyl-N-(4-chloro-2,6-dimethylphenyl)carbamate, mp 158°-160° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)[CH:21]=1)[CH2:10][C:9]2([CH3:33])[CH3:32])=[O:5])C.Cl>C(O)C.O1CCCC1.[OH-].[Na+].O>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:20]2[CH:21]=[C:16]([CH:11]3[CH2:10][C:9]([CH3:33])([CH3:32])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:17]=[N:18][CH:19]=2)=[CH:27][CH:26]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1ccc2c(c1)C(C)(C)CC(c1cncc(-c3ccc(C(C)(C)C)cc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2cncc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 91.2 %

Procedure:
A mixture of 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.0 g, 2.3 mmol) in ethanol (10 mL) and tetrahydrofuran (50 mL), 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[5-(4-tert-butyl-phenyl)-pyridin-3-yl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.87 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=415.3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[CH:11][C:10]([NH:13][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)(=[O:24])=[O:23])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: Nc1ccc(C(F)(F)F)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(C(F)(F)F)c2cccnc12)c1ccccn1
Yield: 31.7 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-trifluoromethyl-quinolin-8-ylamine (Intermediate 45) (125 mg, 0.58 mmol), pyridine-2-sulfonyl chloride (Intermediate 18) (125 mg, 0.70 mmol), pyridine (0.09 ml, 1.17 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (65 mg, 31%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]2[NH:25][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:26][CH:27]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)C(=NO)C(=O)c1ccccc1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccccc1
Yield: 34.9 %

Procedure:
Ethyl 2-hydroxyimino-3-phenyl-3-oxopropionate (36.1 g) and 4-nitrobenzylamine (27.9 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(4-nitrophenyl)-5-phenylimidazole-4-carboxylate (19.2 g). 18.0 g therefrom was dissolved in ethyl alcohol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-nitrophenyl)-5-phenylimidazole-4-carboxylic acid (12.8 g), melting point 175-178° C. (decomposition).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]([CH:9]=[CH2:10])=[O:8].[BH4-].[Na+]>C1COCC1>[N:1]1([CH2:10][CH2:9][CH:7]([OH:8])[CH3:6])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(C)=O
Reactant: C1CCNC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)CCN1CCCC1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
Pyrrolidine (2 ml, 24 mmol), THF (20 ml) and methyl vinylketone (2.5 ml, 31 mmol) were mixed together and stirred overnight. NaBH4 (1.17 g, 31 mmol) was added to the reaction mixture and stirred for 3 hours. The reaction was quenched with water (20 ml) and extracted with TBME (2×20 ml). The combined organic extracts were dried over MgSO4, filtered, washed with TBME and concentrated in vacuo. The crude product was purified by column chromatography, eluting with DCM:MeOH:NH3 (94:5:1), to give the title compound as a pale yellow oil (1.3 g, 38%).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].CC[O-].[Na+]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[O:14])[CH2:6][C:5](=[O:7])[CH2:4][CH2:3][CH:2]([CH3:8])[CH3:1])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCC(C)C
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CCC(C)C
Temperature: 25 °C
Yield: 70.4 %

Procedure:
5-methyl-2-hexanone (5.0084 g, 43.9 mmol) and diethyloxalate (5.95 mL, 43.8 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 14.6 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 46. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 6.6035 g (70.3%) of 46. 1H (CDCl3, 400 MHz): δ 6.28 (1H, s), 4.25 (2H, q, J=7.0 Hz), 2.40 (2H, t, 7.6 Hz), 1.54-1.41 (3H, m), 1.27 (3H, t, J=7.3 Hz), 0.82 (6H, d, J=6.3 Hz) ppm. 13C (CDCl3, 100 MHz): δ 203.40, 166.27, 161.85, 101.37, 62.15, 38.74, 33.39, 27.46, 21.99, 13.77 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 21.99, 13.77; CH2 carbons: 62.15, 38.74, 33.39; CH carbons: 101.37, 27.46 ppm. HPLC: 11.038 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CCN(C(C)C)C(C)C>CCCCO>[O:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[CH:3]=2)=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCO
Reactant: Clc1cc(Nc2ccc(Oc3ccccc3)cc2)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2ccc(Oc3ccccc3)cc2)ncn1
Temperature: 200 °C
Yield: 60 %

Procedure:
225 mg of 6-chloro-N-(4-phenoxyphenyl)pyrimidin-4-amine, 82 mg of ethanolamine and 173 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated and the evaporation residue was subjected to MPLC purification (EtOAc:EtOH=10:1). 2-(6-(4-Phenoxyphenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1.[CH:28]([O:41][C:42]([NH:44][C:45]1[CH:50]=[CH:49][N:48]([CH2:51][C:52](O)=[O:53])[C:47](=[O:55])[N:46]=1)=[O:43])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[S:16][C:15]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([C:52](=[O:53])[CH2:51][N:48]4[CH:49]=[CH:50][C:45]([NH:44][C:42]([O:41][CH:28]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[O:43])=[N:46][C:47]4=[O:55])[CH2:22][C:21]3=[O:26])(=[O:19])=[O:18])=[N:14][C:13]=2[CH:27]=1
Reactant: O=C(O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2cc(Cl)ccc2s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4cc(Cl)ccc4s3)C(=O)C2)c(=O)n1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(5-chloro-benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(benzhydryloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.98 (brs, 1H), 8.40 (m, 2H), 7.96 (s, 1H), 7.79 (m, 1H), 7.45 (d, 4H), 7.38 (t, 4H), 7.30 (t, 2H), 6.96 (t, 1H), 6.80 (s, 1H), 4.83 (s, 2H), 4.72 (s, 0.8H), 4.46 (s, 0.8H), 4.28 (s, 1.2H), 4.22 (t, 1.2H), 4.06 (t, 0.8H), 3.99 (t, 1.2H), 3.87 (t, 0.8H).