Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.C(N(CC)C(C)C)(C)C.[NH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1>C(#N)C>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[N:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1CSCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1

Procedure:
A solution of 3,4,5-trifluoronitrobenzene (5.00 g, 28.24 mmol) in acetonitrile (60 mL) is cooled to 0° C. and treated with N,N-diisopropylethylamine (7.38 mL, 42.35 mmol) followed by thiomorpholine (2.98 mL, 29.65 mmol). The ice bath is removed and the reaction mixture stirred at room temperature under nitrogen for approximately 24 h, during which additional thiomorpholine (0.1 eq) is added. The solvent is removed under reduced pressure, and the residue is diluted with ethyl acetate, washed with 1N hydrochloric acid (until the washings are acidic), saturated aqueous sodium bicarbonate and saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound, mp 104-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[Cl:15][S:16](O)(=[O:18])=[O:17]>ClCCl>[Cl:15][S:16]([C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:18])=[O:17]
Reactant: CCOc1cc(OC)ccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CCOc1cc(OC)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 25 °C
Yield: 94 %

Procedure:
2-Ethoxy-4-methoxybenzoic acid (9.5 g, 48.5 mmol) was added in portions to cold chlorosulfonic acid (60 mL, Aldrich) stirring at −3 to 0° C. (ice-acetone bath) over 15 min and warmed slowly to room temperature and heated to 60-65° C. for 40 min. The resulting dark solution was carefully poured with stirring into a large excess of ice and then 500 mL of dichloromethane was added. After stirring for 15 min, the layers were separated and the aqueous layer was extracted with dichloromethane (3×250 mL). The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off, and the filtrate was evaporated to a low volume. This was triturated with ether/hexane and filtered to give 5-chlorosulfonyl-2-ethoxy-4-methoxybenzoic acid as a colorless solid (13.4 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[C:10]=[S:11]>C(#N)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:10](=[S:11])[NH:9][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:19])=[O:20])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(N)cc1
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Solvent: CC#N
Product: Nc1ccc(NC(=S)Nc2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,4-diaminobenzene (0.324 g, 3.0 mmol) in acetonitrile was added 4-isothiocyanatobenzenesulfonamide (0.642 g, 3.0 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture went clear and a white precipitate formed. The solid was filtered, washed with acetonitrile and dried to afford 4-(3-(4-aminophenyl)thioureido)-benzenesulfonamide as a white sold (0.829 g, 86%). 1H NMR (400 MHz, DMSO) δ 9.65 (s, 2H), 7.71 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.26 (s, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.52 (d, J=6.8 Hz, 2H), 5.08 (s, 2H); MS (ESI), 323 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].[Br:39]C(Br)(Br)Br>C(#N)C>[CH2:20]([Br:39])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
Triphenylphosphine (2.52 g; 9.62 mmol) is added portionwise to a vigorously stirred solution of oleyl alcohol (1.00 g; 3.72 mmol; Fluka, 99%) and tetrabromomethane (1.61 g; 4.84 mmol) in acetonitrile (15 ml) at 0° C. The heterogeneous medium is stirred for 1 h at room temperature. The supernatant is then transferred into a round-bottomed flask and the residual paste is triturated with ether (10 ml) and then filtered. The combined organic solutions are concentrated under reduced pressure to give a colorless oil which is purified by chromatography on a column of silica gel (eluent: hexane) to give oleyl bromide (1.21 g; 98%) in the form of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:13]O>>[NH2:1][CH2:2][C:3]([F:8])([F:7])[C:4]([O:6][CH3:13])=[O:5]
Reactant: NCC(F)(F)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(F)(F)CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, 3-amino-2,2-difluoropropanoic acid (500 mg, 4 mmol) was solubilized in MeOH (10 mL). At 0° C., SOCl2(1 mL) was added dropwise. The reaction mixture was then stirred at room temperature overnight. Evaporation of the reaction mixture gave methyl 3-amino-2,2-difluoropropanoate, as its HCL salt, as a white solid (570 mg, 81%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.63 (t, J=16 Hz, 2 H) 3.87 (s, 3 H) 9.07 (br. s., 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:27](O)=[O:28])=[CH:22][CH:21]=1)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:61][C:62]1[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:17])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:27](=[O:28])[NH:68][C:65]2[CH:66]=[CH:67][C:62]([Br:61])=[CH:63][CH:64]=2)[CH2:30][CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:37])[CH3:39])([CH3:34])[CH3:35])=[CH:22][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCO[Si](C)(C)C(C)(C)C)C(=O)O)cc1
Reactant: Nc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(CCO[Si](C)(C)C(C)(C)C)C(=O)Nc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-2-{4-[2-(2-tert-butoxycarbonylamino-phenylcarbamoyl)-vinyl]-phenyl}-4-(tert-butyl-dimethyl-silanyloxy)-butyric acid (2.5 g, 4.52 mmol), EDCI (1.2 g, 4.97 mmol) and HOBt (671 mg, 4.97 mol) in CH2Cl2 (50 mL) was added 4-bromo-phenylamine (786 mg, 4.57 mmol). This mixture was stirred overnight at room temperature and then diluted with CH2Cl2 (50 mL), washed with saturated aqueous NaHCO3 solution, water and brine, dried with Na2SO4, and evaporated to obtain a yellow residue. MS: calc'd 708 (MH+), exp 708 (MH+).
Reaction SMILES: CON(C)[C:4](=[O:21])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[CH3:23][Li]>C1COCC1.CCOCC>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[CH:5]/[C:4](=[O:21])[CH3:23])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1ccc(/C=C/C(=O)N(C)OC)cc1OC1CCCC1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(C)=O)cc1OC1CCCC1
Reaction time: 0.08 h
Yield: 90 %

Procedure:
To a solution of (E)-N-methoxy-N-methyl-3-(3-cyclopentoxy-4-methoxyphenyl)-prop-2-enamide (318 mg, 1.05 mmol) in 2.5 mL of THF cooled to 0° C. was added CH3Li (1.5 mL of 1.4M ether solution). The resulting solution was stirred for 5 min, diluted with ether and transferred to a separatory funnel. After washing with H2O, 1M H3PO4, and brine, the organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (3:1, hexanes:ethyl acetate) provided (E)-4-(3-cyclopentoxy-4-methoxyphenyl)-but-3-en-2-one as a white solid (234 mg, 90%). 1H-NMR (300 MHz): δ 2.38 (s, 3), 3.89 (s, 3), 6.59 (d, 1, J=16), 7.46 (d, 1, J=16).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[C:11]([C:13](=[O:18])N(OC)C)[N:10]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[C:13]([C:11]1[N:10]([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[N:9]=[C:8]([N:3]2[C:4]([CH3:7])=[CH:5][CH:6]=[C:2]2[CH3:1])[CH:12]=1)(=[O:18])[CH3:29]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)c1cc(-n2c(C)ccc2C)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 287d (7.82 g, 1.0 eq., 20.0 mmol) and THF (100 mL) under N2 protection. A solution of MeMgBr (3.0 M in ether) (17 mL, 2.5 eq., 50.0 mmol) was added at −78° C. The mixture was stirred at room temperature for 3 h and quenched with saturated NH4Cl solution. It was then concentrated under reduced pressure and the residue was extracted with ethyl acetate (3×50 mL). The combined organic layer was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 287e as colorless oil (5.40 g, 78%). MS-ESI: [M+H]+ 347.0. 1H NMR (500 MHz, CDCl3) δ 6.57 (s, 1H), 5.91 (s, 2H), 4.93 (bs, 1H), 4.71 (t, J=5.5 Hz, 2H), 3.62 (t, J=5.5 Hz, 2H), 2.57 (s, 3H), 2.16 (s, 6H), 1.28 (s, 9H).
Reaction SMILES: [OH:1][C@:2]1([C:14]2[S:15][C:16]([C:19]3[CH:24]=[C:23]([NH:25][C:26]4[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=4)[CH:22]=[C:21]([CH2:36]OS(C)(=O)=O)[CH:20]=3)=[CH:17][N:18]=2)[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[N-:42]=[N+:43]=[N-:44].[Na+]>CN1C(=O)CCC1>[N:42]([CH2:36][C:21]1[CH:20]=[C:19]([C:16]2[S:15][C:14]([C@@:2]3([OH:1])[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[C:4]([CH3:12])([CH3:13])[CH2:3]3)=[N:18][CH:17]=2)[CH:24]=[C:23]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:22]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COS(C)(=O)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN=[N+]=[N-])cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
A solution of the product of Step 1 (250 mg, 0.407 mmol) in anhydrous NMP (5 ml) was treated with sodium azide (132 mg, 2.034 mmol, 5.0 equiv) and stirred at 23° C. for 18 h. The reaction was partitioned between EtOAc (2×75 ml) and water (85 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated to afford methyl (1S,4R)-4-{5-[3-(azidomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (220 mg, 96%), as an orange oil. MS ESI: [M+H]+ m/z 562.1
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C[OH:11]>>[CH3:9][C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N+:1]=1[O-:11]
Reactant: Cc1cc(C)nc(C)c1
Reactant: CO
Product: Cc1cc(C)[n+]([O-])c(C)c1

Procedure:
In a 500 mL round bottom flask equipped with a magnetic stirrer and thermometer were added 36.7 g (164 mmol) of 77% 3-chloroperbenzoic acid (Aldrich) and 200 mL of methylene chloride. This slurry was cooled to 5° C. and a solution of 16.6 g (137 mmol) of collidine (Aldrich) in 50 mL of methylene chloride was added over 30 min while maintaining the temperature at 5-10° C. The mixture was then allowed to warm to room temperature over 1 hr and then stirred overnight. The crude reaction mixture was transferred slowly to a beaker containing 200 g of basic alumina, which resulted in a slight warming of the mixture. The mixture was stirred and filtered and the alumina was mixed with 300 mL of 2:1 CHCl3:CH3OH. The solvent was removed on a rotary evaporator at room temperature. The alumina was washed with ether and the solvent was removed to yield 24.7 g of a clear liquid, which solidified to give a white, waxy solid. This yield was slightly high due to the presence of some salt. TLC (silica gel developed with methanol) showed a single major spot (Rf=0.45) along with a minor spot (Rf=0.55). The major spot was the desired N-oxide. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.96 (s), 2.51 9 (s) and 2.28 (s). The minor spot corresponded to the starting collidine. 1H NMR (CDCl3, 300 MHz) δ (ppm): 6.78 (s), 2.48 (s) and 2.26 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH:25][CH3:26])=[O:24])[CH:18]=1>CN(C)C(=O)C.C(OCC)C>[CH3:26][NH:25][C:23]([C:19]1[CH:18]=[C:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([F:9])[CH:4]=2)[CH:22]=[CH:21][N:20]=1)=[O:24]
Reactant: Nc1ccc(O)cc1F
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 121.2 %

Procedure:
A solution of intermediate 4-amino-3-fluorophenol, (500 mg, 3.9 mmol) in N,N-dimethylacetamide (6 mL) cooled to 0° C. was treated with potassium tert-butoxide (441 mg, 3.9 mmol), and the brown solution was allowed to stir at 0° C. for 25 min. To the mixture was added 4-chloro-N-methyl-2-pyridinecarboxamide, (516 mg, 3.0 mmol) as a solution in dimethylacetamide (4 mL). The reaction was heated at 100° C. for 16 h. The mixture was cooled to room temperature, quenched with H2O (20 mL), and extracted with ethylacetate (4×40 mL). The combined organics were washed with H2O (2×30 mL), dried (MgSO4), and evaporated to afford a red-brown oil. 1H-NMR indicated the presence of residual dimethylacetamide, thus the oil was taken up in diethylether (50 mL) and was further washed with brine (5×30 mL). The organic layer was dried (MgSO4) and concentrated to give 950 mg of the desired product, starting material 1, as a red-brown solid, which was used in the next step without purification.
Reaction SMILES: Br.[N:2]1[CH2:3][CH2:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH2:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:2]1[CH2:3][CH2:4][N:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: O=C(O)c1cccnc1
Reactant: NC1=Nc2ccccc2C2=NCCN12
Agent: Br
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=Nc2ccccc2C2=NCCN12)c1cccnc1
Temperature: 80 °C
Yield: 82.6 %

Procedure:
To a suspension of 2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine hydrobromide (500 mg, 1.87 mmol) and nicotinic acid (346 mg, 2.81 mmol) in N,N -dimethylformamide (25 ml) at room temperature was added benzotriazole-1-yl-oxy-tris-pyrrolidino -phosphonium hexafluorophosphate (1.46 g, 2.81 mmol) followed by N,N-diisopropylethylamine (1.30 ml, 7.49 mmol). The mixture was heated at 80° C. for 4 hours. After cooling to room temperature, the mixture was quenched with aqueous saturated NaHCO3 solution. The resulting precipitate was collected by filtration, washed with water and diethyl ether, and dried under reduced pressure to give N-(2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (450 mg, 83% yield).
Reaction SMILES: [CH3:1][CH:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:23][CH3:24])[N:14]2C2CCCCO2)=[C:10]([NH2:25])[N:9]=1)[CH3:3].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>CO>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:3][CH:2]([O:4][CH2:5][CH2:6][O:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([O:23][CH3:24])[NH:14]2)=[C:10]([NH2:25])[N:9]=1)[CH3:1]
Reactant: COc1nc2c(N)nc(OCCOC(C)C)nc2n1C1CCCCO1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCOC(C)C)nc2[nH]1
Reaction time: 0.17 h

Procedure:
To 2-({2-[(1-methylethyl)oxy]ethyl}oxy)-8-(methoxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (4.5 g, 14 mmol) in methanol (30 ml) was added trifluoroacetic acid (8 ml), stirred for 10 min and held at room temperature for 2 days. Filtered to give the crude product which was purified by preparative hplc (Gilson GX-281 instrument with YMC C18 5.0 um column (250×20 mm) eluting with water containing TFA (0.1%): acetonitrile 30-60%. This gave the title compound 2.1 g.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Br:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(Br)c2)nc(N2CCOCC2)cc1=O
Yield: 59.9 %

Procedure:
The product is prepared according to the procedure described in example 5, using 200 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 199 mg of 3-bromo-4-fluoroaniline, and 228 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 1.5 ml of pyridine and 1.5 ml of N,N-dimethylformamide. 185 mg of N-(3-bromo-4-fluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].[H-].[Na+].C(O)(=O)C>CN(C)C=O>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:9]=1
Reactant: O=C(NCCCl)Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NCCN1c1cccnc1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a mixture of 150 g of N-(2-chloroethyl)-N'-(3-pyridyl) urea dissolved in 500 ml of tetrhydrofuran and 500 ml of dimethylformamide, 31.6 g of sodium hydride (60% oily suspension) was added under ice-cooling over 20 minutes. After stirring under ice-cooling for 10 minutes and at room temperature for 2 hours, 10 ml of acetic acid was added and the solvent was distilled off. Saturated saline water and chloroform were added to thr residue and insolubles were separated by filtration. The chloroform layer was washed with sodium hydrogen carbonate solution, dried and the solvent was distilled off. The residue was recrystallized from a mixture of chloroform and hexane to give 108.5 g of 1-(3-pyridyl)-2-imidazolidinone.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)[NH2:33]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:24])[F:25])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]3[O:29][N:33]=[C:32]([C:34]4[CH:39]=[N:38][CH:37]=[CH:36][N:35]=4)[N:31]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: NC(=NO)c1cnccn1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3cnccn3)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 50 mg (0.36 mmol, 1.5 eq.) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 2. Yield: 34 mg (27% of theory)
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]1>O1CCCC1>[OH:4][C:5]1([CH3:1])[CH2:6][CH2:7][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:9][CH2:10]1
Reactant: C[Mg]Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.3 %

Procedure:
A solution of methyl magnesium chloride (3M in tetrahydrofuran, 57 ml, 171 mmol) was added to a solution of tert-butyl 4-oxocyclohexylcarbamate (12 g, 56 mmol) (WO9613262) in tetrahydrofuran (240 ml) at −78° C. The mixture was allowed to warm to ambient temperature and was stirred for 18 h. The mixture was quenched by the addition of saturated ammonium chloride solution (100 ml) and the volatile solvents were removed under reduced pressure. The residue was taken up in water (200 ml) and dichloromethane (400 ml) and solid citric acid was added until the layers separated. The organic phase was washed with saturated sodium bicarbonate solution, water, brine, dried over MgSO4, and the solvent removed under reduced pressure to give a gum which was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 80:20) as eluant to give the less polar diastereoisomer of tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate (680 mg) as a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[S:11])[CH:7]=[CH:8][N:9]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)=O>C(O)C>[CH3:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[S:11][CH:14]=[C:15]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[N:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CCCc1cc(C(N)=S)ccn1
Solvent: CCO
Product: CCCc1cc(-c2nc(-c3ccc(C)cc3)cs2)ccn1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
A mixture of prothionamide (1.03 g, 5.70 mmol) and 2-bromo-4′-methylacetophenone (1.22 g, 5.70 mmol) in ethanol (20 ml) was heated at 70° C. with stirring for 0.5 h, and then cooled to 0° C. A yellow precipitate formed was filtered, washed with cold ethanol, and dried to give 2-propyl-4-(4-p-tolylthiazol-2-yl)pyridine (fatostatin) 1 HBr salt (1.78 g, 83%) as yellow needles. mp: 190-193° C.; 1H NMR (600 MHz, DMSO-d6): δ 8.88 (d, J=6.2 Hz, 1H), 8.54 (s, 1H), 8.46 (d, J=1.4 Hz, 1H), 8.36 (dd, J=1.4, 6.2 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H), 7.31 (d, J=7.6 Hz, 2H), 3.03 (t, J=7.6 Hz, 2H), 2.35 (s, 3H), 1.80 (m, 2H), 0.96 (t, J=7.6 Hz, 3H); 13C NMR (150 MHz, DMSO-d6): δ 161.3, 158.5, 156.9, 146.2, 143.2, 138.4, 130.4, 129.5, 126.3, 122.3, 120.3, 119.5, 35.0, 22.4, 20.9, 13.4; HRMS (m/z): [M+H]+ calcd for C18H19N2S, 295.1269; found, 295.1269.
Reaction SMILES: Br[C:2]1[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[Br:16][C:17]1[CH:18]=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Br:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[CH:18][C:17]=3[Br:16])[CH2:22][CH2:23]2)[C:3](=[O:14])[N:4]([CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc(Br)c2c(c1)CCN2
Reactant: CCC(CC)n1cc(Br)nc(Br)c1=O
Agent: Cl
Product: CCC(CC)n1cc(Br)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dibromo-1-(1-ethylpropyl)-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 133-135° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (d, J=2.6 Hz, 1 H), 6.81 (s, 1 H), 6.78 (d, J=2.2 Hz, 1 H), 4.81-4.78 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.11 (t, J=7.7 Hz, 2 H), 1.87-1.73 (m, 2 H), 1.70-1.60 (m, 2 H), 0.89 (t, J=7.3 Hz, 6 H); HRMS (ESI) calcd for C18H22N3O2Br2 (M+H)+: 470.0079; found m/z 470.0084.