Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[OH-].[Li+]>O1CCCC1.O>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:15])=[O:2])=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
Methyl 4-(2-methoxy-2-oxoethyl)benzoate (13.6 g) was dissolved in tetrahydrofuran (180 mL) and water (60 mL), and lithium hydroxide (2.75 g) was added. The reaction mixture was heated at room temperature for 24 hr, stirred and concentrated under reduced pressure. The residue was diluted with water, and washed with ethyl acetate. The aqueous layer was adjusted with 2.5N hydrochloric acid to pH 5-6, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (13.0 g) as a colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)=O.[CH:12]1([CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>C(O)C>[Br:11][C:8]1[N:7]=[CH:6][C:5]([C:3]2[N:19]=[C:17]([NH:16][CH2:15][CH:12]3[CH2:14][CH2:13]3)[S:18][CH:2]=2)=[CH:10][CH:9]=1
Reactant: NC(=S)NCC1CC1
Reactant: O=C(CBr)c1ccc(Br)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2csc(NCC3CC3)n2)cn1
Yield: 61 %

Procedure:
Slurry crude 2-bromo-1-(6-bromo-pyridin-3-yl)-ethanone (11.5 g, ca. 48%), N-cyclopropylmethyl thiourea (2.2 g, 16.9 mmol) and sodium bicarbonate (1.7 g, 20 mmol) in ethanol (100 mL) at room temperature. Stir the mixture at reflux for 1 h under a nitrogen atmosphere. Turn off heat and stir the mixture for an additional 16 h at room temperature. Filter the slurry, then wash the solids with ethanol (50 mL), water (2×50 mL) and hexane (excess). Dry the solid in a vacuum oven for 20 h at 50° C. to obtain the title compound as a tan solid (3.2 g, 61% yield over 2 steps). MS (ES+) m/z: 312 (M+2)+.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23](O)[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])[CH3:3].CS([Cl:35])(=O)=O>C(Cl)Cl.O>[Cl:35][CH:23]([C:10]1[CH:9]=[C:8]([CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:30])[CH3:29])[CH:13]=[CH:12][C:11]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(Cl)C(C)(C)C)c1
Reaction time: 22 h
Yield: 43.4 %

Procedure:
To a stirred solution of 69.16A (0.200 g, 0.46 mmol) in DCM (5.00 mL) at 0° C. was added TEA (0.077 mL, 0.55 mmol), followed by methanesulfonyl chloride (0.043 mL, 0.55 mmol). The reaction was then stirred for 22 hours, diluted with water, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.16B as a colorless oil (0.090 g, 43% yield) and a further product 69.16C as a clear oil (0.050 g, 21% yield).
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[CH2:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8].CN1C=CN=C1>>[CH3:8][C:7]([CH3:10])([CH3:9])[CH2:6][O:11][Si:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CO
Reactant: C[Si](C)(C)Cl
Agent: Cn1ccnc1
Product: CC(C)(C)CO[Si](C)(C)C
Temperature: 0 °C
Yield: 85.8 %

Procedure:
6.50 g (56.7 mmol) of chlorotrimethylsilane were added dropwise to a solution of 5.00 g (56.7 mmol) of neopentyl alcohol (2,2-dimethyl-1-propanol) and 11.6 g (142 mmol) of 1-methylimidazole while stirring at 0° C. The reaction mixture was stirred for a further 2 hours at 0° C. and for 2.5 hours at 20° C. The upper phase was separated off to give 7.80 g (theory: 9.09 g) of 2,2-dimethyl-1-trimethylsilyloxypropane as a colorless oil having a purity of 96% (GC).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:17][CH3:18])[O:15][CH3:16])([CH3:13])[C@H:10]([OH:19])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-:3])=[O:2].[C:31](OC(=O)C)(=[O:33])[CH3:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH:14]([O:15][CH3:16])[O:17][CH3:18])([CH3:13])[C@H:10]([O:19][C:31](=[O:33])[CH3:32])[C@@H:9]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][C:21]3=[S:29])[C:8]=2[CH:30]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](n2c(=S)oc3ccccc32)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
200 mg (0.46 mmol) of the compound obtained in Example 1 was dissolved in 2 ml of dichloromethane, to which 87 μl (0.93 mmol) of acetic anhydride, 0.13 ml (0.93 mmol) of triethylamine and 17 mg (0.14 mmol) of 4-dimethylaminopyridine were added in that order. The reaction was stirred for 2 hours at room temperature, 10 ml of saturated NaHCO3 solution was added and extraction was performed with 30 ml of dichloromethane. The extract was washed with brine and dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 211 mg (yield: 97%) of the target compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[CH2:24]([O:23][C:21]([O:12][C:11]1[C:5]2[O:4][CH2:3][CH:2]([OH:1])[CH2:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: Oc1cccc2c1OCC(O)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cccc2c1OCC(O)C2
Yield: 100.2 %

Procedure:
23.05 g of 3,4-dihydro-3,8-dihydroxy-2H-1-benzopyran was dissolved in 320 ml of tetrahydrofuran, and 16.7 g of triethylamine was added. With stirring under cooling, a solution of 17.9 g of ethyl chloroformate in 100 ml of tetrahydrofuran was added dropwise. The mixture was worked up in the same way as in Example 1 to give 33.1 g (yield 100%) of 3,4-dihydro-8-ethoxycarbonyloxy-3-hydroxy-2H-1-benzopyran.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].[CH3:21][S:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][NH:31][CH2:30][CH2:29][C:27]=2[N:28]=1.CC(C)([O-])C.[Na+]>C1COCC1.CCOC(C)=O.CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C>[CH3:21][S:22][C:23]1[N:24]=[CH:25][C:26]2[CH2:32][N:31]([C:2]3[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=3)[C:5]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)=[O:6])[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: CSc1ncc2c(n1)CCNC2
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 80 °C
Yield: 79.6 %

Procedure:
A mixture of 3-bromo-N-[3-(trifluoromethyl)phenyl]benzamide (379 mg, 1.10 mmol), 2-(methylsulfanyl)-5,6,7,8-tetrahydropyrido[4,3-d]-pyrimidine (200 mg, 1.10 mmol), RuPhos (15.4 mg, 0.033 mmol), Cl—RuPhos-Pd precatalyst (24 mg, 0.033 mmol), and sodium-t-butoxide (148 mg, 1.54 mmol) in anhydrous THF (30 ml) was heated at 80° C. under nitrogen for 21 hours. Upon cooling, the reaction mixture was diluted with EtOAc and the insolubles were filtered off (celite). The filtrate was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 1:1 hexanes:EtOAc) to obtain a yellow, crystalline solid (389 mg, 80%).
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:18])=[O:17].CCN(C(C)C)C(C)C.[CH2:35]([N:37]=[C:38]=[O:39])[CH3:36]>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([NH:14][C:38]([NH:37][CH2:35][CH3:36])=[O:39])=[N:11][C:10]=2[CH3:15])=[CH:5][C:4]=1[S:16]([N:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: Cc1nc(N)sc1-c1ccc(Cl)c(S(=O)(=O)N2CCN(C)CC2)c1
Reactant: CCN=C=O
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(Cl)c(S(=O)(=O)N3CCN(C)CC3)c2)s1
Temperature: 120 °C

Procedure:
A stirred solution of 5-[4-Chloro-3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-4-methyl-thiazol-2-ylamine hydrobromide (174d) (0.1 g, 0.26 mmol) in DMF (1 ml) at room temperature is treated with DIPEA (0.07 g, 0.52 mmol) and ethyl isocyanate (0.025 ml, 0.33 mmol). The reaction mixture is heated to 120° C. for 1 hour and then allowed to cool to room temperature. Purification by preparative LC-MS affords the titled compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH3:14].ClC1C2C(=CC=CC=2)N=CC=1NC=O.Cl.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[CH2:36][O:37][NH2:38])([O-:33])=[O:32].Cl.C(ON)C>C(O)(C)C>[CH3:14][C:13]1[N:38]([O:37][CH2:36][C:35]2[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=2[N+:31]([O-:33])=[O:32])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1
Reactant: NOCc1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Nc1cnc2ccccc2c1Cl
Agent: CCON
Agent: Cl
Agent: O=CNc1cnc2ccccc2c1Cl
Solvent: CC(C)O
Product: Cc1nc2cnc3ccccc3c2n1OCc1ccccc1[N+](=O)[O-]
Yield: 47.4 %

Procedure:
The method of Part B of Example 20 was followed using N-(4-chloroquinolin-3-yl)acetamide (10.6 g, 48.0 mmol) in lieu of 4-chloroquinolin-3-ylformamide and O-(2-nitrobenzyl)hydroxylamine hydrochloride (10.8 g, 52.8 mmol) in lieu of O-ethylhydroxylamine hydrochloride in isopropanol (120 mL). Chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent to provide 7.6 g of 2-methyl-1-[(2-nitrobenzyl)oxy]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[N:56][C:55]([Cl:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[N:56][C:55]([Cl:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 200 mg, 0.56 mmol) and triphenylphosphine (192 mg, 0.73 mmol) in methylene chloride (4.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (128 mg, 0.73 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyrazine (145 mg, 1.12 mmol) and 2,6-lutidine (0.28 mL, 2.24 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 13/7 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (137 mg, 52%) as a light yellow foam: [α]23589=−27.35° (c=0.49, chloroform); EI-HRMS m/e calcd for C20H21Cl2N3O4S (M+H)+ 470.0703. found 470.0705.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ncc(Br)cc1N
Solvent: c1ccncc1
Product: COc1ncc(Br)cc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-bromo-2-methoxypyridin-3-amine (1.231 mmol) was dissolved in pyridine (3 ml) at 0° C. Benzene sulfonyl chloride (1.847 mmol) was added drop wise and the reaction mixture was stirred at RT for 2 h. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate (100 mL). The ethyl acetate layer was washed with water, separated and dried over sodium sulfate. The organic layer was evaporated to dryness. The crude material obtained was purified by (silica column, EtOAc/Hexane as eluent) to obtain the title compound. 1HNMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.77 (m, 2H), 7.68 (d, J=2.4 Hz, 1H), 7.64 (m, 1H), 7.55 (m, 1H), 3.61 (s, 3H); MS (m/z): 343 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Se](=O)=[O:12]>O1CCOCC1>[N+:8]([C:7]1[C:2]([CH:1]=[O:12])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Cc1ncccc1[N+](=O)[O-]
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-Methyl-3-nitropyridine (24 g, 173.91 mmol) was dissolved in 1,4-dioxane (500 mL) and to the mixture was added selenium dioxide (23 g, 208.7 mmol) and the mixture was heated under reflux for 16 h. After completion of reaction, the mixture was cooled to rt and filtered through Celite™ and the filtrate was concentrated under reduced pressure to give thick oily mass. The oily mass was purified by silical gel column chromatography using 20% of ethyl acetate and hexane as eluent to give 3-nitro-2-pyridinecarbaldehyde as an off white solid: 1H-NMR (CDCl3) δ: 7.7 (m, 1H), 8.3 (d, 1H), 9.0 (d, 1H), 10.3 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with benzoyl chloride (9.1 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([O:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Cc1ccc(O)cc1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Cc1ccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-phenol to give (1H-pyrazol-3-yl)-(1-p-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 317(MH+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18]>C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: NCCOCCO
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCOCCO
Yield: 93.2 %

Procedure:
A suspension of 30.0 g (202.5 mmol) of phthalic anhydride, 20 mL (21.0 g, 199.4 mmol) of 2-(2-aminoethoxy)-ethanol in 400 mL of benzene was added 1.0×10-2 g (5.3×10-5 mmol) of TsOH.H2O. The reaction flask was connected to a Dean-Stark condenser and then heated to reflux for 14 h. The solvent was removed at reduced pressure and the residue was purified by SiO2 column chromatography (hexanes/AcOEt 1:1 then CHCl3 /MeOH 20:1) gave 43.7 g (93.1%) of 13 as a light yellow syrup. This syrup slowly crystallized on standing at room temperature overnight as needle-like crystals. mp 66°-66.5° C. Rf (hexanes/AcOEt 1:1) 0.17. 1H NMR (CDCl3) d 2.41 (t, 1H, J=6.2 Hz, OH), 3.57-3.93 (m, 8H), 7.69-7.87 (m, 4H). 13C NMR (CDCl3) d 37.52, 61.62, 68.24, 72.24, 123.36, 131.97, 134.00, 168.38 (C=O). Anal Calcd for C12H13NO4 : C, 61.28; H, 5.53; N, 5.96. Found: C, 61.34; H, 5.62; N, 5.94.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]CC.O>C1(C)C=CC=CC=1>[CH2:2]([O:3][CH2:4][CH:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(O)CO
Temperature: 25 °C
Yield: 82.3 %

Procedure:
(R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol (11 grams), powdered potassium hydroxide (20 grams) and hexadecyl bromide (27.96 grams) in toluene (150 ml) were stirred and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 40 ml. The reaction mixture was cooled to room temperature; water was added (100 ml) and the resulting mixture was extracted with dichloromethane (3×75 ml). The combined organic phase was washed with water (50 ml) and the solvent removed under reduced pressure. The residue was dissolved in 200 ml mixture of 90:10:5 methanol:water:concentrated hydrochloric acid (v/v) and the resulting solution was refluxed for 2 hours, followed by cooling to room temperature and addition of water (100 ml). The product was extracted with dichloromethane (3×100 ml), and the organic phase was washed consecutively with water (100 ml), saturated aqueous solution of sodium carbonate (100 ml) and again with water (100 ml). The solvent was removed under reduced pressure and the product was crystallized from hexane (200 ml) to give 21.69 grams (yield 82%) of pure 1-hexadecyl-glycerol, upon drying in a desiccator under reduced pressure.
Reaction SMILES: [CH2:1]([SH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.O.O.C([O-])(=O)C.[Na+].[C:16]1([N:22]2[C:26](=[O:27])[CH:25]=[C:24](Br)[C:23]2=[O:29])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[C:16]1([N:22]2[C:26](=[O:27])[CH:25]=[C:24]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:23]2=[O:29])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C=C(Br)C(=O)N1c1ccccc1
Reactant: CCCCCCS
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCSC1=CC(=O)N(c2ccccc2)C1=O
Yield: 48.1 %

Procedure:
To hexanethiol (111 μL, 0.79 mmol) and sodium acetate trihydrate (108 mg, 0.79 mmol) in methanol (60 mL) was added in N-phenyl monobromomaleimide (200 mg, 0.79 mmol) in methanol (60 mL) dropwise over 1 hour with vigorous stirring. After 5 minutes solvent was removed in vacuo. Purification by column chromatography (gradient elution in 10% ethyl acetate in petroleum ether to 30% ethyl acetate in petroleum ether) afforded the desired compound as a pale yellow solid (109 mg, 0.38 mmol) in 48% yield. δH (600 MHz, CDCl3) 7.45 (dd, 2H, J=7.1 and 8.0, 2×H-12), 7.36 (d, 2H, J=6.0, H-11), 7.35 (d, 2H, J=8.1, 2×H-13), 6.19 (s, 1H, H-2), 2.96 (t, 2H, J=7.9, H2-10), 1.81-1.76 (m, 2H, H2-9), 1.50-1.45 (m, 2H, H2-8), 1.34-1.32 (m, 4H, H2-6 and H2-7), 0.91 (t, 3H, J=6.9, H3-5); δC (125 MHz, CDCl3) 168.59 (C═O), 166.96 (C═O), 152.20 (C3), 131.53 (C14), 129.21 (2×Ar—H), 127.93 (C11), 126.09 (2×Ar—H), 117.24 (C2), 32.03 (C10), 31.33 (CH2), 28.68 (CH2), 27.78 (CH2), 22.59 (CH2), 14.11 (C5); IR (oil, cm−1) 2931 (w), 1703 (s); MS (CI+) m/z (relative intensity): 290 ([M+H], 100); Exact Mass Calcd for [C16H20NO2S]+H requires m/z 290.1215 Found 290.1224 (CI+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][C@H:8]([CH3:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:6][C@H:5]1[CH3:20])(=[O:3])[CH3:2].[N:21]#[C:22][NH2:23]>>[C:1]([N:4]1[C@H:5]([CH3:20])[CH2:6][N:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:22]([NH2:23])=[NH:21])=[CH:13][CH:12]=2)[C@@H:8]([CH3:10])[CH2:9]1)(=[O:3])[CH3:2]
Reactant: N#CN
Reactant: CC(=O)N1C[C@H](C)N(c2ccc([N+](=O)[O-])cc2)C[C@H]1C
Product: CC(=O)N1C[C@H](C)N(c2ccc(NC(=N)N)cc2)C[C@H]1C
Temperature: 95 °C

Procedure:
The title compound was prepared from (2R,5S)-1-acetyl-2,5-dimethyl-4-(4-nitrophenyl)piperazine (Method 30, 6.5 g, 26.29 mmol) and cyanamide (2.43 g, 57.84 mmol) by the procedure of Method 31 and heating for 10 h at 95° C. The bicarbonate salt was dried in vac oven at 60° C. overnight. It was obtained as a solid (10.23 g, >100% contaminated with solvent). M/z 290.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[O-:20][CH2:21][CH3:22].[Na+]>C(O)C>[CH2:21]([O:20][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:5]2[N:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1)[CH3:22]
Reactant: Cc1ccc(-n2c(=O)c(Cl)nc3cccnc32)cc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2cccnc2n(-c2ccc(C)cc2)c1=O

Procedure:
Preparation as in Example 26 but using 2-chloro-3,4-dihydro-4-(4-methylphenyl)-3-oxopyrido[2,3-b]pyrazine and sodium ethoxide in ethanol gave the title compound which was identified by NMR Delta 1.50 (t) 3H, delta 2.43 (s) 3H, delta 4.59 (q) 2H, delta 7.05-7.45 (m) 5H, delta 7.91 (q) 1H, delta 8.27 (q) 1H.
Reaction SMILES: [C:1]([Cu])#[N:2].Br[C:5]1[CH:10]=[C:9]([F:11])[C:8]([NH2:12])=[C:7]([F:13])[CH:6]=1>CN(C=O)C>[NH2:12][C:8]1[C:9]([F:11])=[CH:10][C:5]([C:1]#[N:2])=[CH:6][C:7]=1[F:13]
Reactant: N#C[Cu]
Reactant: Nc1c(F)cc(Br)cc1F
Solvent: CN(C)C=O
Product: N#Cc1cc(F)c(N)c(F)c1
Temperature: 220 °C
Yield: 78.4 %

Procedure:
A solution of CuCN (135 mg, 1.51 mmol) and 4-bromo-2,6-difluorobenzenamine (200 mg, 0.96 mmol) in DMF (4 mL) was sealed in a microwave vial and degassed with Ar. The mixture was heated in microwave at 220° C. for 17.5 min. Ammonium hydroxide (10 mL) and water (10 mL) were added to the mixture and it was extracted with EtOAc (2×20 mL). The organics were combined, washed with sat. NaHCO3 and brine, dried (Na2SO4) and concentrated. Purification by flash chromatography yielded 116 mg of Intermediate 383.1 as a white solid. LCMS 155.3 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 4.27 (bs, 2H) 7.12 (dd, J=5.87, 2.20 Hz, 2H).