Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[C@H:3]([OH:5])[CH3:4].CC([O-])(C)C.[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.[Cl-].[Na+]>[CH2:13]([O:5][C@H:3]([CH3:4])[C@H:2]([OH:6])[CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H](O)[C@@H](C)O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@@H](C)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A solution of (2R,3R)-butane-2,3-diol in THF was admixed at room temperature with potassium tert-butylate and the mixture was refluxed for 15 minutes. The mixture was cooled to ca. 50° C. and admixed with benzyl bromide. The mixture was refluxed for 3 hours, then stirred overnight at room temperature. The mixture was diluted with acetic ester and sodium chloride solution and then washed with 1 N hydrogen chloride solution (1×) and sodium chloride solution (2×). The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified by means of chromatography (hexane/acetic ester 1:1) (yield: 43%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)C.[OH-].[Na+]>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)[C:5]([OH:7])=[O:6])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 134.4 %

Procedure:
To a suspension of 3,4-dihydroxybenzoic acid (25.4 g, 0.17 mole) in ethanol (250 ml), 5N NaOH aq. (270 ml) and benzyl chloride (102 g, 0.81 mole) were added, and the mixture was reacted with stirring for 6 hours under reflux. The reaction mixture was cooled to room temperature, allowed to stand at same temperature overnight and acidified with conc. hydrochloric acid (40 ml). The precipitate was filtered, washed with hot ethanol and dried under reduced pressure to give 38.2 g of 3,4-dibenzyloxybenzoic acid as pale yellow crystals having a m.p. of 184°-186° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[C:10]([CH2:11]O)=[C:9]([CH2:13][O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3=[N:25][N:26]=[C:27]([C:28]4[CH:32]=[C:31]([CH3:33])[O:30][N:29]=4)[N:17]3[N:16]=2)[N:8]=[N:7]1.ClCC1N=NNC=1.[NH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH3:33][C:31]1[O:30][N:29]=[C:28]([C:27]2[N:17]3[N:16]=[C:15]([O:14][CH2:13][C:9]4[N:8]=[N:7][N:6]([CH3:5])[C:10]=4[CH2:11][N:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)[C:24]4[C:19]([C:18]3=[N:25][N:26]=2)=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:32]=1
Reactant: C1CCNCC1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO)nn23)no1
Agent: ClCc1c[nH]nn1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CN4CCCCC4)nn23)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Thionyl chloride (625 μl, 8.6 mmol) was added to a stirred suspension of [1-methyl-4-({[3-(5-methylisoxazol-3-yl)[1,2,4]triazolo[3,4-α]phthalazine-6-yl]oxy}methyl)-1H-[1,2,3]triazol-5-yl]methanol (672 mg, 1.71 mmol) in CH2Cl2 (50 ml) and the mixture was stirred at room temperature for 1 h under N2, during which period the solid dissolved and then precipitated. The reaction mixture was concentrated under reduced pressure and then azeotroped with toluene (2×50 ml) and used without further purification. A portion of the crude chloromethyltriazole (125 mg, 0.30 mmol) and piperidine (0.30 ml, 3.0 mmol) in CH2Cl2 (6ml) were stirred at room temperature for 48 h under N2. The mixture was then concentrated under reduced pressure while dry loading onto silica and purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 solution as eluent to yield the desired phthalazine (126 mg, 90%), which was then recrystallised CH2Cl2/iso-hexanes. 1H NMR (360 MHz, CDCl3) δ 8.67 (1H, d, J=8.0 Hz), 8.14 (1H, d, J=8.0 Hz), 7.93 (1H, t, J=8.0 Hz), 7.75 (1H, d, J=8.0 Hz), 6.94 (1H, s), 5.77 (2H, s), 4.12 (3H, broad s), 3.70-3.60 (2H, m), 2.59 (3H, s), 2.40-2.30 (4H, m), 1.75-1.33 (6H, m).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=1>>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-(trifluoromethyl)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.42 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.55-7.57 (3H, m), 7.66-7.68 (2H, m), 8.05 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H11F3N4O, 345. Found, 345.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:38][C:39]1[CH:40]=[C:41]([CH:46]=[CH:47][C:48]=1[NH2:49])[C:42]([O:44][CH3:45])=[O:43]>CN(C=O)C>[CH3:45][O:44][C:42](=[O:43])[C:41]1[CH:46]=[CH:47][C:48]([NH2:49])=[C:39]([NH:38][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:40]=1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Reactant: COC(=O)c1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N)c(NC(=O)CCCCNC(=O)OC(C)(C)C)c1
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
In DMF (20 ml), 5-t-butoxycarbonylamino valeric acid (manufactured by Aldrich Corporation) (1.45 g), WSCI hydrochloride (1.74 g), and HOBt (1.25 g) were dissolved and the whole was stirred for 15 minutes. Then, the solution was added with methyl 3,4-diaminobenzoate (1.00 g) and stirred at room temperature for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and then washed with a saturated aqueous ammonium chloride solution and a 1 mol/l sodium hydroxide aqueous solution. Subsequently, the resultant was subjected to extraction with chloroform and the extract was then washed with a saturated saline solution, followed by drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.46 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.C([O-])([O-])=O.[K+].[K+]>C(O)CCC>[CH:33]1([NH:36][C:2]2[N:7]=[C:6]([C:8]3[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=3[C:16]3[CH:17]=[C:18]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=4)(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[CH:5]=[CH:4][N:3]=2)[CH2:35][CH2:34]1
Reactant: NC1CC1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(NC3CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-3-fluorobenzenesulfonamide (100 mg, 0.20 mmol) and cyclopropylamine (141 μL, 2.0 mmol) and K2CO3 (283 mg, 2.0 mmol) in 1-butanol (5 mL) the title compound was obtained as a white powder (43 mg, 0.08 mmol, 42.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.51 (s, 1H), 8.05 (d, J=5.0 Hz, 1H), 7.48-7.65 (m, 5H), 7.33 (t, J=7.4 Hz, 1H), 7.19-7.23 (m, 3H), 6.09 (d, J=4.7 Hz, 1H), 3.25-3.30 (m, 1H), 2.67 (bs, 1H), 1.35 (d, J=7.0 Hz, 6H), 0.63 (d, J=4.7 Hz, 2H), 0.46 (bs, 2H). MS (ESI): 510.4 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2.[OH-].[Na+].Cl>CO.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[C:3]2[CH:27]=[CH:28][CH:29]=[CH:30][C:2]1=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCOc4ccccc43)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCOc4ccccc43)nc2c1
Reaction time: 0.13 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-2-phenylquinoxaline-6-carboxylate (166.8 mg, 0.34 mmol, 1.00 equiv, 80%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (84 mg, 2.10 mmol, 5.00 equiv) in water (1.5 mL) dropwise with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the aqueous solution was adjusted to 3-4 with 1N aqueous hydrogen chloride and concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-2): Column, SunFire Prep C18, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 35% in 8 min, up to 70% in 8 min, up to 100% in 1.5 min); Detector, uv 220 & 254 nm. This resulted in 40 mg (31%) of 3-(2,3-dihydrobenzo[b][1,4]oxazin-4-yl)-2-phenylquinoxaline-6-carboxylic acid as a orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[C:12]([C:13](=O)[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].[C:16]1([S:22]([N:25]=C=O)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[C:16]1([S:22]([N:25]=[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:14]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(=O)c2ccccc2o1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Solvent: CC#N
Product: COC(=O)c1cc(=NS(=O)(=O)c2ccccc2)c2ccccc2o1
Reaction time: 24 h

Procedure:
Combine chromone-2-carboxylic acid methyl ester (0.341 g, 1.66 mmol) and benzenesulfonyl isocyanate (0.365 g, 1.88 mmol) in acetonitrile (5.0 mL) and reflux. After 24 hours, quench the reaction with methanol (1 mL). Concentrate in vacuo and triturate with hexane. Filter to obtain a paste. Recrystallize the paste from methanol to obtain a solid. Recrystallize from methanol to give the title compound as a solid: mp; 144°-146° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:38])[CH2:20][C:21]2[CH:37]=[CH:36][C:24]3[N:25]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[O:27][C:23]=3[CH:22]=2)=[CH:14][CH:13]=1)[CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][CH:5]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:38])[CH2:20][C:21]2[CH:37]=[CH:36][C:24]3[N:25]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH3:35])[O:27][C:23]=3[CH:22]=2)=[CH:16][CH:17]=1)[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(CCCO)c1ccc(NC(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C(CCCO)CC(=O)O)cc3)cc2o1
Temperature: 40 °C
Yield: 57.5 %

Procedure:
A solution of ethyl 6-hydroxy-3-{4-[2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino]-phenyl}-hexanoate [460 mg, Reference Example 23 (a)] in a mixture of ethanol (30 mL) and water (10 mL) was treated with sodium hydroxide solution (5mL, 1M) and then heated at 40° C. for 2 hours. The mixture was evaporated and the residue was dissolved in water (50 mL). This solution was washed three times with ethyl acetate, then acidified with dilute hydrochloric acid (a white precipitate was formed) and then extracted three times with ethyl acetate. The combined extracts were washed with brine, then dried and then evaporated. The residual white foam was dissolved in sodium hydroxide solution (50 mL, 0.5M) and the solution was washed twice with ether then acidified with dilute hydrochloric acid. The resulting white precipitate was filtered and then dried to give the title compound (250 mg) as a white solid. LC-MS: RT=2.88 minutes (100% by ELSD); MS (ES+), 488 (MH+).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][C:12](=S)[NH:13][CH2:14][C:15]1[N:16]=[C:17]2[CH:23]=[C:22]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]([CH3:35])[CH:25]=3)[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2=[N:19][CH:20]=1)(C(C)(C)C)(C)C>FC(F)(F)C(O[Hg]OC(=O)C(F)(F)F)=O.O1CCOCC1>[CH3:34][O:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:35])[CH:25]=[C:24]2[C:22]1[N:21]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[N:19]=[CH:20][C:15]3[N:16]([C:12]([CH2:11][CH2:10][CH2:9][OH:8])=[N:13][CH:14]=3)[C:17]=2[CH:23]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=S)CCCO[Si](C)(C)C(C)(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Agent: O=C(O[Hg]OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(CCCO)n43)n1COCC[Si](C)(C)C)cn2C
Temperature: 65 °C
Yield: 18.1 %

Procedure:
A flask was charged with 4-(tert-butyldimethylsilyloxy)-N-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)butanethioamide (0.158 g, 0.241 mmol) and 1,4-dioxane (3 mL). To the mixture was added bis(2,2,2-trifluoroacetoxy)mercury (0.103 g, 0.241 mmol). The mixture was heated to about 65° C. for 1 h. The mixture was then filtered and concentrated under reduced pressure. The material was purified using silica gel chromatography with an elution gradient of 15 to 100% EtOAc/heptane followed by 0 to 5% MeOH/DCM to give 3-(7-(5-methoxy-1-methyl-1H-indol-3-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)propan-1-ol (0.022 g, 18%): LC/MS (Table 2, Method b) Rt=2.59 min; MS m/z 506 (M+H)+.
Reaction SMILES: Cl.[NH2:2]O.C(=O)(O)[O-].[Na+].O.[CH2:10]=[C:11]([C:13]1[NH:23][C:16]2[CH:17]=[N:18][C:19]([C:21]#[N:22])=[CH:20][C:15]=2[N:14]=1)[CH3:12]>C(O)C>[CH2:10]=[C:11]([C:13]1[NH:23][C:16]2[CH:17]=[N:18][C:19]([C:21](=[NH:2])[NH2:22])=[CH:20][C:15]=2[N:14]=1)[CH3:12]
Reactant: C=C(C)c1nc2cc(C#N)ncc2[nH]1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=C(C)c1nc2cc(C(=N)N)ncc2[nH]1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (37.7 mg, 0.54 mmol), sodium bicarbonate (68.4 mg, 0.81 mmol), and water (0.54 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (114 mg, 0.27 mmol) dissolved in ethanol (1.3 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-N-hydroxy-3-[(1R or S)-1-(trans-4-methylcyclohexyl)ethyl]-2-(prop-1-en-2-yl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C24H29ClN6O [M+H]+ 453. found 453.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:8](N(CCO)CCO)=[O:9].[C]=O>>[CH:1]1([NH:7][CH:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(CCO)CCO
Reactant: NC1CCCCC1
Agent: [C]=O
Product: O=CNC1CCCCC1
Yield: 100 %

Procedure:
To 198 grams of cyclohexylamine (2.0 grams), 399 grams of formyldiethanolamine (3.0 mole) were added, and the mixture was placed in a stirred autoclave maintained at a temperature of 150° to 155° C. and a carbon monoxide pressure of 1260 psig. After the reaction was stopped, the contents of the autoclave were removed and distilled at 15 mm Hg. The 256 grams of overhead fraction (B.P. 155°-161° C.) was shown by proton NMR analysis to be cyclohexylformamide. This corresponds to yield of 100%.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].[NH4+].[Cl-]>C1COCC1>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1Nc1ccncc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
Potassium tert-butoxide (898 mg, 8.0 mmol) was added to a stirred solution of 4-aminopyridine (376 mg, 4.00 mmol) in anhydrous THF (5 mL) under a nitrogen atmosphere at 0° C. After 15 min stirring at 0° C., 2,4-difluoro-1-nitrobenzene (0.44 mL, 4.0 mmol) in anhydrous THF (5 mL) was added and stirring at 0° C. continued for 1 h. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (50 mL). The aqueous phase was extracted with EtOAc (×2) and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a yellow solid (557 mg, 60%). LCMS (Method C): RT 1.26 min [M+H]+ 234.12
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]1[NH:19][NH:18][C:17]([C:21]([F:24])([F:23])[F:22])(O)[CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:19]1[C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)=[CH:16][C:17]([C:21]([F:24])([F:22])[F:23])=[N:18]1)#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: OC1(C(F)(F)F)CC(c2ccco2)NN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1nc(C(F)(F)F)cc1-c1ccco1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 2-fluorobenzonitrile (0.605 g, 5 mmol) and 5-furyl-3-trifluoromethyl-3-hydroxypyrazoline (1.1 g, 5 mmol) in DMF (10 mL) was added Cs2CO3 (1.63 g, 5 mmol), and the resulting mixture was stirred at 110° C. for 16 hours. The mixture was diluted with EtOAc, washed with brine (×5), dried over MgSO4, and purified by column chromatography with a gradient solvent (hexane to ethyl acetate) to give 1-(2-cyanophenyl)-5-furyl-3-trifluoromethylpyrazole and 1-(2-cyanophenyl)-3-furyl-5-trifluoromethylpyrazole (1.27 g, 83.8%) in a ratio of 95 to 5. 1H NMR (CDCl3) δ7.82 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.77 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.66 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.39 (d, J=1.4 Hz, 1H), 6.96 (s, 1H), 6.37 (dd, J=3.3 Hz, J=1.4 Hz, 1H), 6.04 (d, J=3.3 Hz, 1H); 19F NMR (CDCl3): δ−62.98; ESMS(+): 304 (M+H, 100).
Reaction SMILES: [SH2:1].[C:2]([C:4]1[CH:8]=[N:7][N:6]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[N:5]=1)#[N:3].C(N(CC)CC)C>C(O)C>[C:12]([O:11][C@@H:10]1[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:21][C@H:9]1[N:6]1[N:5]=[C:4]([C:2](=[S:1])[NH2:3])[CH:8]=[N:7]1)(=[O:14])[CH3:13]
Reactant: S
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ncc(C#N)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)OC[C@H]1O[C@@H](n2ncc(C(N)=S)n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 98 %

Procedure:
Hydrogen sulfide was passed through a suspension of 2.0 g of 7 in ethanol (60 ml) to which 3.5 ml of triethylamine had been added. After 2 1/2 hr passage of hydrogen sulfide was ceased and the solvent was removed. The resultant syrup was dissolved in a minimum of chloroform and added to a silica gel column (2 × 38 cm) packed in chloroform. The column was eluted with chloroform (0.25 liter) and chloroform-ethyl acetate (9:1, 0.5 liter); 20 ml fractions were collected. Fractions 19-34 provided 2.6 g (98%) of 9 as a syrup; nmr (DMSO-d6) δ 6.36 (d, 1, J1',2' 2.0 Hz, 1'--H), 8.39 (s, 1,5--H); (CDCl3) δ 6.24 (d, 1, J1'2' 3.0 Hz, 1'--H), 8.32 (s, 1, 5--H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C2[C:18](=CC=CC=2)[CH:17]=[CH:16][C:15]1=[O:24].[Cl-].ClC1C=CC2C(=CC=CC=2)[N+]=1C1CCCCC1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C[N+]1C2C=CC=CC=2SC=1SC.C(N(CC)CC)C>>[CH:8]1([N:7]2[C:1]3[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]([CH3:18])=[CH:16][C:15]2=[O:24])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: O=c1ccc2ccccc2[nH]1
Agent: CSc1sc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Clc1ccc2ccccc2[n+]1C1CCCCC1
Solvent: CCN(CC)CC
Product: Cc1cc(=O)n(C2CCCCC2)c2ccccc12

Procedure:
1-Cyclohexyl-1,2-dihydro-4-methyl-2-quinolone is prepared using N-cyclohexylaniline as starting material. The quinolone (0.482 g, 2 mmol) is transformed to the 2-chloro-1-cyclohexylquinolinium chloride with a procedure similar to Example 3, and is then reacted with 3-methyl-2-methylthiobenzothiazolium tosylate (0.74 g, 2 mmol) and triethylamine (0.28 mL, 2 mmol) to yield the product.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:26]=1[C:27](O)=[O:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:30]([CH3:34])=[CH:31][CH:32]=[CH:33][C:25]=1[Cl:24])=[O:28]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Cl)cn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Yield: 45.6 %

Procedure:
A solution of 4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (89.5 mg, 0.25 mmol), 2-chloro-6-methylbenzoic acid (47 mg, 0.28 mmol), DIEA (175 μL, 1.0 mmol) and HBTU (133 mg, 0.35 mmol) in DMF (3 mL) was stirred at room temperature for 4 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation was chromatographed on 25 g of silica gel, eluting with 3:1 ethyl acetate:hexane to give N-[(2-chloro-6-methylphenyl)carbonyl]-4-(5-chloro-1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (54 mg). LR(+)LSIMS : m/z 962 (2M+NH4), 945 (2M+H), 490 (M+NH4), 473 (M+H (2 Cl)).