Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[CH3:16][C:17]1[O:18][CH:19]=[CH:20][C:21]=1[SH:22].C(=O)([O-])[O-].[K+].[K+]>>[F:15][C:10]1[C:9]([C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[S:22][C:21]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=Cc1cc(-c2cccnc2F)c(Br)s1
Reactant: Cc1occc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1occc1Sc1sc(C=O)cc1-c1cccnc1F
Yield: 97 %

Procedure:
With 5-bromo-4-(2-fluoropyridin-3-yl)thiophene-2-carbaldehyde (250 mg) as a starting material, and using 2-methyl-3-furanthiol (0.114 mL) and potassium carbonate (193 mg), an operation similar to that of Reference Example 1 was performed to give the title compound as a pale-yellow oil (yield 271 mg, yield 97%).
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23]([C:26]1([CH:30](O)[CH2:31][C:32]#[CH:33])[CH2:29][CH2:28][CH2:27]1)[CH2:24][CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH:30]([C:26]1([CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH2:29]1)[CH2:31][C:32]#[CH:33])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C#CCC(O)C1(CCC)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC(O[Si](C)(C)C(C)(C)C)C1(CCC)CCC1
Reaction time: 1 h
Yield: 153.8 %

Procedure:
t-Butyldimethylsilyltrifluoromethanesulfonate (1.8 mL, 7.88 mmol) was added to a solution of triethylamine (2.2 mL, 15.8 mmol) and alcohol 4 (650 mg, 3.94 mmol) in CH2Cl2 (5.0 mL) at 0° C. The reaction was stirred for 1 h and then saturated aqueous NaHCO3 was added. The mixture was extracted with CH2Cl2. The organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. FCC (silica gel, 100% hexane) gave 1.7 g (100%) of the silyl ether 5 as a clear, colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]([Cl:28])=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[N:20]2)=[CH:15][CH:14]=1)[CH3:9])C.[OH-].[Na+]>CCO.O>[Cl:28][C:27]1[N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][N:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]([OH:29])=[O:3])=[CH:18][CH:17]=2)[N:20]=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: CCOC(=O)CCCN(C)CCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(CCCC(=O)O)CCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Yield: 53.8 %

Procedure:
A solution of this ester from step 1 (0.1 g, 0.23 mmol) and NaOH (20 mg, 0.47 mmol) in EtOH/water (1.1, 5 mL) was stirred at room temperature for 16 h. After the ethanol was removed, the aqueous solution was acidified with 10% HCl to pH=2, extracted with ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated. The crude material was triturated with ether to yield the title compound (48 mg, 50%); 1H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.01 (d, J=9.2 Hz, 2H), 7.76 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H), 7.30 (m, 1H), 7.15 (d, J=8 Hz, 2H), 7.08 (m, 1H), 4.15 (t, J=12, 6 Hz, 2H), 3.27 (m, 4H), 2.84 (m, 2H), 2.76 (s, 3H), 2.18 (m, 2H); LC/MS (ESI+) m/z: 98%.
Reaction SMILES: [C:1]1(/[C:7](/[CH2:37][CH3:38])=[C:8](\[C:24]2[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:26][CH:25]=2)/[C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C2CCCCO2)[N:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.Cl>[NH:14]1[C:15]2[C:11](=[CH:10][C:9](/[C:8](/[C:24]3[CH:25]=[CH:26][C:27](/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:28][CH:29]=3)=[C:7](/[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)\[CH2:37][CH3:38])=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]ncc3c2)cc1
Temperature: 70 °C

Procedure:
To a solution of (E)-ethyl 3-(4-((E)-2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (3.5 g, 6.9 mmol) in ethyl alcohol (69 mL), HCl (6 mL, 2M in diethyl ether) was added at room temperature. The resulting mixture was then heated at 70° C. for 2 h. Upon completion, the mixture was cooled down to room temperature and concentrated to give the crude product. This crude material was purified on a silica gel column eluted with 0-100% ethyl acetate in hexanes affording an off-white solid (2.5 g). 1H NMR (300 MHz, DMSO-d6): δ 13.10 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.53 (d, 1H), 7.48 (d, 1H), 7.39 (d, 2H), 7.27-7.11 (m, 6H), 6.89 (d, 2H), 6.45 (d, 1H), 4.20 (q, 2H), 2.43 (q, 2H), 1.22 (t, 3H), 0.87 (t, 3H); LCMS: 423 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Mg].[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[O:23].Cl>O1CCCC1.C(OCC)(=O)C>[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2([OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)c1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cl
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1ccccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Several drops of a 12 mL tetrahydrofuran solution of 8.2 g of 1-bromo-2-isopropylbenzene were added to a 5 mL tetrahydrofuran solution of 1.2 g of magnesium under a nitrogen atmosphere to initiate the reaction, after which the rest was gradually added drop-wise at a rate at which heating reflux was maintained. Upon completion of the dropping, the reaction mixture was refluxed for 0.5 hour in an oil bath, and then cooled to room temperature. A reagent prepared as above was gradually added drop-wise under ice cooling and a nitrogen atmosphere to a suspension of 3 g of 5-chloro-1H-indol-2,3-dione in 22 mL of tetrahydrofuran. Upon completion of the dropping, the temperature was raised to room temperature, and then the reaction mixture was stirred for 2 hours at that temperature. A 3N hydrochloric acid aqueous solution was poured into the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate, and the drying agent was then filtered off and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/2; v/v) to obtain 4.9 g of the titled compound (pale yellow, amorphous).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[CH:12](=[O:14])[CH3:13]>C1COCC1>[CH3:13][CH:12]([OH:14])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C#CCCCC
Reactant: CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC#CC(C)O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 1-hexyne (116, 2 g, 24.3 mmol) in 30 mL of freshly distilled THF at −78° C. was added n-BuLi (2.5 M solution in hexanes, 11 mL, 27 mmol) under argon (FIG. 2M). The resultant yellow solution was stirred at −78° C. for 30 min and 0° C. for 15 min. Acetaldehyde (˜2 mL) was added to this solution at −78° C. and the reaction mixture was allowed to stir at rt for 3 h. The reaction was quenched with saturated NH4Cl and extracted with Et2O (3×30 mL). The combined organic solution was washed with water, dried (MgSO4), filtered, and concentrated in vacuo. Chromatography on silica gel (EtOAc:hexanes, 1:99, then 10:90) gave 117 as a colorless oil (2.1 g, 73%). 1H NMR (CDCl3) δ4.48-4.52 (q, 1 H, J=6.0 Hz, CH), 2.17-2.22 (d of t, 2 H, J=6.7 Hz and 1.5 Hz, CH2), 1.37-1.65 (complex m, 7 H, 4 CH2 and 1 CH3), 0.88-0.93 (t, 3 H, J=7.2 Hz, CH3).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[Na+].[OH:16][CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:18][CH2:19][C:20]([O-:22])=[O:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.CCOCC>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3](=[O:4])[CH2:2][O:22][C:20](=[O:21])[CH2:19][CH2:18][CH:17]([OH:16])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCCCCCCC(O)CCC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCCC(O)CCC(=O)OCC(=O)c1ccc2ccccc2c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 26.6 %

Procedure:
A suspension of 20.00 g of 2-bromo-2′-acetonaphtone, 18.01 g of 4-hydroxy-undecanoic acid sodium salt, and 0.5 g of tetrabutylammonium bromide in 180 ml of dimethylformamide was stirred for 6 hours at 50° C. Then, the reaction mixture was diluted with ether and washed with water, 2N HCl, saturated sodium bicarbonate, and brine. Then, the mixture was dried, filtered, and evaporated to dryness. The resulting solid was purified by recrystallization to yield 7.92 g of colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.O.[NH2:19][NH2:20]>O1CCCC1>[NH:19]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1)[NH2:20]
Reactant: NN
Reactant: COC(=O)c1ccc(-c2cnc(Cl)nn2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1

Procedure:
To a solution of methyl 4-(3-chloro-1,2,4-triazin-6-yl)benzoate (1.1 g, 0.0044 mol) in tetrahydrofuran (30 mL) was added hydrazine hydrate (1.1 mL, 0.022 mol) at RT with stirring. The mixture was stirred at RT for 1 h, and concentrated under reduced pressure to give the desired product (quantitatively). Analytical LCMS: (M+H)+=245.9.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N+:6]([O-])[CH:7]=[CH:8][C:9]=1[CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([OH:3])=[O:2].[C-]#N.[Na+].[CH2:20]([N:22](CC)CC)C.Cl[Si](C)(C)C>CN(C)C=O>[C:1]([C:4]1[C:9]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:8][C:7]([C:20]#[N:22])=[N:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1c[n+]([O-])ccc1C1CCCCC1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C2CCCCC2)c(C(=O)O)cn1

Procedure:
4-Cyclohexylnicotinic acid hydrochloride (4.5 g, 0.018 mol) is dissolved in methylene chloride (40 ml). This solution is mixed with a cold solution of metachloroperbenzoic acid (10.82 g, 0.063 mol) in CH2Cl2 (80 ml), and the resulting mixture is stirred at room temperature overnight. The precipitate obtained is filtered and the filtrate evaporated to dryness. The residue is suspended in ether. The precipitate is filtered, washed with ether and dried to yield 3-carboxy-4-cyclohexyl-pyridine N-oxide, m.p. 168°-169°. (c) To a solution of 3-carboxy-4-cyclohexyl-pyridine N-oxide (3.09 g, 0.014 mol), sodium cyanide (2.47 g, 0.05 mol) and triethylamine (7.08 g, 0.07 mol) in absolute dimethylformamide (50 ml), chlorotrimethylsilane (7.6 g, 0.07 mol) is added. The reaction mixture is then heated for 28 h at 85°. After cooling, the inorganic salts are filtered, washed with diethyl ether, and the filtrate is evaporated at 50° in vacuo. The dark residue is purified by chromatography on Florisil® (ethyl acetate/methanol 4:1) to yield 5-carboxy-2-cyano-4-cyclohexyl-pyridine; m.p. 225°-230°, Rf =0.55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: NCCc1ccccn1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCCc3ccccn3)nc21

Procedure:
This compound was prepared by a procedure similar to that described in Example 33 starting with 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.00 g (8.20 mmol) of 2-(2-aminoethyl)-pyridine yielding 0.082 g of pure product; mp 173-174° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.[CH2:8]([NH2:16])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.OP([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:7][C:5]1[S:6][C:2]([NH:16][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3][N:4]=1
Reactant: NCCc1ccccc1
Reactant: Nc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(NCCc2ccccc2)s1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine (360 mg), phenethylamine (0.38 ml), and K2HPO4 (522 mg) in 2 ml of DMF is heated under nitrogen at 100° C. for two hours, then partitioned between water and ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. Flash chromatography of the residue on silica using 4-5% methanol in dichloromethane provides 261 mg of the title compound. Recrystallization of 238 mg of this from 10 ml of 1:1 acetonitrile toluene affords 205 mg of crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.CCOCC>C(O)(C)C>[O:8]=[C:3]1[C:2]([NH:1][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: Nc1ccc[nH]c1=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCOCC
Solvent: CC(C)O
Product: CCOC(=O)C(=CNc1ccc[nH]c1=O)C(=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
3-Aminopyridin-2(1H)-one (9.00 g, 81.7 mmol) was treated with diethyl ethoxymethylenemalonate (24.6 ml, 123 mmol) and heated to 100° C. After 3 hours, the reaction was cooled down and diluted with isopropyl alcohol. The solid that crashed out was collected by suction filtration and washed well with IPA and then ether to give diethyl 2-((2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (14.5 g, 63.3% yield) as a greenish solid. MS(M+H)+ 281.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].I[CH3:16]>CN(C)C=O>[CH3:16][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: CI
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of sodium hydride (0.27 g; 6.8 mM) in dimethylformamide (4 ml) at 0° C. under nitrogen, was added 6-nitroindole (1 g; 6.2 mM) in dimethylformamide (12 ml). After stirring at room temperature for 0.5 h, iodomethane (0.42 ml; 6.8 mM) in dimethylformamide (1 ml) was added and stirring continued for 1 h. The reaction mixture was then quenched with water, and poured onto excess water with stirring. Filtration afforded the title compound (1.03 g; 94%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH:25]([OH:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[C:37](Cl)(=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>C(Cl)Cl>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH:18]4[O:27][C:37](=[O:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C1c2ccccc2C(O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)OC1c2ccccc2C(=O)N1CCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 2-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-2,3-dihydro-3hydroxy-1H-isoindol-1-one (1.4 g, 3.5 mmol) in DCM (30 ml) was added Et3N (1.2 ml, 8.8 mmol) followed by decanoyl chloride at 0 C. under nitrogen. After stirring for 1 h in the cooling bath, the solvent was removed using a stream of nitrogen. The remaining residue was diluted with EtOAc and the precipitated triethylamine hydrochloride was filtered off. The filtrate was concentrated and the remaining oil was flushed through alumina with ether to give 1.6 g (83%) of the desired product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[O:28])[C:17]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:18]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:4][CH:3]([OH:5])[C:2]([F:7])([F:6])[F:1])[CH2:31][CH2:30]3)=[O:28])[C:17]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:37][C:36]=3[O:45][CH2:46][CH3:47])=[N:16]2)=[CH:13][CH:14]=1
Reactant: FC(F)(F)C1CO1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCNCC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(O)C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
1,1,1-trifluoro-2,3-epoxypropane (9 uL, 0.10 mmol) was added to a mixture of [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[piperazin-1-yl]-methanone (30 mg, 0.048 mmol) and triethylamine (20 uL, 0.144 mmol) in anhydrous methanol (1.0 mL). The reaction was stirred overnight. Evaporation of the solvent and chromatography of the residue over silica gel using 0-5% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-trifluoromethyethyl)-piperazin-1-yl]-methanone, which was dissolved in dilute hydrochloric acid (0.5 N, 1 mL) and lyophilized to give [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-2-trifluoromethyethyl)-piperazin-1-yl]-methanone hydrochloride as an off-white powder (38 mg, 84%). LR-MS (APCI): 703.5 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:7](/[C:8](/O)=[CH:9]\[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20].[N:30]1([C:36](=[S:38])[NH2:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[C:7]([C:8]2[N:37]=[C:36]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[S:38][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([Cl:16])[N:11]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[F:29])(=[O:21])=[O:20]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: NC(=S)N1CCOCC1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Yield: 48 %

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step A using N-{2-chloro-3-[(E)-2-(2-chloro-4-pyrimidinyl)-1-hydroxyethenyl]phenyl}-2,6-difluorobenzenesulfonamide (4.05 g, 8.83 mmol) and 4-morpholinecarbothioamide (1.29 g, 8.83 mmol), the title compound was obtained as a bright yellow solid (2.61 g; 48% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.87 (s, 1H), 8.29 (d, J=5.5 Hz, 1H), 7.64-7.74 (m, 1H), 7.46-7.56 (m, 2H), 7.39 (dd, J=7.1, 1.7 Hz, 1H), 7.23 (t, J=9.1 Hz, 2H), 6.19 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.6 Hz, 4H), 3.54 (t, J=4.3 Hz, 4H).
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([CH3:5])=[CH:3][CH:2]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](OCC)=[O:19].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>O1CCCC1.C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:19])[CH2:5][C:4]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1ccccn1
Reactant: Cc1ccnc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cc1ccnc2ccccc12)c1ccccn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
In a 3-neck 3-liter round bottom flask equipped with two addition funnels is dissolved lepidine (10.0 mL, 75.63 mmol) in tetrahydrofuran (200 mL). One addition funnel is charged with ethyl picolinate (20.43 mL, 151.26 mmol) and the other with 0.5 M potassium bis(trimethylsilyl)amide (166.4 mL, 83.19 mmol) in toluene. The solution is cooled to −78° C. and the base added to the reaction mixture dropwise over 40 min. The reaction mixture is stirred an additional 1.5 h and ethyl picolinate is added rapidly. The ice bath is removed and the reaction mixture stirred at ambient temperature for 3 h. The reaction is quenched with water (20 mL) and after 5 min formic acid added until the pH is slightly less than 7. The mixture is concentrated in vacuo and partitioned between ethyl acetate (300 mL) and brine-sodium bicarbonate (300 mL) mixture. The organic layer is washed with brine and sodium bicarbonate, dried over sodium sulfate, and concentrated. The product is chromatographed on SiO2 (27-30% acetone in hexane) to yield 15.31 g (82%) of a yellow-brown solid.
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([O:19][CH3:20])[N:15]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccc(OC)nc2c1=O
Temperature: 28 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
A solution of 2-[(6-methoxy-pyridin-3-ylamino)-methylene]-malonic acid diethyl ester (260.0 g, 1.365 mol, 1.0 eq) in diphenyl ether (500 mL) is heated to reflux. While the ethanol formed is removed by azeotropic distillation the reflux temperature reached 245° C. The reaction mixture is kept at 245° C. for 3 hours, then it is cooled to 28° C., a brown solid precipitated and is collected by filtration and washed with hexane (500 mL). The solid is dried under vacuum to afford 6-methoxy-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester as a brown powder (74.2 g, 32% yield).
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:16][NH2:17]>CCO>[CH3:16][NH:17][C:3]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCc1cccnc1
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1cccnc1
Yield: 76.8 %

Procedure:
In 50 ml of EtOH was dissolved 2.3 g (0.01 mole) of 1-methylthio-1-(3-pyridylmethyl)amino-2-nitroethylene with heating and, then, a solution of 1.2 g (0.015 mole) of 40% aqueous methylamine in 10 ml of EtOH was added dropwise over a period of 30 minutes while refluxing. The mixture was further refluxed for 2 hours, after which it was concentrated. The crystals were collected by filtration and recrystallized from acetonitrile to give 1.6 g of the title compound as white prisms.