Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH:6]([C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1)=O)C.CN([BH3-])C.[Li+].Cl.O.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:3][CH2:4][CH:6]([C:19]#[C:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)C(C#Cc1ccccc1)CNc1ncnc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]N(C)C
Solvent: O
Solvent: C1CCOC1
Product: OCC(C#Cc1ccccc1)CNc1ncnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.1 %

Procedure:
200 mg of 4-[2-ethoxycarbonyl-4-phenyl-3-butynylamino]quinazoline and 1 ml of a 1 M tetrahydrofuran solution of lithium dimethylamino borohydride were added to 10 ml of tetrahydrofuran, and the obtained mixture was then stirred at a room temperature for 1 hour. Thereafter, 20 ml of 1 N hydrochloric acid was added to the reaction solution, and the obtained mixture was then stirred for 10 minutes. Thereafter, sodium bicarbonate water was added to the reaction solution for neutralization. The obtained solution was extracted with 40 ml of ethyl acetate twice, and it was then dried over sodium sulfate. The sodium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by flash chromatography (manufactured by Biotage AB; Isolera™), so as to obtain 37 mg of 4-[2-hydroxymethyl-4-phenyl-3-butynylamino]quinazoline.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].IC.[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([S:26][CH3:27])[N:19]=1.O>CN(C)C=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH3:1])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([S:26][CH3:27])[N:19]=1
Reactant: CC(C)(C)[O-]
Reactant: CSc1nc(Nc2ccc(F)cc2F)ccc1C#N
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(N(C)c2ccc(F)cc2F)ccc1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
3.05 mL (5.04 mmol) of potassium 2-methylpropan-2-olate and then 286 μL (1.8 eq) of iodomethane are added dropwise under nitrogen to a solution of 700 mg (2.52 mmol) of 6-(2,4-difluorophenylamino)-2-(methylthio)nicotinonitrile in 20 mL of N,N-dimethyl formamide. The reaction medium is stirred at room temperature for 24 hours and then 126 μL (0.8 eq, 2.02 mmol) of iodomethane is added. The reaction medium is stirred at room temperature for 2 additional hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on anhydrous magnesium sulfate, filtered, and evaporated to yield 660 mg (90%) of 6-((2,4-difluorophenyl)(methyl)amino)-2-(methylthio)nicotinonitrile in the form of a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:9][N:8]=[C:7]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:6]=2[CH:21]=1
Reactant: COC(OC)N(C)C
Reactant: O=C1CCN=C(c2c(F)cccc2F)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: CN(C)C=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2C1=O

Procedure:
8-Chloro-1-(2,6-difluorophenyl)-3,4-dihydro-benzo[c]azepin-5-one (4aa) (4.2 g, 15 mmol) was dissolved in toluene (100 mL) and N,N-dimethylformamide dimethyl acetal (19 mL) and heated at 80° C. for 2 h. The solution was evaporated in vacuo and the resulting residue was purified by column chromatography (silica gel, 0 to 75% EtOAc/hexanes) to afford 5aa (2.6 g, 78%) as a pale brown solid MS m/z=361 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:21])[C:5]([CH3:22])=[CH:4][CH:3]=1.[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:22][C:5]1[C:6]([F:21])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:12]#[N:13])[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2cc(C#N)cc(C(F)(F)F)c2)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Oc2c(Cl)ccc(CBr)c2F)cc(C(F)(F)F)c1
Temperature: 75 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of 3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]-5-(trifluoromethyl)benzonitrile (12.2 g, 37.0 mmol) and N-bromosuccinimide (6.59 g, 37.0 mmol) in carbon tetrachloride (300 mL) was added AIBN (0.304 g, 1.850 mmol) and the mixture was stirred at 75° C. for 4 hours. More AIBN (0.304 g, 1.850 mmol) was added and the reaction mixture was stirred overnight at 75° C. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The crude oil was purified via silica gel chromatography to give 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-(trifluoromethyl)benzonitrile (7.33 g, 17.94 mmol, 49% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 (s, 1H), 7.42 (s, 1H), 7.31-7.36 (m, 2H), 7.24 (d, 1H), 4.48 (s, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[C:6]([OH:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.P([O-])([O-])([O-])=O.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CC(C)=O>[CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:6]([OH:16])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCCCCCCC1(O)C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CCCCCCCCC1(O)C=C(SC)C(=O)C1=CCCCCCC(=O)O
Yield: 49.9 %

Procedure:
To a solution of 16 mg of 2-methylthio-4-hydroxy-5-(6-methoxycarbonylhexylidene)-4-octyl-2-cyclopentenone obtained in Example 101, dissolved in 1 ml of acetone, 11 ml of 0.1M phosphate buffer of pH 8 was added. Under stirring, 1.5 mg of pig liver esterase was added, and the mixture was stirred at 30-35° C. for 130 hours. After the mixture was adjusted to pH 4 with 0.1N hydrochloric acid, ammonium sulfate was added to saturation and the mixture was filtered with addition of ethyl acetate. The filtrate was extracted with ethyl acetate, the organic layers were combined and washed with saturated aqueous sodium chloride. After drying over anhydrous magnesium sulfate, filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 7.7 mg (yield 47%) of 2-methylthio-5-(6-carboxyhexylidene)-4-hydroxy-4-octyl-2-cyclopentenone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])=[O:15].[Na+]>C(O)C.O.C(Cl)Cl.CCOC(C)=O>[OH:15][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C[O-]
Reactant: N#Cc1ccc(CBr)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(CO)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A stirred solution containing α-bromo-2-nitro-p-tolunitrile (1.228 g, 5.095 mmol) and sodium formate (0.8664 g, 12.74 mmol) in ethanol:water (4:1, 25 mL) was refluxed for 2 h. The reaction was cooled to room temperature, diluted with 20% CH2Cl2/EtOAc, washed with H2O (3×), dried (MgSO4) and concentrated. Purification by flash chromatography (1,2 and 3% MeOH/CHCl3 gradient) gave 0.695 g (77%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ4.71 (d, 2 H), 5.75 (t, 1 H), 7.89 (dd, J=7.9 Hz, 1 H), 8.14 (d, J=7.9 Hz, 1 H), 8.32 (s, 1 H).
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:8][N:7]=[C:6]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O1CCCC1>[CH2:16]([O:15][C:13]([NH:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:3]=[O:2])[C:6]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:7][CH:8]=1)=[O:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O
Temperature: 25 °C
Yield: 102.9 %

Procedure:
(EX-1D) A solution of [5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1-pyrimidinyl]acetaldehyde dimethyl acetal (17.24 g, 42.11 mmol) in 103.0 mL tetrahydrofuran was added 35.0 mL 1 N HCl. The resulting biphasic mixture was allowed to heated to reflux for 12 hours. The reaction mixture was allowed to cool to room temperature and the volatiles were removed under vacuum. The resulting residue was diluted with water (200 mL) and the pH was adjusted to 7 by addition of solid NaHCO3. The resulting emulsion was extracted with dichloromethane (4×150 mL). The combined organic solutions were washed with water (1×200 mL), dried (MgSO4), filtered, and concentrated to give 15.74 g crude [5-[(benzyloxycarbonyl)amino]-2-phenyl-6-oxo-1,6-dihydro-1 pyrimidinyl]acetaldehyde.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].CS(O[CH:18]1[CH2:21][N:20]([CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19]1)(=O)=O.CCN(C(C)C)C(C)C>CC#N>[CH:22]([N:20]1[CH2:21][CH:18]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])[CH2:6][CH2:7]2)[CH2:19]1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C(N1CCNCC1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1)C(F)(F)F

Procedure:
To a solution of 2,2,2-trifluoro-1-piperazin-1-yl-ethanone (6 g, 32.94 mmol) and 1-benzhydrylazetidin-3-yl methanesulfonate (12.5 g, 39.38 mmol) in CH3CN (60 mL) was added DIPEA (12 mL, 68.89 mmol) at room temperature. The resulting mixture was refluxed for 2 h. The solvent was removed by evaporation and the residue was partitioned between CH2Cl2 and aq NaHCO3. The organic layer was washed with aq NaHCO3 (2×) and then extracted with 1N HCl (2×). The aqueous layer was cooled and then the pH adjusted with 1N NaOH until basic (pH=10). The resulting mixture was extracted with CH2Cl2 (2×). The organic layer was dried over MgSO4 and concentrated. The title compound was purified by reverse phase chromatography. MS m/z (M+H+) 404.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([OH:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.O.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1>CC(O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH:10]([O:12][CH:23]([CH3:28])[CH3:24])[CH3:11])[C:7]([C:13]([F:14])([F:15])[F:16])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(C(C)O)c(C(F)(F)F)cc1NC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1cc(C(C)OC(C)C)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 18 h
Yield: 43.7 %

Procedure:
A solution of 2-acetylamino-5-(1-hydroxy-ethyl)-4-trifluoromethyl-benzoic acid methyl ester (500 mg, 1.64 mmol) in i-PrOH (5 mL) was treated by addition of p-toluenesulfonic acid monohydrate (99.9 mg, 0.517 mmol) and stirred at 80° C. for 18 h. The reaction mixture was cooled then concentrated in vacuo. The residue was purified by column chromatography (silica gel, 5:1 hexanes/EtOAc) to give title product (69 mg, 14% yield) as colorless crystals. m.p.: 87-90° C., API-ES: m/z 306 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:36]=[CH:35][C:13]([N:14]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH3:34])=[CH:27][CH:26]=3)[C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].[CH:43]1[C:56]2[NH:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[S:48][C:47]=2[CH:46]=[CH:45][CH:44]=1.O>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:21]([C:18]1[CH:17]=[CH:16][C:15]([N:14]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH3:34])=[CH:27][CH:26]=2)[C:13]2[CH:35]=[CH:36][C:10]([CH:9]=[CH:8][C:5]3[CH:6]=[CH:7][C:2]([N:55]4[C:56]5[CH:43]=[CH:44][CH:45]=[CH:46][C:47]=5[S:48][C:49]5[C:54]4=[CH:53][CH:52]=[CH:51][CH:50]=5)=[CH:3][CH:4]=3)=[CH:11][CH:12]=2)=[CH:20][CH:19]=1)[CH2:22][CH2:23][CH3:24]
Reactant: c1ccc2c(c1)Nc1ccccc1S2
Reactant: CCCCc1ccc(N(c2ccc(C=Cc3ccc(Br)cc3)cc2)c2ccc(CCCC)cc2)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(N(c2ccc(C=Cc3ccc(N4c5ccccc5Sc5ccccc54)cc3)cc2)c2ccc(CCCC)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of tris(dibenzylideneacetone) dipalladium (Pd2(dba)3) (0.13 g, 0.14 mmol) and bis(diphenylphosphino)ferrocene (DPPF) (0.10 g, 0.17 mmol) in dry toluene (20 ml) under nitrogen atmosphere was added 4-[2-(4-bromophenyl)vinyl]-N, N-bis(4-butylphenyl)aniline (2.60 g, 4.83 mmol) at room temperature, and the resultant mixture was stirred for 10 min. Sodium tert-butoxide (1.3 g) and phenothiazine (0.96 g, 4.83 mmol) were then added to this solution, which was then stirred at 90° C. overnight under nitrogen. The reaction mixture was poured into water (60 ml), extracted three times with ether (100 ml×3) and dried over anhydrous magnesium sulfate. The product was purified by flash column chromatography using 2% ethyl acetate in hexane as eluant and was isolated in 60% (1.91 g) yield as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C1(C)C=CC=CC=1>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:11]1[C:10](=[O:20])[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])=[O:37])=[N:7]2
Reactant: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1)Nc1ccccc1F
Reaction time: 3 h

Procedure:
2-amino-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 mg, 0.18 mmol), toluene (3 mL), triethyl amine (36 mg, 0.36 mmol), and 1-fluoro-2-isocyanatobenzene (49 mg, 0.36 mmol) were added to a flask and heated to reflux. The reaction was complete in 3 hrs and concentrated to dryness. The crude residue was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH) to yield the title compound.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:5][CH:4]=1)C.C(C1(C2C3C(=CC=C(C#CC4C=CC(C(OCC)=O)=CC=4)C=3)SC(C)(C)C=2)CC=CS1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:3]1[S:7][C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)s2)=CC(C)(C)S3)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C2(CC)CC=CS2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(CCc4ccc(C(=O)O)cc4)cc32)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
To a solution of ethyl 4-[[4-(5-ethylthiophen-2-yl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 231, 23.0 mg, 0.05 mmol) in 1.0 mL THF and 1.0 mL EtOH was added NaOH (40.0 mg, 1.0 mmol, 1.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 15.5 mg (72%) of the title compound as an orange solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.03 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz), 7.61 (1H, s), 7.44 (2H, s), 6.90 (1H, d, J=3.5 Hz), 6.83 (1H, d, J=3.5 Hz), 6.10 (1H, s), 2.86 (2H, q, J=7.6 Hz), 1.45 (6H, s), 1.30 (3H, t, J=7.6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][CH2:8][OH:9])([O-:3])=[O:2].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>N1C=CC=CC=1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][O:9][C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1cccc([N+](=O)[O-])c1

Procedure:
3-Nitrophenethyl alcohol (55 g, 0.33 mol) (Aldrich) was dissolved in pyridine (1.2 L) (Aldrich). Acetic anhydride (215 mL, 2.14 mol) (Aldrich) was added slowly, and the mixture was stirred overnight at room temperature (TLC: 30% ethyl acetate in hexanes showed complete conversion). Ice and water (200 mL) were poured into the reaction mixture. The mixture was diluted with ethyl acetate, then successively washed with aqueous 1N hydrochloric acid (pH=˜1), water, and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give acetic acid 2-(3-nitro-phenyl)-ethyl ester as a yellow oil. (Yield 58.86 g, 0.28 mol, 85%).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH3:19][C:20]1[C:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:22][C:23]([CH3:27])=[C:24]([CH3:26])[CH:25]=1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[C:9]([CH3:17])[C:10]([C:11]([N:31]2[CH2:32][CH2:33][N:28]([C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[C:23]([CH3:27])[N:22]=3)[CH2:29][CH2:30]2)=[O:13])=[CH:15][CH:16]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3C)CC2)nc1C
Yield: 62.4 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (300 mg) described in Preparation Example 37 and 1-(3,5,6-trimethylpyridin-2-yl)piperazine (251 mg) described in Preparation Example 92 and by the reaction and treatment in the same manner as in Example 109, the title compound (307 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[CH3:16])[NH2:5].C(OC(N[C:25](=[N:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:26]1C=CC=N1)=O)(C)(C)C>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([N:5]=[C:25]([NH2:26])[N:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[CH3:16]
Reactant: Cc1cc(N)ccc1N1C[C@@H]2C[C@H]1CN2C
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N=C(N)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1N1C[C@@H]2C[C@H]1CN2C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound (Da), 3-methyl-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]aniline, (0.105 g, 0.6 mmol) and 1-(tert-butoxycarbonylamino(tert-butoxycarbonylimino)methyl)pyrazole (H) (0.186 g, 0.6 mmol) were combined in DMF (2 mL) and stirred at ambient temperature for 3 days. The reaction was monitored by LCMS. The homogenous reaction mixture was then diluted with water (20 mL), the solid precipitate formed was isolated by filtration, and purified by column chromatography (silica gel, CH2Cl2 then 2-5% MeOH in CH2Cl2) to give [3-methyl-4-((1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptan-5-yl)phenyl][N,N-bis(tert-butoxycarbonyl)]guanidine; LCMS: purity: 99%; MS (m/e): 460 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)[CH:14]=[CH:15][C:9]=3[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1.[CH3:29][N:30]([CH2:32][C:33](O)=[O:34])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:29][N:30]([CH3:31])[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)[CH:14]=[CH:15][C:9]=3[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1)=[O:34]
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(N)cc2NC3=O)ccc1[N+](=O)[O-]
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(NC(=O)CN(C)C)cc2NC3=O)ccc1[N+](=O)[O-]

Procedure:
A mixture of Example 120 (38 mg, 0.10 mmol), dimethylaminoacetic acid (17 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol) and Et3N (0.1 g) in 1 mL of DMF was stirred overnight. The reaction mixture was partitioned between H2O and ethyl acetate, and the organic layer was separated, washed with brine, dried, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the desired product. MS (DCI) m/e 462 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.03 (s, 1H), 8.10 (s, 1H), 8.01 (d, J=8.59 Hz, 1H), 7.80 (d, J=8.29 Hz, 1H), 7.53 (d, J=1.23 Hz, 1H), 7.43 (s, 1H), 7.21-7.36 (m, 4H), 7.03 (d, J=8.59 Hz, 1H), 4.11 (s, 2H), 4.03 (s, 3H), 2.86 (s, 6H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCC.O1CCCC1>[Br:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][C:14]([C:13]([O:18][CH3:19])=[O:17])([CH3:16])[CH3:15])=[CH:23][CH:22]=1
Reactant: COC(=O)C(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(C)Cc1ccc(Br)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A 1.25M solution of n-butyl lithium in hexane (32 ml) was cooled to 0° C. under an argon atmosphere and diisopropylamine (4.05 g; 5.24 ml) was added slowly. The resulting mixture was cooled to -70° C. and stirred while methyl isobutyrate (4.08g; 4.58 ml) was added dropwise while maintaining the temperature at <-60° C. After a further 30 minutes at -70° C., a solution of 4-bromobenzyl bromide (10.0 g) in anhydrous tetrahydrofuran (20 ml) was added and the temperature was maintained at -70° C. for a further 1.5 hours. The reaction mixture was allowed to attain ambient temperature then heated to reflux for 18 hours. On cooling, the mixture was acidified with 8% aqueous citric acid and extracted with ethyl acetate (3×75 ml). Insoluble material at the interface was removed by filtration and the combined organic phase was washed with brine (20 ml), dried (Mg SO4) and evaporated. The residue was purified by vacuum flash chromatography on silica eluting with a gradient of 0-10% ethyl acetate in hexane to give 1-bromo-4-(2-methoxycarbonyl-2-methylpropyl)benzene (7.79 g); 1H NMR (d6 -DMSO): 1.13 (s, 6 H); 2.79 (s, 2 H), 3.60 (s, 3 H), 7.04 (m, 2 H), 7.46 (d of t, 2 H); mass spectrum (CI+): 272 (M+H)+.