Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1
Reactant: Oc1cccc(Cl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3cccc(Cl)c3)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3-chlorophenol: ESMS m/e: 509.1 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH:9]([CH3:23])[C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])([OH:14])[C:11]#[C:12][CH3:13]>CS(C)=O.[Cl-].[Na+].O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:10]([OH:14])([CH:9]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[CH3:23])[C:11]#[C:12][CH3:13]
Reactant: c1nc[nH]n1
Reactant: CC#CC(O)(c1ccc(Cl)cc1Cl)C(C)Br
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC#CC(O)(c1ccc(Cl)cc1Cl)C(C)n1cncn1
Temperature: 25 °C
Yield: 87.8 %

Procedure:
A suspension of sodium hydride (2.54 g) in dry dimethylsulphonyl (200 ml) was stirred at room temperature under argon and 1,2,4-triazol 21.9 g) was added in portions over 10 minutes, followed by further stirring for 10 minutes. A solution of 5-bromo-4-(2,4-dichlorophenyl)-4-hydroxy-hex-2-yne (17 g) in dry DMSO (50 ml) was added over 15 minutes. The resultant solution was heated at 100° C. for about 100 hours. Concentrated brine solution (200 ml) was added and the mixture extracted with ethyl acetate (3×150 ml). The extracts were combined, washed with water until neutral, dried over anhydrous magnesium sulphate and the solvent removed in vacuo to give 14.38 g of a brown solid. This solid was purified by flash chromatography, eluted with portions of ethyl acetate (50-100%) in hexane). Fractions containing the fastest running major triazole-active spot on thin-layer chromatography were combined to give 2.91 g (18%) of a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[O:8]=[C:9]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][NH:10]1.Br[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([S:38]([C:41]2[CH:47]=[CH:46][C:44]([CH3:45])=[CH:43][CH:42]=2)(=[O:40])=[O:39])[CH:30]=1>C1COCC1>[O:8]=[C:9]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH2:13][CH2:12][CH2:11][N:10]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH3:45])=[CH:46][CH:47]=2)(=[O:40])=[O:39])[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CBr)c3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2=O)CC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.238 mL, 8.60 mmol) in THF (40 mL) n-butyllithium (6.01 mL, 9.61 mmol) was added at 0° C. and the mixture was stirred for 30 min at 0° C. Then a solution of tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate [1198284-94-4] (2.57 g, 9.28 mmol) in THF (10 mL) was added within 3 min and the mixture was stirred for 30 min at 0° C. 3-(bromomethyl)-1-tosyl-1H-indole [58550-81-5] (3.2 g, 8.43 mmol) in THF (10 mL) was dropped to the reaction mixture within 15 min. The mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with TBME (2×150 mL). The combined organic layers were washed with 5% aqueous citric acid and brine, dried over anhydrous Na2SO4, filtered and concentrated (5.3 g, 100%). [1H NMR (400 MHz, DMSO-d8) ♀ ppm 7.88 (d, J=8.28 Hz, 1H), 7.81 (d, J=8.28 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J=7.78 Hz, 1H), 7.36 (d, J=8.03 Hz, 2H), 7.32 (t, J=7.91 Hz, 1H), 7.25-7.21 (m, 1H), 4.58 (s, 2H), 3.75-3.63 (m, 2H), 3.09 (t, J=5.77 Hz, 2H), 2.99 (br. s., 2H), 2.30 (s, 3H), 1.90-1.80 (m, 2H), 1.72-1.57 (m, 4H), 1.39 (s, 9H), 1.36-1.28 (m, 2H); LCMS RtA=1.37 min, [M+H]+=552.3].
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]([NH2:11])=[S:10])[CH:6]=[CH:7][N:8]=1.Cl[CH2:13][C:14](=O)[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CO>[CH2:2]([C:3]1[CH:4]=[C:5]([C:9]2[S:10][CH:13]=[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:11]=2)[CH:6]=[CH:7][N:8]=1)[CH3:1]
Reactant: CCc1cc(C(N)=S)ccn1
Reactant: COC(=O)CC(=O)CCl
Solvent: CO
Product: CCc1cc(-c2nc(CC(=O)OC)cs2)ccn1

Procedure:
A mixture of ethionamide (Aldrich) (1.65 g, 10.0 mmol) and methyl 4-chloroacetoacetate (Fluka) (1.41 g, 10.0 mmol) in 50 mL of anhydrous MeOH was heated at reflux for 18 h. The solvent was evaporated to give an oily residue that was purified by chromatography (gradient elution: 10-50% EtOAc in hexanes) to afford the title compound as a light brown oil. MS m/z: 263 (M+1). Calc'd for C13H14N2O2S: 262.08.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)SC)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:30][OH:31]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([CH2:18][O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[N:16][O:15][N:14]=2)=[N:30][OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CSC(=Nc1ccc(F)c(Cl)c1)c1nonc1CO[Si](C(C)C)(C(C)C)C(C)C
Reactant: NO
Solvent: CCO
Product: CC(C)[Si](OCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 75 °C
Reaction time: 6 h
Yield: 89 %

Procedure:
Methyl N-(3-chloro-4-fluorophenyl)-4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazole-3-carbimidothioate (3.0 g, 6.5 mmol) was dissolved in EtOH followed by addition of 4 mL hydroxylamine (99.9% in water solution). The reaction was stirred at 75° C. for 6 hrs and monitored by HPLC. The reaction was concentrated in vacuo to a yellow oil which was dissolved in chloroform and chromatographed on 120 g of silica gel eluting with (1:4), EtOAc/hexane. The product was concentrated to give the desired product as a white solid (2.57 g, 89%); MF═C19H28ClFN4O3Si; LCMS calculated for C19H29ClFN4O3Si(M+H)+: m/z=443.168.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1.[BH4-].[Na+]>CO>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][C:6]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: COC(=O)c1ccc(C)c(S(C)(=O)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CO)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A round bottom flask was charged with methyl-4-methyl-3-(methylsulfonyl)benzoate (1.5 g, 7.0 mmol) and methanol (15 mL) at 0° C. Sodium borohydride (3.7 g, 100 mmol) was added in portions and the reaction was stirred for 12 h at room temperature. The reaction was quenched with ice and extracted with MTBE. The combined organic phases were concentrated under reduced pressure and the residue was purified by flash chromatography to get the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[F:16])[CH3:2].O[C@H:28]1[CH2:32][CH2:31][O:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)[C:7]=1[F:16])[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O)c1F
Reactant: O[C@H]1CCOC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 7.38 g (RS)-(4-cyano-phenylamino)-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetic acid ethyl ester described in example 3.5 in 220 ml THF were added 1.68 ml (S)-(+)-3-hydroxy-tetrahydrofurane and 6.48 g triphenylphosphine. The mixture was cooled to 0° C. Subsequently, 3.84 ml of diethyl azodicarboxylate were added. The solution was stirred for 3 hrs at room temperature, then evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/EtOAc) to give 6.53 g of (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid ethyl ester as an off-white solid.
Reaction SMILES: [CH:1]1([C:6]2[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:11])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([SiH](CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[N:37]1([S:42]([C:45]2[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=2[CH:47]=O)(=[O:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl.[Au]>[CH:1]1([C:6]2[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([CH3:11])=[C:9]([CH2:47][C:46]3[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=3[S:42]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)(=[O:43])=[O:44])[CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)Cn1c(C)ccc1C1CCCC1
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCCC1
Agent: [Au]
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C2CCCC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Yield: 37.4 %

Procedure:
The general procedure was followed using ethyl 2-(2-cyclopentyl-5-methyl-1H-pyrrol-1-yl)acetate (3.49 g, 14.8 mmol), triethylsilane (7.11 mL, 44.5 mmol), trimethylsilyl trifluoromethanesulfonate (5.36 mL, 29.7 mmol), and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (3.55 g, 14.8 mmol) in dichloromethane of (total volume: 170 ml). Purification on silica gel (Luknova 330 g, 20 mL/min) using 1 to 7% of a 7:1 acetonitrile/methanol solution in dichloromethane over 70 minutes afforded ethyl 2-(5-cyclopentyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (2.54 g, 5.54 mmol, 37% yield) as a viscous gold residue that was approximately 90% pure by 1H-NMR analysis, with the impurity being ethyl 2-(2-cyclopentyl-5-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.96 (dd, 1H), 7.40 (ddd, 1H), 7.22-7.28 (m, 2H, composite of two shifts), 4.56 (s, 2H), 4.23 (s, 2H), 4.18 (q, 2H), 3.28-3.31 (m, 4H), 2.83 (m, 1H), 2.03 (s, 3H), 1.89-1.99 (m, 3H), 1.84-1.88 (m, 4H), 1.49-1.74 (m, 5H, composite of multiple shifts), 1.29 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([CH2:8][CH3:9])=[C:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH3:10][Li].O>CCOCC>[CH3:1][C:2]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)([CH3:10])[CH2:8][CH3:9]
Reactant: CCC(C)=C1C=CC=C1
Reactant: [Li]C
Solvent: O
Solvent: CCOCC
Product: CCC(C)(C)C1=CC=CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 8.00 g (66.6 mmol) of 6-methyl-6-ethylfulvene in 40 ml of ether, 66.0 ml (75.2 mmol) of an ether solution of methyllithium was dropwise added in an nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (165° C./270 mmHg) to obtain 8.40 g (61.66 mmol) of a light yellow liquid (yield: 93%). The analyzed values are given below.
Reaction SMILES: [Na].[N+:2]([NH:5][C:6]([NH2:8])=[NH:7])([O-:4])=[O:3].[CH:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:20](=[O:29])[CH:19]=1)[C:12](OCC)=O)=[O:10]>CO>[N+:2]([NH:5][C:6]1[NH:8][C:9](=[O:10])[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:20](=[O:29])[CH:19]=2)=[CH:12][N:7]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)C(C=O)Cc1ccn(CCN(C)C)c(=O)c1
Reactant: N=C(N)N[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Product: CN(C)CCn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Yield: 39.6 %

Procedure:
To a stirred solution of sodium (2.94 g) in methanol (65 ml) was added nitroguanidine (11.81 g, containing 25% w/w water) and methanol (20 ml). The mixture was stirred at reflux for 60 minutes, and then a solution of ethyl α-formyl-β-(N-(2-dimethylaminoethyl)-2-oxo-4-pyridyl]propionate (25.05 g) in methanol (75 ml) was added dropwise over 90 minutes. The reaction mixture was stirred under reflux for a further 21 hours. The reaction mixture was evaporated under reduced pressure, dissolved in water (150 ml) and extracted with chloroform (3×35 ml). The combined chloroform extracts were washed with water (2×10 ml). The combined aqueous layer and aqueous washings were taken to pH 4 with glacial acetic acid. The solvent was then evaporated under reduced pressure and a solid by-product crystallised from ethanol. The mother liquors were evaporated and another crystallisation from ethanol gave a further solid by-product. The mother liquor was evaporated under reduced pressure to afford 2-nitroamino-5-[1-(2-dimethylaminoethyl)-2-oxopyridin-4-ylmethyl]pyrimidin-4-one (11.26 g) as an oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=2)[C:18]([O:20]C)=[O:19])=[O:11])[S:2]1.[OH-].[Na+]>C1COCC1.O>[S:1]1[CH2:5][CH2:4][C@H:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([OH:23])=[C:17]([CH:22]=2)[C:18]([OH:20])=[O:19])=[O:11])[S:2]1
Reactant: COC(=O)c1cc(NC(=O)CCCC[C@H]2CCSS2)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCC[C@H]1CCSS1)Nc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-methyl 5-(5-(1,2-dithiolan-3-yl)pentanamido)-2-hydroxybenzoate (650 mg, 1.83 mmol) was taken up in 6 mL of THF and NaOH (220 mg, 5.5 mmol) was added as a solution in 6 mL of H2O. The resulting reaction mixture was stirred at room temperature for 8 h and then concentrated under reduced pressure. Enough 1 N HCl was added to the aqueous layer to adjust the pH to 2 and the resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (2×20 mL), brine, dried (Na2SO4) and concentrated under reduced pressure to afford (S)-5-(5-(1,2-dithiolan-3-yl)pentanamido)-2-hydroxybenzoic acid. Mass calculated for C15H19NO4S2: 341.08. found: [M+H]+=342.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)=[CH:7][C:6]=1[CH2:20][N:21](CC1C=CC(OC)=CC=1OC)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C.CCC([O-])(C)C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:26]([O:25][C:23]([C:22]1[N:21]=[CH:20][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)[CH:7]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2ccc(Cl)c(F)c2)ccc1C(=O)OCC
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2cc(Oc3ccc(Cl)c(F)c3)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To an ice-water bath cooled solution of 4-(4-chloro-3-fluoro-phenoxy)-2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (2.529 g) in THF (20 mL) was added a solution of potassium tert-pentoxide (4.5 mL, 1.7 M in toluene); the mixture was stirred at rt for 60 min after addition; then the mixture was quenched with 2 M HCl, diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (30 mL) and treated with thionyl chloride (0.63 mL) overnight. Then concentrated, the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (580 mg). LC MS ESI: 362 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.FC(F)(F)C(O)=O.[NH:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28]2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:14][C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:5]2[N:4]=[N:3][C:2]([N:22]3[CH2:27][CH2:26][C:25]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28]4)[CH2:24][CH2:23]3)=[CH:7][CH:6]=2)[N:9]=1
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Reactant: C1=CC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)n(-c2ccc(N3CCC4(C=Cc5ccccc54)CC3)nn2)n1

Procedure:
The object product (67 mg, 19%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazine (209 mg), spiro[indene-1,4′-piperidine] trifluoroacetate (300 mg) and potassium carbonate (275 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:31])=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:31])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cccc(Cl)c1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2-fluorobenzoic acid: MS (APCl) m/z 420 (M+1).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:10]2[C:9]3[C:14](=[CH:15][CH:16]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=4[CH3:28])[CH:8]=3)[N:13]=[C:12]([N:17]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]3)[N:11]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: Cc1ccccc1-c1ccc2nc(-n3cc(C(=O)O)cn3)nc(NC3CC3)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI/CI): predicted mass C22H19N5O2, 385.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[S:10])[NH2:9])=[CH:4][CH:3]=1.Br.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=O.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:10][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: O=C(CBr)c1ccccn1
Agent: Br
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc(-c3ccccn3)cs2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Fluorobenzenecarbothio-amide (250 mg, 1.61 mmol) and 2-bromo-1-pyridin-2-ylethanone hydrobromide (450 mg, 1.61 mmol) were dissolved in DMF (2 mL), and triethylamine (0.23 mL, 1.61 mmol) was added. The reaction was stirred at room temperature for 90 min, and then heated at 50° C. for 30 min. The mixture was diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SO4. The drying agent was filtered off, and the filtrate was concentrated to afford the title compound. LC-MS 257.1 [M+1]+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:19])=[CH2:18])[CH:12]=1)([CH3:10])=[CH2:9]>C1(C)C=CC=CC=1>[CH3:18][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)([CH3:10])[CH3:9])[CH:12]=1)([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[CH3:19]
Reactant: Oc1ccccc1
Reactant: C=C(C)c1cccc(C(=C)C)c1
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(O)cc1)c1cccc(C(C)(C)c2ccc(O)cc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
A 500-ml three-neck reactor was charged with amberlist-15 (7.5 g, 2.6 mmols), phenol (178.5 g, 633 mmols) and toluene (30 ml). The contents were heated up to 80° C. in nitrogen atmosphere. Under agitation, a mixture of m-diisopropenylbenzene (m-DIPeB, 15.0 g, 31.5 mmols) and toluene (30 ml) was fed thereto over 3 hours at 80° C. After completion of the feed, agitation was carried out at 80° C. for 10 minutes and then Amberlist-15 was removed by filtration. The filtrate was analyzed by liquid matography. Bisphenol M (α, α″-bis(4-hydroxyphenyl)-1,2-diisopropylbenzene, 28.8 g, yield 88%), the intended product, and the o,p-product, the position isomer of bisphenol M (α-(4-hydroxyphenyl)-α″-(2-hydroxyphenyl)-1,3-diisopropylbenzene, 2.79 g, yield 8.5%), were obtained. After completion of the same aftertreatment and purification operations as those in Example 3, bisphenol M was isolated (17.7 g., isolation yield 54%, purity 99.6%).
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH2:17][OH:18].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]2=[N:4][C:3]=1[CH:17]=[O:18]
Reactant: OCc1nc2c(N3CCOCC3)ccnn2c1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1nc2c(N3CCOCC3)ccnn2c1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of compound 14a (3.1 g, 9.9 mmol) in DCM (200 mL) was added Dess-Martin periodinane (4.6 g, 11 mmol). The reaction mixture was stirred at rt for 16 h, diluted with DCM (100 mL), and washed with 10% Na2S2O3 solution (50 mL) and aq Na2CO3 solution (2M, 100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give a residue, which was washed with MeOH (2×20 mL) and Et2O (2×20 mL) to afford compound 14b as an off-white solid. 1H-NMR (400 MHz, CDCl3) δ (ppm): 10.13 (s, 1H), 8.19 (d, J=5.56 Hz, 1H), 6.15 (d, J=5.56 Hz, 1H), 4.01-4.10 (m, 4H), 3.86-3.97 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:3]=1.CC1C=C(C=C(C)C=1CC1C=CC(OCOC)=C(CC2C=CC(F)=CC=2)C=1)C(OC)=O>[Pd].CO>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=2[OH:8])=[CH:15][CH:14]=1
Reactant: Oc1ccc(Br)cc1Cc1ccc(F)cc1
Agent: [Pd]
Agent: COCOc1ccc(Cc2c(C)cc(C(=O)OC)cc2C)cc1Cc1ccc(F)cc1
Solvent: CO
Product: Oc1ccccc1Cc1ccc(F)cc1
Yield: 100 %

Procedure:
A mixture of 4-bromo-2-(4-fluorobenzyl)phenol (compound 78, step a, 6.0 gm, 21.4 mmol), 1.2 g of palladium on activated carbon (10%) and 100 mL of methanol in a glass reaction vessel was shaken at 50 psi H2 over night, filtered and concentrated under reduced pressure. The resulting light orange oil was dissolved in 180 mL dichloromethane and washed 1× with NaHCO3 saturated solution. The organic was dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-(4-fluorobenzyl)phenol (4.52 gm, 100%): 1H NMR (200 MHz, DMSO-d6): δ 9.39 (s, 1H), 7.22 (m, 2H), 7.02 (m, 3H), 6.74 (m, 2H), 3.84 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=methylene chloride-hexanes (1:1); Rf=0.32.