Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1COCC1>[C:17]([O:16][C:15](=[O:21])[NH:14][C@H:3]([C:2](=[S:32])[NH2:1])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=S
Reaction time: 3 h
Yield: 83 %

Procedure:
To a solution of (S)-tert-butyl 1-amino-3-(4-nitrophenyl)-1-oxopropa-2-ylcarbamate, 1, (0.400 g, 1.29 mmol) in THF (10 mL) is added Lawesson's reagent (0.262 g. 0.65 mmol). The reaction mixture is stirred for 3 hours and concentrated to a residue that is purified over silica to provide 0.350 g (83% yield) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.10 (d. J=8.4 Hz, 2H), 8.01 (s, 1H), 7.42 (d, J=8.4 Hz, 2H), 5.70 (d, J=7.2 Hz, 1H), 4.85 (d, J=7.2 Hz, 1H), 3.11-3.30 (m, 1H), 1.21 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[O:22]C.C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22]
Reactant: COc1c(N)c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(I)cc2F)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
1.0M Solution of borontribromide in DCM (6.4 mL, 6.4 mmol) was added to a solution of 5-amino-6,7-difluoro-1-(2-fluoro-4-iodo-phenyl)-4-methoxy-1,3-dihydro-benzoimidazol-2-one (I-11a: 1.4 g, 3.2 mmol) in DCM (50 mL) at 0° C. and the resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (80% ethyl acetate in hexane). The reaction mixture was quenched with water and stirred for 1 hour. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to afford 1.15 g of the product (85.1% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:1][S:2]([O:6][CH:7]([C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10])(=[O:4])=[O:3]
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(OS(C)(=O)=O)c1ccc(C(=O)OCC)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methanesulfonyl chloride (341 mg, 2.97 mmol) was added dropwise to a solution of ethyl 4-(1-hydroxybutyl)benzoate (504 mg, 2.27 mmol) and triethylamine (477 mg, 4.58 mmol) in dichloromethane (5 mL) at 0° C. The reaction was stirred at 0° C. for 2 hours. The reaction was diluted with ethyl acetate and washed with saturated ammonium chloride, saturated sodium bicarbonate, and brine. The organics were dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1-(methylsulfonyloxy)butyl)benzoate. 1H NMR (400 MHz, CDCl3, δ): 8.02-8.10 (d, J=8.19 Hz, 2H), 7.44 (d, J=8.19 Hz, 2H), 5.50-5.61 (m, 1H), 4.37 (q, J=7.22 Hz, 2H), 1.97-2.11 (m, 1H), 1.78-1.88 (m, 1H), 1.39 (t, J=7.22 Hz, 3H), 1.28-1.52 (m, 2H), 0.94 (t, J=7.41 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH2:8]O)=[CH:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[S:3]1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1COCC1>[CH3:1][N:2]1[C:7]([CH2:8][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[S:3]1
Reactant: C1COCCN1
Reactant: CN1Sc2sccc2C=C1CO
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1Sc2sccc2C=C1CN1CCOCC1
Yield: 84 %

Procedure:
To a solution of the product from Step C (0.79 g, 3.42 mmol) and triethylamine (1.04 g, 10.3 mmol) in anhydrous THF (30 mL) at ambient temperature was added methanesulfonic anhydride (0.89 g, 5.13 mmol) with stirring. After 30 min morpholine (2 mL) was added and the mixture stirred for 1 h at ambient temperature and then heated at reflux temperature for 1 h. The volatiles were evaporated and a saturated aqueous solution of sodium bicarbonate (80 mL) was added. This mixture was extracted with ethyl acetate (2×100 mL) and the combined extracts were dried (MgSO4) and evaporated to give a viscous oil which was purified by column chromatography (silica, 30 to 50% ethyl acetate/hexane) to give a white solid (0.82 g, 84%): mp 104°-106° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.O/[C:16](=[C:18]1\[C:19](=[O:25])[NH:20][C:21](=[O:24])[CH2:22][CH2:23]\1)/[CH3:17]>C(O)C.Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]/[C:16](=[C:18]3\[C:19](=[O:25])[NH:20][C:21](=[O:24])[CH2:22][CH2:23]\3)/[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: C/C(O)=C1\CCC(=O)NC1=O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: Cl
Solvent: CCO
Product: C/C(Nc1ccc(N2CCN(C)CC2)cc1)=C1\CCC(=O)NC1=O
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-methyl-1-piperazinyl)-benzenamine (43 mg, 0.23 mmol) and (3Z)-3-(1-hydroxyethylidene)-piperidine-2,6-dione (35 mg, 0.23 mmol) in absolute ethanol (1.5 mL) is added concentrated ethanolic hydrogen chloride (2 drops), which caused the precipitation of a white solid. The mixture is heated in a 65° C. oil bath for 20 minutes. Then N,N-dimethylformamide (0.4 mL) is added to the mixture and the temperature of the oil bath is increased to 70° C. An additional volume of N,N-dimethylformamide (0.6 mL) is added and the temperature of the oil bath is increased to 135° C., at which setting it stirred for 30 minutes. The mixture is stirred overnight at 130° C. After cooling to room temperature, the semi-solid reaction mixture is triturated with methanol. The solid that formed is collected by filtration and washed with diethyl ether, water, and methanol to give (3Z)-3-(1-{[4-(4-methylpiperazin-1-yl)phenyl]amino}ethylidene)piperidine-2,6-dione as a light beige solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](OC)=O)[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C[Mg]Cl.[Cl-].[NH4+].[O:35]1CC[CH2:37][CH2:36]1>>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH:36]([OH:35])[CH3:37])[CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:6]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC(O)Cc1cccc(Nc2nccc(-c3sc(N)nc3-c3ccccc3)n2)c1

Procedure:
To a suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-(3-methoxycarbonyl-phenyl)-amine (800 mg, 2.0 mmol) in tetrahydrofuran (30 ml) is added a solution of methyl magnesium chloride (6 ml of a 20% THF solution) without cooling. The temperature of the reaction mixture rises to about +45° C. and the starting material dissolves immediately yielding a yellow clear solution. After an additional hour the solution is poured onto crushed ice and ammonium chloride. The colorless precipitate is filtered and washed with ethyl acetate and tetrahydrofuran. The organic phases are pooled, dried and concentrated under reduced pressure. Chromatography of the resulting solid gives the N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-[3-(2-hydroxy-2-methyl-ethyl)-phenyl]-amine, m.p. 219–220° C.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([CH3:15])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[NH2:16][C:17]1[C:18]([CH3:24])=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1.O>C(O)COCCO>[CH3:24][C:18]1[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:17]=1[N:16]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH3:15])[C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[CH2:12][CH2:13]1
Reactant: Cc1cccc2c1=NC(=O)C1CCOC=21
Reactant: Cc1cc(O)ccc1N
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc(O)ccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Temperature: 250 °C
Yield: 68.5 %

Procedure:
4-Oxo-6-methyl-2,3-dihydrofuro[3,2-c]quinoline (201 mg, 1.0 mmol) was dissolved in 10 ml of diethylene glycol in a pressure tube and 4-amino-m-cresol (308 mg, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 250° C. for 15 hours. The reaction mixture was diluted in 20 ml of salt water and the aqueous layer was extracted by methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 210 mg of desired compound as solid in 81% of yield.
Reaction SMILES: [CH2:1]([O:3]C=CC#N)[CH3:2].[Na].[CH2:9]([O:11][C:12](=[O:16])[CH:13]=[CH:14][OH:15])[CH3:10].Cl.[CH2:18](O)[CH3:19]>>[CH2:9]([O:11][C:12](=[O:16])[CH2:13][CH:14]([O:3][CH2:1][CH3:2])[O:15][CH2:18][CH3:19])[CH3:10]
Reactant: CCOC=CC#N
Reactant: CCO
Reactant: CCOC(=O)C=CO
Agent: Cl
Agent: [Na]
Product: CCOC(=O)CC(OCC)OCC

Procedure:
A complicated synthesis of β-ethoxyacrylonitrile (I) by a plurality of steps has been described, which entails the tranposition of the sodium salt of β-hydroxyacrylic acid ethyl ester with ethanol in the presence of HCl to form β,β-diethoxypropionic acid ethyl ester, the preparation of the amide by reaction with ammonia, and further dehydration with phosphorus pentoxide, β-ethoxyacrylonitrile (I) being formed as a by-product (S. M. McElvain and R. L. Clark, J. Amer. Chem. Soc., 69, (1947) 2657).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)=[N:7][CH:8]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C(N(CC)CC)C>ClC(Cl)Cl.CN(C)C1C=CN=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:28][C:29]1[CH:34]=[C:33]([NH:27][C:4]2[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[N:10]=3)[N:5]=2)[CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccnc(F)c4)n3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 mg of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]pyrimidin-4-amine (1-4-1, 0.277 mmol, 1. eq.), 78.0 mg of (2-fluoropyridin-4-yl)boronic acid (0.553 mmol, 2 eq.) and 205 mg of copper (II) acetate were suspended in 4 ml of trichloromethane. 154 μl of triethylamine (1.11 mmol, 4 eq.) and 16.9 mg of N,N-dimethylpyridin-4-amine (138 mmol, 0.5 eq.) were added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered off over Celite 545 and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC to yield 13 mg (0.03 mmol, 10.9%) of the analytically pure target compound.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([OH:18])=O)[CH2:4][CH2:3][CH2:2]1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[CH2:14][CH2:15][C:16]([N:22]([CH:19]([CH3:21])[CH3:20])[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:18])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1cc(F)ccc1OCC1CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cc(F)ccc1OCC1CCC1
Yield: 17 %

Procedure:
A solution of 3-(2-cyclobutylmethoxy-5-fluoro-phenyl)-propionic acid (195 mg, 0.77 mmoles) and benzoic acid N′-isopropyl-hydrazide (115 mg, 0.64 mmoles) in DMF (5 mL) was treated with diisopropylethylamine (0.28 mL, 1.61 mmoles), and PyBroP (450 mg, 0.97 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (45 mg, 14%). LC-MS m/e 413.32(M+H+)
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[F:24][C:21]1[CH:20]=[CH:19][C:18]([C@H:7]2[CH2:6][C@H:5]([OH:4])[CH2:10][CH2:9][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:23][CH:22]=1
Reactant: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(F)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)C[C@@H]1c1ccc(F)cc1
Yield: 99 %

Procedure:
A suspention of (±)-(2R,4R)-tert-butyl 4-acetoxy-2-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.40 mmol) and potassium carbonate (1.0 g) in methanol:water 10:1 (11 mL) was stirred for 1 hour then diluted with ethyl acetate (40 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (±)-(2R,4R)-tert-butyl 2-(4-fluorophenyl)-4-hydroxypiperidine-1-carboxylate (117 mg, 99% yield). 1H NMR (400 MHz, d6-DMSO): 7.17 (m, 4H), 5.34 (br d, 1H), 4.73 (d, 1H), 4.34 (br d, 1H), 3.41 (m, 1H), 2.67 (m, 1H), 2.42 (br d, 1H), 1.57 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [Mg].[CH3:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14]#N.CC[O:23]CC>>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=1[C:14](=[O:23])[CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH3:2])=[CH:4][CH:5]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: CCOCC
Agent: [Mg]
Product: Cc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
To an oven-dried three-neck round bottom flask fitted with a condenser and addition funnel charged flushed with nitrogen was added magnesium (2.82 g; 116 mmol) and anhydrous ether (100 mL). A solution of 4-methylbenzyl bromide (12.91 g; 69.7 mmol) in ether (50 mL) was added dropwise via the addition funnel at room temperature. After the addition, the reaction mixture was heated at 40° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and was cannulated to another dried flask charged with a solution of 2,4-dichlorobenzonitrile (10.0 g; 58.0 mmol) in ether (150 mL) under a nitrogen atmosphere. The resulting reaction mixture was stirred at 40° C. for 6 hours. The reaction was cooled to room temperature and quenched slowly with 2N aq. HCl. Partitioned between ethyl acetate and 2N aq. HCl. The organic portion was washed with 2N aq. HCl, water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was filtered through a silica gel plug (eluted with 20% ethyl acetate/hexane), and recrystallized from hexane to afford product: m/e=279 (M+1).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19].FC(F)(F)[C:22](O)=[O:23]>>[Cl:11][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([CH3:18])[C:13]=1[OH:19])[CH:22]=[O:23]
Reactant: Cc1cccc(Cl)c1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: Cc1cc(C=O)cc(Cl)c1O
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
Hexamethylenetetramine (19.60 g, 139.8 mmol) was added in portions to a solution of 2-chloro-6-methylphenol (20.00 g, 117.2 mmol) in trifluoroacetic acid (200 mL). There was a slight exotherm and effervescence was noted. The reaction mixture was heated in an oil-bath at 84-86° C. for 5 h, then it was cooled and evaporated (˜50° C., 0.2 mm). The residue was evaporated from hexane, then ice-water (500 mL) was added and the mixture was stirred for 20 min. Ether (100 mL) was added and the reaction was brought to approx. pH 5 by the careful portionwise addition of solid sodium hydrogen carbonate (49 g). The resulting mixture was extracted with ether (2×250 mL), and the ether layers were washed with brine, dried (MgSO4), filtered and concentrated to about 100 mL. The mixture was then left to crystallize over the weekend to give a solid which was filtered off and washed with ice-cold ether to give 3-chloro-4-hydroxy-5-methylbenzaldehyde (6.9 g, 35%) as a yellow solid. The mother liquor was evaporated and dichloromethane (30 mL) was added. The yellow solid was filtered off (2.9 g, 14%). The remaining solution was purified by HPLC (7% ethyl acetate/hexanes) to give a yellow solid (7.8 g, 39%). The overall yield was17.6 g (88%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=O)[CH2:4][CH2:3]1.[C-:11]#[N:12].[Na+].[NH4+:14].[Cl-].N.CO.N>CO>[NH2:14][CH:9]([C:11]#[N:12])[CH2:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: CN1CCC(CC=O)CC1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(CC(N)C#N)CC1

Procedure:
The above aldehyde (1 equiv) is mixed with NaCN (1.1 equiv) and NH4Cl (1.1 cquiv) in 2 Molar NH3/MeOH (4 equiv NH3). The flask is fitted with a reflux condenser and the mixture is refluxed. At the end of each of the first 3 h an additional equivalent of NH3 in MeOH is added. The reaction mixture is cooled and the excess solids are filtered away on a frit. The filtrate is concentrated by rotary evaporation and the residue is triturated with diethyl ether and the mixture is filtered again. The filtrate is concentrated on a rotovap. The product is purified, if necessary, by flash chromatography on silica with EtOAc/hexanes as an eluent to yield 1-amino-1-cyano-2-(1-methyl-piperid-4-yl)-ethane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][C:14]1[C:30]([CH3:31])=[CH:29][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([CH3:32])[CH:15]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][C:14]2[C:30]([CH3:31])=[CH:29][C:17]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:28])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([CH3:32])[CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(N)cc1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(NS(=O)(=O)c2ccc(OC)cc2)cc1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
A solution of 2.2 g (12.5 mmol) of para-methoxybenzenesulfonyl chloride in 10 mL of tetrahydrofuran is added over 10 minutes at 0° C. to a solution of 3.5 g (12.5 mmol) of 5-(4-amino-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester as the free base (Example 2) and 2.5 g (2×12.5 mmol) of triethylamine in 40 mL of tetrahydrofuran. The ice bath is removed and the solution is permitted to stir at ambient temperature for 24 hours. The triethylammonium chloride is removed by filtration, the solvent is removed; the residue is taken up in diethyl ether, and the solution washed with 2×25 mL of 2N hydrochloric acid solution, brine, dried (magnesium sulfate), and evaporated leaving 5.0 g of a colored oil which crystallizes on standing. Recrystallization from 35 mL of isopropyl ether in the presence of charcoal affords 3.3 g of the title compound as off-white crystals; mp 90°-92° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:13][C:12]([C:28]([C:34]([F:37])([F:36])[F:35])([C:30]([F:33])([F:32])[F:31])[OH:29])=[N:11]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:27][CH2:26][CH2:25][N:24]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH2:13][C:12]([C:28]([C:34]([F:35])([F:36])[F:37])([C:30]([F:31])([F:33])[F:32])[OH:29])=[N:11]1
Reactant: OC(C1=NN(c2ccc(F)cc2F)C(c2ccc(N3CCCNCC3)cc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccc(F)cc3F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(homopiperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 409, triethylamine (22.0 uL, 0.16 mmol) and methanesulfonyl chloride (5.0 uL, 0.07 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:28](=O)([O-])[O-:29].[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:28]=[O:29])=[CH:11][CH:10]=[C:9]2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(-c2cccn2-c2ccc(F)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2ccc(C=O)n2-c2ccc(F)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
1.67 g (5.3 mmol) of 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 33) were dissolved in 30 ml of dimethylformamide, 0.50 ml (5.3 mmol) of phosphorous oxychloride was added to the resulting solution, and the mixture was then stirred at 60° C. for 2 hours. At the end of this time, the reaction mixture was gradually added to ice-water and the pH of the mixture was adjusted to a value of 8-9 by the addition of sodium carbonate. The mixture was then extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 5:1 by volume mixture of hexane and ethyl acetate, to give 0.90 g (yield 50%) of the title compound as a white powder, melting at 135-137° C.