Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[P:2]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.C1(C)C=CC=CC=1>CN(C)C=O.[Zn]>[CH:9]1([PH:2][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: Cl
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C1CCC(PC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
1.09 g (4.68 mmol) of chlorodicyclohexylphosphine was added dropwise in a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mg-atoms) of zinc (powder) in 10 cm3 of N,N-dimethylformamide and the mixture was stirred at room temperature for one hour. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm--3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, and the toluene layer was determined by gas chromatography, giving dicyclohexylphosphine in 67% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:26])[S:16]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:26])[S:16]([C:19]2[CH:20]=[N:21][C:22]([NH:28][NH2:29])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN([C@@H]1CC[C@H](COCc2ccccc2)C1)S(=O)(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: CN([C@@H]1CC[C@H](COCc2ccccc2)C1)S(=O)(=O)c1ccc(NN)nc1
Yield: 86 %

Procedure:
According to process 5.2, starting with 0.58 g of N-{(1R,3S)-3-[(benzyloxy)methyl]-cyclopentyl}-6-chloro-N-methylpyridine-3-sulfonamide and 0.15 mL of hydrazine hydrate, 0.49 g of N-{(1R,3S)-3-[(benzyloxy)methyl]cyclopentyl}-6-hydrazinyl-N-methylpyridine-3-sulfonamide is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Nc1ccc(F)c(Br)c1Nc1ccccc1
Temperature: 90 °C
Yield: 90.1 %

Procedure:
To a mixture of (2-bromo-3-fluoro-6-nitrophenyl)phenylamine (2.4 g, 7.7 mmol) in MeOH (40 mL) and water (15 mL) were added NH4Cl (2.38 g, 46.3 mmol) and iron powder (1.72 g, 30.9 mmol) and the reaction mixture heated at 90° C. for 1 h. After cooling to RT, the crude mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (1.95 g, 90%). LCMS (Method C): RT 3.48 min [M+H]+ 281.1/283.1.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[CH3:18][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17]
Reactant: O=C1Nc2ccc(Cl)cc2C1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: CC1(c2ccccc2)C(=O)Nc2ccc(Cl)cc21
Temperature: 50 °C

Procedure:
10 g of 3-phenyl-5-chlorooxindole were dissolved in 100 ml of acetone and 20 ml of water, 2.9 g of potassium carbonate and 2.9 ml of methyl iodide were added and the mixture was warmed at 50° C. for 3 hours and concentrated; water was added to the residue, which was extracted with ethyl acetate, and the extract was dried over magnesium sulfate, and the solvent was removed. The residue was recrystallized from ethanol. Melting point 180°-181° C.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([N:9]=[CH:10][C:11]([Br:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:15][C:11]1[CH:10]=[N:9][C:8]2=[N:7][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[CH:14]=[C:13]2[CH:12]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2cc(Br)cnc2n1
Product: CC(C#N)(Cn1cc2cc(Br)cnc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-2H-pyrazolo[3,4-b]pyridin-2-yl)-2-methylpropionitrile (35 mg, described in Example 204) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (30.7 mg, 50%). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, CHLOROFORM-d): 1.99 (s, 3H), 4.94 (d, J=1.6 Hz, 2H), 7.76 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 8.20 (s 1H), 8.26 (d, J=2.1 Hz, 1H), 8.37 (s 1H) and 8.74 (d, J=2.1 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: Cl.[CH2:2]([N:9]([C@H:17]([C@@H:25]([OH:39])[CH2:26][C@@H:27]([NH:35]C(=O)C)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)CCC>[CH2:2]([N:9]([C@H:17]([C@@H:25]([OH:39])[CH2:26][C@@H:27]([NH2:35])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To 40 ml of 4N hydrochloric acid, was added 10.86 g of (2S,3S,5S)-2-(N,N-dibenzylamino)-5-acetylamino-1,6-diphenyl-3-hexanol, and the resulting solution was refluxed for 6 hours and cooled to room temperature. To the reaction mixture, was added 30 ml of n-butanol, and the resulting mixture was neutralized with dropwise addition of a 10% solution of sodium hydroxide. The organic layer of n-butanol was separated, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure, thereby obtaining 9.29 g (100%) of the title compound as a colorless resin. This compound was found to be a single compound by high performance liquid chromatography (HPLC), and hence used in the subsequent process without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[N:7][CH:8]=1.C1COCC1.Br[CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>C(N(CC)CC)C>[O:15]=[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][N:7]=2)[CH2:14][CH2:13][N:12]([CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:11]1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=C1CNCCN1c1ccc(C(F)(F)F)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CN1CCN(c2ccc(C(F)(F)F)cn2)C(=O)C1)OCc1ccccc1

Procedure:
1.12 g of 1-(5-trifluoromethylpyridin-2-yl)piperazin-2-one, 40 ml of THF and 0.87 ml of benzyl bromoacetate are placed in 1.5 ml of triethylamine in a round-bottomed flask equipped with a magnetic stirrer. The mixture is reacted under a stream of nitrogen overnight at room temperature. The solvent is evaporated off and the residue is purified by flash chromatography on a Biotage® column, using 1/1 hexane/ethyl acetate as eluent. 2.9 g of title product are isolated in the form of a white solid.
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](O)([OH:16])[C:12]([F:19])([F:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[C:12]([F:19])([F:18])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC1(O)CCN(Cc2ccccc2)CC1(F)F
Agent: N#N
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: OC1CCN(Cc2ccccc2)CC1(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 1-benzyl-3,3-difluoropiperidine-4,4-diol (WO2008/121687 and WO2005/040120) (2.88 g, 11.85 mmol) in dry MeOH (58 mL) was added NaBH4 (672 mg, 17.76 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. for 15 min. Aq. 0.1M NaHCO3 (5 mL) was then added and the mixture further stirred for 5 min, dried (MgSO4), filtered and concentrated under reduced pressure. The crude residue was purified by FC (hept-EA, 2:1→1:1) and the title compound obtained as a beige oil. LC-MS-conditions 08: tR=0.42 min; [M+H]+=228.32.
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH:6]([SiH:10]([Cl:12])[Cl:11])[SiH:7]([Cl:9])[Cl:8])[Cl:5]>>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH:6]1[SiH:10]([Cl:12])[Cl:11]
Reactant: C#C
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[SiH](Cl)Cl
Product: Cl[SiH](Cl)C1[Si](Cl)(Cl)C=C[Si]1(Cl)Cl
Reaction time: 8 h
Yield: 31.7 %

Procedure:
Hydrosilation of acetylene with tris(dichlorosilyl)methane in the presence of H2PtC6. Into the same apparatus as described in Example 1 were placed 220 μl of a 0.1 M H2PtCl6 /IPA solution and the flask placed under a dry nitrogen atmosphere. The IPA was removed from the flask under vacuum and 5.31 g of tris(dichlorosilyl)methane and 30 ml of dried benzene added to form a mixture. Acetylene gas was blown into the mixture at a rate of 90 ml per minute for 8 hours. The resulting mixture was vacuum distilled at 67 Pa to yield a mixture comprising 4.51 g of 1,1,3,3-tetrachloro-2-dichlorosilyl-1,3-disilacyclopent-4-ene (TCD-GC area 31.7%) and 3,3,5,5-tetrachloro-4-dichlorosilyl-3,5-disilahepta-1,6-diene (TCD-GC area 8.6%). 1,1,3,3-Tetrachloro-2-dichlorosilyl-1,3-disilacyclopent-4-ene =1H-NMR (CDCl3, ppm):1.33 (d, 3.9 Hz, 1H, SiCHSi), 5.73 (d, 3.9 Hz, 1H, SiH), 7.43 (s, 2H, CH=CH).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[OH-].[Na+].O.Cl[C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[N:11]=1>CC(C)=O>[Cl:17][C:12]1[CH:13]=[C:14]([Cl:16])[N:15]=[C:10]([NH:4][C:3]([NH2:5])=[NH:2])[N:11]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: N=C(N)Nc1nc(Cl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.7 %

Procedure:
A solution of 141.8 g (1.48 mole) of guanidine hydrochloride, 59.3 g (1.48 m) of sodium hydroxide and 709 ml of water was added to a solution of 183.4 g (0.74 m) of 2,4,6-trichloropyrimidine in 2127 ml of acetone causing a mild exothermic reaction. After stirring for 1 hour at room temperature, a mixture of solid and oil had formed. Refrigeration caused complete crystallization. The crystals were filtered, then suspended in 1200 ml of water and stirred for 1 hour, filtered, washed with water, then acetone and air dried to give 53.0 g (35%) of 4,6-dichloro-2-guanidinopyrimidine, mp>360°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CC(C)=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[CH:15]=[C:16]3[C:11]([C:10]([CH3:24])=[C:9]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:8]3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)=[CH:18][CH:19]=1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc12
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2ccc3c(C)c(-c4ccccc4)n(Cc4ccccc4)c3c2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-6-yl)-phenol (0.291 g, 0.747 mmol) was reacted with K2CO3 (0.134 g, 0.971 mmol) and methyl bromoacetate (0.149 g, 0.971 mmol) in acetone (5 ml) to give the product (0.305 g, 0.661 mmol, 88%) as a white solid, mp 145-148° C. 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 3.70 (s, 3H), 4.81 (s, 2H), 5.39 (s, 2H), 6.86 (d, J=7.2 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 7.13 (t, J=7.2 Hz, 1H), 7.18 (t, J=7.0 Hz, 2H), 7.34 (dd, J=1.4, 8.1 Hz, 1H), 7.39-7.44 (m, 3H), 7.49 (t, J=7.0 Hz, 2H,) 7.56-7.62 (m, 4H); [ESI(+)], m/z 462 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:27])([CH3:26])[CH2:3][CH2:4][O:5][C:6]([NH:8][CH2:9][C@@H:10]([NH:18]C(=O)OC(C)(C)C)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:7].C(OCC)C.CC1C=CC(S(O)(=O)=O)=CC=1>CCO.CCO.O>[NH2:18][C@@H:10]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH2:9][NH:8][C:6](=[O:7])[O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:27])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOC(=O)NC[C@@H](N)CC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-tert-butyl 1-(2-(trimethylsilyl)ethoxycarbonylamino)-3-cyclohexylpropan-2-ylcarbamate (8.5 g, 0.0213 mol) was dissolved into a minimal volume of ethyl ether (120 mL) and added to a solution of tosic acid (4.46 g, 0.023 mol) in 25 mL of absolute EtOH. This solution was placed on a rotary evaporator and ethyl ether was removed at ambient temp. The flask was then lowered into the water bath (temperature: 60° C.) and the selective de-protection of the Boc group proceeded concurrently with removal of the remainder of solvent. The reaction was completed by 2 h and gave an off-white solid. This material was cooled to rt and dissolved in 100 mL of a mixture EtOH:H2O (1:1, v/v). This was washed with hexanes:EtOAc (5:1, v/v, 3×12 mL), basified with 1N NaOH (pH>10), and extracted with EtOAc (3×50 mL). The combined organic extracts were washed (3×5 mL 1N NaOH, 3×5 mL brine), dried, decanted and stripped to give the free base of (S)-2-(trimethylsilyl)ethyl 2-amino-3-cyclohexylpronylcarbamate (5.24 g, 82%). 1H NMR (400 MHz, CDCl3): 5.09 (brs, 1H), 4.14 (t, J=8.4 Hz, 2H), 3.23 (m, 1H) 2.88 (m, 2H), 1.75-1.48 (m, 5H), 1.5-0.75 (m, 10H), 0.05 (s, 9H). MS (E/Z): 301 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:9]#[N:10])[C:5](Br)=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[C:4]([C:9]#[N:10])[C:5]([C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=2[F:21])=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: N#Cc1nc(N)cnc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: N#Cc1nc(N)cnc1-c1ccc(Cl)cc1F
Temperature: 80 °C

Procedure:
To a 200 mL round-bottomed flask were added a stirbar, 5-amino-3-cyano-2-bromopyrazine (4.09 g, 20.5 mmol), 4-chloro-2-fluorophenylboronic acid (3.90 g, 22.4 mmol), Pd(dppf)Cl2.CH2Cl2 (839 mg, 1.03 mmol) and K2CO3 (8.36 g, 60.5 mmol). The flask was flushed with nitrogen and then charged with toluene (17.5 mL), water (17.5 mL) and DMF (10.5 mL), all of which were sparged with N2. The flask was heated at 80° Celsius for 19 hours before cooling to rt and adding MgSO4 until the mixture was a thick paste. The reaction mixture was then stirred with EtOAc and filtered through a thick pad of celite. The pad was rinsed with EtOAc until the filtrate was colorless. The filtrate was concentrated to dryness and subjected to FCC to give 6-amino-3-(4-chloro-2-fluorophenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C11H6ClFN4, 248.03; m/z found, 249.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.67-7.60 (m, 2H), 7.46 (dd, J=8.4, 2.0, 1H), 7.37 (s, 2H).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:9]=12)=[NH:4].[S:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=O)=[CH:34][CH:33]=1)(=[O:31])(=[O:30])[NH2:29]>>[F:17][C:14]([F:15])([F:16])[C:13]1[N:8]2[N:7]=[CH:6][C:5]([C:3]3[N:4]=[C:36]([C:35]4[CH:34]=[CH:33][C:32]([S:28]([NH2:29])(=[O:31])=[O:30])=[CH:40][CH:39]=4)[O:1][N:2]=3)=[C:9]2[N:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:12]=1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: N=C(NO)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2nc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)no2)cc1

Procedure:
The title compound was prepared from N-hydroxy-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamidine (example B.1) (195 mg, 0.5 mmol) and commercially available 4-sulfamoyl-benzoic acid (101 mg, 0.5 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (155 mg, 56%). MS (ISN) 553.3 [(M−H)−]; mp 292° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[CH3:39][N:40]1[CH:44]=[C:43]([S:45](Cl)(=[O:47])=[O:46])[N:42]=[CH:41]1>>[CH3:39][N:40]1[CH:44]=[C:43]([S:45]([N:11]2[CH2:12][CH2:13][CH:8]([CH2:7][N:6]3[C:2](=[O:1])[C:3]([CH2:25][C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)([CH2:32][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[NH:4][C:5]3=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)=[O:16])[CH2:9][CH2:10]2)(=[O:47])=[O:46])[N:42]=[CH:41]1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Product: Cn1cnc(S(=O)(=O)N2CCC(CN3C(=O)C(Cc4ccncc4)(Cc4ccncc4)NC3=CC(=O)c3ccc(C#N)cc3)CC2)c1

Procedure:
According to the procedure of Example 13, the title compound of 40B (100 mg, 0.20 mmol) and 1-methylimidazol-4-ylsulfonyl chloride (50 mg, 0.30 mmol) were reacted to generate the title compound as a white solid (9 mg, 0.014 mmol, 7% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.[H-].[Na+].[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C>CN(C)C=O>[CH2:15]([N:9]1[CH2:10][CH2:11][N:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]1=[O:12])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC=Cc1ccccc1
Reactant: O=C1NCCN1c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1N(C/C=C/c2ccccc2)CCN1c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
To a solution of 150 g of 1-(3-pyridyl)-2-imidazolidinone dissolved in 1500 ml of N,N-dimethylformamide was added 40 g of sodium hydride (60% oily dispersion). After the mixture was stirred at room temperature for 10 minutes, 154 g of cinnamyl chloride (trans-form) was added dropwise under ice-cooling and the mixture was stirred for 2 hours. After addition of 10 ml of acetic acid, the solvent was distilled off under reduced pressure and to the residue was added water, followed by extraction with chloroform. After washing with saturated aqueous sodium hydrogen carbonate and saturated saline water, the extract was dried. Chloroform was distilled off, and isopropyl ester was added to the residue. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 238.1 g of (E)-1-cinnamyl-3-(3-pyridyl)-2-imidazolidinone as colorless prisms.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=1[S:49](Cl)(=[O:51])=[O:50].[Cl-].[NH4+]>O1CCCC1>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:49]([C:43]3[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=3[F:41])(=[O:51])=[O:50])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:12]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccc(F)cc2F)c1)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 85.3 %

Procedure:
To a suspension of sodium hydride (60% in oil, 26.0 mg) in tetrahydrofuran (3 mL) was added tert-butyl {[5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (156 mg) at room temperature, and the mixture was stirred for 15 min. After stirring, 15-crown-5 (143 mg) and 2,4-difluorobenzenesulfonyl chloride (159 mg) were added dropwise and the mixture was further stirred at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a colorless oil (yield 208 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:51])=[C:33]([S:35]([N:38]([C:46]2[N:47]=[CH:48][S:49][CH:50]=2)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])(=[O:37])=[O:36])[CH:34]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.C(OCC)(=O)C.O>[C:41]([O:40][C:39]([N:38]([C:46]1[N:47]=[CH:48][S:49][CH:50]=1)[S:35]([C:33]1[C:32]([F:51])=[CH:31][C:30]([O:21][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)=[C:29]([Cl:28])[CH:34]=1)(=[O:37])=[O:36])=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c3cscn3)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Example 655 from above can be made as follows. To a solution of tert-butyl 4-(5-chloro-2-hydroxyphenyl)piperidine-1-carboxylate (Preparation 231, 38 mg, 0.122 mmol) and potassium carbonate (50.6 mg, 0.366 mmol) in dimethyl sulfoxide (1 mL) was added tert-butyl [(5-chloro-2,4-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 453, 50 mg, 0.122 mmol). The mixture was stirred at room temperature for 16 hours before diluting with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was acidified to pH 4 with saturated citric acid solution (aqueous) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (30 mL), dried over sodium sulphate, filtered and concentrated in vacuo to afford tert-butyl 4-[2-(4-{[(tert-butoxycarbonyl)(1,3-thiazol-4-yl)amino]sulfonyl}-2-chloro-5-fluorophenoxy)-5-chlorophenyl]piperidine-1-carboxylate as a white foam. This was dissolved in dichloromethane (1 mL), trifluoroacetic acid added (200 μL) and reaction stirred for 16 hours at room temperature before concentrating in vacuo. Purification by preparative HPLC afforded the title compound.