Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]([Cl:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH2:29])(=[O:28])=[O:27].Cl>O.CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([NH:29][C:8]1[C:17]([Cl:18])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)(=[O:28])=[O:27]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: Clc1nc2ccccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1Cl
Yield: 101 %

Procedure:
In the presence of potassium carbonate (625 mg), 2,3-dichloroquinoxaline (275 mg) and 2-chlorobenzenesulfonamide (264 mg) were allowed to react in the solution of dimethylformamide (4 mL) for 3 hours at 90° C. To the reaction mixture, water and hydrochloric acid were added and extracted with ethyl acetate. The residue was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate and concentrated to obtain the title compound (493 mg) having the following physical data.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:40][CH3:41])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Yield: 99.5 %

Procedure:
To a mixture of ethyl 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylate (1.80 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (15 mL), and the mixture was heated under reflux for 4 hrs. 1N Hydrochloric acid (15 mL) and water were added to the reaction mixture, and the precipitated crystals were collected by filtration to give 1-benzyl-3-({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1H-pyrazole-4-carboxylic acid as crystals (1.70 g, yield 98%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 162-163° C.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH2:10]([O:17][C:18](=[O:30])[C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]I)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I[C:32]1[CH:33]=[C:34]([N:38]2[S:42](=[O:44])(=[O:43])[N:41]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[C:40](=[O:54])[CH2:39]2)[CH:35]=[CH:36][CH:37]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:10]([O:17][C:18](=[O:30])[C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH2:39][C:40](=[O:54])[N:41]([CH2:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)[S:42]2(=[O:43])=[O:44])[CH:33]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CI)C(=O)OCc1ccccc1
Reactant: COc1ccc(CN2C(=O)CN(c3cccc(I)c3)S2(=O)=O)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CN(c3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)c3)S2(=O)=O)cc1
Temperature: 50 °C
Reaction time: 0.42 h

Procedure:
Onto zinc foil (99.9% Aldrich 35, 602-6,118.5 mg, 1.813 mmol) is cut in small pieces is added DMF (freshly distilled from CaH2 under argon, 0.4 mL) and 1,2-dibromoethane (0.006 mL, 0.065 mmol) under argon. The mixture is heated at 50° C. for 10 min, then allowed to cool and trimethylsilyl chloride (0.003 mL, 0.026 mmol) is added. The reaction is stirred for 25 min and a solution of (R)-2-t-butoxycarbonylamino-3-iodo-propionic acid benzyl ester (Fluka, 342 mg, 0.844 mmol) in DMF (1 mL) is added. After 1 h, the mixture is decanted to a solution of the title C compound, 5-(3-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (300 mg, 0.65 mmol), tri-o-tolylphosphine (29.9 mg, 0.13 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (29.9 mg, 0.033 mmol) in DMF (2 mL). After stirring for 1.5 h, the resulting reaction mixture is poured onto water (100 mL), extracted with EtOAc (2×100 mL). The combined EtOAc layers are washed with water (1×200 mL) and brine (1×200 mL), dried over anhydrous MgSO4, filtered and concentrated to give a yellow oil. This is chromatographed on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 12:88 over 40 min. Fractions containing product are combined and concentrated to yield (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a clear oil: [M+NH4]+=627.0, [M−HCO2]−=654.1.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:13]([O:15][CH2:16][CH2:17][O:18][C:19](ON1C(=O)CCC1=O)=[O:20])=[O:14]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][C:19]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:20])=[O:14])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: NC1(C(=O)O)CC1
Reactant: COc1ccc(C(=O)OCCOC(=O)ON2C(=O)CCC2=O)cc1OC
Product: COc1ccc(C(=O)OCCOC(=O)NC2(C(=O)O)CC2)cc1OC
Yield: 72.9 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.122 g, 1.21 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 3,4-dimethoxybenzoate (0.4 g, 1.01 mmol) were reacted to provide 0.260 g (68% yield) of the title compound (14) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 171.8-173.6° C. 1H NMR (CDCl3, 400 MHz): δ=7.69 (d, 1H), 7.47 (s, 1H), 7.13 (d, 1H), 6.83 (d, 1H), 5.52 (s, 0.3H), 5.43 (s, 0.7H), 3.98 (d, 6H), 1.62 (m, 5H), 1.31 (br s, 2H). MS (ESI) m/z 375.99 (M+Na)+; 352.02 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:6]([O:8]C)=O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:6]([C:5]2[CH:10]=[C:11]([CH3:13])[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:8])=[CH:17][N:16]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: COC(=O)c1cc(C)cc(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C)cc(C(=O)Cc2ccc(Cl)nc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-methoxy-5-methylbenzoate (9.0 g, 50 mmol) and 2-chloro-5-methylpyridine (7.0 g, 55 mmol) in tetrahydrofuran (90 mL) was dropwise added lithium hexamethyldisilazide (75 mL, 75 mmol, 1M In THF) at 0° C. under nitrogen atmosphere, and stirred at room temperature for 18 hours. After completion of the nucleophilic attack reaction, the reaction mixture was neutralized with a saturated ammonium chloride solution (150 mL) and extracted with ethyl acetate (300 mL×2). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated by vacuum distillation, and the concentrate (7.58 g, 55%) was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][NH:21][CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:26])=[C:7]([F:25])[CH:8]=2)[N:3]=1.C(OC(C)C)(C)C>N12CCCN=C1CCCCC2.C(O)C.O>[CH:22]1([N:21]2[C:2]3[N:3]=[C:4]4[CH:5]=[C:6]([F:26])[C:7]([F:25])=[CH:8][C:9]4=[CH:10][C:11]=3[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20]2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: CCO
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Yield: 74.9 %

Procedure:
A stirred suspension of 5.27 g of ethyl 2-(2-chloro-6,7-difluoroquinoline-3-carbonyl)-3-cyclopropylaminoacrylate in 2.22 g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 120 cm3 of ethanol is heated at a temperature close to 75° C. for 35 minutes. After cooling to about 20° C., the reaction mixture is taken up in 100 cm3 of water and extracted once with 100 cm3 and twice with 50 cm3 of trichloromethane. The combined organic extracts are washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at a temperature close to 20° C. The dry extract obtained is taken up in 30 cm' of diisopropyl ether, drained and recrystallized from a mixture of 75 cm3 of ethanol and 75 cm3 of dimethylformamide. 3.57 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 229°-230° C.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[CH:14][C:15](Cl)=[N:16][CH:17]=1)=O)C1C=CC=CC=1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])=[N:16][CH:17]=1
Reactant: O=C(Nc1ccc(Cl)nc1)OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccc(Cl)cc2Cl)nc1

Procedure:
5-Amino-2-chloropyridine(643 mg)in 3 mL of chloroform containing 505 mg of triethylamine was stirred with 853 mg of benzyl chloroformate for 4 hours at 60 degrees C. The mixture was then diluted with 20 mL of chloroform and washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated to give 700 mg of 5-benzyloxycarbonylamino-2-chloropyridine. 5-Benzyloxy carbonylamino-2-chloropyridine (272 mg) and 163 mg of 2,4-dichlorophenol were stirred overnight at room temperature in 1 mL of dimethylformamide containing 138 mg of potassium carbonate. The reaction mixture was evaporated to dryness under high vacuum and partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated. Hydrogenolysis in methanol over palladium on carbon gave 5-amino-2-(2,4-dichlorophenoxy) pyridine. The 5-amino-2-(2,4-dichlorophenoxy)pyridine was treated with 4-(trifluoromethylmercapto)phenylisocyanate under conditions similar to those in Example 1 to give N-[2-(2,4-dichlorophenoxy)pyrid-5-yl]-N'-[4-trifluoromethyl mercapto)phenyl]urea.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:21][CH:22]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]benzamide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 114 mg of the title compound (89%) as a yellow powder in 96.3% purity by HPLC (Rt: 4.4, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][C:2](=[CH2:32])[C:3]#[C:4][C@@H:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][C@H:12]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9]>CO.[Ni]>[CH3:9][CH:8]([CH3:10])[CH2:7][CH2:6][CH:5]([N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13][C@H:12]1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=1)[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:32]
Reactant: C=C(C)C#C[C@H](CCC(C)C)N1CC[C@@H](CC(=O)OC)C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C[C@@H]1CCN(C(CCC(C)C)CCC(C)C)[C@H](c2ccc(C(F)(F)F)cc2)C1
Yield: 72.5 %

Procedure:
A solution of methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Example 1, Step 1, 8.4 g, 18.9 mmol) in MeOH (250 ml) was hydrogenated over Raney Nickel (˜6 g) at 50 psi for 18 hrs. The catalyst was removed by filtration—washing with CH2Cl2. The filtrate was evaporated and the residue was partitioned between CH2Cl2/H2O. The aqueous layer was extracted with CH2Cl2 (×1). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 3% EtOAc/isohexane) to give the alkane (6.24 g) as an oil. 1H NMR (500 MHz, CDCl3): δ 0.64-0.74 (1H, m), 0.81 (6H, t J 6.5), 0.85 (6H, t, J 6.8), 0.93-0.97 (3H, m), 1.19-1.42 (7H, m), 1.52-1.58 (1H, m), 1.72-1.78 (2H, m), 1.86-1.94 (1H, m), 2.11-2.27 (4H, m), 2.92 (1H, brd, J 11.6), 3.58 (1H, dd, J2.6, 11.1), 3.64 (3H, s), 7.40 (2H, brs), 7.54 (2H, d, J 8.2). Further chromatography of mixed fractions (silica 2.5% EtOAc/isohexane) gave the cis alkene: methyl{(2S,4R)-1-[(1S,2Z)-4-methyl-1-(3-methylbutyl)pent-2-en-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (415 mg) as an oil. 1H NMR (500 MHz, CDCl3): δ 0.68 (3H, d, J 6.6), 0.77 (3H, d, J 6.5) 0.83-0.86 (6H, m), 1.02-1.30 (4H, m), 1.37-1.43 (1H, m), 1.51-1.63 (3H, m), 1.71-1.78 (2H, m), 1.83-1.91 (1H, m), 2.13-2.27 (2H, m), 2.37-2.43 (1H, m), 3.02-3.06 (1H, m), 3.20 (1H, q, J 7.8), 3.42 (1H, dd, J 2.9, 11.1), 3.63 (3H, s), 5.20-5.28 (2H, m), 7.44 (2H, brd, J 7.5), 7.54 (2H, d, J 8.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:19]=2>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[N:22][CH:21]=[C:20]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH:19]=3)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Brc1cnc2cc(CCN3CCCCC3)cnc2c1
Product: COc1ncc(-c2cnc3cc(CCN4CCCCC4)cnc3c2)c(OC)n1

Procedure:
The title compound was prepared by the method described in Example 156, using 2,4-dimethoxypyrimidin-5-ylboronic acid and the product from Example 155 in place of 2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine and the product from Example 154. 1H NMR (CDCl3, 300 MHz) δ 1.40–1.55 (m, 6H), 2.45 (m, 4H), 2.65 (m, 4H), 3.70 (s, 3H), 3.80 (s, 3H), 8.35 (m, 1H), 8.75 (m, 1H), 8.80 (s, 1H), 8.95 (m, 1H), 9.30 (m, 1H). MS (ESI) [M+H]+ at 380.
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:23]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:23]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:12]=[CH:13][C:14]([N:17]5[CH2:21][CH2:20][CH2:19][C:18]5=[O:22])=[CH:15][CH:16]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C1CCCCC1
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: O=C1CCCN1c1ccc(-n2cc3c(n2)CCN(C2CCCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (45 mg, 0.15 mmol) in dichloromethane (3 ml) was added cyclohexanone (29 mg, 0.30 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 22 hours. A further 2 eq. of cyclohexanone (29 mg, 0.30 mmol) was added, and after a further 20 minutes a further 2 eq. of sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 3 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E22). MS (ES+) m/e 379 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:26]=[C:25]([CH:27]4[CH2:29][CH2:28]4)[NH:24][N:23]=3)[C:18]([CH2:30][O:31][Si](C(C)(C)C)(C)C)=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.B(Cl)(Cl)Cl.C(Cl)Cl.O>C(Cl)Cl>[CH:27]1([C:25]2[NH:24][N:23]=[C:22]([NH:21][C:19]3[C:18]([CH2:30][OH:31])=[CH:17][N:16]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:20]=3)[CH:26]=2)[CH2:28][CH2:29]1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ncc(CO[Si](C)(C)C(C)(C)C)c(Nc3cc(C4CC4)[nH]n3)n2)c1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: NS(=O)(=O)c1cccc(-c2ncc(CO)c(Nc3cc(C4CC4)[nH]n3)n2)c1
Temperature: 20 °C
Reaction time: 30 h
Yield: 10.1 %

Procedure:
A mixture of N-tert-butyl-3-(5-((tert-butyldimethylsilyloxy)methyl)-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)benzenesulfonamide (400 mg, 0.718 mmol), BCl3/CH2Cl2 (10 mL, 10 mmol, 13.9 eq, 1 M) in CH2Cl2 (10 mL) was stirred at 20° C. under a nitrogen atmosphere for 30 h. Water (50 mL) was added into the mixture. The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed (sat NaHCO3, brine), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel chromatography (CH2Cl2/MeOH 500:1 to 15:1 as eluent) to afford compound 3-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-(hydroxymethyl)pyrimidin-2-yl)benzenesulfonamide (Compound 124) (28 mg, 10%) as yellowish solid. LC-MS (m/z)=387.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.81-0.82 (m, 2H), 0.94-0.98 (m, 2H), 1.92-1.95 (m, 1H), 4.61 (d, J=5.2 Hz, 2H), 5.65 (t, J=5.2 Hz, 1H), 6.54 (s, 1H), 7.44 (s, 2H), 7.72 (t, J=8 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.35 (d, J=5.6 Hz, 1H), 8.51 (d, J=7.6 Hz, 1H), 8.84 (s, 1H), 8.92 (s, 1H), 12.18 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.Br.[NH2:47][CH:48]1[C:54]2=[N:55][C:56]([C:60]3[CH:65]=[CH:64][N:63]=[CH:62][N:61]=3)=[CH:57][C:58](=[O:59])[N:53]2[CH2:52][CH2:51][NH:50][CH2:49]1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:47][CH:48]2[C:54]3=[N:55][C:56]([C:60]4[CH:65]=[CH:64][N:63]=[CH:62][N:61]=4)=[CH:57][C:58](=[O:59])[N:53]3[CH2:52][CH2:51][NH:50][CH2:49]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a solution of 0.040 g (0.199 mmol) of 4amino-5-chloro-2-methoxy-benzoic acid dissolved in 5 mL of anhydrous dimethylformamide was added 0.06 mL (0.43 mmol) of triethylamine, 0.077 g (0.20 mmol) of O-(benzotriazol-1-yl)-N,N,N′N,′-tetramethyluroniumhexafluorophosphate (HBTU). The resulting mixture was stirred at room temperature for 5 min and added slowly at −10° C. to a solution of 0.090 g (0.21 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-5H-1,4a,7-triaza-benzocyclohepten-4-one dihydrobromide (2:1) dissolved in a mixture of 5 mL of anhydrous dimethylformamide and 0.09 mL (0.64 mmol) of triethylamine. The resulting mixture slowly increases to room temperature and was stirred for 16 hours. After evaporation, the reaction mixture was diluted in dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was washed saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 97/3/0.3 to afford 0.022 g (23%) of the pure product as a powder.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[C:18]1[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)CCC>[C:1]([NH:5][CH2:6][CH:7]([OH:25])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=1[C:18]1[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NCC(O)COc1ccc(C#N)cc1C1=NNC(=O)CC1
Solvent: CCCCO
Product: CC(C)(C)NCC(O)COc1ccc(C#N)cc1-c1ccc(=O)[nH]n1

Procedure:
A mixture of 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5-cyanophenyl]-4,5-dihydro-3(2H)-pyridazinone and chloramil was heated under reflux in n-butanol to give 6-[2-(3-t-butylamino-2-hydroxypropoxy)-5-cyanophenyl]-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[NH:15][CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:33](Cl)([Cl:35])=[O:34]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:33]([Cl:35])=[O:34])[CH:16]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[CH:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(Cl)Cl
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Product: CCOc1nc(C(C)(C)C)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
Using the procedure as described in example 1, cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-1H-imidazole was reacted with phosgene to give cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride. The carbonyl chloride was then coupled with 2-piperazinone (Alfa) to give cis-4-[2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one hydrochloride. HR-MS (ES, m/z) calculated for C30H33N6O3Cl2 [(M+H)+] 595.1986, observed 595.1985.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].BrC(Br)C.[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.B(OC)(OC)OC.Cl>[Zn].O1CCCC1>[F:8][C:2]([F:9])([CH:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=Cc1ccccc1
Agent: CC(Br)Br
Agent: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1
Temperature: 90 °C
Reaction time: 10 h
Yield: 61.5 %

Procedure:
A mixture of 48 g of ethyl bromodifluoroacetate, 4.5 g of dibromoethane and 50 g of tetrahydrofuran was added dropwise to a mixture of 15 g of zinc, 21 g of benzaldehyde, 60 mL of trimethyl borate, and 50 g of tetrahydrofuran at a temperature of 60° C., followed by stirring for 10 hours at 90° C. Thereafter, 100 g of 10 wt % hydrochloric acid was added to quench the reaction. By filtration, the insoluble was removed, and the filtrate was washed with saturated sodium chloride water. The reaction solution after washing was concentrated under reduced pressure. The concentrate was purified by distillation, obtaining 28 g of the target compound, ethyl 2,2-difluoro-3-hydroxy-3-phenylpropionate as colorless oily matter (yield 60%).