Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16](Cl)=[O:17])[CH:12]=[N:11]2)[CH:5]=1.[NH3:20]>O1CCCC1>[F:1][CH:2]([F:19])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH2:20])=[O:17])[CH:12]=[N:11]2)[CH:5]=1
Reactant: N
Reactant: Cc1c(C(=O)Cl)cnn1-c1cc(OC(F)F)n(C)n1
Solvent: C1CCOC1
Product: Cc1c(C(N)=O)cnn1-c1cc(OC(F)F)n(C)n1

Procedure:
0.98 g (3.38 mmol) 1-(5-Difluoromethoxy-1-methyl-3-pyrazolyl)-5-methyl-4-pyrazolecarbonyl chloride was dissolved in 20 ml tetrahydrofuran and 50 ml aqueous ammonia (33%) was added with stirring. After stirring for 3 hours at room temperature, the mixture was concentrated to half and acidified with dilute hydrochloric acid. The precipitate was suction filtered off, washed with a small amount of water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:11][C:12]=2[N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:26]Br.O>C(O)(=O)C>[Br:26][C:11]1[C:12]([N+:13]([O-:15])=[O:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[S:16][C:17]([F:18])([F:20])[F:19]
Reactant: O=[N+]([O-])c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br
Reaction time: 1 h
Yield: 56.6 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-nitro-5-[(trifluoromethyl)thio]pyrrole (0.35 g, 0.0011 mol) and sodium acetate (0.11 g, 0.0013 mol) in acetic acid is treated with a solution of bromine (0.21 g, 0.0013 mol) in acetic acid, stirred for one hour, poured into water and extracted with ethyl acetate. The combined organic extracts are washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Flash chromatography of the residue using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a yellow solid (0.25 g, mp 160°-165° C.) which is identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH3:12]S(C)=O.CI.[OH-].[K+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: CS(C)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25 g (0.159 mol) of 5-fluoro-2-nitrophenol are added to 125 ml of DMSO. 22.5 g (0.159 mol) of methyl iodide are then added, followed by dropwise addition, while keeping the temperature below 25° C., of 17.8 g of aqueous 50% potassium hydroxide solution. The mixture is stirred for one hour at ambient temperature and a further 22.5 g (0.159 mol) of methyl iodide are then added. After stirring for 24 hours, the reaction medium is poured into 125 ml of water and then extracted with 60 ml of dichloromethane. The organic phase is washed with 90 ml of aqueous sodium hydroxide solution (1N) and then with 60 ml of water. After drying over MgSO4, the organic phase is concentrated under reduced pressure. 20.59 g (76%) of 4-fluoro-2-methoxy-1-nitrobenzene (1) are thus recovered.
Reaction SMILES: COC(=O)[C@H:4]([NH:16][CH2:17][CH2:18][NH:19][C:20]([O:22]C(C)(C)C)=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[CH2:5][C@H:4]1[NH:16][CH2:17][CH2:18][NH:19][C:20]1=[O:22]
Reactant: COC(=O)[C@@H](Cc1ccc2ccccc2c1)NCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCN[C@@H]1Cc1ccc2ccccc2c1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
##STR197## (2R)-2-((2-(tert-butoxycarbonylamino)ethyl)amino)-3-(2-naphthyl)propionic acid methylester (3.4 g, 9.1 mmol) was stirred for 1 h in a mixture of TFA (5 ml) and methylene chloride(5 ml). The volatiles were removed in vacuo and the residue was dissolved in a mixture of water (40 ml) and methanol (100 ml). Sodium hydrogencarbonate (2.3 g) was added and the mixture was stirred overnight. The solvent was removed in vacuo and the residue was dissolved in water (40 ml) and extracted with ethyl acetate (10×50 ml). The combined organic phases were dried (magnesium sulphate) and the solvent was removed in vacuo to afford 1.96 g of (3R)-3-((2-naphthyl)methyl)piperazin-2-one.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH:11]([O:27][CH:28]([OH:31])[CH2:29][CH3:30])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:32](Cl)([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(N(CC)CC)C>[S:32]([C:35]1[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=1)([O:31][CH:28]([O:27][CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:10])[CH2:29][CH3:30])(=[O:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCC(OC(O)CC)C(C)OCc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(OC(CC)OS(=O)(=O)c1ccc(C)cc1)C(C)OCc1ccccc1
Temperature: 65 °C
Reaction time: 36 h

Procedure:
In 24 ml of triethylamine were dissolved 1.3 g (3 mmole) of 1-(2-benzyloxy-3-octadecyloxy)propanol and 1.7 g (9 mmole) of tosyl chloride, and the solution was warmed at 65° C. and stirred for 1.5 days. The reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in chloroform. The solution was washed with water, dried over potassium carbonate. The solvent was distilled off under reduced pressure, and the residue was subjected to separation and purification by chromatography on a column of 40 g of silica gel. From the eluate of n-hexane-ethyl acetate (4:1), there was obtained the objective compound in the form of a colorless oil. Yield of 1.4 g (83%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:37]=[C:36]([OH:38])[C:30]3[CH2:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[CH:28]=2)=[O:26])=[N:20]1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:37]=[C:36]([O:38][C:9]3[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[C:30]3[CH2:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[CH:28]=2)=[O:26])=[N:20]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)nc3)c3c(c2)OC(C)(C)C3)n1
Yield: 47.5 %

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (634 mg, 2.76 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (396 mg, 1.33 mmol), Et3N (0.96 mL, 6.89 mmol), and Cu(OAc)2 (501 mg, 2.76 mmol) in CH2Cl2 (15 mL) was stirred at room temperature with 4A molecular sieves for 4 days, then filtered through celite, washed with CHCl3, concentrated, and purified by column chromatography with 30-60% EtOAc in hexanes to give a white foam (246 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1 H) 8.45 (d, J=2.53 Hz, 1 H) 7.65 (d, J=8.59 Hz, 1 H) 7.21-7.35 (m, 2 H) 7.10 (d, J=111.37 Hz, 2 H) 6.78 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 2.89 (s, 2 H)) 1.48 (s, 6 H); LCMS for C21H19N5O3 m/z 390.00 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH:15]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[N:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[N:17]1[C:22]2[O:23][CH2:24][CH2:25][O:26][C:21]=2[CH:20]=[C:19]([CH2:27][N:28]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:15][CH2:14][N:9]3[C:7]4=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]4[CH:12]=[CH:11][C:10]3=[O:13])[CH2:38][CH2:37]2)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(nn1)OCCO2)C1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(nn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
A suspension of [3-(methyloxy)-6-oxopyrido[2,3-b]pyrazin-5(6H)-yl]acetaldehyde (240 mg, assuming 191 mg of aldehyde) and 1,1-dimethylethyl (6,7-dihydro[1,4]dioxino[2,3-c]pyridazin-3-ylmethyl)-4-piperidinylcarbamate (305 mg) in chloroform (10 mL) and methanol (1.5 mL) was stirred at room temperature under argon for 1 h before addition of sodium triacetoxyborohydride (553 mg). The reaction was stirred at rt overnight. A saturated solution of sodium bicarbonate (20 mL) was added to the reaction and the aqueous was extracted with 10% MeOH/DCM (3×50 mL). The combined organic phases were dried (MgSO4), evaporated and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford 358 mg of the title compound (60%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:12]=[C:11]([C:13]2[S:17][C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:15][C:14]=2[C:24]2[C:25]([F:42])=[C:26]([NH:30][S:31]([C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:10]=[CH:9][N:8]=1>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[C:11]([C:13]2[S:17][C:16]([N:18]3[CH2:23][CH2:22][N:21]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:19]3)=[N:15][C:14]=2[C:24]2[C:25]([F:42])=[C:26]([NH:30][S:31]([C:34]3[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=3[F:41])(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCNCC3)sc2-c2ccnc(Cl)n2)c1F)c1cc(F)ccc1F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Yield: 32.9 %

Procedure:
Methanesulfonyl chloride (0.05 mL, 0.7 mmol) was added to a stirring solution of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-piperazinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (0.40 g, 0.66 mmol) and TEA (0.32 mL, 2.3 mmol) in DCM (10 mL) at rt. LCMS analysis indicated clean conversion to product. The reaction was quenched with water and the whole was extracted with DCM. The combined organic extracts were dried over MgSO4, filtered, and the filtrate was concentrated onto silica gel. Purification by flash chromatography afforded the title compound of Step D (0.14 g, 30% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.25-7.63 (m, 5H), 6.50 (d, J=5.3 Hz, 1H), 3.69 (br. s., 4H), 3.27 (br. s., 4H), 2.93 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([C@H:4]1[C@@H:8]2[C@H:9]3[C@@:14]([CH3:17])([CH2:15][CH2:16][C@@:7]2([CH:31]=[O:32])[CH2:6][CH2:5]1)[C@:13]1([CH3:30])[CH2:18][CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C:24](=[O:25])[CH:23]=[CH:22][C@:21]2([CH3:29])[C@H:12]1[CH2:11][CH2:10]3)=[CH2:3].OO.[O-:35]Cl=O.[Na+]>CC#N.O.O>[CH3:3][C:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:14]([CH3:17])([CH2:15][CH2:16][C@@:7]2([C:31]([OH:35])=[O:32])[CH2:6][CH2:5]1)[C@@:13]1([CH3:30])[C@@H:12]([C@:21]2([CH3:29])[C@@H:20]([CH2:19][CH2:18]1)[C:26]([CH3:28])([CH3:27])[C:24](=[O:25])[CH2:23][CH2:22]2)[CH2:11][CH2:10]3)=[CH2:1]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@@H](CC[C@@H]4[C@@]5(C)C=CC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [O-][Cl+][O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
The betulone aldehyde prepared from the last step is dissolved in a mixture of NaH2PO4.H2O (877 mg) and CH3CN—H2O (17 mL) and the suspension cooled to 0-5° C. 30% aqueous H2O2 (220 μL) and a solution of NaClO2 (200 mg) in water (16 mL) are then successively added, the mixture warmed to room temperature and stirred at this temperature for 1 h. The reaction is quenched by addition of Na2S2O5 (380 mg), and extracted with ethyl acetate. The organic extract is washed with water and brine, dried (Na2SO4), filtered, and concentrated. The residue is then subjected to column chromatography to afford betulonic acid (550 mg) as white solid.
Reaction SMILES: NC1N=N[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:6](N)[N:7]=1.ClC1C(Cl)=CC=CC=1C(Cl)=[O:21]>C(#N)C>[Cl:15][C:11]1[C:10]([Cl:16])=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:5]([C:6]#[N:7])=[O:21]
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Solvent: CC#N
Product: N#CC(=O)c1cccc(Cl)c1Cl

Procedure:
There is disclosed an improved process for the preparation of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine which process comprises the step of reacting 2,3-dichlorobenzoylchloride with cuprous cyanide in presence of acetonitrile and a cosolvent to produce dichlorobenzoyl cyanide, said dichlorobenzoyl cyanide is reacted with aminoguanidine bicarbonate to produce an intermediate product, which is cyclized in presence of aqueous potassium hydroxide to produce 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine.
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH:5]1[C:17]2[C:12](=[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]3=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[C:7]1[CH:33]=[CH:32][CH:31]=[CH:30][C:8]1=[C:9]1[CH:29]=[CH:28][CH:27]=[CH:26][C:10]1=2.[C:36](Cl)([Cl:38])=[O:37]>ClCCl>[Cl:38][C:36]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]3=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[C:7]1[CH:33]=[CH:32][CH:31]=[CH:30][C:8]1=[C:9]1[CH:29]=[CH:28][CH:27]=[CH:26][C:10]1=2)=[O:37]
Reactant: C[Si](C)(C)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)OCC1c2c(c3ccccc3c3ccccc23)-c2c1c1ccccc1c1ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17-(trimethylsilyl)oxymethyl-tetrabenzo(a,c,g,i)fluorene (0.177 g, 0.38 mmol) in dichloromethane (5 ml) was added phosgene (1.5 ml, 2.9 mmol; 7.5 equiv; 1.93M in toluene). The reaction mixture was heated under reflux for 2 h and then stirred at room temperature for 48 h, under nitrogen. The solvent was removed in vacuo to give compound (37) as a yellow solid which was recrystallized from dichloromethane/n-hexane (36.9 mg, 21%); m.p. 188°-189° C.; (Found: C, 80.9; H, 4.29; N, 0.45 C31H19O2Cl requires: C, 81.1; H, 4.14%); νmax (CH2Cl2) 3060 (CH stretching, aromatic), 1775 (CO, chloroformate), 1610, 1500 (aromatic rings), 1160, 1140 (CO stretching) cm-1 ; δH (CDCl3, 200 MHz) 8.79-8.60 (6H, m, aromatic), 8.20-8.15 (2H, m, aromatic), 7.76-7.57 (8H, m, aromatic), 5.17 (1H, t, 3J=5.7 Hz, CH), 4.77 (2H, d, 3J=5.7 Hz, CH2); δc (CDCl3, 50 MHz) 150.5 (CO, chloroformate), 140.3, 137.2, 131.6, 130.5, 128.2, 127.7 (quaternary aromatic C's), 127.5, 127.0, 126.3, 126.2, 125.1, 124.5, 123.5, 123.4 (aromatic CH's), 74.6(CH2), 46.5(CH).
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.N1C=CC=CC=1>C(O)C.[Pd]>[F:18][C:15]([F:16])([F:17])[C:11]1[CH:10]=[C:9]([CH2:8][C:7]2[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCO
Product: Nc1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
10% Degussa Pd on carbon (15 mg, 0.4 mmol) was flushed with nitrogen then diluted in ethanol (2 mL). A solution of 4-(4-nitrobenzyl)-2-(trifluoromethyl)pyridine (100 mg, 0.35 mmol) in ethanol (2 mL) and pyridine (14 mg, 0.18 mmol) was subsequently added, and the mixture was flushed again with nitrogen prior to placing a hydrogen balloon on the flask. The mixture was stirred at rt overnight then filtered through Celite® and concentrated. The residue was dissolved in ethyl acetate and filtered through a silica gel plug, eluting with 50-100% ethyl acetate in hexanes, to give 4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine as a clear colorless oil (76 mg, 85%). 1H NMR (CHCl3-d) δ 8.57 (d, J=5.0 Hz, 1H), 7.47 (s, 1H), 7.26 (m, 1H), 6.93 (m, 2H), 6.65 (m, 2H), 3.92 (s, 2H), 3.57 (br s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>C(#N)C>[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:7]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)c(F)c1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2,4-difluorobenzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=95%, [M+H]+=401.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[F:12][C:13]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:14]=1[C:15]([NH:17][C:18]1[S:19][C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[C:21](C2C=CC=CN=2)[N:22]=1)=[O:16]>>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([C:21]2[N:22]=[C:18]([NH:17][C:15](=[O:16])[C:14]3[C:13]([F:12])=[CH:42][CH:41]=[CH:40][C:39]=3[F:43])[S:19][C:20]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc([Mg]Br)cc1
Reactant: O=C(Nc1nc(-c2ccccn2)c(-c2cccc(C(F)(F)F)c2)s1)c1c(F)cccc1F
Product: CN(C)c1ccc(-c2nc(NC(=O)c3c(F)cccc3F)sc2-c2cccc(C(F)(F)F)c2)cc1

Procedure:
Compound 110 was prepared from 22a and N,N-dimethyl-4-aminophenylmagnesium bromide as described for the preparation of Compound 107.
Reaction SMILES: C([O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=O)[N:15]([CH2:16][C:17](OC)=[O:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:18][CH2:17][CH2:16][N:15]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:4])[C:10]=2[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)CN1C(=O)CCCc2c(OC(C)=O)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCN1CCCCc2c(O)cccc21
Temperature: 0 °C
Yield: 81.2 %

Procedure:
Methyl (6-acetoxy-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate (1080 mg) was dissolved in THF (15 ml) under an argon atmosphere, and the resultant solution was stirred at 0° C. Lithium aluminum hydride (355 mg) was added to the solution, and the mixture was stirred at 0° C. After disappearance of the raw materials was confirmed, the reaction solution was added to water (100 ml), and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=2/1) to obtain the object compound (624 mg, yield 81%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:22])=[C:10]([C:19]([OH:21])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[NH:38][NH2:39]>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH3:22])=[C:10]([C:19]([NH:39][NH:38][C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:21])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)c(C)nc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)OC(C)(C)C)c(C)nc21
Reaction time: 18 h
Yield: 54.7 %

Procedure:
Intermediate 60 (0.253 g, 0.83 mmol), EDC (0.223 g, 1.17 mmol) and HOBT (0.135 g, 1.0 mmol) in DMF (5 ml) was stirred at 20° C. for 30 minutes. t-Butyl carbazate (0.110 g, 0.83 mmol) was added and stirring continued for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in DMF (5 ml) additional EDC (0.159 g0) and HOBT (0.112 g) added. After 30 minutes t-butyl carbazate (0.019 g) was added and stirring continued for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between DCM and water. The organic phase was washed with aqueous sodium hydrogen carbonate then evaporated in vacuo. The material was applied to a SPE cartridge (silica, 10 g) and eluted with cyclohexane:ethyl acetate (1:1 followed by 2:1) to afford Intermediate 62 as a white solid (0.19 g). LCMS showed MH+=419; TRET=2.35 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[N:18][CH:19]=2)[NH:14][N:13]=1.[NH3:30]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:30])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[N:16][C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[N:18][CH:19]=2)[NH:14][N:13]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(-c2n[nH]c3nc(Oc4ccc(F)cc4F)ncc23)c1
Solvent: CO
Product: NS(=O)(=O)c1ccc(Cl)c(-c2n[nH]c3nc(Oc4ccc(F)cc4F)ncc23)c1
Reaction time: 0.33 h

Procedure:
4-Chloro-3-[6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-benzenesulfonyl chloride (34 mg, 0.735 mmol) was added to a solution of 2M NH3 in MeOH (1 mL), and the reaction mixture was stirred for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (40% EtOAc in hexanes) to give 15 mg of 4-chloro-3-[6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-benzenesulfonamide, MS (M+H)=418.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([N:20]([CH2:37]/[CH:38]=[N:39]/[S:40]([C:42]([CH3:45])([CH3:44])[CH3:43])=[O:41])[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CCOCC>[C:13]([O:17][C:18]([N:20]([CH2:37][CH:38]([NH:39][S:40]([C:42]([CH3:45])([CH3:44])[CH3:43])=[O:41])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(C/C=N/S(=O)C(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1ccncc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(CC(NS(=O)C(C)(C)C)c1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
4-Bromopyridine (360 mg, 2.28 mmol) in ether (5 mL) was added dropwise to a solution of n-butyllithium (2.5 M, 1.0 μL, 2.5 mmol) in ether (15 mL) at −78° C. After 30 min, benzyl 4-((tert-butoxycarbonyl) {(2E)-2-[(tert-butylsulfinyl)imino]ethyl}amino)piperidine-1-carboxylate (364 mg, 0.759 mmol) in ether (6 mL) was added to the mixture. After 1 h, the reaction was warmed to ambient temperature, quenched with saturated ammonium chloride solution (2 mL), and partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography chromatography (75%-100% ethyl acetate/hexanes) to give the title compound (230 mg). MS 559.2 (M+1)