Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=2)[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)[C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(NC(C)c2ccc(F)c(F)c2)c2cccc(N)c2)cc1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 7.76 g of N-[1-(3,4-difluorophenyl)ethyl]-N-[(3-nitrophenyl)-(p-tolyl)methyl]amine [prepared as described in step (a) above], 9.65 g of nickel chloride hexahydrate and 3.07 g of sodium borohydride were reacted, to obtain 1.67 g of isomer A and 2.37 g of isomer B of the title compound, each as a pale yellow oil.
Reaction SMILES: [I-].[CH3:2]C(C)([O-])C.[K+].[CH3:8][C:9]([CH3:19])(/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17])[C:10]([O:12][CH3:13])=[O:11]>CS(C)=O.O1CCCC1>[C:16]([CH:15]1[CH2:2][CH:14]1[C:9]([CH3:19])([CH3:8])[C:10]([O:12][CH3:13])=[O:11])(=[O:18])[CH3:17]
Reactant: COC(=O)C(C)(C)/C=C/C(C)=O
Reactant: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)C1CC1C(C)=O
Reaction time: 14 h

Procedure:
A solution of trimethylsulfoxium iodide (506 mg, 2.297 mmol) and potassium tert-butoxide (258 mg, 2.297 mmol) in dimethylsulfoxide (6 mL) was stirred for 1.5 hours and then transferred via syringe to a solution of methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate (340 mg, 1.998 mmol) in tetrahydrofuran (6 mL). The reaction mixture was stirred for 14 hours and then partitioned between diethyl ether (25 mL) and a 5:1 v:v mixture of water:saturated aqueous sodium bicarbonate solution (12 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (20 mL, 10 mL). The combined organics were washed with water (3×10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 2-(2-acetylcyclopropyl)-2-methylpropanoate which was carried on without further purification. MS ESI calc'd. for C10H17O3 [M+H]+ 185. found 185.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:30])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH:19](N4CCCC4)[CH2:18][N:17]([CH3:27])[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:31].Br.C(O)(=[O:39])C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:30])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][C:19](=[O:39])[CH2:18][N:17]([CH3:27])[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:31]
Reactant: CN1CC(N2CCCC2)CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Reactant: CC(=O)O
Agent: Br
Solvent: C1COCCO1
Product: CN1CC(=O)CCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-hydroxy-2-methyl-4-pyrrolidin-1-yl-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (40 mg, 0.08 mmol) and 33% hydrogen bromide in acetic acid (0.5 mL) in dioxane (1 mL) was stirred at room temperature for 1.5 hour. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1>CCCCCC.CCOC(C)=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]=[O:12])=[CH:13][CH:14]=1
Reactant: OCc1ccc(Oc2nccs2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1ccc(Oc2nccs2)cc1

Procedure:
Using the alcohol prepared above and the procedures described in Example 84E, except chromatography using 4:1 hexane-EtOAc was used for purification, provided 4-(thiazol-2-yloxy)benzaldehyde. 1H NMR (CDCl3) δ10.00 (s, 1H), 7.95 (m, 2H), 7.46 (m, 2H), 7.30 (d, 1H), 6.95 (d, 1H). MS (DCl/NH3) (M+H)+ 206 and (M+H+NH3)+ 223.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[S:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][S:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCSCC1
Reactant: O=Cc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)ccc1OC1CCSCC1

Procedure:
In a manner similar to the method described in Example 128a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-thiopyran-4-yl ester prepared in Example 130a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 241.
Reaction SMILES: O[CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1.O=S(Cl)[Cl:15]>CCOCC>[Cl:15][CH2:2][C:3]1[C:4]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=2[S:6][CH:7]=1
Reactant: Cc1cccc2c(CO)csc12
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1cccc2c(CCl)csc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
290 mg of 3-hydroxymethyl-7-methyl-benzo[b]thiophene are dissolved in ether, 0.6 ml SOCl2 added and the mixture stirred for 2 hours at room temperature. The reaction mixture is poured onto ice and the organic phase washed neutral, dried and concentrated under vacuum. The crude 3-chloromethyl-7-methyl-benzothiophene thus obtained is dissolved in acetone, mixed with an aqueoug solution of 170 mg of KCN and refluxed for 18 hours. The reaction mixture is concentrated, the residue partitioned between water and ether and the organic phase washed, dried, concentrated and chromatographed over silica-gel (eluant: toluene) to yield the title product is an oil.
Reaction SMILES: [N:1]1([C:19]([O:21]C(C)(C)C)=O)[C@H:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12.[CH3:26][O:27][C:28]([NH:30][C@@H:31]([C@@H:35]([CH3:38])[CH2:36][CH3:37])C(O)=O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:26][O:27][C:28]([NH:30][C@@H:31]([C@@H:35]([CH3:38])[CH2:36][CH3:37])[C:19]([N:1]1[C@H:5]([C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])[CH2:4][C@@H:3]2[CH2:16][CH2:17][CH2:18][C@H:2]12)=[O:21])=[O:29]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCC[C@@H]21
Reaction time: 8 h
Yield: 132.1 %

Procedure:
To a solution of commercially available (2S,3aS,6aS)-2-benzyl 1-tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (10.0 g, 35.489 mmol) in methylene chloride (100 mL) was added (2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoic acid (10.072 g, 53.23 mmol), HATU (21.59 g, 56.78 mmol), and DIPEA (18.59 mL, 106.46 mmol). The reaction was stirred overnight, at which time it was concentrated in vacuo, diluted in ethyl acetate and washed with HCl (1N). The aqueous layer was backextracted with ethyl acetate, and the combined organics were dried over sodium sulphate, filtered and concentrated. The resulting oil was diluted in a small amount of chloroform and filtered to remove tetramethyl urea precipitate. The resulting oil was purified by normal phase chromatography (50% ethyl acetate in hexanes) to give (2S,3aS,6aS)-benzyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)octahydrocyclopenta[b]pyrrole-2-carboxylate (19.53 g, >99% yield) which was used without further purification. LCMS-ESI+ calc'd for C23H33N2O5: 417.23. Found: 417.37.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][C@H:16]1[C@@:30]([C:32]2[C:36]3[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:35]=3[NH:34][CH:33]=2)([CH3:31])[C@@H:29]2[C@:19]([CH3:44])([C@H:20]3[C@:26]([CH3:42])([CH2:27][CH2:28]2)[C@@H:25]([CH3:43])[C:23](=[O:24])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1.O.S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(Cl)Cl>[CH3:15][C@H:16]1[C@@:30]([C:32]2[C:36]3[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:35]=3[NH:34][CH:33]=2)([CH3:31])[C@@H:29]2[C@:19]([CH3:44])([C@H:20]3[C@:26]([CH3:42])([CH2:27][CH2:28]2)[C@@H:25]([CH3:43])[C@@H:23]([OH:24])[CH2:22][CH2:21]3)[CH2:18][CH2:17]1
Reactant: C[C@@H]1CC[C@@]2(C)[C@@H]3CCC(=O)[C@H](C)[C@@]3(C)CC[C@@H]2[C@@]1(C)c1c[nH]c2cc(O)ccc12
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=S(=O)([O-])[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CC[C@@]2(C)[C@@H]3CC[C@H](O)[C@H](C)[C@@]3(C)CC[C@@H]2[C@@]1(C)c1c[nH]c2cc(O)ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
L-Selectride (45 μl of a 1.0M solution in tetrahydrofuran) was added to a 2-ml reaction vial at -78° C. containing 2.0 mg of radarin A in 1.0 ml of dry tetrahydrofuran. After the mixture was stirred for 30 min at -78° C., water (50 μl) was added and the mixture was allowed to warm to room temperature (15 min). Anhydrous magnesium sulfate was added and the solution was then passed through a small silica column. The product obtained upon evaporation of the solvent was redissolved in 1.0 ml methylene chloride and extracted with water (5×1 ml). The organic phase was dried and evaporated to yield radarin B (1.9 mg, 95% yield) which was identical to the natural product based on 1H NMR and HPLC analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(Cl)Cl.[CH3:56][NH:57][CH2:58][CH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1>CN(C=O)C>[CH3:56][N:57]([CH2:58][CH:59]1[CH2:64][CH2:63][O:62][CH2:61][CH2:60]1)[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([C:5]2[NH:6][C:7](=[O:12])[C:8]3[C:3]([CH:4]=2)=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=3)=[CH:21][CH:20]=1
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)O)cc3)cc12
Reactant: CNCC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(C(=O)N(C)CC4CCOCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To 4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoic acid (35 mg, 0.125 mmol), TBTU (40 mg, 0.125 mmol) was added 0.36M N,N-diisopropylethylamine/CH2Cl2 (0.35 mL, 0.125 mmol) and anhydrous DMF (0.9 mL). The reaction mixture was stirred at RT for 45 min after which time methyl-(tetrahydro-pyran-4-ylmethyl)-amine (19 mg, 0.15 mmol) in anhydrous DMF (0.45 mL) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was passed through a Si—NH2 cartridge (1 g), eluting with DMF (2× column volumes), MeOH (2× column volumes) and the solvent removed in vacuo and the crude product purified by reverse phase preparative HPLC-MS to obtain N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(tetrahydro-pyran-4-ylmethyl)-benzamide as a yellow foam (24 mg, 48%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][C:12]1([CH3:20])[C:16](=[O:17])[CH:15]([CH3:18])[NH:14][C:13]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:4]1[CH:3]=[C:2]([N:14]2[CH:15]([CH3:18])[C:16](=[O:17])[C:12]([CH3:20])([CH3:11])[C:13]2=[O:19])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC1NC(=O)C(C)(C)C1=O
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 4-bromo-2-chlorobenzonitrile (199 mg), 3,3,5-trimethylpyrrolidine-2,4-dione (100 mg), cesium carbonate (346 mg), tris(dibenzylideneacetone)dipalladium(0) (65 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (82 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 135 mg, 69%).
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][OH:17])[C:3]=1[CH2:18][CH3:19].C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH2:18][CH3:19]
Reactant: CCc1c(CO)cn(S(=O)(=O)c2ccccc2)c1Br
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Product: CCc1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Yield: 48.9 %

Procedure:
Using [5-bromo-4-ethyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (1.05 g), tetra-n-propylammonium perruthenate (54.3 mg), N-methylmorpholine N-oxide (543 mg) and molecular sieves 4A powder (522 mg), a procedure as in Reference Example 6 was performed to give the title compound as white crystals (yield 0.51 g, 49%).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].[CH3:30][C:31]([CH3:41])([C:37]([O:39][CH3:40])=[O:38])[C:32]([O:34][CH2:35]I)=[O:33].[K+].[Br-]>CC(C)=O>[CH3:40][O:39][C:37]([C:31]([CH3:41])([CH3:30])[C:32]([O:34][CH2:35][O:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16])=[O:33])=[O:38]
Reactant: COC(=O)C(C)(C)C(=O)OCI
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)C(=O)OCOC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
To a dry round bottomed flask equipped with a reflux condenser and stirring bar were added piroxicam (1.50 g, 4.53 mmol), potassium carbonate (1.24 g, 8.98 mmol), iodomethyl methyl 2,2-dimethylmalonate (1.48 g, 5.17 mmol) and dry acetone (15 mL). The heterogenous reaction mixture was heated to reflux under a nitrogen atmosphere for 3 hours. Chromatographed title product was isolated according to the method of Example 5, 0.95 g (43.2%) light yellow solid which was recrystallized from toluene-hexane to give light yellow crystals: mp 112°-114° C.; IR (KBr) 1690, 1680 cm-1 ; 1H NMR (CDCl3) delta 1.28 (s, 6H), 3.11 (s, 3H), 3.62 (s, 3H), 5.76 (s, 2H), 7.08-7.18 (m, 1H), 7.70-7.88 (m, 4H), 7.89-7.99 (dd, J=8 Hz, J=4 Hz, 1H), 7.30-7.44 (m, 2H), 9.42 (s, 1H); precise mass calcd for C22H23N3O6S m/e 489.1205, found 489.1230.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[C:15]([C:16]2[C:17]3[N:18]([N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14][NH:13][C:12](=[O:31])[CH2:11]1)C1C=CC=CC=1.[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[OH:8][CH2:9][CH:10]1[C:15]([C:16]2[C:17]3[N:18]([N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14][NH:13][C:12](=[O:31])[CH2:11]1
Reactant: [H][H]
Reactant: COc1ccc(C2=NNC(=O)CC2COCc2ccccc2)c2cc(C(F)(F)F)nn12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C2=NNC(=O)CC2CO)c2cc(C(F)(F)F)nn12
Yield: 25.3 %

Procedure:
The compound of Example 322 (60 mg) was dissolved in ethanol (25 mL) and ethyl acetate (25 mL). To this solution, 10% palladium carbon (30 mg) was added and the mixture was stirred at room temperature for 8 hours in a stream of hydrogen gas (1 atm). The insoluble material was removed by filtration through Celite. Evaporation of the solvent and subsequent purification by thin-layer chromatography (silica gel, ethyl acetate:methanol=10:1) afforded the title compound as a pale yellow powder (12 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=N[C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.[CH3:31]C1C2C(=O)NC([C@H]3[C@H](C)CNC3)=NC=2N(C2CCOCC2)N=1.C(=O)C1C=CC=NC=1>>[CH3:31][C:23]1[C:18]2[C:17](=[O:30])[NH:16][C:15]([C@H:3]3[C@H:2]([CH3:1])[CH2:6][N:5]([CH2:7][C:8]4[CH:13]=[N:12][CH:11]=[CH:14][CH:9]=4)[CH2:4]3)=[N:20][C:19]=2[N:21]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:22]=1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: Cc1nn(C2CCOCC2)c2nc([C@@H]3CNC[C@H]3C)[nH]c(=O)c12
Agent: O=Cc1cccnc1
Product: Cc1nn(C2CCOCC2)c2nc([C@@H]3CN(Cc4cccnc4)C[C@H]3C)[nH]c(=O)c12

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 3-methyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and nicotinaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.53 (m, 2H), 7.83 (d, J=7.9 Hz, 1H), 7.36-7.33 (m, 1H), 4.74-4.68 (m, 1H), 4.12-4.07 (m, 2H), 3.79-3.76 (m, 1H), 3.68-3.65 (m, 1H), 3.59-3.52 (m, 2H), 3.47 (s, 1H), 3.34 (t, J=8.7 Hz, 1H), 2.99 (d, J=9.9 Hz, 1H), 2.82-2.80 (m, 1H), 2.61-2.57 (m, 1H), 2.54 (s, 3H), 2.42-2.28 (m, 2H), 1.95 (t, J=8.7 Hz, 1H), 1.87-1.78 (m, 2H), 1.19 (d, J=7.1 Hz, 3H). MS: (M+H m/z 409.2).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][C:12]=1[O:19][CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([NH:8][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[C:12]([O:19][CH3:20])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
To a stirred solution of benzylamine (3.94 mL, 36 mmol) and 4,3-dimethoxybenzaldehyde (5.0 g, 30 mmol) in chloroform (120 mL), was added sodium triacetoxyborohydride (9.53 g, 45 mmol). The mixture was stirred at rt for 18 hrs prior to addition of saturated NaHCO3. The organic phase was separated and the aqueous phase extracted with chloroform. The combined extracts were washed with brine, dried over MgSO4 and evaporated to afford the crude product. Purification by flash column chromatography afforded the title compound as a pale yellow oil (5.47 g, 71%). 1H NMR (270 MHz, CDCl3) δ 3.74 (2H, s), 3.80 (2H, s), 3.86 (3H, s), 3.88 (3H, s), 6.80-6.89 (3H, m), 7.22-7.34 (5H, m); HRMS (ESI+) calcd. for C16H20NO2 (M++H) 258.1489, found 258.1478; LC/MS (ES+) tr=0.79 min, m/z 258.2 (M++H).
Reaction SMILES: CO[C:3]([CH2:5][CH:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])[CH2:7]CC(OC)=O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:30]CC>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][CH:6]([CH2:5][CH2:3][OH:4])[CH2:7][OH:30]
Reactant: COC(=O)CCC(CC(=O)OC)OCc1ccccc1F
Reactant: CCOCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCC(CO)OCc1ccccc1F
Temperature: 0 °C
Yield: 35.5 %

Procedure:
27 g (0.1 mol) of 2-(2-fluorobenzyloxy)-butane-1,4-dicarboxylic acid dimethyl ester were added dropwise, at 10° C., to a dispersion of 4.5 g of lithium aluminium hydride in 100 ml of absolute ether. After completion of the addition, the mixture was heated for 1 hour under reflux, and was cooled and hydrolysed with 35 ml of ice-water. After decanting the ether phase, the residue was repeatedly digested with ethanol. The combined organic phases were freed from the solvent and the residue was taken up in chloroform and chromatographed on a short silica gel column. The eluate was freed from the solvent and the residue was distilled. 7.5 g (35.5% of theory) of 2-(2-fluorobenzyloxy)-butane-1,4-diol of boiling point 155° C./0.5 mm Hg were obtained.
Reaction SMILES: COC(C1[C@@H](C2C=CC(C#N)=CC=2)NC(=S)N(C2C=CC=C(C(F)(F)F)C=2)C=1C)=O.[CH3:31][O:32][C:33]([C:35]1[CH:36]([C:54]2[CH:59]=[CH:58][C:57]([C:60]#[N:61])=[CH:56][CH:55]=2)[N:37]=[C:38]([NH:52][NH2:53])[N:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=2)[C:40]=1[CH3:41])=[O:34]>>[CH3:31][O:32][C:33]([C:35]1[C@@H:36]([C:54]2[CH:55]=[CH:56][C:57]([C:60]#[N:61])=[CH:58][CH:59]=2)[N:37]=[C:38]([NH:52][NH2:53])[N:39]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:50])[F:51])[CH:43]=2)[C:40]=1[CH3:41])=[O:34]
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(NN)=NC1c1ccc(C#N)cc1
Agent: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)N[C@@H]1c1ccc(C#N)cc1
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(NN)=N[C@@H]1c1ccc(C#N)cc1

Procedure:
Intermediate 10 (593 mg) was prepared from Intermediate 9 (3.39, 7.9 mmol) according to an analogous procedure to that described for Intermediate 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([N:7]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:8]=1
Reactant: ClCCOCCCl
Reactant: Nc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Br)cc1N1CCOCC1
Yield: 29 %

Procedure:
To a CEM snap top microwave vial (10 ml) equipped with a magnetic stir bar (3×10 mm) was added 5-Bromo-2-fluoroaniline (1.00 g, 5.26 mmol), sodium iodide (2.37 gm, 15.8 mmol), potassium carbonate (1.45 gm, 10.5 mmol), and 2-chloroethyl ether (1.30 gm, 9.09 mmol) in dimethylformamide (6.5 mL). The reaction was capped and irradiated in a CEM Explorer microwave at 120° C. for 4 hours then forced air-cooled. Purification by column chromatography [default gradient (ISCO); EtOAc/hexanes] afforded 397 mg (29%) an oil; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.00 (t, J=1.7 Hz, 4H) 3.69-3.73 (m, 4H) 7.10-7.15 (m, 3H); MS (EI) m/z 259.0 [M+·].
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[C:14]([N:16]=[C:17]([NH2:19])[NH2:18])#[N:15].[OH-].[K+]>COCCO.O>[NH2:15][C:14]1[N:16]=[C:17]([NH2:19])[N:18]=[C:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([S:3][C:2]([F:12])([F:1])[F:13])[CH:5]=2)[N:8]=1
Reactant: N#Cc1cccc(SC(F)(F)F)c1
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: Nc1nc(N)nc(-c2cccc(SC(F)(F)F)c2)n1

Procedure:
2.9 g of m-trifluoromethylthiobenzonitrile (b.p. 86°-88° C./40 mm Hg) and 1.4 g of dicyanodiamide are dissolved in 3 ml of methylcellosolve and the mixture is then combined with 0.3 g of caustic potash and refluxed for 5 hours. After cooling, the mixture is diluted with water and extracted with ether, and the extract, after evaporation, is recrystallized from methanol. Melting point of the obtained material: 172°-174° C.; yield: 2.4 g.
Reaction SMILES: [Cl:1][C:2]1[C:8]([S:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)=[CH:7][C:5]([NH2:6])=[C:4]([N+:20]([O-])=O)[CH:3]=1.O.[OH-].[Na+]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:6])=[CH:7][C:8]=1[S:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[CH:15]2
Reactant: Nc1cc(Sc2cccc3cnccc23)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(Cl)c(Sc2cccc3cnccc23)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-Chloro-5-(5-isoquinolylsulfanyl)-2-nitroaniline 1.78 g (5.4 mmol) was dissolved in concentrated hydrochloric acid 30 ml, stannous chloride dihydrate 4.30 g (19.1 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, 50% sodium hydroxide was added to alkalize the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from ethyl acetate-n-hexane to give 4-chloro-5-(5-isoquinolylsulfanyl)-1,2-benzenediamine 1.45 g (89.5%).