Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([N+:27]([O-])=O)[CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:14]=[C:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:16]=1)[NH2:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(C(=O)OCc2ccccc2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1
Yield: 0.1 %

Procedure:
3,5-dibenzyloxycarbonylnitrobenzene (3.91 g, 10 mol) was dissolved in ethyl acetate (50 ml) and tin(II)chloride dihydrate (11.27 g, 50 mmol) was added and the mixture stirred and heated at 70° under an atmosphere of nitrogen for 1 h. The mixture was poured carefully onto 5% sodium hydrogencarbonate solution (200 ml) and a further aliquot of ethyl acetate (100 ml) was added. After shaking the organic layer was separated and the aqueous layer was extracted with more ethyl acetate (50 ml). The combined organic layers were washed with brine, and dried, filtered and evaporated to leave a pale yellow solid (3.25 g, 90%), 1H NMR (CDCl3) δ 8.1 (1H, d), 7.5 (12H, m), 5.4 (4H, s), 3.8 (2H, bs).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][C:5]1=[O:17])(=[O:3])[CH3:2].[CH3:18][CH2:19][O:20][C:21](OCC)(OCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:21]([O:20][CH2:19][CH3:18])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]1=[O:17])(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1OC)N(C(C)=O)C(=O)C2
Reactant: CCOC(OCC)(OCC)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1

Procedure:
10.0 g of 1-acetyl-5,6-dimethoxy-2-indolinone, 29.2 ml of triethyl orthobenzoate and 100 ml of acetic anhydride are stirred for 48 hours at 120° C. The solvent is eliminated and the residue evaporated with toluene, combined with ether and the precipitate formed (starting compounds is suction filtered. The filtrate is concentrated by evaporation and separated through a silica gel column with toluene, then with toluene/ethyl acetate (10:1). The product is triturated with ether, suction filtered and dried in vacuo at 100° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH:23]1(Br)[CH2:27][CH2:26][CH2:25][CH2:24]1.O>CN(C=O)C.ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC2CCCC2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a cold (10°) stirred solution of N-tertiarybutoxycarbonyl-L-tyrosine (11.25 g, 40 mM) in dry DMF (150 ml) under argon was added sodium hydride (2.76 g, 80% dispersion in oil, 92 mM). After one hour at 10° cyclopentyl bromide (5.96 g, 40 mM) was added and the reaction was allowed to warm and stir to room temperature overnight. Water (200 ml) and dichloromethane (300 ml) were then added and the aqueous layer was separated. The separated aqueous layer was washed with dichloromethane, acidified with hydrochloric acid and re-extracted with dichloromethane (300 ml×2). These latter dichloromethane extracts were dried and concentrated in vacuo to an oil. Column chromatography of this material on silica eluting with ethyl acetate gave the title compound as a foam (7.05 g). This was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([CH2:11]Cl)[C:8]([CH2:13]Cl)=[CH:7][C:6]=1[O:15][CH3:16].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>C(O)(=O)C>[C:17]([O:20][CH2:13][C:8]1[CH:7]=[C:6]([O:15][CH3:16])[C:5]([O:4][CH2:3][CH2:2][Cl:1])=[CH:10][C:9]=1[CH2:11][O:20][C:17](=[O:19])[CH3:18])(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: COc1cc(CCl)c(CCl)cc1OCCCl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(COC(C)=O)c(COC(C)=O)cc1OCCCl
Reaction time: 2 h
Yield: 86 %

Procedure:
To a solution of 5.67 g (20 mmol) of 36 in 75 mL of acetic acid was added a solution of 3.5 g of anhydrous sodium acetate (42.7 mmol) in 100 mL of acetic acid. This mixture was refluxed with stirring for 2 h. Solids were removed by filtration and washed with acetic acid. The filtrate was evaporated to approximately 30 mL, then poured into water and extracted with ether. The organic phase was washed with aqueous sodium carbonate, water, and brine. After drying over sodium sulfate, the solution was filtered and evaporated to give 5.69 g (86%) of 2-[(acetyloxy)methyl]-4-(2-chloroethoxy)-5-methoxybenzyl acetate (37) as a white solid, mp 79-80° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:22]([O-])=O>[Pd].C(OCC)(=O)C.CO>[CH3:21][O:20][CH2:19][CH2:18][NH:17][C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C:5]3[CH:4]=[C:3]([NH2:22])[C:2]([NH2:1])=[CH:7][CH:6]=3)=[N:9][C:10]=2[CH:16]=1
Reactant: COCCNc1ccc2[nH]c(-c3ccc(N)c([N+](=O)[O-])c3)nc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCNc1ccc2[nH]c(-c3ccc(N)c(N)c3)nc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of [2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-(2-methoxy-ethyl)-amine (0.5 g, 1.5 mmol) in 4:1 ethyl acetate/methanol (50 ml) under nitrogen, was added 5% palladium on carbon (120 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL), and the combined filtrate and washings were concentrated to give the crude 4-[5-(2-methoxy-ethylamino)-1H-benzoimidazol-2-yl]-benzene-1,2-diamine which was used in the next step without any purification.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:16])[C:3]=1[C:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH3:30].[CH3:31][CH2:32]OC(C)=O.CCCCCC>CS(C)=O.O>[CH2:27]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([F:14])([F:15])[F:13])[CH:7]=2)[C:2]([CH3:1])=[C:3]([C:17]([O:19][CH2:31][CH3:32])=[O:18])[C:4]1=[O:16])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCBr
Reactant: CCOC(C)=O
Reactant: Cc1c(C(=O)[O-])c(=O)[nH]c2cc(C(F)(F)F)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: O
Product: CCCCn1c(=O)c(C(=O)OCC)c(C)c2ccc(C(F)(F)F)cc21
Temperature: 50 °C
Yield: 40 %

Procedure:
A solution of 1.0 g (3.3 mmol) 4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylate (for synthesis see example 1, section a)) in DMSO (9 ml) was treated with 461 mg (3.3 mmol) K2CO3 and 360 μl (3.3 mmol) 1-bromobutane at RT and was subsequently heated at 50° C. for 90 mins. After cooling to RT the RS was diluted with water (30 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. After CC (EtOAc/hexane 1:8) of the residue, 480 mg (1.4 mmol, 40%) ethyl 1-butyl-4-methyl-2-oxo-7-(trifluoromethyl)-1H-quinoline-3-carboxylate was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[OH:7])(=[O:3])[NH2:2].C([O:18][CH2:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28])[OH:21])(=[O:17])N>>[C:1](=[O:3])([OH:17])[OH:4].[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C@@H:20]([OH:21])[CH2:19][OH:18].[C:1]([O:4][CH2:5][C@@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])[OH:7])(=[O:3])[NH2:2]
Reactant: NC(=O)OC[C@@H](O)c1ccccc1Cl
Agent: NC(=O)OC[C@H](O)c1ccccc1Cl
Product: O=C(O)O
Product: OC[C@H](O)c1ccccc1Cl

Procedure:
(R)-1-o-Chlorophenyl-1,2-ethanediol carbonate was prepared using the same synthetic method described in Example 2, except that (S)-2-carbamoyloxy-1-o-chlorophenylethanol (10.98 g) was used instead of (D/L)-1-m-chlorophenyl-1,2-ethanediol. The crude (R)-2-carbamoyloxy-1-o-chlorophenylethanol prepared in this manner was used in the synthetic method described in Example 6 for (D/L)-1-m-chlorophenyl-1,2-ethanediol carbonate to yield (R)-2-carbamoyloxy-1-o-chlorophenylethanol (4.02 g, yield 54%). An analytically pure sample of (R)-2-carbamoyloxy-1-o-chlorophenylethanol ethanediol (3.35 g, yield 45%, m.p. 133° C., [α]D =-63.9 (c=2.22, methanol)) was obtained by recrystallization from ethyl acetate.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:15]1O[C:17](/[C:20](/[F:36])=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)=[N:18][N:19]=1)[C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[C:8]([F:14])[CH:7]=1.C([O-])(=O)C.[NH4+:41].C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[F:36]/[C:20](/[C:17]1[N:41]=[C:15]2[CH:5]([C:6]3[CH:11]=[C:10]([F:12])[C:9]([F:13])=[C:8]([F:14])[CH:7]=3)[CH2:4][CH2:3][CH2:2][N:19]2[N:18]=1)=[CH:21]\[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[C:24]([O:34][CH3:35])[CH:23]=1
Reactant: [NH4+]
Reactant: COc1cc(/C=C(\F)c2nnc(C(CCCCl)c3cc(F)c(F)c(F)c3)o2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C(\F)c2nc3n(n2)CCCC3c2cc(F)c(F)c(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 130.4 %

Procedure:
A solution of 2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (81 mg) and ammonium acetate (358 mg) in acetic acid (2 mL) was stirred at 150° C. for three hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate) to obtain 98 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([N:5]([CH2:43][CH2:44][CH2:45][CH3:46])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([CH2:21][O:22][Si](C(C)(C)C)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:16][C:15]=2[CH3:40])=[C:8]([O:41][CH3:42])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:43]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[C:15]([CH3:40])=[CH:16][C:17]([CH2:21][OH:22])=[C:18]([CH3:20])[CH:19]=2)=[C:8]([O:41][CH3:42])[CH:7]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2C)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2cc(C)c(CO)cc2C)c(OC)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
In 30 ml of tetrahydrofuran was dissolved 2.7 g (4.26 mmol) of dibutyl[4-[2-[4-(tert-butyldiphenylsiloxymethyl)-2,5-dimethylphenyl]vinyl]-3-methoxyphenyl]amine, and 13.0 ml of tetrabutylammonium fluoride (1 mol solution in tetrahydrofuran) was added dropwise thereto with stirring at room temperature. The mixture was stirred for 3 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residue was purified by silica gel column chromatography to give 1.57 g of a yellow liquid (yield: 93.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([S:12][CH3:13])[N:3]=1.CN(C)[C:16](=[O:18])C.O1CCCC1.[H-].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:18][CH3:16])[N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1nc(Cl)c(C(=O)O)c(Cl)n1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(SC)nc(Cl)c1C(=O)O
Reaction time: 0.33 h

Procedure:
A mixture of 4,6-dichloro-5-carboxy-2-methylthiopyrimidine (prepared in Example 320(1)) 5.00 g, N,N-dimethylacetamide 50 ml, tetrahydrofuran 20 ml and sodium hydride (60%) 1.673 g is stirred for 20 minutes on an ice bath. Methanol 5 ml is dropped thereto over a period of 30 minutes and the mixture is stirred for 15 minutes. The reaction mixture is diluted with a 10% aqueous citric solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The resulting solid is triturated with hexane in ice to give 4-chloro-5-carboxy-6-methoxy-2-methylthiopyrimidine as a slightly brown crystalline powder, 4.61 g. mp 179–181° C.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH:14]1([NH2:18])[CH2:17][CH2:16][CH2:15]1>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:18][CH:14]3[CH2:17][CH2:16][CH2:15]3)[NH:7][C:6]=2[CH:8]=1
Reactant: NC1CCC1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Product: O=S1(=O)N=C(NC2CCC2)Nc2cc(Cl)sc21
Temperature: 0 °C
Yield: 53 %

Procedure:
A solution of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (257 mg, 1.0 mmol) in cyclobutylamine (1.0 ml) was stirred for 18 h at 90° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (10 ml) at 0° C. followed by adjustment to pH 2 with 4M hydrochloric acid. The product was isolated by filtration, washed with water, and recrystallised from methanol/ethyl acetate followed by drying in vacuo at room temperature to give 155 mg (53%) of the pure title compound; mp 315-317° C. dec.; 1H-NMR (DMSO-d6): δ1.58-1.75 (m, 2H), 1.89-2.05 (m, 2H), 2.19-2.30 (m, 2H), 4.16 (m, 1H), 7.06 (s, 1H), 7.62 (br s, 1H), 10.83 (br s, 1H); MS: m/e 291/293 (M+); (C9H10N3Cl1O2S2) calc C, 37.05; H, 3.45; N, 14.40; found C, 37.18; H, 3.48; N, 14.19.
Reaction SMILES: [H][H].[H-].[Na+].[CH2:5]([O:7][C:8](=[O:16])[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6].[O:17]([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:5]([O:7][C:8](=[O:16])[C:9]([CH3:15])([CH2:27][CH2:26][CH2:25][CH2:24][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: [H][H]
Reactant: BrCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCCCOc1ccccc1)C(=O)OCC

Procedure:
After the development of hydrogen was finished 30 g (1 mol) of a 80% suspension of sodium hydride in mineral oil were added portionwise to 191 g (1.1 mols) of methylmalonic acid diethyl ester in 300 ml of absolute toluene and 50 ml of dry dimethylformamide were added and after that, 252 g (1.1 mols) of 4-phenoxy-1-bromobutane (J.O.C. 27, 1290 (1962)) were added. The mixture was refluxed for about 13 hours until the medium had a neutral reaction. It was worked up as in 4(a). Boiling point0.08 : 137° C
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:37]=[C:38](B2OC(C)(C)C(C)(C)O2)[S:39][CH:40]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:38]3[S:39][CH:40]=[C:36]([F:35])[CH:37]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CC1(C)OB(c2cc(F)cs2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(F)cs2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Temperature: 85 °C

Procedure:
To a 30 mL sealed cap glass vessel containing tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol) and 2-(4-fluorothiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (137 mg, 0.599 mmol) dissolved in DME and water (4:1) was added tetrakis(triphenylphosphine)palladium(0) (105 mg, 0.399 mmol) and potassium phosphate, tribasic (212 mg, 1 mmol). The cap was sealed, and the reaction mixture was heated at 85° C. for 1 hour and then cooled to room temperature. The mixture was diluted with water (10 mL) and extracted with EtOAc (2×25 mL). The organic layers were combined, dried over sodium sulfate, and solvent removed via rotary evaporation to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(4-fluorothiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the resulting mixture was stirred at room temperature for 1 hour to give crude product, which was purified via preparative HPLC, eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to minimal volume, and lyophilized to give a TFA salt of the title compound (86 mg, 59%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (d, J=9.60 Hz, 1H), 2.03-2.18 (m, 1H), 3.53-3.68 (m, 1H), 3.75 (d, J=11.62 Hz, 1H), 3.85 (br s, 1H), 4.01 (d, J=12.38 Hz, 2H), 4.32 (td, J=8.53, 4.17 Hz, 1H), 4.45 (s, 2H), 7.32 (t, J=1.64 Hz, 1H), 7.40 (d, J=5.31 Hz, 1H), 7.95 (br s, 3H), 8.65 (s, 1H), 8.98 (d, J=1.77 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C16H16F2N4O2S, 367. found, 367.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][NH:21][CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[N:25]4[C:19]([CH2:20][N:21]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:22][C:23]5[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:24]=54)=[N:18][N:17]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](c4nsc5ccccc54)CC3)n1-2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3nsc4ccccc43)CC2)C1
Reaction time: 20 h

Procedure:
To a solution of trans-1-(4-benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (35 mg, 0.080 mmol) and triethylamine (0.022 ml, 0.16 mmol) in dichloromethane (0.8 ml) was added methanesulfonyl chloride (0.013 ml, 0.16 mmol) at room temperature. Stirring for 20 h was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (34 mg, 82%) as white solid: MS m/e: 514 ([M+H]+)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)[CH:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:26]2[CH:25]=[C:24]([C:23]3[C:18]4[C:19](=[N:20][C:15]([NH:14][CH:11]5[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]5)=[N:16][CH:17]=4)[NH:21][N:22]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccc(Cl)cc5)c4)nn(COCC[Si](C)(C)C)c3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCC(Nc2ncc3c(-c4cccc(NCc5ccc(Cl)cc5)c4)n[nH]c3n2)CC1
Reaction time: 4 h

Procedure:
To a stirred solution of {4-[3-[3-(4-chloro-benzylamino)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (120 mg, 0.177 mmol) in dichloromethane (3 mL) was added TFA (3 mL) at room temperature. The resulting mixture was stirred for another four hours at this temperature. The solvent was evaporated under reduced pressure and the residue was treated with saturated aqueous NaHCO3 (5 mL) and extracted with EtOAc (30 mL). The organic phase was washed with brine (5 mL) and dried to give crude product. It was purified by prep-HPLC to give N-{3-[3-(4-chloro-benzylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine as solid. (Yield 25 mg, 31%).
Reaction SMILES: C1(C[O:8][CH2:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[O:23][C:22]4=[O:30])=[CH:18][CH:19]=3)[CH2:14][C@H:13]2[CH3:31])=[O:11])C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[OH:8][CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([N:21]3[CH2:25][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[O:23][C:22]3=[O:30])=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[CH3:31])=[O:11]
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)C[C@@H](C)N3C(=O)COCc2ccccc2)C(=O)O1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1CN(c2ccc3c(c2)C[C@@H](C)N3C(=O)CO)C(=O)O1

Procedure:
A mixture of methyl (5R)-3-[(2R)-2,3-dihydro-1-[(phenylmethoxy)acetyl]-2-methyl-1H-indol-5-yl]-2-oxo-5-oxazolidinecarboxylate (Step 1, 0.301 g, 0.71 mmol) and Pearlman's catalyst (0.032 g) in methanol (30 mL) is shaken on a Parr apparatus under a 36 psi hydrogen atmosphere for approximately 24 h, during which additional Pearlman's catalyst (0.044 g) is added. The catalyst is removed by filtration through a pad of Celite, and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a Biotage Flash 40S silica gel cartridge (2% MeOH/CH2Cl2 eluent) to give the title compound, MS (ESI+) for C16H18N2O6 m/z 335 (M+H)+.
Reaction SMILES: [F:1][C:2](S(O)(=O)=O)([F:4])[F:3].[K+].[Br-].CCC[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24][CH2:25]N2CCCCC2)=O)=[CH:18][CH:17]=1.Cl.[C:33]1([O:39][CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:40][O:39][C:33]1[CH:38]=[CH:37][C:36]([C:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=2)([C:24]2[CH:25]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[C:2]([F:4])([F:3])[F:1])=[CH:35][CH:34]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COc1ccccc1
Reactant: CCCCOc1ccc(C(=O)CCN2CCCCC2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(C(c2ccc(OC)cc2)(c2ccc(OC)cc2)C(F)(F)F)cc1

Procedure:
A solution of 9.0 g (0.044 mol) of 4-methoxy-α,α,α-trifluoroacetophenone, 90 ml of anisole and 5 ml of trifluoromethyl sulfonic acid was stirred for 48 hours. At the end of this period, the product was worked up as in Example 6 to give 14.2 g (80%) of white crystalline 9; m.p. 196°-197° C., IR (KBr) 3010 (C--H, ar), 2840 (OCH3), 1610 and 1510 (Ar), 1150 (C--F) 825 cm-1 (parasubstituted phenyl); NMR δ 3.80 (s, 3H), 6.75 (d, J=8 Hz, 2H); 7.05 (d, J=8 Hz 2H); mass spectrum m/e, 402 (parent ion), 333 (P-69), 163 (P-239), 135 (P-267). Analytical: calculated for C23H2O3F3 ; C, 68.65; H, 5.22; F, 14.2%. Found: C, 68.48; H, 530; F, 14.2%.