Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[N:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1)(=O)C1C=CC=CC=1.Cl.CON.N1C=CC=CC=1.CS(C)=O>C(O)C>[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]3[N:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)[CH2:16][C@:14]2([C:26]2[CH:27]=[C:28]([NH:32][C:33]([C:35]3[CH:40]=[N:39][C:38]([O:41][CH3:42])=[CH:37][N:36]=3)=[O:34])[CH:29]=[CH:30][CH:31]=2)[N:15]=1
Reactant: COc1cnc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)cn1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Solvent: CS(C)=O
Product: COc1cnc(C(=O)Nc2cccc([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(N)=N4)c2)cn1
Temperature: 50 °C

Procedure:
A mixture of N-[3-[(4aR,7aS)-2-benzamido-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamide (479 mg, 819 μmol), O-methylhydroxylamine hydrochloride (709 mg, 8.19 mmol) and pyridine (663 μL, 8.19 mmol) in ethanol (20 mL) is heated at 50° C. in a capped flask overnight. Dimethyl sulfoxide (4 mL) is added and the mixture is heated to 70° C. for 4 hours to obtain a solution. The reaction is cooled and most of the solvent is removed in vacuo. Water is added and the pH is adjusted to ˜12 with 1 N sodium hydroxide. The mixture is extracted with ethyl acetate (5×). The combined organic extracts are dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 30 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane gradient. The mixture is purified again on a SCX column using 3:1 dichloromethane:methanol and then 2:1 dichloromethane:7 N ammonia in methanol to remove residual dimethyl sulfoxide. The mixture is purified a final time over silica gel with a 20 minute 0.5% to 10% gradient of 7 N ammonia methanol in dichloromethane to give N-[3-[(4aR,7aS)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]phenyl]-5-methoxy-pyrazine-2-carboxamide. This material is dissolved in dichloromethane (1 mL) and methanol (0.5 mL) and 1 M hydrogen chloride in diethyl ether (0.66 mL, 660 μmol) is added. The solvent is removed in vacuo to give the title compound (329 mg, 78%). ES/MS (m/e): 481 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Br[C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:35][C:31]1[CH:30]=[C:29]([C:6]2[CH:5]=[C:4]([NH:17][C:18]3[N:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][N:19]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=2)[CH:34]=[N:33][CH:32]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Nc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(N)c2)c1
Temperature: 80 °C

Procedure:
A mixture of N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (4.00 g, 10.6 mmol), 5-bromopyridin-3-amine (2.01 g, 11.6 mmol), Pd(dppf)Cl2—CH2Cl2 (0.431 g, 0.527 mmol) in 1,4-dioxane (52.7 mL, 0.2 M) and Na2CO3 (10.6 mL, 2 M) was purged with argon and heated to 80° C. for 4 hours. The reaction mixture was filtered through a CELITE plug and washed with dichloromethane. The eluent was diluted with water and extracted with dichloromethane (3×). The combined organic layers were concentrated in vacuo and purified by silica gel column chromatography (methanol/ethyl acetate) to afford N-[3-(5-aminopyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine. MS APCI calc'd for C17H15F3N5 [M+H]+ 346. found 346.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]([NH:9][C:10]([CH3:22])([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:8])(=O)C.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[SH:4][CH2:5][CH:6]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][C:10]([CH3:22])([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)NC(C)(C)C(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(NC(=O)C(CS)Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.6 %

Procedure:
Benzyl 2-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]isobutyrate (0.45 g) is dissolved in a mixture of methanol (5 ml) and water (3 ml) under nitrogen, and thereto is added triethylamine (0.22 g), and the mixture is stirred at room temperature for 5 hours. After the reaction, the reaction mixture is acidified with saturated aqueous citric acid solution, and methanol is distilled off under reduced pressure. To the residue is added water, and the mixture is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate, and then distilled under reduced pressure. The residue is purified by a silica gel column chromatography (eluant, chloroform) to give the title compound (0.35 g).
Reaction SMILES: O[CH2:2][CH2:3][C:4]12[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2.[BrH:13].S(=O)(=O)(O)O>O>[Br:13][CH2:2][CH2:3][C:4]12[C:10]([CH3:12])([CH3:11])[CH:7]([CH2:8][CH2:9]1)[CH2:6][CH2:5]2
Reactant: Br
Reactant: CC1(C)C2CCC1(CCO)CC2
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)C2CCC1(CCBr)CC2

Procedure:
A stirred mixture of 1-(2-hydroxyethyl)-7,7-dimethyl-norbornane (42.0 g, 0.25 mole), 48% hydrobromic acid (63.0 ml) and concentrated sulphuric acid (14 ml) was heated under reflux for 4 hours, cooled, poured into water (500 ml) was extracted with ether. The combined extracts were washed with water, sodium bicarbonate solution and water. After drying (MgSO4) the solvent was evaporated in vacuo to yield the title product (50.9 g), m.p. 68°-71° [from light-petroleum (b.p. 40-60°)] (Found: C, 57.0: H, 8.1; Br, 34.2. C11H19Br requires C, 57.0; H, 8.3; Br, 34.5%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]([NH:12][CH3:13])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([O:31]N1C(=O)CCC1=O)([O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])=O>C1COCC1>[CH:1]1([CH2:7][C@H:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:9]([N:12]([CH3:13])[C:22]([O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])=[O:31])[CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(NC)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CCC([C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)N(C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of (S)-tert-butyl 1-cyclohexyl-3-(methylamino)pentan-2-ylcarbamate in THF (20 mL) was added TeocOSu (398 mg, 1.53 mmol), followed by TEA (0.5 mL). The reaction mixture was stirred for 30 min at rt, and concentrated. The residue was partially purified through chromatography on silica gel to give (2S)-tert-butyl 1-cyclohexyl-3-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)pentan-2-ylcarbamate. MS ESI +ve m/z 465 (M+Na).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[O:19]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:29]4[CH:30]=[CH:31][C:26]([O:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:27][CH:28]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(Oc5ccccc5)cc4)cc3CC[C@@H]12
Yield: 79.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-phenoxyphenylboronic acid (167 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 206 mg (80%) of the title compound as a white solid. mp 148°-150.COPYRGT.. FDMS: m/e=397. α[D]589 =+64.51 (c=0.62, chloroform).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]([C:6]([O:8][CH:9]1[CH2:14][CH:13]2[CH2:15][CH:10]1[CH:11]=[CH:12]2)=[O:7])([CH3:5])[CH3:4].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH:20]=[CH:19]1.[CH3:25][Si:26]([CH3:37])([CH3:36])[C:27]([O:30][C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])([CH3:29])[CH3:28]>O1CCCC1>[CH3:17][Si:2]([CH3:1])([CH3:16])[C:3]([C:6]([O:8][C:9]1[CH:10]2[CH2:15][CH:13]([CH:14]=1)[CH:12]([C:19]1=[CH:20][C:21]([O:23][C:18]1=[O:24])=[O:22])[CH2:11]2)=[O:7])([CH3:5])[CH3:4].[CH3:37][Si:26]([CH3:25])([CH3:36])[C:27]([O:30][C:31](=[O:35])[C:32]([CH3:34])=[CH2:33])([CH3:29])[CH3:28]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C(=O)OC1CC2C=CC1C2)[Si](C)(C)C
Agent: C=C(C)C(=O)OC(C)(C)[Si](C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C(=O)OC1=CC2CC1CC2C1=CC(=O)OC1=O)[Si](C)(C)C
Yield: 50 %

Procedure:
2.57 g (0.01 mol) of 2-(2-trimethylsilyl-2-propyl)carbonyloxy-5-norbornene obtained in Example 3, 1.0 g (0.01 mol) of purified maleic anhydride, 1.36 g (0.006 mol) of (2-trimethylsilyl-2-propyl)methacrylate, and 0.067 g (1.5 mole %) 2,2-azobisisobutyronitrile as a radical initiator are added to a polymerization flask. The mixture is dissolved in 3.2 g of purified tetrahydrofuran and is polymerized at 65° C. for 24 hours under nitrogen atmosphere. After the polymerization, polymerization product is precipitated with methanol, is saved by a glass filter, and is then dried at 40° C. for 12 hours to give 2.47 g of copolymer 2-(2-trimethylsilyl-2-propyl)carbonyloxy -5-norbornene-maleic anhydride-(2-trimethylsilyl-2-propyl)methacrylate (yield 50%) as a white solid. Mn is 6,520 and glass transition temperature is not observed. The 1H-NMR spectrum in FIG. 7 showed the synthesis of a copolymer with desired structure.
Reaction SMILES: [N:1]1([CH2:10][C:11]([OH:13])=O)[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].Cl.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH:29]([CH3:33])[C:28]1=[O:34])(=[O:26])=[O:25])([O-:17])=[O:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:33][CH:29]1[N:30]([C:11](=[O:13])[CH2:10][N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH2:31][CH2:32][N:27]([S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26])[C:28]1=[O:34]
Reactant: CC1NCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])C1=O
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(CC(=O)N2CCN(S(=O)(=O)c3ccccc3[N+](=O)[O-])C(=O)C2C)c(=O)[nH]c1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
To a solution of (thymin-1-yl)-acetic acid (55 mg, 0.30 mmol), 1-(2-nitro-benzenesulfonyl)-3-methyl-piperazin-2-one HCl salt (100 mg, 0.30 mmol), and PyBOP (156 mg, 0.45 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.08 mL) at room temperature. After stirring for additional 2 h at 40° C., the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in reduced pressure and the residue was purified by column chromatography to give the titled compound (100 mg, 72%). 1H NMR (500 MHz; DMSO-d6) δ 11.31 (s, 1H), 8.33 (d, 1H), 8.10 (d, 1H), 8.04˜7.93 (m, 2H), 7.35 (s, 1H), 4.85˜4.60 (m, 2.5H), 4.55˜4.40 (m, 0.5H), 4.20˜4.10 (m, 0.5H), 4.05˜3.90 (m, 1.5H), 3.78˜3.60 (m, 1H), 3.30 (m, 1H), 1.74 (s, 3H), 1.42 (d, 1H), 1.27 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:24]=[CH:23][C:17]([C:18](OCC)=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1.C([BH-](CC)CC)C.[Li+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]2[CH:25]=[CH:26][C:27]([CH3:29])=[CH:28][C:4]=2[N:3]=1
Reactant: CCOC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(CO)cc3)cc12
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)benzoate (Example 70) (1.0 eq.) in THF (0.1 M) at 0° C. was added 1.0 M lithium triethylborohydride in THF (10 eq.) and warmed to room temperature over 2 hours. 1N HCl aqueous solution was added slowly to quench the reaction, and the mixture was heated to reflux for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution. The two phases were separated, and the aqueous layer was extracted with ethyl acetate (EA). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by RP-HPLC using a 10-50% MeCN in water gradient followed by extraction in DCM to give (4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)methanol. 1H NMR (Acetone-d6): δ 8.77 (s, 1H), 8.69 (s, 1H), 8.26 (d, 1H), 7.40 (s, 1H), 7.21-7.28 (m, 4H), 7.13 (d, 1H), 6.5 (br, 2H), 4.56 (s, 2H), 4.1 (br t, 1H), 3.10-3.23 (m, 4H), 2.44 (s, 3H). LRMS [M+H]=344.2
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:25][CH2:24]1.Cl>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=2[C:11]([NH:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[N:7][C:2]([NH:32][C:31]2[CH:33]=[CH:34][CH:35]=[C:29]([N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)[CH:30]=2)=[N:3][CH:4]=1
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
2-[(2,5-Dichloro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (200 mg, 0.61 mmol) and 3-(4-methyl-1-piperazinyl)aniline (117 mg, 0.61 mmol) were combined in a vessel with 8 mL isopropanol and 12N HCl (51 μL, 0.61 mmol). The vessel was sealed and heated with stirring at 95° C. for 18 h. The reaction was cooled to room temperature and the solid was filtered off and washed with diethyl ether to give 120 mg (40%) of an off-white solid as the HCl salt. Mass (M+H)+=480, 481, 482.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[F:8][C:9]1[C:14]([S:15](Cl)(=[O:17])=[O:16])=[C:13]([F:19])[C:12]([F:20])=[C:11]([F:21])[C:10]=1[F:22].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:8][C:9]1[C:10]([F:22])=[C:11]([F:21])[C:12]([F:20])=[C:13]([F:19])[C:14]=1[S:15]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(O)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(O)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-methyl-1,3-butane diol (0.79 g, 7.5 mmol) and TEA (0.37 g, 3.6 mmol) in CH2Cl2 (7 mL) at) 0° C. was added pentafluorobenzenesulfonyl chloride (0.80 g, 3.0 mmol). The solution was stirred at 0° C. for 1.5 h. Saturated aqueous NaHCO3 (10 mL) was added to the solution and the mixture was stirred at rt for 15 min. The organics were extracted with CH2Cl2 and washed with 0.5 M HCl (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with (30% ethyl acetate in hexanes) yielded the desired product as a white crystalline low melting point solid (0.69 g, 66%). 1H NMR (400 MHz CDCl3) δ 4.49 (t, 2H, J=7.0 Hz), 1.97 (t, 2H, J=7.0 Hz) 1.27 (s, 6H). Anal. Calcd. For C11H11F5O4S: C, 39.53; H, 3.32. Found: C, 39.54; H, 3.22.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH2:16][CH2:17][CH3:18])[C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[N:14]=1)[C:9]([OH:11])=O)[CH2:3][CH3:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[NH2:33][C@@H:34]([CH2:48][C:49]1[CH:54]=[C:53]([F:55])[CH:52]=[C:51]([F:56])[CH:50]=1)[C@H:35]([OH:47])[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[CH:40]=1>C1COCC1.C(N(CC)CC)C.ClCCl>[F:55][C:53]1[CH:54]=[C:49]([CH:50]=[C:51]([F:56])[CH:52]=1)[CH2:48][C@H:34]([NH:33][C:9](=[O:11])[C:8]1[CH:12]=[C:13]([CH3:15])[N:14]=[C:6]([N:5]([CH2:2][CH2:3][CH3:4])[CH2:16][CH2:17][CH3:18])[CH:7]=1)[C@H:35]([OH:47])[CH2:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH3:46])[CH:40]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)c1cc(C(=O)O)cc(C)n1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(C)n1
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To 2-(dipropylamino)-6-methylisonicotinic acid hydrochloride (approx. 0.4 mmol) in THF (3 mL) was added triethylamine (0.17 mL), followed by dichloromethane (2 mL) and then CDI (0.071 g, 0.44 mmol). After stirring for 1 h, a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (0.163 g, 0.400 mmol), triethylamine (0.11 mL), and dichloromethane (approx. 2 mL) was added to the CDI mixture. The mixture was allowed to stir overnight, after which an additional 0.12 mL of triethylamine and 0.045 g of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride was added. After stirring for several more hours, the mixture was partitioned between dichloromethane and aq. sodium bicarbonate. The organic layer was dried with sodium sulfate, concentrated, and the residue was chromatographed on silica gel using MeOH-dichloromethane (5/95) to give 0.04 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](Cl)[C:3]=1[Cl:12].[Cu](C#N)[C:14]#[N:15].Cl.C>CN(C=O)C.CO.C1(C)C=CC=CC=1.O>[Cl:12][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[C:4]=1[C:14]#[N:15]
Reactant: N#C[Cu]C#N
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1.831 kg of 1,2,3-trichloro-4-nitrobenzene and 0.861 kg of copper cyanide in 1.21 L of DMF is heated to 155° C. for 2 hours, then cooled to room temperature. A solution of 3.24 kg of ferric chloride hexahydrate, 0.806 L of concentrated hydrochloric acid, and 4.87 L of water is added and the solution heated to 65° C. for 20 minutes. The mixture is cooled, stirred with 0.55 kg of charcoal and 4 L of toluene, and filtered. The organic phase is separated and the aqueous phase extracted with toluene. The combined toluene layers are washed with water and 6 N HCl, dried and concentrated to give a slurry. The slurry is dissolved in 1.5 L of methanol, and stored at 5° C. for 24 hours. The nitrile product is collected by filtration, washed with 1.5 L cold methanol and dried at 40° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:28])[F:27])[CH:4]=1.C(N(C(C)C)CC)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22]([C:39](=[O:41])[CH3:40])[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)=[C:5]([C:26]([F:29])([F:27])[F:28])[CH:4]=1
Reactant: CC(=O)Cl
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)n[nH]c2C1
Reaction time: 16 h
Yield: 30.4 %

Procedure:
To a solution of (4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (63 mg, 0.15 mmol) and diisopropylethylamine (70 L, 0.40 mmol) in DMF (3.0 mL) was added acetyl chloride (11 μL, 0.15 mmol). The mixture was stirred for 16 hour. The solvent was removed under reduced pressure and the residue was diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic extracts were washed with saturated brine (1×20 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% (10% CH3OH in CH2Cl2 with 0.01% NH4OH) in CH2Cl2) and further purified by reverse phase chromatography (Isco CombiFlash Rf unit, 12 g Redisep c18 gold column, 0% to 100% acetonitrile in water) to give 1-(3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone as a white solid (20 mg, 94%): mp 176-180° C.; 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.71-7.68 (m, 1H), 7.56-7.49 (m, 2H), 4.94-4.55 (m, 3H), 3.66-3.62 (m, 2H), 3.10 (br s, 2H), 2.85-2.48 (m, 4H), 2.10-2.08 (m, 3H), 1.73 (m, 4H); ESI MS m/z 439 [M+H]+.
Reaction SMILES: O=P(Cl)(Cl)Cl.CN([CH:9]=[O:10])C.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)([O-:13])=[O:12].CC([O-])=O.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:9]=[O:10])([O-:13])=[O:12]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 65 %

Procedure:
POCl3 was added to DMF at 0-10° C. after which 50 ml of CCl4 was added at room temperature. A solution of 4.5 g (24 mmol) 1a in 50 ml of CCl4 was added slowly to the reaction mixture at about 10° C. during 1 hour. The reaction mixture was refluxed for 15 min. and a solution of 50 g of NaOAc, 3H2O in 50 ml of H2O was added and refluxing was continued for 15 min. The mixture was cooled, extracted with ether and dried over Na2SO4. 8.0 g (65%) of 2a was isolated by column chromatography using EtOAc:petroleum ether as eluent.