Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@@H:3]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]([OH:15])=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH2:27][C:28]1([C:31]#[N:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH4+].[Cl-]>CN(C=O)C.C(OCC)(=O)C>[C:31]([C:28]1([NH:27][C:13](=[O:15])[C@@H:12]([NH:11][C@@H:3]([C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=2)[C:2]([F:1])([F:26])[F:25])[CH2:16][S:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:30][CH2:29]1)#[N:32]
Reactant: O=C(O)[C@H](CSCc1cccnc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@H](CSCc2cccnc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(pyridin-3-ylmethylsulfanyl)-propionic acid was dissolved in DMF (5 mL) and 1-aminocyclopropanecarbonitrile (142 mg, 1.2 mmol), HATU (456 mg, 1.2 mmol) and NMM (0.44 mL, 4 mmol) were added. After stirring for 2 h at rt, saturated NH4Cl and ethyl acetate were added and stirring was continued for 20 min. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with MgSO4 and the solvent was removed under the reduced pressure to give N-(1-cyanocyclopropyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-(pyridin-3-ylmethylsulfanyl)propionamide as an oil. The crude was used in the next step without further purification.
Reaction SMILES: ClC1N=C(NC2CCCCC2)C(C)=C(C)N=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([CH2:25][CH3:26])=[C:20]([CH3:27])[N:19]=1.ClC1N=C(Cl)C(C)=C(C)N=1.[F:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1>>[Cl:17][C:18]1[N:23]=[C:22]([NH:43][C:42]2[CH:44]=[CH:45][C:39]([F:38])=[CH:40][CH:41]=2)[C:21]([CH2:25][CH3:26])=[C:20]([CH3:27])[N:19]=1
Reactant: CCc1c(C)nc(Cl)nc1Cl
Reactant: Nc1ccc(F)cc1
Agent: Cc1nc(Cl)nc(Cl)c1C
Agent: Cc1nc(Cl)nc(NC2CCCCC2)c1C
Product: CCc1c(C)nc(Cl)nc1Nc1ccc(F)cc1

Procedure:
The titled compound was synthesized according to the procedure described for preparation of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine (Example 1, Step D) using 2,4-dichloro-5-ethyl-6-methylpyrimidine instead 2,4-dichloro-5,6-dimethylpyrimidine and 4-fluoroaniline instead of cyclohexylamine. The titled compound was obtained as a white solid. MS (ESI) m/z 266.7, 268.7 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[N+]([O-])(O)=[O:13]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:13])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: OCCCCCCCCCBr
Product: O=C(O)CCCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
9-Bromo-1-nonanol (4 g, 18 mmol) was placed in a flask, cooled on an ice bath, and concentrated nitric acid (40 mL) was slowly added. The solution was stirred at 0° C. for 30 minutes then allowed to warm to room temperature and stirring continued overnight. The solution was poured onto ice and extracted with DCM (3×150 mL). The combined extracts were washed with water (3×150 mL) and the solvent then removed in vacuo to give an oil 3.82 g (94%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[N:6][C:7]=1F.Cl.[NH:33]1[CH2:38][CH2:37][CH2:36][C@@H:35]([OH:39])[CH2:34]1>>[Br:1][C:2]1[C:7]([N:33]2[CH2:38][CH2:37][CH2:36][C@@H:35]([OH:39])[CH2:34]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: O[C@@H]1CCCNC1
Agent: Cl
Product: O[C@@H]1CCCN(c2nc(-c3n[nH]c4cnc(-c5cccnc5)cc34)ccc2Br)C1
Yield: 29.9 %

Procedure:
Following the procedures as described in Example 241 and starting with 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-piperidin-3-ol hydrochloride, 291 was obtained as an off-white solid (11.0 mg, 29.9%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.31 (d, J=1.8 Hz, 1H), 9.24 (s, 1H), 9.01 (s, 1H), 8.60 (d, J=4.0 Hz, 1H), 8.44 (d, J=8.1 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.0, 4.8 Hz, 1H), 4.93 (d, J=4.4 Hz, 1H), 3.97 (d, J=11.6 Hz, 1H), 3.83 (d, J=12.2 Hz, 1H), 3.74 (dd, J=9.2, 4.8 Hz, 1H), 2.99-2.81 (m, 2H), 2.02 (d, J=9.1 Hz, 1H), 1.88 (d, J=13.3 Hz, 1H), 1.72 (dd, J=22.7, 10.5 Hz, 1H), 1.39 (dd, J=22.0, 8.0 Hz, 1H); ESI MS m/z=451.1 (M+1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[N:17]1([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.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]>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:20]4[CH2:21][CH2:22][N:17]([C:23]5[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][N:24]=5)[CH2:18][CH2:19]4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1
Reactant: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C[C@H]2CCN(c3ccc(N4CCN(c5ccc(C#N)cn5)CC4)cc3)[C@H]2C1
Temperature: 70 °C

Procedure:
The product of Example 7C (281.2 mg, 1.0 mmole), the product of Example 48A (226 mg, 1.2 mmole), tris(dibenzylideneacetone)dipalladium (18.3 mg, 0.02 mmole), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (25.0 mg, 0.04 mmole) and sodium tert-butoxide (145 mg, 1.5 mmole) were dissolved in 5 ml of toluene and heated at 70° C. under N2 for 24 hours. The mixture was cooled to room temperature, diluted with water and extracted with dichloromethane (5×). The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by chromatography (eluting with a mixture of 5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.43 (d, J=1.70 Hz, 1H) 7.62 (dd, J=8.98, 2.20 Hz, 1H) 6.92 (d, J=8.81 Hz, 2H) 6.64 (d, J=9.15 Hz, 1H) 6.56 (d, J=9.15 Hz, 2H) 4.01-4.15 (m, 1H) 3.79-3.88 (m, 4H) 3.45-3.55 (m, 1H) 3.14-3.23 (m, 1H) 3.08-3.14 (m, 4H) 2.97-3.04 (m, 1H) 2.55-2.75 (m, 4H) 2.36 (s, 3H) 2.09-2.22 (m, 1H) 1.92 (m, 1H); MS (M+H)+=389.
Reaction SMILES: I[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(NC(C)C)(C)C>C1COCC1.CCOCC.[Cu](I)I>[CH3:10][Si:11]([CH3:13])([CH3:12])[C:14]#[C:15][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: OCCCCCC#CI
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#CC#CCCCCCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a solution of 7-iodo-6-heptynol (100 mg, 0.42 mmol), trimethylsilylacetylene (0.072 ml, 0.5 mmol), diphenyldichloropaladium (10 mg) and copper iodide (3 mg) in 5 ml of THF was added diisopropylamine (0.150 ml) at rt in argon atmosphere. After stirring 1 hr at rt, the mixture was diluted with ether, washed with NH4Cl solution, water and brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (hexanes:ethyl acetate=4:1) gave 50 mg of product (50% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][CH2:19]O.S(=O)(=O)(O)O>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[O:14][CH2:19][CH2:18][Br:17])=[CH:15][CH:16]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: OCCBr
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Clc1ccc(C(OCCBr)c2ccc(Cl)cc2)cc1
Yield: 8380.7 %

Procedure:
A mixture of 4,4′-dichlorobenzhydrol (4.40 g, 0.17 mmol) and 2-bromoethanol (3.0 g, 24.0 mmol) in benzene (50 ml) was treated with sulfuric acid (0.25 ml) and the resulting mixture was heated under reflux for 1 h. The cooled mixture was diluted with ethyl acetate (200 ml), washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent gave an oil which was chromatographed on silica gel using a mixture of toluene and hexane (1:1) as eluent to give the title compound as a clear oil (5.13 g, 82%).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH:12]([CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)=[O:13].O>C1COCC1.C(OCC)(=O)C>[OH:13][CH:12]([C:11]1[N:7]([CH3:6])[N:8]=[N:9][CH:10]=1)[CH:14]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1nncc1C(O)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (9.60 mL, 24.0 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (2.00 g, 24.0 mmol, prepared according to PCT Int. Appl., 2008098104) in dry THF (100 mL) at −50° C. The reaction became heterogeneous and yellow during addition. After 15 min, a solution of tert-butyl 3-formylazetidine-1-carboxylate (4.45 g, 24.0 mmol) in dry THF (10 mL) was added dropwise by syringe. The reaction mixture became homogeneous and was allowed to slowly warm to 0° C. Water (10 mL) and ethyl acetate (100) mL were added. The biphasic mixture was warmed to 23° C. The mixture was partitioned between half-saturated aqueous sodium chloride solution (100 mL) and ethyl acetate (300 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Celite (14 g) was added to the filtrate and the solvents were removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a silica gel column. Elution with ethyl acetate initially, grading to 5% methanol-ethyl acetate provided the title compound as a white foam.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][O:10]CC1C=CC=CC=1)(=[O:3])[CH3:2].[H][H]>C(O)(=O)C.[Pd]>[C:1]([O:4][C@H:5]([CH3:18])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H](C)CCCCOCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)O[C@H](C)CCCCO
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
Next, the alkali-stable group was converted to a primary hydroxyl group in one of two representative alternative processes. Palladium (10%) on carbon (3.2 g) was added to a Pyrex® hydrogenation vessel and a solution of 5-(R)-acetoxy-1-benzyloxyhexane (65.5 g, 0.26 mole) in acetic acid (65 ml) was added under an argon atmosphere. The reaction vessel was filled with hydrogen gas (75 psi), shaken for five minutes, evacuated, and this process was repeated again and finally the reaction vessel was brought to 75 psi with hydrogen and hydrogenated for 12 hours. Exothermic reaction and rapid absorption of hydrogen was observed during first 2-3 hours. The vessel was replenished with hydrogen whenever the hydrogen was consumed. After 12 hours the reaction mixture was filtered, and the solids were washed with ethyl acetate (75 ml). The combined filtrates were concentrated under reduced pressure and then the residue was dissolved in ethyl acetate (200 ml). The solution was washed with saturated aqueous sodium bicarbonate solution (2×100 ml) and saturated aqueous sodium chloride solution (100 ml) and then dried over magnesium sulfate (10 g). Evaporation of the solvent under reduced pressure gave 39.84 g of 5-(R)-acetoxy-1-hydroxyhexane (yield=95%, 91% pure by gas chromotagraphy).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.[C:36](Cl)(=O)[CH2:37]C.[NH4+].[Cl-]>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:9]([CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH2:36][CH3:37])[CH2:16]2)=[N:10][NH:11][C:12]1=[O:13]
Reactant: COc1cccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)c1
Reactant: CCC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3cccc(OC)c3)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 4 mL screwcap vial was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-3′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.226 mmol). Added to the vial was 4N HCl in dioxane (2.0 mL). The vial was capped and the solution was stirred at room temperature for 2 h. The solution was concentrated in vacuo. Into the vial were place dichloromethane (1 mL) and N,N-diisopropylethylamine (0.14 mL). The solution was cooled in an ice bath. Into a separate vial, propanoyl chloride (0.217 mmol) was taken up in dichloromethane (1 mL) and then 0.5 ml, of this solution was added to the cold reaction. The vial was capped and stirred for 1 h, allowing the ice bath to slowly warm to room temperature. Since it was determined that the reaction was not complete, additional 0.10 mL of propanoyl chloride solution in dichloromethane was added to the reaction. After 1 h, the reaction was complete. Dichloromethane (1 mL) and saturated aq NH4Cl were added to the reaction. The vial was lightly agitated and the liquid phases were allowed to separate. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (21 mg, 21%). MS(ES)+ m/e 424.9 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[NH:9][CH:10]=[N:11]2.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][NH:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH2:20][CH2:21][CH2:22][C:23]#[N:24]
Reactant: Ic1cccc(CNc2ncnc3nc[nH]c23)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCCCn1cnc2c(NCc3cccc(I)c3)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 68.3 %

Procedure:
A mixture of N6 -(3-iodobenzyl)adenine (2, 50 mg, 140 μmol), 4-bromobutyronitrile (300 mg, 2.0 mmol), and potassium carbonate (150 mg, 1.1 mmol) in DMF (2 mL) was stirred for 12 h at 80° C. Following the addition of 10 mL of half saturated sodium chloride, an oil separated. The oil was chromatographed on a preparative silica TLC plate (chloroform:methanol, 95:5, Rf 0.31) to give compound 22 (40 mg, 66%). MS (EI) m/z 418 (M+), 350, 291, 232, 187.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH:16][S@](C(C)(C)C)=O)[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C@@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[S@](=O)N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reaction time: 0.5 h

Procedure:
(S)-N-((3aS,4S,6aR)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-yl)-2-methylpropane-2-sulfinamide (855 mg, 2.67 mmol) from Step B and 2 N HCl (10 mL, 40.0 mmol) were combined in methanol (10 mL). After 30 minutes, the solvent was removed and the crude material was purified on a silica gel cartridge (Analogix®, Burlington, Wis., RS-25) loading with 10% methanol (2 N ammonia)/dichloromethane solution and eluting with 2-10% methanol (2 N ammonia)/dichloromethane to give (3aS,4S,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.44 (d, J=7.4, 2H), 7.36 (t, J=7.5, 2H), 7.28 (t, J=7.3, 1H), 3.52 (q, J=13.0, 2H), 3.29 (q, J=7.3, 1H), 2.84 (dd, J=3.7, 9.3, 1H), 2.55-2.43 (m, 3H), 2.37-2.30 (m, 1H), 2.24 (d, J=5.3, 1H), 1.74-1.64 (m, 2H), 1.62-1.53 (m, 1H), 1.34 (dd, J=5.0, 10.1, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO.O.C(O)C>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]3[CH2:13][CH2:14][NH:15][CH:16]([CH3:17])[C:11]3=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC1=NCCn2c1ccc2-c1ccc(Cl)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CC1NCCn2c(-c3ccc(Cl)cc3)ccc21
Yield: 74 %

Procedure:
6-(p-Chlorophenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (1.0 g) was dissolved in a mixture of 100 ml of methanol and 10 ml of water under argon. The solution was treated portionwise with 0.5 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 100 ml of methylene chloride and washed with 50 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 70 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.1 g of brown oil, was dissolved in a 30-fold amount of ethanol with the addition of a 5-fold amount of methylene chloride and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 1.1 g (74%) of 6-(p-chlorophenyl)-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1 ); m.pt.: 196°-198° C. (dec.)
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-])=O>C(O)C.[Ni]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[O:14][CH3:15]
Reactant: COc1ccc2ccccc2c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: COc1ccc2ccccc2c1N

Procedure:
1-nitro-2-methoxynaphthalene (1 g.) is hydrogenated in absolute ethanol (200 ml.) over Raney nickel catalyst (1 g.) at 25°C and an initial pressure of 40 psi until the theoretical amount of hydrogen is absorbed, The catalyst is removed, the filtrate concentrated to dryness under vacuum, and the residue recrystallized from methanol to yield 1-amino-2-methoxynaphthalene.
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21](O)=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:31][CH2:28][CH2:29][CH3:30])=[O:22])[C:16]2[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=2[S:14]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CN(CC1Sc2ccccc2N(CC(=O)O)C1=O)OCc1ccccc1
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of {2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-acetic acid (0.13 mmol) in anhydrous DMF, propylamine (0.13 mmol) is added followed by DIEA (0.13 mmol) and HATU (0.13 mmol). The reaction mixture is stirred overnight and the desired product 2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide is obtained and used in the next step without further purification. MS: (ES+): 428.2 [M+1].
Reaction SMILES: C[C@@H]1CN(CC2C=NC(C)=NC=2)C[C@H]1C1NC(=O)C2C=NN(C3CCOCC3)C=2N=1.Cl.[CH2:32]([C@@H:34]1[CH2:38][NH:37][CH2:36][C@H:35]1[C:39]1[NH:40][C:41](=[O:54])[C:42]2[CH:47]=[N:46][N:45]([CH:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)[C:43]=2[N:44]=1)[CH3:33].C([BH3-])#N.[Na+].[CH:59]([C:61]1[CH:62]=[C:63]([CH:66]=[CH:67][CH:68]=1)[C:64]#[N:65])=O>>[CH2:32]([C@H:34]1[C@H:35]([C:39]2[NH:40][C:41](=[O:54])[C:42]3[CH:47]=[N:46][N:45]([CH:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)[C:43]=3[N:44]=2)[CH2:36][N:37]([CH2:59][C:61]2[CH:62]=[C:63]([CH:66]=[CH:67][CH:68]=2)[C:64]#[N:65])[CH2:38]1)[CH3:33]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1
Agent: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: Cl
Agent: [BH3-]C#N
Product: CC[C@@H]1CN(Cc2cccc(C#N)c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

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 6-[(3S,4S)-4-ethylpyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one hydrogen chloride, sodium cyanoborohydride and 3-formylbenzonitrile provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.01 (s, 1H), 7.73-7.41 (m, 4H), 4.79 (m, 1H), 4.72 (s, 1H), 4.12-4.09 (m, 2H), 3.82-3.70 (m, 2H), 3.61-3.54 (m, 2H), 3.27 (t, J=8.3 Hz, 1H), 3.02-2.97 (m, 2H), 2.71-2.70 (m, 1H), 2.37-2.30 (m, 2H), 2.20-2.14 (m, 1H), 1.90-1.87 (m, 2H), 1.61-1.60 (m, 1H), 1.51-1.49 (m, 1H), 0.91 (t, J=7.5 Hz, 3H). MS: (M+H m/z 433.2).
Reaction SMILES: [Na+:1].[Na+].[CH2:3]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O-:23])=[O:22])[CH:15]=[C:16]([CH:20]=1)[C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+].[Na+].[CH2:26](NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCCC.[Na+].[Na+].CC(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCCCCCC.[Na+].[Na+].CC(C)CCCCCCCCCCCCCNC1C=C(C([O-])=O)C=C(C=1)C([O-])=O.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCCCCCCCCC.[Na+].[Na+].C(NC1C=C(C([O-])=O)C=C(C=1)C([O-])=O)CCCCCCCCCCCCCCCCCC>>[Na+:1].[Na+:1].[CH2:3]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O-:23])=[O:22])[CH:15]=[C:16]([CH:20]=1)[C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCNc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Reactant: CCCCCCCCNc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Agent: CC(C)CCCCCCCCCCCCCNc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Agent: CCCCCCCCCCC(C)Nc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Agent: CCCCCCCCCCCCCCCCCCCNc1cc(C(=O)[O-])cc(C(=O)[O-])c1
Product: CCCCCCCCCCCCCCCCNc1cc(C(=O)[O-])cc(C(=O)[O-])c1

Procedure:
Similarly, the alkylaminoisophthalic acids in Example 9 provide: 5-octylaminoisophthalic acid disodium salt, 5-nonylaminoisophthalic acid disodium salt, 5-decylaminoisophthalic acid disodium salt, 5-undecylaminoisophthalic acid disodium salt, 5-dodecylaminoisophthalic acid disodium salt, 5-(1-methylundecylamino)isophthalic acid disodium salt, 5-tridecylaminoisophthalic acid disodium salt, 5-tetradecylaminoisophthalic acid disodium salt, 5-pentadecylaminoisophthalic acid disodium salt, 5-(14-methylpentadecyl)aminoisophthalic acid disodium salt, 5-heptadecylaminoisophthalic acid disodium salt, 5-octadecylaminoisophthalic acid disodium salt, and 5-nonadecylaminoisophthalic acid disodium salt,.