Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:11]=3[C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2ccc(O)cc12
Temperature: 60 °C

Procedure:
To a mixture of 2-(4-fluorophenyl)-5-hydroxybenzofuran-3-carboxylate (1 g, 3.5 mmol, 1 eq) in a 1:1 mixture of MeOH/THF at ambient temperature was added 5 eq. of NaOH and heated to 60° C. for 3 h. The mixture was cooled to ambient temperature and to 0° C. in an ice-water bath, it was acidified slowly with 1.5 N HCl and then concentrated. The mixture with white precipitates was diluted with water and filtered to get the solid. It is further washed with water and dried in vacuum. Yield: 0.9 g (94.6%). 1H NMR (400 MHz, DMSO-d6): δ 6.82-6.85 (m, 1H), 7.35-7.40 (m, 3H), 7.46-7.49 (d, 1H, J=8.84 Hz), 8.02-8.05 (m, 2H), 9.4 (s, 1H), 13.05 (s, 1H). LCMS: (ES−) m/z=271.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4](Cl)[N:3]=1.CS(C)=O.O.[NH2:16][NH2:17]>O>[Cl:1][C:2]1[N:3]=[C:4]([NH:16][NH2:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: NN
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(Cl)nc(NN)c1

Procedure:
A solution of 30.6 g of 2,6-dichloropyridine-4-carbonitrile and 100 ml of dimethylsulfoxide was cooled to 0° C. in an ice bath and 26 g of hydrazine hydrate was added dropwise at a rate such that the temperature remained below 30° C. A heavy yellow precipitate formed and, after 2 hours, the reaction mixture was poured into 200 ml of water. The yellow solid was collected by filtration and dried to give 6-chloro-2-hydrazinopyridine-4-carbonitrile melting at about 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:6]([CH3:16])[N:5]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:20])[N:3]=1.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:16][C:6]1[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[C:2]([CH3:1])[N:3]=[C:4]([O:17][CH2:18][C:19]([N:21]([CH3:28])[CH:22]2[CH2:23][CH2:24][N:25]([C:35]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:36])[CH2:26][CH2:27]2)=[O:20])[N:5]=1
Reactant: Cc1nc(OCC(=O)N(C)C2CCNCC2)nc(C)c1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)N1CCCCC1
Product: Cc1nc(OCC(=O)N(C)C2CCN(C(=O)N3CCCCC3)CC2)nc(C)c1NC(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from Compound 31 and 1-piperidinecarbonyl chloride in the same manner as in Example 32.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:26]([OH:31])(=[O:30])[C@H:27]([CH3:29])[OH:28]>C1COCC1.ClCCl>[O:28]([C@@H:27]([CH3:29])[C:26]([OH:31])=[O:30])[Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[C@H](O)C(=O)O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
A solution of t-butylchlorodiphenylsilane, TBDPSCl, (7.9 g, 28.9 mmoL) in THF (20 mL) was slowly added via canula into a solution of triethylamine (7.4 mL, 53.1 mmol), DMAP(catalytic amount) and L-(+)-lactic acid 9 (2.0954 g, 26.16 mmol) in THF (20 mL) and dichloromethane (20 mL) at room temperature. The resulting mixture, a white suspension, was stirred at room temperature for 2 days. The reaction mixture was washed sequentially with water, 3N HCl and water, dried over Na2SO4, filtered and solvent was removed under vacuum. The product was purified by column chromatography on silica using EtOAc/hexane=1/3 and 1/1 as eluent to obtain 4.965 g (58%) of 10.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][CH:37]=[CH2:38])[CH2:31][CH2:30]1.C(N(CC)CC)C.[OH:46][N:47]=[C:48](Cl)[CH3:49]>C(Cl)Cl>[CH3:49][C:48]1[CH2:38][CH:37]([CH2:36][O:35][C@H:32]2[CH2:31][CH2:30][C@H:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[O:46][N:47]=1
Reactant: CC(Cl)=NO
Reactant: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC3CC(C)=NO3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution (40 mL) of 4′-({5-oxo-4-[4-(prop-2-en-1-yloxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (2.7 g) and triethylamine (7.5 mL) in methylene chloride was added N-hydroxyethanimidoyl chloride (5 g) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 28%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:26][CH2:25][C:24]2[C:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=3[S:29][C:23]=2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:54]=[C:48]3[CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][N:47]3[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1.CC(O[Na])=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.O.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:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[C:22](=[O:34])[C:23]3[S:29][C:28]4[CH2:30][CH2:31][CH2:32][CH2:33][C:27]=4[C:24]=3[CH2:25][CH2:26]2)=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:54]=[C:48]3[CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][N:47]3[N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CN1CCn2nc(Nc3cc(Br)cn(C)c3=O)cc2C1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)O[Na]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C)C4)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 68 %

Procedure:
A 25 mL sealed tube was charged with (2-{6-oxo-8-thia-5-azatricyclo[7.4.0.02,7]-trideca-1(9),2(7)-dien-5-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methyl acetate 111a (571 mg, 1.2 mmol), 5-bromo-1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)pyridin-2(1H)-one 146a (400 mg, 1.2 mmol), CH3COONa (195 mg, 2.4 mmol), K3PO4 (631 mg, 2.4 mmol), PdCl2(dppf) (97 mg, 0.12 mmol) suspended in CH3CN (25 mL) and H2O (1 mL). The mixture was heated at 110° C. for 2 hours. It was then evaporated and the residue was purified by column chromatography eluting with 20:1 methylene chloride/methanol to give 259a as a brown solid (500 mg, 69%). MS: (M+H)+ 613.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH2:14])=[CH:11][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+]>C1COCC1>[C:1]([C:4]1[C:5](=[O:31])[N:6]([CH3:30])[C:7]2[C:12]([C:13]=1[NH:14][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[CH:11][C:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=[C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[Cl:29])[N:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1c(NCc2ccccc2)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of the product from Example 2 (50 mg), potassium carbonate (14 mg) and benzyl bromide (12 μL) in THF (2 mL) was stirred overnight. No progress of the reaction was observed. The reaction mixture was cooled to 0° C., followed by addition of sodium hydride (60% in mineral oil) (4 mg). The reaction was stirred for 10 min and benzyl bromide (12 μL) was added. The suspension was allowed to come to room temperature and stirred overnight. The reaction was quenched with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification on a preparative silica TLC plate eluted with 45% ethyl acetate in hexane afforded the title compound. HPLC/MS: 561.9 (M+1), 563.9 (M+3); Rt=5.09 min.
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][C@@H:18]([C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[Li+].[OH-]>>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)[S:24][C:20]=1[C@H:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=1)[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1[C@@H](C)Oc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 2 c], (R)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with LiOH to obtain (R)-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid as light brown solid. According to chiral HPLC (Chiralpak-ADH), the enantiomeric excess amounts to 89%. MS: 459.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:11]=2[NH2:23])=[C:5]([CH3:24])[CH:4]=1.[C:25](OCC)(=[O:29])[C:26]([CH3:28])=O>C(O)C>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:11]3[N:23]=[C:26]([CH3:28])[C:25](=[O:29])[N:16]([C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:12]=3[N:13]=[CH:14][N:15]=2)=[C:5]([CH3:24])[CH:4]=1
Reactant: CC[C@H](COC)Nc1ncnc(-c2cc(C)c(OC)cc2C)c1N
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(-c3cc(C)c(OC)cc3C)ncnc21
Reaction time: 18 h

Procedure:
(R)-6-(4-Methoxy-2,5-dimethyl-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine (0.22 g, 0.68 mmol) was diluted in ethanol (7 ml) and ethyl pyruvate was added (0.76 ml, 6.8 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. After concentrating the solution the product was purified by reverse phase HPLC to yield 8.0 mg of (R)-4-(4-methoxy-2,5-dimethyl-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one (Example 1013a). 1H NMR (300 MHz, CDCl3) δ ppm 9.05 (s, 1 H), 7.21 (s, 1 H), 6.79 (s, 1 H), 4.86 (m, 1 H), 3.91 (s, 3 H), 2.55 (m, 3 H), 2.38 (m, 1 H), 2.22 (s, 3 H),), 2.22 (s, 3 H), 2.04 (m, 1 H), 1.25 (m, 1 H), 0.89 (t, J=7.51 Hz, 3 H), 0.77 (m, 1 H), 0.50 (m, 1 H), 0.39 (m, 1 H), 0.18 (m, 1 H). MS (EI) 379.3 [(M+H)+, 100].
Reaction SMILES: [F-:1].[K+].[F:3][CH:4]([F:25])[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7](Cl)[C:6]=1[C:21]([O:23][CH3:24])=[O:22].O>CC#N.C1OCCOCCOCCOCCOCCOC1>[F:3][CH:4]([F:25])[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([F:1])[C:6]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1F
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
The reagent was prepared by dissolving 0.37 g (0.001 mol) of 18-crown-6 in 30 ml of dry CH3CN (distilled over CaH2) and then adding 3.25 g (0.056 mol) of dry KF (dried in an oven at 50° C./67 Pa). After the heterogeneous system was mechanically stirred for 30 minutes, 10 g (0.028 mol) of product of Example 103 was added and the resulting mixture was refluxed for 6 days. The reaction mixture was poured into H2O, extracted with diethyl ether (2×), dried (MgSO4) and solvent removed in vacuo affording 9.45 g of a brown oil. The crude product was purified by HPLC using 1% ethyl acetate/cyclohexane as eluting solvent affording 6.72 g (70%) of product as a white solid; mp 40°-41° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21].Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([O:9][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)C(C)Br
Reactant: Oc1noc2cc(Cl)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1noc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-chloro-1,2-benzisoxazol-3-ol (6.8 g, 40.1 mmol), potassium carbonate (8.3 g, 60 mmol) and methyl 2-bromopropionate (10.0 g, 60.1 mmol) in N,N-dimethylformamide is stirred at room temperature overnight and diluted with water. The resultant aqueous mixture is acidified with concentrated hydrochloric acid (pH5-pH6) and extracted with methylene chloride. The combined organic extracts are diluted with hexanes, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and ethyl acetate/hexanes solutions gives the title product as a gold oil which is identified by NMR spectral analyses.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.O1C[CH2:27][CH2:26][CH2:25]1.CN1CCCC1=O.C([Mg]Cl)(C)C>C(OCC)(=O)C.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH:26]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1)([CH3:27])[CH3:25]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(C(C)C)nncc3c2)c1
Reaction time: 0.17 h

Procedure:
A 50-mL round-bottom flask under argon was charged with ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (106 mg, 0.32 mmol), iron(III) acetylacetonate (5.7 mg, 0.032 mmol), tetrahydrofuran (2.2 mL), and 1-methyl-2-pyrrolidinone (0.22 mL). Isopropylmagnesium chloride (0.24 mL, 0.49 mmol) was added via a syringe to the resulting red solution, causing an immediate color change to brown, and then finally to dark brown. The resulting mixture was stirred for 10 min, and the reaction was diluted with ethyl acetate and carefully quenched with 10% HCl solution. The mixture was washed with saturated aqueous NaHCO3 solution and the organic layer was dried (MgSO4) and concentrated in vacuo. CombiFlash purification (20% to 50% ethyl acetate in hexanes) afforded the title compound as a cream amorphous solid. MS (ES+): 335.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CS(O[CH2:9][CH2:10][CH2:11][CH:12]([NH:20]C(OC(C)(C)C)=O)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=O)=O>C1COCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH2:20])[CH2:11][CH2:10][CH2:9][N:2]([CH3:3])[CH3:1])=[CH:18][CH:17]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)NC(CCCOS(C)(=O)=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Product: CN(C)CCCC(N)c1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Dimethylamine (84 mg, 1.85 mmol) and 4-(tert-butoxycarbonylamino)-4-(4-chlorophenyl)butyl methanesulfonate (Intermediate 56) (700 mg, 1.85 mmol) were dissolved in THF (10 mL) and sealed into a microwave tube. The reaction was heated to 120° C. for 40 minutes in the microwave reactor and cooled to room temperature. The reaction mixture was concentrated and then dissolved in DCM (10.00 mL) and TFA (2 mL). The reaction was stirred at 20° C. for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness to afford 1-(4-chlorophenyl)-N4,N4-dimethylbutane-1,4-diamine (366 mg, 87%) as a yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([C:17]3[N:21](C4CCCCO4)[CH:20]=[N:19][CH:18]=3)[CH:15]=2)[N:10](C2CCCCO2)[N:9]=1.O1CCOCC1.Cl>CC#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([C:17]3[NH:21][CH:20]=[N:19][CH:18]=3)[CH:15]=2)[NH:10][N:9]=1
Reactant: Fc1ccccc1-c1nn(C2CCCCO2)c2cnc(-c3cncn3C3CCCCO3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Fc1ccccc1-c1n[nH]c2cnc(-c3cnc[nH]3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
In a 50 mL round bottom flask was added 3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazol-5-yl)-1H-pyrazolo[3,4-c]pyridine (150 mg, 0.33 mmol) and 4 N HCl— dioxane (5 mL). The mixture was stirred at 25° C. for 2 h. The solvent was distilled off. The crude product was purified via reverse phase HPLC eluting with 35% CH3CN in aqueous 10 mmol NH4HCO3 solution to afford 218 as a white solid (20 mg, 21%). 1H NMR (500 MHz, DMSO) δ 13.93 (s, 1H), 12.21 (s, 1H), 9.05 (s, 1H), 8.20 (s, 1H), 7.86 (t, J=7.0, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.56-7.54 (m, 1H), 7.46 (t, J=10.0, 1H), 7.41 (t, J=7.5, 1H). ESI MS m/z=280 (M+1)
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[N:5][N:6]([CH3:13])[C:7]=1[N:8]=[CH:9]OCC)#[N:2].[NH3:22]>C(O)C>[NH2:22][C:1]1[N:2]=[CH:9][N:8]=[C:7]2[N:6]([CH3:13])[N:5]=[C:4]([C:14]3[O:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)[C:3]=12
Reactant: CCOC=Nc1c(C#N)c(-c2ccc([N+](=O)[O-])o2)nn1C
Reactant: N
Solvent: CCO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(N)ncnc21

Procedure:
A mixture of 20.0 grams of 4-cyano-5-ethoxymethyleneamino-1-methyl-3-(5-nitro-2-furyl)-pyrazole, 200 milliliters of ethanol and 100 millilitres of concentrated aqueous ammonia solution (S.G., 0.88) was heated at reflux for one hour and cooled. The crystalline solid precipitated was collected, washed with water and dried. Recrystallisation from dimethylformamide gave 4-amino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having decomposition point 305° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[N:12]=1)[C:5]([N:7](C)[CH3:8])=O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+].C([O-])(O)=O.[Na+]>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:31]=[N:30][N:29]=2)[CH:10]=[C:11]([CH3:13])[N:12]=1
Reactant: Cc1cc(C(=O)N(C)C)cc(Cl)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc(-c2nnnn2C)cc(Cl)n1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
To a solution of 2-Chloro-6,N,N-trimethyl-isonicotinamide (2.3 g) in acetonitrile (30 ml) at −15° C. was added DCM (20 ml) pre-cooled triflic anhydride (3 mL) dropwise. This was stirred for 10 min at −10° C. and then sodium azide (4.6 g) was added. This was allowed to warm to room temperature and after 2 h, the reaction was neutralised with a cold 5% NaHCO3(aq) solution and extracted with EtOAc. The organic layer was separated, dried and concentrated in vacuum. Flash chromatography (100:0 to 40:60 gradient cyclohexane:EtOAc) afforded the title compound (260 mg). Rt=1.21 min (method D).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:20]/[C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/CCCCc1ccccc1
Reaction time: 2.5 h
Yield: 77.6 %

Procedure:
A stirred solution of 5-phenylpentanal (9.96 g, Reference Example 6) in anhydrous tetrahydrofuran (100 ml) at room temperature was treated with (tert-butoxycarbonylmethylene)triphenylphosphorane (27.5 g). The resulting orange solution was stirred for 2.5 hours then evaporated. The residual crude product was subjected to flash chromatography on silica eluting with a mixture of hexane and ethyl acetate (19:1, v/v) to afford the title compound (12.4 g) as a colourless oil. NMR (CDCl3): δ1.45 (s,9H), 1.65 (m,4H), 2.18 (q,2H), 2.61 (t,2H), 5.70 (d,1H), 6.82 (dt,1H), 7.10-7.30 (m,5H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2].Br[CH2:26][CH2:27][CH2:28][S:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH:12]1[CH2:13][CH2:14][N:15]([CH2:26][CH2:27][CH2:28][S:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH2:16][CH2:17]1)=[CH:9][CH:8]=[C:7]([F:18])[CH:6]=2)[CH3:2]
Reactant: CCc1c(C2CCNCC2)c2ccc(F)cc2n1-c1ccccc1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C2CCN(CCCSc3ccc(F)cc3)CC2)c2ccc(F)cc2n1-c1ccccc1
Temperature: 80 °C
Yield: 57.7 %

Procedure:
A mixture of 2-ethyl-6-fluoro-1-phenyl-3-piperidin-4-yl-1H-indole (70 mg, TFA salt), 1-(3-Bromo-propylsulfanyl)-4-fluoro-benzene (44 mg), potassium iodide (5 mg) and potassium carbonate (55 mg) in DMF (3 ml) is heated at 80° C. for 3 h, and allowed to cool to r.t. overnight. Ethyl acetate (50 ml) and water (25 ml) are added and the organic phase is washed with water, dried and concentrated in vacuo. The crude product is purified by flash chromatography (98:2 CH2Cl2:MeOH) to give 50 mg pure product (64%) as brown solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[C:7]2[CH:32]=[CH:31][CH:30]=[CH:29][C:8]=2[S:9][C:10]=1[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=1)[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])(=[O:5])[CH3:4]>C(O)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:11]([C:10]2[S:9][C:8]3[CH:29]=[CH:30][CH:31]=[CH:32][C:7]=3[C:6]=2[CH:3]([OH:5])[CH3:4])[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:19][C:20]=1[C:25]([F:28])([F:26])[F:27]
Reactant: CCS(=O)(=O)N(Cc1ccc(F)c(C(F)(F)F)c1)c1sc2ccccc2c1C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCS(=O)(=O)N(Cc1ccc(F)c(C(F)(F)F)c1)c1sc2ccccc2c1C(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium borohydride (0.14 g, 3.7 mmol) was added to a solution of N-(3-acetyl-benzo[b]thiophen-2-yl)-N-(4-fluoro-3-trifluoromethyl-benzyl)-ethanesulfonamide (0.268 g, 0.582 mmol) in ethanol (10 mL), and the resulting mixture was stirred at room temperature for 3 h. The solvent was evaporated, the residue partitioned between dichloromethane and water, the organic layer separated, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo to yield a residue. The residue was purified by flash column chromatography (SiO2), eluting with an ethyl acetate-heptane (10-40%) gradient to yield N-(4-fluoro-3-trifluoromethyl-benzyl)-N-[3-(1-hydroxy-ethyl)-benzo[b]thiophen-2-yl]-ethanesulfonamide as a colorless solid.