Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[S:21]>>[Br:2][C:3]1[C:8]([CH2:9][NH:10][C:20]([NH:19][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])=[S:21])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: NCc1cccnc1Br
Agent: Cl
Product: S=C(NCc1cccnc1Br)Nc1cccc(Cl)c1Cl
Yield: 55 %

Procedure:
Prepared in 55% yield by treatment of the product of Example 142A with 2,3-dichlorophenylisothiocyanate according to the procedure described for Example 141B. MS (ESI−) m/z 389.9 (M+H)+; 1H NMR (DMSO-d6) δ 4.71 (d, J=4.4 Hz, 2H), 7.37 (dd, J=8.0, 8.0 Hz, 1H), 7.48 (dd, J=7.5, 4.7 Hz, 1H), 7.55 (dd, J=8.1, 1.7 Hz, 1H), 7.58-7.63 (m, 1H), 7.69 (dd, J=7.6, 1.9 Hz, 1H), 8.29 (dd, J=4.7, 2.0 Hz, 1H), 8.44 (br s, 1H), 9.70 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[CH3:15].[N:16]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[NH2:16])=[CH:5][C:4]=1[CH3:15]
Reactant: O=N[O-]
Reactant: COC(=O)CNc1ccc(OC)c(C)c1
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1ccc(OC)c(C)c1
Reaction time: 1 h
Yield: 7.5 %

Procedure:
N-(4-methoxy-3-methylphenyl)glycine, methyl ester (Intermediate 96, 5 g, 0.0239 mol) was dissolved in a mixture of glacial acetic acid (45 ml) and water (3 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (1.7 g, 0.0251 mol) in water (5 ml) over 30 minutes and the reaction was stirred for one hour. Zinc dust (6 g, 0.093 mol) was added over 11/2 hours at the same low temperature and stirred at room temperature for 1 hour. The reaction was poured into water (150 ml) and extracted with ethyl acetate (2×100 ml). The organic extract was washed with 8% sodium bicarbonate solution until effervescence had ceased, then dried (MgSO4) and evaporated to give a yellow oil. This was purified by flash column chromatography on silica (Merck 9385; 100 g) eluting with ether-hexane 1:1 to give the title compound as an orange oil (0.4 g, 7%).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+:21]=[N-:22])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.[CH2:26]([O:28][C:29]#[CH:30])[CH3:27].N1C(C)=CC=CC=1C.O>C(#N)C.[Cu](I)I>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[N:22]=[N:21]4)[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reactant: C#COCC
Agent: I[Cu]I
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOc1cn(C[C@H]2CN(c3ccc(C4=CCS(=O)(=O)CC4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.3 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl)oxazolidin-2-one (Reference Example 2) (733 mg, 2.0 mmol) was dissolved in dry acetonitrile (8 ml). Ethoxyacetylene (420 mg, 6.0 mmol), 2,6-lutidine (236 mg, 2.2 mmol) and copper iodide (38 mg, 10 mmol %) were added and the resulting mixture was stirred at room temperature for 12 hours. Water was added and the mixture was extracted with dichloromethane (3×100 ml). The combined organic layers were concentrated under vacuum and the residue was purified by flash chromatography on silica gel with 5% of methanol in dichloromethane to give the title product (666 mg).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])C(OCC)=O)[CH3:3].O>C(O)C>[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
To a stirred solution of concentrated HCl (18.00 mL) diluted to 72.00 mL with 95% Ethanol was added 2-(4-bromo-2-nitro-phenyl)-malonic acid diethyl ester (2.50 g, 6.94 mmol). The resulting mixture was then heated at reflux under N2 for 4 h. The reaction mixture was allowed to cool to ambient temperature and poured into H2O (250 mL). This aqueous mixture was then extracted with 2×150 mL of Diethyl ether. The Et2O layer was extracted with H2O and 5% NaHCO3 washed with brine, dried (MgSO4), and filtered. Evaporation of the filtrate in vacuo gave the intermediate title compound as a yellow liquid (1.52 g, 76%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[C:9]2[C:8](=[O:18])[N:7]([CH3:19])[CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>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.O>[CH3:19][N:7]1[C:8](=[O:18])[C:9]2[C:10]([NH:12][C@@H:13]3[CH2:17][CH2:16][O:15][CH2:14]3)=[N:11][C:2]([C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[CH:32][CH:31]=3)=[CH:3][C:4]=2[N:5]=[CH:6]1
Reactant: Cn1cnc2cc(Cl)nc(N[C@@H]3CCOC3)c2c1=O
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc(-c3cc4ncn(C)c(=O)c4c(N[C@@H]4CCOC4)n3)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-7-chloro-3-methyl-5-(tetrahydrofuran-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one (16 mg, 0.057 mmol), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (19 mg, 0.063 mmol), Pd(PPh3)4 (6.6 mg, 0.0057 mmol), K2CO3 (24 mg, 0.17 mmol), 2-propanol (3 mL) and H2O (1 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature and worked-up. The residue was purified using slilica gel flash column chromatography (eluent: 0-10% methanol in dichloromethane) to afford (R)-3-methyl-7-(4-(4-methylpiperazin-1-yl)phenyl)-5-(tetrahydrofuran-3-ylamino) pyrido[4,3-d]pyrimidin-4(3H)-one as a slightly yellow solid. HPLC-MS calculated C23H28N6O2(M+H+): 421.24, found: 421.20.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].S(Cl)([Cl:18])=O>N1C=CC=CC=1.C(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:4]=1[O:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)COc1cc(C)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COc1cc(C)ccc1CCl
Yield: 55.4 %

Procedure:
By the method of Example 1, Step H, 9.21 g (0.044 mole) of methyl (2-hydroxymethyl-5-methylphenoxy)acetate was reacted with 7.40 g (0.062 mole) of thionyl chloride and 5 drops of pyridine in 50 mL of methylene chloride, yielding 5.57 g of methyl (2-chloromethyl-5-methylphenoxy)acetate as an orange liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:10])[CH2:8][CH3:9])=[CH:3][CH:2]=1.N1C=CC=C(C(O)CC)C=1>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([OH:10])[CH2:8][CH3:9])=[CH:3][CH:2]=1
Reactant: CCC(=O)c1ccncc1
Agent: CCC(O)c1cccnc1
Product: CCC(O)c1ccncc1

Procedure:
The title compound was prepared from 1-(pyridin-4-yl) propan-1-one (purchased from Waterstone Technology) following a procedure similar to the one described for the synthesis of 1-(pyridin-3-yl) propan-1-ol (Example 233, Step A). Mass Spectrum (ESI) m/z=138.0 (M+1).
Reaction SMILES: O(C1C=CC(NC(=O)N[C@@H](CC2C=CC=CC=2)/C=C/C(O)=O)=CC=1)C1C=CC=CC=1.[N:31]1([CH2:36][CH2:37][NH:38][C:39](=[O:68])/[CH:40]=[CH:41]/[C@@H:42]([NH:50][C:51]([NH:53][C:54]2[CH:59]=[CH:58][C:57]([O:60][C:61]3[CH:66]=[CH:65][C:64](F)=[CH:63][CH:62]=3)=[CH:56][CH:55]=2)=[O:52])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)CCC[CH2:32]1.Cl.O(C1C=CC(N=C=O)=CC=1)C1C=CC=CC=1>C(Cl)Cl.O1CCOCC1.C1COCC1>[CH3:32][NH:31][CH2:36][CH2:37][NH:38][C:39](=[O:68])/[CH:40]=[CH:41]/[C@@H:42]([NH:50][C:51]([NH:53][C:54]1[CH:59]=[CH:58][C:57]([O:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[CH:56][CH:55]=1)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(F)cc2)cc1)NCCN1CCCC1
Agent: Cl
Agent: O=C(O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccccc2)cc1
Agent: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNCCNC(=O)/C=C/[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
(E)-(S)-4-[3-(4-Phenoxy-phenyl)-ureido]-5-phenyl-pent-2-enoic acid. To a solution of (E)-(S)-4-tert-butoxycarbonylamino-5-phenyl-pent-2-enoic acid (Example 11, step A) (2.12 g, 7.26 mmol) in CH2Cl2 (73 mL) was added 4 M HCl in 1,4-dioxane (25 mL), and the resulting solution was stirred at rt for 15 min. The solvent was removed. To a solution of the resulting residue and TEA (0.74 g, 7.26 mmol) in THF (73 mL) cooled to 0° C., was added 4-phenoxy phenyl isocyanate (1.53 g, 7.26 mmol), and the mixture was stirred for 30 min. The solution was brought to rt and was stirred for an additional 3 h. The solvent was removed, and the resulting yellow oil was purified by column chromatography on silica gel using a gradient of 0–35% (MeOH (10% acetic acid)/CH2Cl2). The purified product was recrystallized from CH2Cl2 and was washed with hexanes to afford 1.45 g (50%) of the desired product as a grey solid. Rf=0.47 (5% MeOH (1% NH4OH)/CH2Cl2). MS (electrospray): mass calculated for C24H22N2O4, 402.16; m/z found, 403.1 [M+H]+, 425.1 [M+Na]+, 827.3 [2M+Na]+. 1H NMR (400 MHz, DMSO-d6): 12.34 (br s, 1H), 8.51 (s, 1H), 7.40–7.20 (m, 9H), 7.08–7.05 (m, 1H), 6.93–6.91 (m, 4H), 6.86 (d, J=5.0 Hz, 1H), 6.35 (d, J=8.5 Hz, 1H), 5.77 (dd, J=15.6, 1.6 Hz, 1H), 4.70–4.61 (m, 1H), 2.93 (dd, J=13.7, 6.1 Hz, 1H), 2.84 (dd, J=13.7, 7.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][CH3:12])[C:5]2[C:13](I)=[N:14][N:15]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:14]=[C:13]3[C:5]2=[C:6]([CH2:8][CH2:9][N:10]3[CH2:11][CH3:12])[N:7]=1
Reactant: CCNCCc1nc(Cl)cc2c1c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN1CCc2nc(Cl)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 55 °C

Procedure:
2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N-ethylethanamine (160 mg, 0.270 mmol) and RuPhos pre-catalyst (19.6 mg, 0.027 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in toluene (1.8 mL) before a solution of 2M NaOtBu in THF (0.34 ml, 0.675 mmol) was added. The reaction mixture was heated at 55° C. for 1 hour before it was diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-50% EtOAc-hexanes) gave 7-chloro-3-ethyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C29H25ClN4 [M+H]+ 465. found 465.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[O:22][CH2:21][CH2:20][O:19]3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(OC(=O)C)C.[Pd]>[O:19]1[CH2:20][CH2:21][O:22][CH:18]1[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:4]2[CH:5]=[CH:6][C:7]([NH2:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:13][CH:14]=1
Reactant: Cc1cc(Oc2ccc(C3OCCO3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(Oc2ccc(C3OCCO3)cc2)ccc1N
Reaction time: 48 h
Yield: 72.9 %

Procedure:
A 500 mL round bottom flask containing 2-{4-[(3-methyl-4-nitrophenyl)oxy]phenyl}-1,3-dioxolane (1.89 g, 6.27 mmol) in 60 mL ethylacetate was purged with nitrogen gas and treated with 10% palladium on carbon (650 mg, 0.63 mmol). A balloon with H2 gas was attached and gas was allowed to bubble through the solution while allowing gas to escape the flask via needle. The needle was removed, and the reaction stirred under H2 atmosphere for 2 days. The reaction was filtered through Celite, concentrated and purified via silica gel column chromatography (0% to 100% ethylacetate/hexane gradient) to provide 1.24 g 4-{[4-(1,3-dioxolan-2-yl)phenyl]oxy}-2-methylaniline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]1([C:15]([OH:17])=O)[CH2:11][C@H:10]1[CH:12]([F:14])[F:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([C:25]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH2:27][CH2:26]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].C1CCN2C(=NCCC2)CC1>O1CCCC1.CCOC(C)=O>[F:14][CH:12]([F:13])[C@@H:10]1[CH2:11][C@:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:15](=[O:17])[NH:31][S:28]([C:25]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH2:27][CH2:26]1)(=[O:29])=[O:30]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)O)C[C@H]1C(F)F
Reactant: C=CCCCCCC1(S(N)(=O)=O)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCCCCCC1(S(=O)(=O)NC(=O)[C@@]2(NC(=O)OC(C)(C)C)C[C@H]2C(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
To a solution of (1R,2R)-1-(tert-butoxycarbonylamino)-2-(difluoromethyl)cyclopropanecarboxylic acid (100 mg, 0.398 mmol) in Tetrahydrofuran (4 mL) was added CDT (84 mg, 0.517 mmol) and the formed solution was stirred at r.t. for 3 h. 1-(hept-6-enyl)cyclopropane-1-sulfonamide (104 mg, 0.478 mmol) and DBU (0.120 mL, 0.796 mmol) were added and the reaction continued at r.t. overnight. The reaction was diluted with EtOAc. Washed with 5% citric acid, brine, dried over MgSO4, filtered and concentrated. The residue was purified by Biotage column, eluted with gradient 5%˜70% EtOAc-Hexane to afford the desire produce tert-butyl (1R,2R)-2-(difluoromethyl)-1-(1-(hept-6-enyl)cyclopropylsulfonylcarbamoyl)cyclopropylcarbamate (45 mg, 0.100 mmol, 25.09% yield). 1H NMR (400 MHz, CHLOROFORM-D) ppm 0.95 (s, 2 H) 1.28-1.36 (m, 2 H) 1.36-1.47 (m, 6 H) 1.52 (s, 9 H) 1.58-1.67 (m, 2 H) 1.72 (d, J=10.54 Hz, 1 H) 1.78-1.95 (m, 2 H) 1.97-2.12 (m, 3 H) 4.88-5.05 (m, 2 H) 5.23 (b, NH) 5.65-5.92 (m, 2 H) 9.20 (b, NH).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([CH2:15][C:16]#[C:17][C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]3=[N:22][CH:23]=2)[CH2:9]1)=O)(C)(C)C.C(N(C(C)C)C(C)C)C.[CH2:44]([S:46](Cl)(=[O:48])=[O:47])[CH3:45]>C(Cl)Cl.O1CCOCC1>[CH2:44]([S:46]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH:10]([CH2:15][C:16]#[C:17][C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:32])[CH3:33])[C:21]3=[N:22][CH:23]=2)[CH2:9]1)(=[O:48])=[O:47])[CH3:45]
Reactant: CCS(=O)(=O)Cl
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1CC#Cc1cnc2c(ccn2COCC[Si](C)(C)C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(C)C(CC#Cc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
To a flask containing a solution of (+/−)-4-methyl-3-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid tert-butyl ester (505 mg, 1.04 mmol) in methylene chloride (4 mL) was added a 25% solution of anhydrous HC1 in dioxane (3 mL). The mixture was lightly capped and stirred for 45 minutes. The solvent was stripped on the rotovap and the remainder was taken up in methylene chloride (15 mL) and stripped. This was repeated one more time to provide a yellow foamy solid. The crude material was taken up in dry methylene chloride and cooled to 0° C. (ice bath) under argon atmosphere. Ethyl diisopropyl amine was added and the material was stirred for 5 minutes. Ethane sulfonyl chloride (0.1 mL, 1.1 mmol) was slowly added via syringe and the material was stirred for 10 minutes. The cooling bath was removed and stirring continued for 1.5 hours. The crude mixture was taken up in water (40 mL) and methylene chloride (40 mL) and shaken in a reparatory funnel. The organic phase was collected and the aqueous phases were back extracted with methylene chloride (2×30 ml), the organics combined, dried (MgSO4), filtered and stripped. The remainder was purified by preparative TLC eluting with 50% ethyl acetate in hexanes. The product band was collected providing 395 mg of (+/−)-2-[3-(1-ethanesulfonyl-4-methyl-piperidin-3-yl)-prop-1-ynyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine as a viscous yellow oil. MS (M+H)+=477.
Reaction SMILES: C1(P(C2C=CC=CC=2)([CH:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)C=CC=CC=1.[OH-].[Na+].O>C1COCC1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([CH2:9][N:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:11]2=[O:20])=[CH:16][CH:15]=1
Reactant: COc1ccc(CN2C(=O)c3cc(OC)ccc3C2P(=O)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2Cc3ccc(OC)cc3C2=O)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of 3-(diphenyl-phosphinoyl)-6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (1.49 g, 3.1 mmol) in THF (40 mL) containing a solution of sodium hydroxide (2.5 M, 12.4 mL, 30.8 mmol) was heated under reflux for 14 h. The solution was then cooled to RT and water (40 mL) added. The mixture was extracted with diethyl ether and the combined organic extracts washed with water and brine. The organic layer was then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography (SiO2, Hexane:Acetone 6:4) to afford the title product (661 mg, 76%) as a light yellow solid. MS m/e=283.2 (M).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:30][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:30])[CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][B:19]1[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
A solution of ethyl 2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (104 mg, 0.27 mmol) in THF (2.7 mL) was cooled to 0° C. and treated with methyl iodide (0.084 mL, 1.35 mmol) and NaHMDS (0.41 mL, 1 M solution in THF, 0.41 mmol). After stirring for 16 h at room temperature, additional methyl iodide (0.042 mL, 0.77 mmol) was added and the mixture was warmed to 35° C. for 6 hours. The reaction was quenched with saturated NH4Cl solution (2 mL), diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, sat'd aq sodium chloride, dried over MgSO4 and concentrated. Purification by column chromatography (5-40% ethyl acetate in heptane) gave ethyl 2-(tert-butoxycarbonyl(methyl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (59 mg, 55%). Rf 0.34 (20% ethyl acetate in heptane). 1H NMR (CDCl3, 300 MHz) δ 4.72-4.68, 4.43-4.38 (m, 1H, rotamers), 4.15 (q, J=7.3 Hz, 2H), 2.81, 2.77 (s, 3H, rotamers), 1.87-1.61 (m, 2H), 1.53-1.23 (m, 28H), 0.78 (t, J=7.3 Hz, 2H). ESI MS found for C20H38B1N1O6 m/z [400.5 (M+1)].
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[CH2:4][N:5]=[C:6]([NH2:20])[NH:7][C:8]1[N:12]=[CH:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=[NH:18])[N:9]=1.[Na].[CH:24]([CH:26]([CH3:32])[C:27](OCC)=O)=[O:25]>CO>[OH:25][C:24]1[C:26]([CH3:32])=[CH:27][N:19]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:10]2[CH:11]=[N:12][C:8]([NH:7][C:6]([NH2:20])=[N:5][CH2:4][C:3]([F:2])([F:21])[F:22])=[N:9]2)[N:18]=1
Reactant: N=C(N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reactant: CCOC(=O)C(C)C=O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Cc1cnc(CCCCn2cnc(NC(N)=NCC(F)(F)F)n2)nc1O
Yield: 11.7 %

Procedure:
A solution of 5-(3-[2-(2,2,2-trifluoroethyl)guanidino]-1,2,4-triazol-1-yl)valeramidine hydrochloride (1 g.) in MeOH (14 ml.) was treated with the sodium salt of ethyl 2-formylpropionate (1.95 g.) and the suspension heated under reflux for 3.5 hours. This suspension was evaporated and the residue partitioned between water and ether. The aqueous layer was acidified with glacial HOAc to pH 3 and further extracted with ether. Neutralisation with aqueous ammonia (s.g. 0.880) and extraction with EtOAc gave a white solid which was crystallised twice from acetonitrile to give 4-hydroxy-5-methyl-2-[4-(3-[2-(2,2,2-trifluoroethyl)guanidino]-1,2,4-triazol-1-yl)butyl]pyrimidine (0.127 g.; 12%), m.p. 235°-237°.
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3]1.[I:12]I.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N>[I:12][C:5]1[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:3][NH:2][CH:6]=1
Reactant: II
Reactant: CCOC(=O)c1ccn(C)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: CCOC(=O)c1n[nH]cc1I
Temperature: 80 °C
Reaction time: 1 h
Yield: 166 %

Procedure:
To a stirred solution of ethyl 1-methyl-1H-pyrazole-3-carboxylate (5 g, 32.4 mmol) in CH3CN (200 mL) under Ar was added I2 (4.94 g, 19.46 mmol) and after 5 min CAN (10.67 g, 19.46 mmol). The reaction mixture was stirred for 1 hr at 80° C., concentrated, quenched with a 10% aq. Na2S2O3 solution, and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 25-45%) to afford the title product (9.04 g, 32.3 mmol, 100% yield) as a white solid. tR: 3.78 min (HPLC 1); tR: 0.80 min (LC-MS 2); ESI-MS: 281 [M+H]+ (LC-MS 2); Rf=0.45 (hexane/EtOAc 1:1).
Reaction SMILES: [CH2:1]([C:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2].C(=O)=O.CO.C(#N)C>>[CH2:1]([C@:3]1([C:28]#[N:29])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[N:9]=2)[C:4]1=[O:27])[CH3:2]
Reactant: CCC1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Agent: O=C=O
Solvent: CO
Solvent: CC#N
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)C1=O
Yield: 29 %

Procedure:
3-Ethyl-1-(2-((4-(morpholin-4-yl)phenyl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Example 2 was resolved by SFC (column: CHIRALCEL OJH, 20 mmID×250 mmL, manufactured by Daicel Chemical Industries, mobile phase: carbon dioxide/methanol/acetonitrile=660/170/170), and the compound having a longer retention time was recrystallized (hexane/ethyl acetate) to give the title compound (58 mg).