Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:34])=O)(C)(C)C.[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([O:51][CH3:52])=[C:40]([CH:42]=[N:43][C:44]([O:46][Si](C)(C)C)=[CH2:45])[CH:41]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])[CH2:45][C:44](=[O:46])[NH:43][CH:42]3[C:40]3[CH:41]=[C:36]([CH3:35])[CH:37]=[CH:38][C:39]=3[O:51][CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Reactant: C=C(N=Cc1cc(C)ccc1OC)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(C)ccc2OC)C12C(=O)Nc1cc(Cl)ccc12
Yield: 2.3 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 10.31 mmol) prepared in Example 1c was reacted with 1-(5-methyl-2-methoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (51 mmol) in toluene to give the title compound as a white solid (143 mg).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]1OCC[O:23]1.Cl>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:22]=[O:23]
Reactant: COCCNc1ccc(C#N)c(Oc2ccc(Br)c(C3OCCO3)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: COCCNc1ccc(C#N)c(Oc2ccc(Br)c(C=O)c2)n1
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a solution of 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-(2-methoxy-ethylamino)-nicotinonitrile (8) (1.0 g, 2.38 mmol) in THF (50 mL) was added HCl solution (1M/H2O, 20 mL). After overnight, the THF was evaporated under vacuum. The aqueous solution was extracted with EtOAc (2×50 mL). The organic layer was washed with water (3×50 mL), dried over MgSO4, filtered and evaporated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 25%-100% EtOAc/hexanes gradient, to afford the desired product 780 mg (87% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 10.34 (s, 1H), 7.80 (d, J=2.7 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 7.30 (dd, J=8.8, 2.9 Hz, 1H), 6.13 (d, J=8.2 Hz, 1H), 5.24 (br. s., 1H), 3.42 (t, J=4.9 Hz, 2H), 3.35-3.27 (m, 5H).
Reaction SMILES: [CH:1]1([N:4]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])[C:5]([C:7]2[C@@H:8]([CH2:31][OH:32])[NH:9][CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[C:47](=O)([O:53]C(C)(C)C)[O:48][C:49]([CH3:52])([CH3:51])[CH3:50]>O1CCOCC1>[CH:1]1([N:4]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])[C:5]([C:7]2[C@@H:8]([CH2:31][OH:32])[NH:9][CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1.[CH:1]1([N:4]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=2[Cl:41])[C:5]([C:7]2[C@@H:8]([CH2:31][OH:32])[N:9]([C:47]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:53])[CH2:10][CH2:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]3[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: O=C(C1=C(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)CCN[C@@H]1CO)N(Cc1cccc(Cl)c1Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)[C@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.2 %

Procedure:
Compound 6 was prepared as described in Example 10. Into a 10 mL round bottom flask was added Compound 6 (546 mg, 858 μmol) and dioxane (1.9 mL). The reaction was added sodium bicarbonate (180 mg, 2.15 mmol) and di-tert-butyl carbonate (337 mg, 1.54 mmol). The reaction was stirred overnight at room temperature. Solvent was removed under vacuum and the residue partitioned between water (10 mL) and ethyl acetate (10 mL). The organic layer was separated and the aqueous layer was extracted further with ethyl acetate (2×10 mL). The organic layers were combined and dried over sodium sulfate. The solution was filtered and solvent removed under vacuum. The residue was purified by column chromatography (0->2% MeOH/DCM) to give 19A (465 mg, 74%). ESI-MS:m/z 735.3 (M+H)+
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[S:8][CH:9]=[CH:10][C:11]=1I.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CCCC)CCCC)CCC>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH2:23]([C:22]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[C:21]=1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Ic1ccsc1-c1sccc1I
Reactant: CCCCCCCCC#CCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCc1c(CCCCCCCC)c2ccsc2c2sccc12
Temperature: 130 °C
Yield: 84.8 %

Procedure:
To a two-necked RB flask under nitrogen was added 1.39 g (3.3 mmol) of 3,3′-diiodo-2,2′-bithiophene, 222 mg (0.33 mmol) of Pd(OAc)2, 2.5 g (10 mmol) of 9-octadecyne, tributyl amine 1.85 g (10 mmol), and 10 mL of anhydrous DMF. The mixture was heated at 130° C. for 4 hours. After cooling down to room temperature, 50 mL of ether ethyl was. The organic phase was washed with water several times, dried by MgSO4, concentrated under reduced pressure. The residue was further purified by flash chromatography on silica gel (hexane as eluent) to afford the pure product as a colorless liquid (1.16 g, yield: 85%). 1H NMR (300 MHz, CDCl3) δ 7.46 (d, 2H, J=5.43 Hz), 7.37 (d, 2H, J=5.42 Hz), 3.01 (t, 4H, J=7.89 Hz), 1.68 (m, 4H), 1.51 (m, 4H), 1.30 (m, 16H), 0.89 (t, 6H, J=6.7 Hz). 13C NMR (400 MHz, CDCl3) δ 137.47, 131.58, 131.32, 123.55, 123.38, 31.87, 31.52, 30.43, 30.16, 29.48, 29.27, 22.63, 14.04. MS: m/z=414.7 [M]+ (Calcd.: 414.7).
Reaction SMILES: COCC[O:5][C:6](=[O:98])[C:7]1[CH:19]=[C:18]([NH:20][C:21]([C:23]2[C:24]([C:75]([NH:77][C:78]3[CH:79]=[C:80]([C:91]([O:93]CCOC)=[O:92])[CH:81]=[C:82]([CH:90]=3)[C:83]([O:85]CCOC)=[O:84])=[O:76])=[CH:25][C:26]([C:52]([NH:54][C:55]3[CH:56]=[C:57]([C:68]([O:70]CCOC)=[O:69])[CH:58]=[C:59]([CH:67]=3)[C:60]([O:62]CCOC)=[O:61])=[O:53])=[C:27]([C:29]([NH:31][C:32]3[CH:33]=[C:34]([C:45]([O:47]CCOC)=[O:46])[CH:35]=[C:36]([CH:44]=3)[C:37]([O:39]CCOC)=[O:38])=[O:30])[CH:28]=2)=[O:22])[CH:17]=[C:9]([C:10]([O:12]CCOC)=[O:11])[CH:8]=1.CN(C)C=O.[OH-].[Na+:105]>C(O)C>[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[Na+:105].[C:24]1([C:75]([NH:77][C:78]2[CH:79]=[C:80]([C:91]([O-:93])=[O:92])[CH:81]=[C:82]([CH:90]=2)[C:83]([O-:85])=[O:84])=[O:76])[CH:25]=[C:26]([C:52]([NH:54][C:55]2[CH:56]=[C:57]([C:68]([O-:70])=[O:69])[CH:58]=[C:59]([CH:67]=2)[C:60]([O-:62])=[O:61])=[O:53])[C:27]([C:29]([NH:31][C:32]2[CH:33]=[C:34]([C:45]([O-:47])=[O:46])[CH:35]=[C:36]([CH:44]=2)[C:37]([O-:39])=[O:38])=[O:30])=[CH:28][C:23]=1[C:21]([NH:20][C:18]1[CH:17]=[C:9]([C:10]([O-:12])=[O:11])[CH:8]=[C:7]([CH:19]=1)[C:6]([O-:98])=[O:5])=[O:22]
Reactant: COCCOC(=O)c1cc(NC(=O)c2cc(C(=O)Nc3cc(C(=O)OCCOC)cc(C(=O)OCCOC)c3)c(C(=O)Nc3cc(C(=O)OCCOC)cc(C(=O)OCCOC)c3)cc2C(=O)Nc2cc(C(=O)OCCOC)cc(C(=O)OCCOC)c2)cc(C(=O)OCCOC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C([O-])c1cc(NC(=O)c2cc(C(=O)Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)c(C(=O)Nc3cc(C(=O)[O-])cc(C(=O)[O-])c3)cc2C(=O)Nc2cc(C(=O)[O-])cc(C(=O)[O-])c2)cc(C(=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 8.23 g of the product of Example 1 and 45.0 ml of dimethylformamide is warmed until solution is achieved. The solution is cooled to room temperature and 90.0 ml of 1N sodium hydroxide is added with stirring. The solution is stirred for 20 minutes and diluted with 250 ml of ethanol. The product is collected and washed with ethanol and ether to yield a pale yellow powder. The product is purified by a series of precipitations from 28.6% aqueous ethanol, then from 33.3% aqueous ethanol, and is dried to yield 1.67 g of the product of the Example as a pale yellow powder.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>CCN(C(C)C)C(C)C>[OH:17][CH:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:12][CH2:13]1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCC(O)CC2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To the solution of 6-chloronicotinamide (5.0 g, 32 mmol) in DIPEA (50 mL), piperidin-4-ol (3.2 mg, 32 mmol) was added and the mixture was stirred at 110° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The residue was further purified by silica gel chromatography (DCM: MeOH=20:1) to afford the title compound (5.3 g, 75%) as a yellowish solid. [LCMS RtB=1.39 min, [M+H]+=222.1].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1B(O)O>>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:36]5[S:35][CH:39]=[CH:38][CH:37]=5)[CH:3]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: OB(O)c1cccs1
Reactant: Brc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Product: c1cc(-c2cccs2)cc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Yield: 42 %

Procedure:
In a similar manner as described in Example 29 from 2-(3-bromophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (200 mg, 0.39 mmol) and thiophene-2-boronic acid, N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-[3-(2-thienyl)phenyl]pyrazolo[1,5-a]pyridin-7-amine (84 mg, 42%) was obtained as a yellow foam. 1H NMR (CDCl3): δ 8.00 (d, 1H), 7.95 (s,1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.56 (d, 1H), 7.45 (t, 1H), 7.34–7.27 (m, 3H), 7.09 (m, 1H), 6.39 (d, 1H), 6.17 (m, 2H), 5.16 (m, 1H), 4.35 (m, 1H), 4.01 (m, 1H), 2.16 (m, 4H), 1.82–1.56 (m, 12H); MS m/z 521 (M+1). U16951-72
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:15]1[N:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:22])[C:18]([OH:32])=[C:17]([OH:33])[N:16]=1)[NH:11][CH2:12][CH2:13]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].FC(F)(F)C(O)=O>O1CCOCC1>[CH2:1]([O:8][CH2:9][CH:10]1[C:15]2=[N:20][C:19]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:22])=[C:18]([OH:32])[C:17](=[O:33])[N:16]2[CH2:13][CH2:12][NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc(C(COCc2ccccc2)NCCCl)nc(O)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCNC2COCc1ccccc1
Temperature: 15 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2-{2-(benzyloxy)-1-[(2-chloroethyl)amino]ethyl}-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide in dry 1,4-dioxane under nitrogen atmosphere potassium tert-butoxide (3 eq.) was added in one portion. The resulting suspension was aged at 120° C. for 2 hours. The reaction mixture was cooled to about 15° C. then acidified with trifluoroacetic acid to pH=3-4. The solvent was removed under reduced pressure and the residue, dissolved in the minimum amount of MeOH, was applied on cation-exchange resin cartridges (Varian MEGA BOND ELUTE SCX), the cartridges washed with MeOH and the crude product was eluted with 1M ammonia in methanol. The pooled eluants were concentrated to dryness under reduced pressure to get 9-[(benzyloxy)methyl]-N-(4-fluorobenzyl)-3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrazino[1,2-a]pyrimidine-2-carboxamide as a brown oil (85% yield). The crude product was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) and product was obtained after freeze drying of appropriate fractions.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2I.[Cl:25][C:26]1[CH:31]=[N:30][CH:29]=[C:28]([Sn](CCCC)(CCCC)CCCC)[N:27]=1>CN(C=O)C.C(Cl)Cl.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.[Cu]I>[Cl:25][C:26]1[N:27]=[C:28]([C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[CH:10]=3)[N:14]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:13]=2)[CH:29]=[N:30][CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(I)nn2C1CCCCO1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1cncc(Cl)n1)nn2C1CCCCO1
Temperature: 105 °C
Yield: 97.7 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 14 (1.00 g, 2.272 mmol) and 2-chloro-6-(tributylstannyl)pyrazine 1b (1.375 g, 3.41 mmol) in DMF (9 mL) followed by Pd(PPh3)4 (0.131 g, 0.114 mmol) and CuI (7.70 μL, 0.227 mmol). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 105° C. for 1 h. The resulting mixture was diluted with DCM. The organic layer was separated, washed with water, dried, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 0-15% EtOAc in Hexanes) to give 3-(6-chloropyrazin-2-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.95 g, 2.22 mmol, 98% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 427.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[C:4]([O:10][CH2:11][CH3:12])[N:3]=1.C(#N)C.[C:16](=S)=[S:17].OO>O>[Cl:1][C:2]1[N:3]=[C:4]([O:10][CH2:11][CH3:12])[N:5]2[C:16](=[S:17])[NH:9][N:8]=[C:6]2[CH:7]=1
Reactant: S=C=S
Reactant: CCOc1nc(Cl)cc(NN)n1
Agent: OO
Solvent: CC#N
Solvent: O
Product: CCOc1nc(Cl)cc2n[nH]c(=S)n12
Temperature: 0 °C

Procedure:
A mixture containing 20 g of 93 percent purity (99 mmol) 4-chloro-2-ethoxy-6-hydrazinopyrimidine in a solvent composed of 90 mL of acetonitrile and 26 mL of water was prepared under nitrogen in a 500 mL flask equipped with a condensor and an opening covered by a septum through which the syringe of a syringe pump was inserted. To this was added 11.3 g (148 mmol) of carbon disulfide and, after a 15-min reaction period, 16.7 g of 30 percent aqueous hydrogen peroxide (147 mmol) was added over a 15-min period by means of the syringe with stirring and cooling to hold the temperature at about 25° C. The mixture was allowed to react for another 4 hours and then was cooled to about 0° C. The precipitated product and sulfur by-product were recovered by vacuum filtration and washed with water, a 1:1 mixture of water and acetonitrile, and finally acetonitrile. The wet cake was slurried in 1 L of water at 70° C. and about 600 mL of acetonitrile was added to dissolve the solid. The resulting mixture was gravity filtered and the filtrate was allowed to cool over the weekend. The mixture was further cooled in a refrigerator and the crystals that formed were recovered by vacuum filtration, washed with acetonitrile, and dried to constant weight to obtain 14.1 g (62 percent of theory) of the title compound as an amber solid which decomposed on heating above 187° C.
Reaction SMILES: C[Si](C)(C)OC1CNC(=O)C1.BrCC(OCC)=O.[H-].[Na+].C[Si](C)(C)[O:23][CH:24]1[CH2:28][N:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:26](=[O:35])[CH2:25]1.Cl>C(#N)C>[OH:23][CH:24]1[CH2:28][N:27]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:26](=[O:35])[CH2:25]1
Reactant: CCOC(=O)CN1CC(O[Si](C)(C)C)CC1=O
Agent: CCOC(=O)CBr
Agent: C[Si](C)(C)OC1CNC(=O)C1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)CN1CC(O)CC1=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 51.5 g. 4-trimethylsilyloxypyrrolidin-2-one in 500 ml. anhydrous acetonitrile are added 133 ml. ethyl bromoacetate. The solution is heated to 50° C. and 26.7 g. of 80% sodium hydride (dispersion in mineral oil) are slowly added in small amounts. When the addition is completed, the reaction mixture is heated under reflux for 30 minutes and then cooled to ambient temperature. To the reaction mixture obtained containing ethyl 2-(4-trimethylsilyloxypyrrolidin-2-on-1-yl)-acetate (b.p. 160° C./3 mm.Hg) are added 50 ml. 1 N hydrochloric acid. The reaction mixture is stirred for 30 minutes and then evaporated to dryness. The residue obtained is chromatographed on a silica gel column, using ethyl acetate as the elution agent, 45 g. ethyl 2-(4-hydroxypyrrolidin-2-on-1-yl)-acetate being obtained; b.p. 180° C./0.8 mm.Hg; Rf 0.17 (silica gel; eluant ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:55])[C:32]([CH:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:41]=2)[CH2:36][CH2:35]1)=[O:33]>C1(C)C=CC=CC=1.CCO>[CH3:30][N:31]([CH3:55])[C:32]([CH:34]1[CH2:35][CH2:36][N:37]([C:40]2[CH:41]=[C:42]([C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]5([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:18][CH2:17][CH2:16]5)=[CH:11][CH:10]=4)[C:5]([N+:27]([O-:29])=[O:28])=[CH:4][CH:3]=3)[CH:43]=[CH:44][CH:45]=2)[CH2:38][CH2:39]1)=[O:33]
Reactant: CN(C)C(=O)C1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)CCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)C(=O)C1CCN(c2cccc(-c3ccc([N+](=O)[O-])c(Nc4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)n3)c2)CC1
Temperature: 100 °C
Yield: 91 %

Procedure:
To a solution of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (4.1 g, 9.8 mmol) in toluene/EtOH/saturated NaHCO3 (200/200/20 mL), were added N,N-dimethyl-1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidine-4-carboxamide. (4.2 g, 12 mmol), Pd(PPh4)3 (563 mg, 0.49 mmol). The mixture was heated at 100° C. for 18 h. The mixture was filtered through celite, separated and evaporated. The residue was purified with silica gel column chromatography (hexane/ethyl acetate/methanol, 85:15:1.5) to give the titled compound as a pale red solid (5.4 g, 91%)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:11][C:12]1[C:13]([C:20]2[C:21](F)=[N:22][CH:23]=[C:24]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:28][CH:27]=3)[CH:25]=2)=[C:14]([NH2:19])[CH:15]=[N:16][C:17]=1[Cl:18]>C1COCC1.O>[Br:11][C:12]1[C:13]2[C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:28][CH:27]=4)[CH:23]=[N:22][C:21]=3[NH:19][C:14]=2[CH:15]=[N:16][C:17]=1[Cl:18]
Reactant: Nc1cnc(Cl)c(Br)c1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1ncc2[nH]c3ncc(-c4ccc(CN5CCCCC5)cc4)cc3c2c1Br
Yield: 16.9 %

Procedure:
Sodium bis(trimethylsilyl)amide (3.9 mL, 3.90 mmol) was added to a solution of 5′-bromo-6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine (187 mg, 0.39 mmol) in anhydrous THF (7.0 mL) and the resultant solution stirred at ambient temperature for 20 min. The reaction mixture was diluted with water (20 mL) and extracted with DCM: MeOH (4:1, 3×20 mL). The combined organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica, 4 g column, ISCO, 0-15% MeOH in DCM) to afford the title compound as a beige powder (30 mg, 17%). 1H NMR (CDCl3, 400 MHz): 9.17 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.67 (s, 1H), 7.65 (d, J=7.5 Hz, 2H), 7.49 (d, J=7.5 Hz, 2H), 3.59 (s, 2H), 2.51-2.47 (m, 4H), 1.68-1.59 (m, 4H), 1.51-1.45 (m, 2H). LCMS (Method A): RT=7.10 min, M+H+=455/457.
Reaction SMILES: [CH:1]([O:4][CH:5]([CH3:23])[CH:6](OS(C1C=CC(C)=CC=1)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[N:29]=[C:28]([SH:34])[N:27]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCC.O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([O:25][CH3:24])[N:27]=[C:28]([S:34][CH:6]([CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH3:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:29]=1
Reactant: CCOC(=O)C(OS(=O)(=O)c1ccc(C)cc1)C(C)OC(C)C
Reactant: COc1cc(OC)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(Sc1nc(OC)cc(OC)n1)C(C)OC(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
After this compound, ethyl 3-(isopropoxy)-2-p-toluenesulfonyloxybutanoate (27.5 g, 0.08 mol) and 4,6-dimethoxy-2-mercaptopyrimidine (13.7 g, 0.08 mol) were added to N,N-dimethylformamide (80 ml) and further anhydrous potassium carbonate (11.1 g) was added thereinto, the mixture was stirred at room temperature for 5 hours. Subsequently, water was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with water and dried, and ethyl acetate was removed under reduced pressure. The residue obtained was isolated by column chromatography (Wako gel C-200 (trade name, produced by Wako Junyaku K.K.), eluted by hexane:ethyl acetate=8:1) to obtain 15.0 g (yield: 54.5%) of the title compound as a colorless oily product.
Reaction SMILES: [C:1](=O)([O-])O.[K+].IC.[F:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C@@H:24]([CH2:29][N:30]([CH3:32])[CH3:31])[CH2:25][C:26]([OH:28])=[O:27])=[O:22]>CO.C(Cl)(Cl)Cl>[F:8][C:9]1[CH:10]=[C:11]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][C@@H:24]([CH2:29][N+:30]([CH3:1])([CH3:32])[CH3:31])[CH2:25][C:26]([O-:28])=[O:27])=[O:22]
Reactant: O=C([O-])O
Reactant: CN(C)C[C@@H](CC(=O)O)NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Agent: [K+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CI
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)CCCCCCCOCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium hydrogencarbonate (24 mg, 0.24 mmol) and iodomethane (106 mg, 0.74 mmol) were added to a solution of (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid (77 mg, 0.19 mmol) in methanol (2.5 mL). The reaction mixture was stirred at room temperature for 16 h, then diluted with chloroform (5 mL). Insoluble material was removed by filtration to afford (R)-3-[8-(3,4-difluoro-benzyloxy)-octanoylamino]-4-trimethylammonio-butyrate as a light yellow solid, m/e=429.3 ([M+H]+).