Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5].[CH3:30][O:31][CH2:32][CH2:33][NH2:34].CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:34][CH2:33][CH2:32][O:31][CH3:30])=[O:20])[CH:13]=[CH:12][C:9]=2[C:10]=1[CH3:11])=[O:5]
Reactant: COCCN
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(-c3cccc(C(=O)O)c3)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC(=O)c1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 3-[2-(2,4-dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-benzoic acid (40 mg, 0.09 mmol) in dichloromethane (2 mL) was added 2-methoxyethylamine (0.02 mL, 0.19 mmol), EDCI (20 mg, 0.1 mmol), DMAP (1 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.02 mL, 0.1 mmol). The reaction mixture was stirred at rt overnight, then concentrated in vacuo and purified by prep-HPLC to afford the desired product (11 mg, 25%). 1H-NMR (CDCl3) δ 8.05 (t, J=1.8 Hz, 1H), 7.77-7.75 (m, 3H), 7.69 (m, 1H), 7.60 (dd, J=8.3, 1.0 Hz, 1H), 7.51 (m, 2H), 7.47 (m, 1H), 7.40 (ddd, J=8.2, 1.9, 0.5 Hz, 1H), 6.62 (t, J=4.5 Hz, 1H), 3.70 (m, 2H), 3.60 (m, 2H), 3.40 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[C:15]([C:17]([N:19]3[CH2:20][CH2:21][N:22]([C:25]4[CH:26]=[CH:27][N+:28]([O-:39])=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)=[O:18])[CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccncc4)CC3)n2)cc1OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4cc[n+]([O-])cc4)CC3)n2)cc1OC
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a dichloromethane (10 ml) solution of 353 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(pyridin-4-yl)piperazine was added 195 mg of m-chloroperbenzoic acid, followed by 1 hour of stirring at 50C. An aqueous sodium thiosulfate solution was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then recrystallization (ethanol-ethyl acetate) was carried out to obtain 294 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-(1-oxidopyridin-4-yl) piperazine 1.5 hydrate as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19](Br)[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][CH:18]=[C:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2Br
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCC=C2c1ccccc1
Temperature: 90 °C
Yield: 68.4 %

Procedure:
A mixture of intermediate 15, ethyl 3-(benzyloxy)-9-bromo-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate, (0.477 g, 1.18 mmol) in acetonitrile (15 ml) and water (15 ml) was treated with phenylboronic acid (0.190 g, 1.53 mmol), sodium carbonate (0.275 g, 2.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.200 g). The reaction mixture was degassed, flushed with argon and heated at 90° C. for 30 min. The reaction mixture was then concentrated in vacuo, diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated. Chromatography of the residue on silica gel (elution gradient of ethyl acetate in hexane) gave 0.325 g (68% yield) of the title material as a clear oil. 1HNMR 400 MHz (CDCl3) δ (PPM): 1.26 (3H, t, J=7.1 Hz, CH3), 2.68 (2H, m, CH2), 4.27 (2H, q, J=7.1 Hz, OCH2), 4.32 (2H, t, J=7.6 Hz, CH2), 5.34 (2H, s, OCH2), 6.73 (1H, t, J=4.8 Hz, CH), 7.3–7.55 (10H, m, aromatics). HRMS (ESI+) calculated for C24H23N2O4 [M+H+]: 403.1658; found: 403.1659.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][N:24]([CH:26](OC)OC)[CH3:25]>CN(C=O)C>[CH3:23][N:24]([CH3:26])[CH:25]=[CH:1][C:2]1[C:7]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1c(C(=O)c2cccc3ccccc23)cccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1c(C(=O)c2cccc3ccccc23)cccc1[N+](=O)[O-]

Procedure:
Following a procedure similar to that described in Preparation 2A above, 57 g (0.195 mole) of 2-methyl-3(1-naphthylcarbonyl)nitrobenzene and 103 ml (0.784 mole) of DMF dimethyl acetal in 300 ml of DMF was heated under reflux for seventeen hours and then taken to dryness to give 2-(2-dimethylaminoethenyl)-3-(1-naphthylcarbonyl)nitrobenzene as an oil.
Reaction SMILES: [NH2:1][NH2:2].[O:3]=[C:4]1[CH:9]([CH2:10][C:11](OC)=[O:12])[S:8](=[O:16])(=[O:15])[C:7]2[S:17][C:18]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:19][C:6]=2[NH:5]1>CO>[S:20]([C:18]1[S:17][C:7]2[S:8](=[O:16])(=[O:15])[CH:9]([CH2:10][C:11]([NH:1][NH2:2])=[O:12])[C:4](=[O:3])[NH:5][C:6]=2[CH:19]=1)(=[O:23])(=[O:22])[NH2:21]
Reactant: NN
Reactant: COC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Solvent: CO
Product: NNC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reaction time: 5.5 h

Procedure:
Anhydrous hydrazine (1 ml) was added to a solution of methyl (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetate (1.0 g) in methanol (10 ml) at ambient temperature with stirring. After 5-6 hours, the methanol was removed under reduced pressure and the residue was treated with water (10 ml). The pH was adjusted to 6.5 and the resulting precipitate was collected, rinsed with water and dried under vacuum to give 0.40 g (2,3-dihydro-6-sulfamoyl-2,4,4-trioxo-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetic acid hydrazide, mp 230° C., dec.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=1.[Br:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[Br:25][C:26]1[CH:31]=[C:30]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=3)[CH:5]=[C:4]([C:21]([F:24])([F:23])[F:22])[N:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CCOc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: CCOc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-4-(3-ethoxy-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.10) (0.25 g, 0.67 mmol) and commercially available 3-bromo-benzene-boronic acid (0.17 g, 0.85 mmol) according to the general procedure IVb. Obtained as a light yellow solid (0.32 g, 97%). MS (EI) 492.0 [(M)+]; mp 108° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH:18]1([N:13]2[C:12]([C:34]3[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 95.2 %

Procedure:
The title compound (117 mg) was prepared according to Example 263 using 192 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 83 mg of 4-methylphenylboronic acid. MS (ESI): exact mass calculated for C18H23N3, 281.19. found, m/z 282.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.32 (m, 2H), 7.23-7.13 (m, 2H), 4.71-4.65 (m, 2H), 4.00-3.41 (m, 2H), 3.32-3.05 (m, 3H), 2.95-2.79 (m, 2H), 2.67-2.58 (m, 2H), 2.43 (s, 3H), 2.28-2.23 (m, 2H), 1.84-1.71 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:28]([O:21][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=1)[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1=Cc2cc(O)cc(Cl)c2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OCc3ccccc3)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 8-chloro-6-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 17a, Step 3 (1.00 g, 3.10 mmole) in anhydrous DMF (10.0 mL) was added KI (51.5 mg, (0.310 mmole), K2CO3 (1.29 g, 9.30 mmole) and benzyl bromide (1.11 ml, 9.30 mmole). The suspension was stirred at room temperature for 2 h and poured into H2O (150 mL) and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine (2×100 mL), dried over MgSO4 and concentrated in vacuo to give a yellow oil. Purification by silica chromatography (6:1 hexanes:EtOAc) gave 1.12 g (87.5% yield) of the product as a yellow crystalline solid: EIHRMS m/z 412.0689 (M+, C20H16ClF3O4, Calc'd 412.0680).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH2:34]([O:36][C:37](=[O:45])C1C=CN=C(N)C=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:45])[C:23]1[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:24]=1)[CH3:35]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: CCOC(=O)c1ccnc(N)c1
Product: CCOC(=O)c1ccnc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)c1

Procedure:
The product from Example 11, Part D (100 mg, 0.30 mmol) and 2-aminoisonicotinic acid ethyl ester (75 mg, 0.45 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E without crystallization (120 mg, 83%). 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1H), 8.31 (d, J=5 Hz, 1H), 7.81 (s, 1H), 7.70 (d, J=8 Hz, 1H), 7.58 (dd, J=5 Hz, 1 Hz, 1H), 7.47 (m, 1H), 7.32 (m, 2H), 7.20 (t, J=9 Hz, 1H), 7.02 (t, J=9 Hz, 2H), 5.27 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.41 (q, J=7 Hz, 2H), 4.24 (d, J=15 Hz, 1H), 2.55 (m, 2H), 1.97 (m, 2H), 1.41 (t, J=7 Hz, 3H). MS: m/z (MH+) 480.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.[OH-].[Na+].O.[SH:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>CCO>[F:2][C:3]([F:17])([F:16])[CH2:4][N:5]=[C:6]([NH2:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:12]=1
Reactant: COC(=O)CCS
Reactant: NC(=NCC(F)(F)F)Nc1nc(CCl)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)CCSCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 1 h

Procedure:
A mixture of 2-[2,2,2-trifluoroethyl]guanidino-4-chloromethylthiazole hydrochloride (4.6 g.) in EtOH (75 ml.) and methyl 3-mercaptopropionate (2.47 ml.) at 5° was treated dropwise with aqueous sodium hydroxide (1.8 g. in 15 ml. of water) over 10 minutes. The resulting solution was allowed to reach room temperature and was stirred for 1 hour. It was then poured into water and the precipitate filtered and crystallised from EtOH to give methyl 3-[2-(2-[2,2,2-trifluoroethyl]guanidino)thiazol-4-ylmethylthio]propionate (1.93 g), m.p. 96°-98°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:27]=2)=[O:25])[CH:20]=[CH:21][CH:22]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:27]=2)=[O:25])[CH:18]=1
Reactant: Nc1cccc(NC(=O)c2ccnc(N3CCOCC3)c2)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3cccc(NC(=O)c4ccnc(N5CCOCC5)c4)c3)c2cc1OC
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 26, 4-chloro-6,7-dimethoxyquinazoline was reacted with N-(3-aminophenyl)-2-morpholinopyridine-4-carboxamide. The material so obtained was purified by column chromatography eluting with 96:3:1 methylene chloride/methanol/saturated aqueous ammonium hydroxide. The material so obtained was triturated under methylene chloride to give the title compound in 33% yield; NMR: 3.51 (m, 4H), 3.71 (m, 4H), 3.93 (s, 3H), 3.96 (s, 3H), 7.11 (d, 1H), 7.18 (s, 1H), 7.24 (s, 1H), 7.35 (m. 1H), 7.44 (d, 1H), 7.57 (d, 1H), 7.86 (s, 1H), 8.23 (s, 1H), 8.29 (d, 1H), 8.46 (s, 1H), 9.49 (s, 1H), 10.34 (s, 1H); Mass: M+H+ 487.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C@H:7]2[NH:11][C:10](=O)[CH2:9][CH2:8]2)[O:4][N:3]=1.B.[CH2:14]1COCC1>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:8][CH2:9][CH2:10][N:11]2[CH3:14])[O:4][N:3]=1
Reactant: C1CCOC1
Reactant: Cc1cc([C@@H]2CCC(=O)N2)on1
Agent: B
Product: Cc1cc([C@@H]2CCCN2C)on1

Procedure:
To a solution of crude 5(S)-(3-methyl-5-isoxazolyl)-2-pyrrolidinone (5.33 g, 32.1 mmol, the product of step 13b) in THF (50 mL) was added borane-THF (99.5 mL, 1.0M, 99.5 mmol) slowly at room temperature. The reaction mixture was heated at reflux for two hours. After removal of THF under vacuum, a solution of formaldehyde (10.0 mL) and formic acid (5.0 mL) was carefully added, and the reaction mixture was refluxed for one hour. Ethyl acetate (300 mL) was added, followed by the addition of sodium carbonate until basic. The organic layer was decanted, and the residue was washed with ethyl acetate (4×20 mL). The combined organic solvents were dried over sodium carbonate. The solvent was evaporated, and the residue was distilled (bp. ~150° C./~50 mm Hg) to give the title compound (3.12 g, 59%; 24% overall yield). The compound was further purified by HPLC chromatography (CHCl3 /MeOH, 20:1 and 10:1). HPLC (analytical Chiralark OD column) analysis indicated >99% ee. [α]D23° =-13.1° (c 0.9, MeOH). MS (DCl/NH3) m/e: 153 (M+H)+. 1H NMR (CDCl3) δ 1.80-2.00 (m, 3H), 1.99 (br s, 1H, NH), 2.14-2.21 (m, 1H), 2.28 (s, 3H), 2.96-3.16 (m, 2H), 4.32 (dd, 1H), 5.95 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][Mg]Br.[NH4+].[Cl-]>C1COCC1>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[CH2:20][CH2:21][C:6]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:13][CH:12]=1)=[O:7]
Reactant: Br[Mg]CCC1OCCCO1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CCC1OCCCO1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-fluoro-N-methoxy-N-methylbenzamide (0.94 mmol; 173 mg) in anhydrous THF (2 mL), at −78° C. under argon, was added a solution of (1,3-dioxan-2-ylethyl)magnesium bromide, 0.5M in THF (1.04 mmol; 2.1 mL). The reaction was stirred 16 hours at room temperature. The mixture was cooled to −78° C. and (1,3-dioxan-2-ylethyl)magnesium bromide, 0.5M in THF (2.00 mmol; 4 mL) was added again. The reaction was stirred overnight at room temperature. The mixture was treated with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, and concentrated in vacuo. The title compound was prepared in quantitative yield, used without further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1COCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
Diethyl malonate (7.41 g, 46.3 mmol) was added to a slurry of NaH (60% oil dispersion, 2.04 g, 50.9 mmol) in THF (200 ml) and stirred for 15 min, before adding a solution of 4-nitrobenzyl bromide (10.0 g, 46.3 mmol) in THF (100 ml) by cannula. The reaction was stirred for 3 h at room temperature then quenched by the addition of water (100 ml). The aqueous layer was separated and extracted with Et2O (200 ml). The combined organic layers were washed with brine (200 ml), dried (MgSO4) and the solvent evaporated in vacuo to give an off-white solid. Trituration with Et2O/hexane (1:5, 100 ml), removal of the solid by filtration and concentration of the filtrate in vacuo gave an oil which was purified by chromatography (SiO2;EtOAc/hexane 1:3) to give the title compound as an oil (9.4 g), containing about 20% diethyl malonate. δH (CDCl3) 8.15 (2H, d, J 8.8 Hz, Ar—H), 7.39 (2H, d, J 8.7 Hz, Ar—H), 4.25-4.11 (4H, m, CH2CH3), 3.67 (1H, t, J 7.8 Hz, CHCH2Ar), 3.32 (2H, d, J 7.8 Hz, CHCH2Ar) and 1.23 (6H, t, J 7.2 Hz, CH2CH3).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]([CH3:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[C:21]#[N:22])C1C=CC=CC=1.O=[C:26]([CH3:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[NH2:22][C:21]1[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C@H:11]([NH2:10])[CH3:23])[N:20]=[C:26]([CH3:33])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: C[C@H](COc1cccc(N)c1C#N)NC(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](C)N)c2c1N

Procedure:
Prepared as in Example 2a from (R)-benzyl(1-(3-amino-2-cyanophenoxy)propan-2-yl)carbamate (Example 86c) and ethyl 3-oxobutanoate as brown solid. MS 304 (MH+).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1([CH3:30])[C@@H:10]([CH:11]=O)[C@H:9]1[C:13]([O:15][CH2:16][C:17]1[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=1[F:29])=[O:14].C(OP([CH:39]([Cl:42])[C:40]#[N:41])(=O)OCC)C>O1CCCC1>[Cl:42]/[C:39](/[C:40]#[N:41])=[CH:11]\[C@@H:10]1[C@@H:9]([C:13]([O:15][CH2:16][C:17]2[C:22]([F:23])=[C:21]([F:24])[C:20]([CH2:25][O:26][CH3:27])=[C:19]([F:28])[C:18]=2[F:29])=[O:14])[C:8]1([CH3:7])[CH3:30]
Reactant: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@H](C=O)C2(C)C)c(F)c1F
Reactant: CCOP(=O)(OCC)C(Cl)C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCc1c(F)c(F)c(COC(=O)[C@@H]2[C@@H](/C=C(\Cl)C#N)C2(C)C)c(F)c1F
Yield: 32.3 %

Procedure:
A solution of 0.14 g of potassium tert-butoxide in 1 ml of tetrahydrofuran was added dropwise to a mixture of 0.35 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3S)-2,2-dimethyl-3-formylcyclopropanecarboxylate, 0.21 g of diethyl(chlorocyanomethyl)phosphonate and 5 ml of anhydrous tetrahydrofuran with ice-cooling under a nitrogen atmosphere. After stirring with ice-cooling for 15 minutes, the reaction mixture was poured into a saturated saline solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.13 g of 2,3,5,6-tetrafluoro-4-methoxymethylbenzyl (1R,3S)-3-((Z)-2-chloro-2-cyanovinyl)-2,2-dimethylcyclopropanecarboxylate represented by the formula (1):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Br[CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH3:20])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CCCBr
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)ccc1Cl
Product: CCCN1CCN(c2ccc(Cl)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-Chloro-3-nitro-phenyl)-piperazine and 1-bromopropane, the title compound was recovered by the procedure described in Example 2. m.p. 249° C. (HCl); MS m/z (rel. intensity, 70 eV) 283 (M+, 27), 254 (87), 165 (bp), 153 (78), 56 (90).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[NH:19][N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:39][CH2:40][CH2:41][N:42]1[CH2:45][CH:44]([OH:46])[CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:39][CH2:40][CH2:41][N:42]4[CH2:45][CH:44]([OH:46])[CH2:43]4)[N:18]=3)[N:15]=2)[N:10]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Reactant: OC1CN(CCCCl)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(O)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.9 %

Procedure:
In a 2-5 mL Biotage microwave vial were mixed N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 94.2 μmol), 1-(3-chloropropyl)azetidin-3-ol (42.3 mg, 283 μmol, Eq: 3.0) and Cs2CO3 (123 mg, 377 μmol) in DMF (2 mL). The mixture was stirred ˜10 min at 25° C. then heated to 100° C. in the Biotage microwave reactor for 30 min. LCMS showed complete reaction, diluted with 10 mL of dichloromethane and filtered through a celite pad, filtrate concentrated under high vacuum at 65° C. and residue dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-(3-hydroxyazetidin-1-yl)propyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (40 mg, 62.1 μmol, 65.9%) as a light yellow semisolid. MS (M+H)+=644; 1H NMR (CDCl3) δ: 9.23 (s, 1H), 8.36 (s, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.08 (s, 1H), 7.58 (d, J=9.1 Hz, 1H), 7.35 (dd, J=8.9, 2.1 Hz, 1H), 6.55 (t, J=74.8 Hz, 1H), 5.75 (s, 2H), 4.43-4.63 (m, 3H), 3.66-3.76 (m, 2H), 3.55-3.65 (m, 2H), 2.88-2.99 (m, 2H), 2.51-2.61 (m, 2H), 2.03-2.17 (m, 3H), 1.65 (s, 9H), 0.92-1.02 (m, 2H), 0.00 (s, 9H).