Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Br)[CH:35]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40][S:19][CH2:20][CH2:21][OH:22])[CH:35]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Reactant: CCOC(=O)c1cccc(-c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2cccc(CSCCO)c2)c1

Procedure:
3′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 3′-Bromomethyl-biphenyl-3-carboxylic acid ethyl ester (3.4 g, 10.65 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (1.0g, 12.78 mmol, 1.2 eq.) and potassium carbonate (4.42 g, 31.95 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2.[Cl:45][C:46]1[S:50][C:49]([CH2:51]Cl)=[CH:48][CH:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[Cl:45][C:46]1[S:50][C:49]([CH2:51][N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[C:5]3([C:15]4=[CH:16][C:17]5[O:21][CH2:20][O:19][C:18]=5[CH:22]=[C:14]4[O:13][CH2:12]3)[C:6]2=[O:11])=[CH:48][CH:47]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: O=C1Nc2ccc(F)cc2C12COc1cc3c(cc12)OCO3
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Product: O=C1N(Cc2ccc(Cl)s2)c2ccc(F)cc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using 5′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 5-chloro-2-(chloromethyl)thiophene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (76%) as a colorless solid: mp 142-144° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.22-7.17 (m, 1H), 7.14-7.13 (m, 1H), 7.12-7.10 (m, 2H), 6.96 (d, 1H), 6.68 (s, 1H), 6.13 (s, 1H), 5.91 (d, 2H), 5.02 (ABq, 2H), 4.73 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.9, 161.0, 157.8, 156.0, 149.0, 142.2, 138.3, 138.2 (d, 4JcF=7.0 Hz) 133.6 (d, 3JcF=33 Hz), 128.3, 127.8, 127.1, 119.5, 115.6 (d, 1JcF=93 Hz), 112.5 (d, 1JcF=100 Hz), 110.8 (d, 3JcF=32 Hz), 103.2, 102.0, 93.9, 79.8, 58.2 (d, 4JcF=7.0 Hz), 39.0; MS (ES+) m/z 430.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH:5]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=1)[NH:6][C:7]([C:9]1[CH:10]=[N:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:13]=1[CH3:14])=[O:8].[OH-].[Na+].Cl>>[Br:29][C:25]1[CH:24]=[C:23]([CH:5]([NH:6][C:7]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[C:13]=2[CH3:14])=[O:8])[CH2:4][C:3]([OH:30])=[O:2])[CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CC(NC(=O)c1cnn(-c2ccc(Cl)c(Cl)c2)c1C)c1cccc(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)NC(CC(=O)O)c2cccc(Br)c2)cnn1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
3-(3-Bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid methyl ester (1.5 g, 2.9 mmol) is treated with aqueous NaOH (1.0 N solution, 60 mL, 60 mmol) and stirred at reflux for 1 hour. After cooling to room temperature, the reaction mixture is acidified with aqueous 1N HCl. The resultant precipitate is collected by filtration and dried in vacuo to afford 3-(3-bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionic acid as a off-white solid (870 mg, 60%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[S:3][C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1.[C:18](#[N:21])[CH:19]=[CH2:20].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.C(OCC)C>CO>[C:18]([CH2:19][CH2:20][N:13]1[CH2:12][CH2:11][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([S:3][C:2]([F:1])([F:16])[F:17])[CH:5]=2)[CH2:15][CH2:14]1)#[N:21]
Reactant: FC(F)(F)Sc1cccc(N2CCNCC2)c1
Reactant: C=CC#N
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Product: N#CCCN1CCN(c2cccc(SC(F)(F)F)c2)CC1
Reaction time: 48 h
Yield: 84.7 %

Procedure:
N-(m-trifluoromethylthiophenyl)-piperazine (10.8 g, 0.047 g.mol.) and acrylonitrile (4.9 g, 0.094 g. mol.) are introduced into a 50 ml round bottomed flask provided with a stirrer and a reflux condenser. 0.1 ml of a 40% solution of benzyltrimethylammonium hydroxide in methyl alcohol is added with cooling and stirring. The mixture is allowed to stand at ambient temperature for 2 days and then heated for 2 hours to 80° C. After cooling, anhydrous diethyl ether (100 ml) is added to the reaction mixture, insoluble materials are filtered off, and the solution obtained evaporated on a water-bath in vacuo. The residue is fractionally distilled and N-(β-cyano-ethyl)-N'-(m-trifluoromethylthiophenyl)-piperazine (11 g, 88% yield) is thus obtained as a clear yellow viscous liquid, b.p. 198°-200°/3 mm Hg, nD23 = 1.5378.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][C:3]=1[CH3:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[CH2:10]([O:9][C:6]1[C:7]2[NH:8][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:1][C:2]=2[C:3]([CH3:17])=[CH:4][CH:5]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(OCc2ccccc2)c(N)c1N
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1ccc(OCc2ccccc2)c2[nH]c(-c3ccccc3)nc12
Reaction time: 18 h

Procedure:
A mixture of 2,3-diamino-4-benzyloxytoluene (5.0 g) and benzaldehyde (5.52 g, 2 mol. equiv.) in xylene (75 ml) was heated under reflux for 3 h, and then left for 18 h at room temperature. The resulting crystalline product was filtered, washed with ether, and recrystallized from ethanol to afford the title compound, 4.13 g, m.p. 221°-224° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=2)[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1
Reactant: COc1cc(Cl)cc(B(O)O)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: COc1cc(Cl)cc(-c2cc(F)c(N)c(F)c2)c1
Yield: 30.1 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2,6-difluoroaniline (100 mg, 0.48 mmol) and 3-chloro-5-methoxyphenylboronic acid (116 mg, 0.62 mmol) as a pale-yellow solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.36 (dd, J 2.2, 8.1, 2H), 7.25 (s, 1H), 7.12 (s, 1H), 6.91 (t, J 1.9, 1H), 5.43 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH2:13]([S:15]([C:18]1[CH:23]=[CH:22][C:21](F)=[C:20]([Cl:25])[CH:19]=1)(=[O:17])=[O:16])[CH3:14]>>[Cl:25][C:20]1[CH:19]=[C:18]([S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])[CH:23]=[CH:22][C:21]=1[O:12][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1ccc(F)c(O)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)ccc2F)c(Cl)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using the product of step (iv) and the product of example 3 step (i).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.[O-2].[Mg+2].S(Cl)(Cl)(=O)=O.N>ClC1C=CC=CC=1.O>[NH2:11][C:9]1[S:10][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=2[N:8]=1
Reactant: NC(=S)Nc1ccc(Br)cc1
Agent: N
Agent: [Mg+2]
Agent: [O-2]
Solvent: Clc1ccccc1
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: Nc1nc2ccc(Br)cc2s1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A solution of N-(4-bromophenyl)thiourea (16.18 g) and magnesium oxide (1.41 g) in chlorobenzene (100 mL) was heated to 50° C., and a solution of sulfuryl chloride (8.43 mL) in chlorobenzene (9 mL) was added dropwise to the solution over 1 hour or longer, followed by stirring at 50° C. overnight. The reaction mixture was returned to room temperature, and water (20 mL) was added thereto. The pH of the mixture was adjusted to about 8 by use of concentrated aqueous ammonia, and the precipitates were recovered through filtration. The obtained solid was recrystallized from 90% ethanol, to thereby yield the title compound (7.95 g).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+].O.C(O)C>ClCCl>[Br:1][C:2]1[C:7]([CH2:8][C:10]#[N:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [C-]#N
Reactant: BrCc1cccnc1Br
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: N#CCc1cccnc1Br
Yield: 83 %

Procedure:
A mixture of 2-bromo-3-bromomethyl-pyridine (840 mg, 3.35 mmol) and sodium cyanide (187.99 mg, 3.68 mmol) is stirred and refluxed for 1 h in a mixture water (10 mL)-ethanol (2 mL). The reaction mixture is diluted with dichloromethane and washed with saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate and the solvent evaporated in vacuo to give 83% of the title compound that is used without further purification. MS (m/z): 197 (M+1), 199 (M+3).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[C:10]([OH:23])=[N:11][C:12]2[C:17]([N:18]=1)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=2.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][C@@H:2]1[N:3]([C:9]2[C:10](=[O:23])[NH:11][C:12]3[C:17]([N:18]=2)=[CH:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=3)[CH2:4][CH2:5][O:6][CH2:7]1
Reactant: COC(=O)c1ccc2nc(O)c(Cl)nc2c1
Reactant: C[C@H]1COCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCOC[C@@H]3C)nc2c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of (3S)-3-methylmorpholine (127 mg, 1.26 mmol) in DMSO (2 mL) was added methyl 3-chloro-2-hydroxyquinoxaline-6-carboxylate (200 mg, 0.84 mmol) and DIEA (217 mg, 1.68 mmol). The resulting solution was stirred at 70° C. for 3 h and then quenched by water (10 mL). The solids were collected by filtration to afford (S)-methyl 3-(3-methylmorpholino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a light yellow solid (200 mg, crude).
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3](=[O:14])[NH:2]1)[CH:7]=[CH:8][CH:9]=2.[CH2:16](Br)[CH:17]=[CH2:18]>>[CH2:18]([N:2]1[C:1](=[O:15])[C:10]2[C:5]3=[C:6]([CH2:11][CH2:12][CH2:13][N:4]3[C:3]1=[O:14])[CH:7]=[CH:8][CH:9]=2)[CH:17]=[CH2:16]
Reactant: O=c1[nH]c(=O)n2c3c(cccc13)CCC2
Reactant: C=CCBr
Product: C=CCn1c(=O)c2cccc3c2n(c1=O)CCC3
Yield: 89 %

Procedure:
Starting from 6,7-dihydropyrido[3,2,1-ij]quinazoline-1,3 (2H,5H)-dione (prepared according to WO 2010/079206) and allyl bromide and using Procedure E, the title intermediate was obtained as a colourless solid (0.393 g; 89% yield).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>>[S:20]=[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Sc1ccccn1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=S)cc1)c1ccccc1
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 2-mercaptopyridine. HPLC-MS: m/z=351.1 (M+1); Rt=3.95 min.
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])[CH:8]=1.C([O-])(O)=O.[Na+].[CH3:29][CH2:30]O>>[NH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([CH3:23])([CH3:22])[C:19]([O:21][CH2:29][CH3:30])=[O:20])[CH:8]=1
Reactant: CC(C)(C(=O)O)c1cc(N)n(-c2ccccc2)n1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cc(N)n(-c2ccccc2)n1
Temperature: 45 °C
Yield: 91 %

Procedure:
Cone. H2SO4 (0.5 mL) was added to a solution of 2-(5-amino-1-phenyl-1 H-pyrazol-3-yl)-2-methylpropanoic acid (0.7 g, 28.5 mmol) in EtOH (10 mL) and the reaction was heated at 45° C. for 2 h. The reaction solution was neutralized with aq NaHCO3 and then extracted with EtOAc (3×20 mL). The combined extracts were washed with aq NaHCO3 solution, dried (Na2SO4), and concentrated in vacuo to give ethyl 2-(5-amino-1-phenyl-1 H-pyrazol-3-yl)-2-methylpropanoate (710 mg, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.62 (d, δ 7.6 Hz, 2 H), 7.52 (t, J=7.6 Hz, 2 H), 7.35 (t, J=7.6 Hz, 1 H), 5.47 (s, 1 H), 5.35 (br s, 2 H), 4.12 (q, J= 7.2 Hz, 2 H), 1.50 (s, 6 H), 1.22 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 274.1(M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[C:11]([CH2:19][CH:20](Br)[CH2:21][Br:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].O.C(Cl)Cl>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH:20]([CH2:21][Br:22])[CH2:19][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)cc1CC(Br)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
(RS)-Acetic acid 4-benzyloxy-2-(2,3-dibromo-propyl)-phenyl ester (5.05 g, 11.3 mmol) was suspended in EtOH (50 ml) and sodium methoxide (620 mg, 11.3 mmol) added and the mixture stirred for 2 hr at ambient temperature. Distilled H2O (100 ml) and CH2Cl2 (100 ml) was then added and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (100 ml) and the combined organic extracts washed with satd. NaCl solution (100 ml). After drying with Na2SO4, filtration and evaporation a yellow oil resulted which was chomatographed over SiO2 (Merck 230-400 mesh) with CH2Cl2 to afford 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran as a yellow oil (3.0 g, 9.39 mmol, 83%), MS: m/e=318.0 (M+).
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[N:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]([CH:53]([CH3:55])[CH3:54])[CH2:41][C@H:42]([C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34]>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([C@H:42]([C:43](=[O:44])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][N:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)[CH2:41][N:40]([CH:53]([CH3:54])[CH3:55])[C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:47][CH:48]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: c1ccc(-c2cnc3[nH]ncc3c2N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.111 mL, 0.636 mmol) was added to a solution of 5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.070 g, 0.159 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0543 g, 0.159 mmol, see Example B) and O-(benzotriazol-1-yl)-N,N,N,N′-tetramethyluronium tetrafluoroborate (“TBTU”) (0.0613 g, 0.191 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was then directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-oxo-3-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.044 g, 48%). MS ESI (+) m/z 503.4 detected.
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:12]=[N+:13]=[N-:14].[Na+].S(=O)(=O)(O)O>CS(C)=O.C(OCC)(=O)C>[N:12]([C@@H:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[OH:1])=[N+:13]=[N-:14]
Reactant: c1ccc2c(c1)CC1OC1C2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=N[C@@H]1Cc2ccccc2C[C@H]1O
Reaction time: 60 h
Yield: 38 %

Procedure:
To a stirred solution of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene (prepared in the manner disclosed in U.S. Pat. No. 4,076,843, 1.7 g, 11.6 mmol) in dimethyl sulfoxide (20 mL) at room temperature under nitrogen was added sodium azide (6.7 g, 0.10 mol) and concentrated sulfuric acid (0.2 mL). After 60 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with brine three times, dried over anhydrous magnesium sulfate, and concentrated under vacuum to yield a residue. The residue was purified by silica gel chromatography (10% ethyl acetate in hexane was used) to obtain the title compound (0.43 g, 38%) and recovered starting material. 1H NMR (400 MHz, CDCl3) δ 7.07-7.18 (m, 4H), 3.92 (m, 1H), 3.73 (m, 1H), 3.22 (m, 2H), 2.87 (m, 2H), 2.35 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:12][NH2:13].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([NH2:7])=[N:12][NH:13]2)=[C:8]([F:10])[CH:9]=1
Reactant: NN
Reactant: N#Cc1c(F)cc(Br)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1n[nH]c2cc(Br)cc(F)c12
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 410.7 %

Procedure:
Five batches of the below reaction were run in sequence in a microwave reactor: To a 5-mL microwave vial was added 4-bromo-2,6-difluorobenzonitrile (3 g, 13.76 mmol), hydrazine (0.864 mL, 27.5 mmol), Hunig's base (4.81 mL, 27.5 mmol) and ethanol (10 mL). The vial was capped and stirred for 10 minutes at 150° C. in a microwave reactor. The reaction mixture was cooled (ice-water bath) and a yellow precipitate formed. The yellow precipitates were collected, combined and the solids were washed with cold ethanol to yield pale yellow rods of the title compound (13.0 g). LC-MS (ES) m/z=230 and 232 (1:1 intensity) [M+H]+.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1O)[C:11]#[N:12]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[C:15]=1[Cl:4])[C:11]#[N:12]
Reactant: N#Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
(I1C): DMF (2 mL) was cooled to −20° C. and treated gradually in dropwise manner with oxalyl chloride (0.216 mL, 2.469 mmol). After 10 min, a solution of 3-bromo-4-hydroxy-5-nitrobenzonitrile (200 mg, 0.823 mmol) in DMF (2 mL) was added slowly via syringe while maintaining internal temperature below −10° C. After addition, the mixture was allowed to warmed to room temperature and then heated at 100° C. for 1.5 h. The reaction mixture was cooled and poured into ice-water, the solid was collected by filtration, rinsed with water and dried to give 172 mg of 3-bromo-4-chloro-5-nitrobenzonitrile as tan solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Br)cc2)nc2cccnc21)Nc1ccccc1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.6 g, 0.020 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) suspension of 2-(4-bromophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (6.4 g, 0.019 mole) in anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 5 hours, cooled to room temperature, and added dropwise to a stirred and chilled (10°-15° C.) solution of aniline (1.9 g, 0.020 mole) and triethylamine (2.1 g, 0.020 mole) in anhydrous dimethylformamide (100 ml). The reaction mixture was stirred at room temperature overnight, filtered, and poured into ice water (500 ml). The mixture was allowed to precipitate and was filtered. The filter cake was triturated in potassium bicarbonate solution (100 ml), filtered, and the cake washed with water (100 ml). Recrystallization from tetrahydrofuran-isopropyl ether and then isopropyl alcohol-ethanol-tetrahydrofuran give 3.8 g (49%) of an off-white solid, mp 242°-243.5° C.
Reaction SMILES: [C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[H-].[Na+].[F:18][C:19]1[C:24](F)=[CH:23][CH:22]=[C:21]([N+:26]([O-:28])=[O:27])[C:20]=1[O:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1)[C:33]#[N:34].Cl>C1COCC1>[CH3:13][C:12]([O:11][C:1](=[O:10])[CH:2]([C:24]1[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[C:20]([O:29][C:30]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:32]([C:33]#[N:34])[CH:31]=2)[C:19]=1[F:18])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Di-tert-butyl malonate (11.22 g, 51.9 mmol) was added dropwise. to a 0° C. solution of NaH (5.09 g, 127 mmol) in THF (150 ml). The reaction mixture was allowed to warm to RT, stirred for an additional 30 mins, and cooled to 0° C. A solution of 3-[(2,3-difluoro-6-nitrophenyl)oxy]-5-(methyloxy)benzonitrile (14.44 g, 47.2 mmol) in THF (50 mL) was added slowly and the reaction mixture was stirred at RT overnight. Dilute HCl was carefully added and the solution was extracted with EtOAc (3×100 mL). The organic layer was dried (Na2SO4), filtered, concentrated, and purified by silica gel chromatography (0-35% EtOAc/hexanes) to afford the title compound (22.9 g, 97%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.88 (dd, J=8.79, 1.46 Hz, 1H) 7.62 (dd, J=8.65, 6.46 Hz, 1H) 6.92 (s, 1H) 6.68-6.79 (m, 2 H) 4.81 (s, 1H) 3.83 (s, 3H) 1.49 (s, 16H).