Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH3:25])[N:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1>CO.CCOC(C)=O.[Pd]>[CH2:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:15]([C:12]2[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[N:16]1)[CH3:25]
Reactant: CCn1nc(-c2ccc(OCc3ccccc3)cn2)c2ncccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCn1nc(-c2ccc(O)cn2)c2ncccc21
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 3-[5-(benzyloxy)pyridin-2-yl]-1-ethyl-1H-pyrazolo[4,3-b]pyridine (224 mg) and 10% Pd—C (50% wet, 78 mg) in MeOH (3 mL) and AcOEt (3 mL) was hydrogenated under balloon pressure at room temperature overnight. The solid was filtrated and washed with MeOH (50 mL×3). The filtrate was concentrated under reduced pressure. The precipitate was collected by filtration and washed with 25% AcOEt in hexane to give the title compound (137 mg).
Reaction SMILES: [OH2:1].[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15](=[O:16])[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([CH3:25])([CH3:24])[CH2:12]2)=[CH:7][CH:6]=1>C1COCC1.CO.O>[C:20]([O:19][C:17]([NH:14][C:13]([CH3:25])([CH3:24])[CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1)[C:15]([OH:1])=[O:16])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(Cl)cc2)CC1(C)C
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CC(C(=O)O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Lithium hydroxide hydrate (6.44 mL, 232 mmol) was added to a stirred solution of tert-butyl 4-(4-chlorophenyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (7.5 g, 23.2 mmol) in THF/MeOH/H2O (30 mL/30 mL/30 mL) at room temperature. The mixture was stirred at room temperature overnight and concentrated in vacuo. The mixture was taken up into water (200 mL), washed with EtOAc (100 mL), acidified with concentrated HCl and extracted into EtOAc (2×200 mL). The mixture was dried over Na2SO4 and concentrated in vacuo. Residual HCl was removed by evaporating from toluene to give 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid (5.0 g, 63.2% yield) as a white solid. LCMS (APCI+) [M−Boc+H]+ 242.0; Rt: 2.8 min.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[CH:31]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:29]=[CH:28][C:20]=3[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1>>[O:8]1[C:13]2[CH:14]=[CH:15][C:16]([NH:18][C:19]3[CH:31]=[C:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:29]=[CH:28][C:20]=3[C:21]([OH:23])=[O:22])=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1Nc1ccc2c(c1)OCCO2
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1Nc1ccc2c(c1)OCCO2

Procedure:
Trifluoroacetic acid 3.0 mL solution of the obtained tert-butyl 2-((2,3-dihydrobenzo[1,4]dioxin-6-yl)amino)-4-phenylbenzoate was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the obtained residue was refined by reversed-phase silica gel column chromatography [eluent; 70-100% acetonitrile/0.1% trifluoroacetic acid aqueous solution] to give 2-((2,3-dihydrobenzo[1,4]dioxin-6-yl)amino)-4-phenylbenzoic acid 5 mg of a yellow solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[S:3])[NH2:2].Cl[CH2:18][CH:19]=O>CC(C)=O>[S:3]1[CH:19]=[CH:18][N:2]=[C:1]1[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: O=CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nccs2)CC1
Reaction time: 14 h

Procedure:
To a solution of tert-butyl 4-thiocarbamoylpiperidine-1-carboxylate (1 g, 4.09 mmol) in acetone (5 mL) was added 2-chloroacetaldehyde (0.32 g, 4.08 mmol). The mixture was heated under reflux for 4 hours. Additional 2-chloroacetaldehyde (0.32 g, 4.08 mmol) was added and heating was continued for another 14 hours. The solvent was removed by evaporation and the crude product was purified by silica gel chromatography to give tert-butyl 4-(thiazol-2-yl)piperidine-1-carboxylate as an oil [530 mg (1.97 mmol); LC-MS=213.1 (M+H); 1H NMR (300 MHz, CDCl3) 7.74 (d, J=3.3 Hz, 1H), 7.26 (d, J=3.3 Hz, 1H), 4.23 (brd, 2H), 3.22 (m, 1H), 2.91 (t, 2H), 2.14 (m, 2H), 1.77 (m, 2H), 1.48 (s, 9H)].
Reaction SMILES: [Br-:1].[Br-].[CH3:3][C:4]1[CH:9]=[CH:8][N+:7]([CH2:10][CH2:11][CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.[CH2:17]([N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[Br-:1].[Br-:1].[CH2:17]([N:21]([CH2:30][CH2:31][CH2:32][CH3:33])[C:22]1[CH:23]=[CH:24][C:25](/[CH:26]=[CH:3]/[C:4]2[CH:5]=[CH:6][N+:7]([CH2:10][CH2:11][CH2:12][N+:13]([CH3:14])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)=[CH:28][CH:29]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Cc1cc[n+](CCC[N+](C)(C)C)cc1
Reactant: CCCCN(CCCC)c1ccc(C=O)cc1
Agent: [Br-]
Product: CCCCN(CCCC)c1ccc(/C=C/c2cc[n+](CCC[N+](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a dry vial was added the salt 6 (708 mg, 2 mmol), 4-dibutylaminobenzaldehyde (467 mg, 2 mmol) and the vial was purged with N2. Ethanol (10 ml) was added via syringe, followed by piperidine (1 ml). Within 5 minutes the color began changing to deep red. The mixture was stirred at room temperature for 12 hours, concentrated and the salt was precipitated with dry ether. Following solvent removal, the salt was again dissolved in EtOH (8 ml) and precipitated with ether. The resulting fluorophore was filtered under a nitrogen atmosphere and dried. Yield: 1.04 g (91%). MS (dual ESI+): 204.69186 (M+H+)2+ HRMS calc. 409.3457. H-NMR (DMSO-D6): 0.92 (t, J=12 Hz, 6H); 1.38 (m, 4H); 1.48 (m, 4H); 2.24 (m, 2H); 3.22l-3.35 (m, 11 H); 3.85 (t, J=9 Hz, 4H); 4.25 (t, J=12 Hz, 2H); 6.8 (d, J=8 Hz, 2H); 6.97 (s, 2H); 7.75 (d, J=8 Hz, 2H); 8.05 (d, J=6 Hz, 2H); 8.95 (d, J=6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1(O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Reactant: Oc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3ccccc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenol. ESMS m/e: 490.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:15][C:16]([OH:18])=O)[CH2:7][CH2:8][C:9]1[O:10][C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:5])[CH3:2].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][C:16](=[O:18])[C:13]2[CH:12]=[C:11]([CH3:14])[O:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(CCc1ccc(C)o1)CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)N1CCc2oc(C)cc2C(=O)C1
Temperature: 0 °C
Yield: 44.3 %

Procedure:
[Ethoxycarbonyl[2-(5-methylfuran-2-yl)ethyl]amino]-acetic acid (0.17 g) prepared in the step 5 was dissolved in 3.5 mL of methylene chloride, then 0.12 g of thionyl chloride and 1 drop of DMF were added thereto and the mixture was heated to reflux for 2 hours. After the reaction solution was cooled, it was diluted with 5 mL of methylene chloride, then 0.18 g of aluminum chloride was added thereto and the mixture was heated to reflux again for 30 minutes. After the reaction solution was cooled, it was poured over 50 mL of ice water, the organic layer was separated, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.07 g of the objective compound as yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cn2cc(Br)ccc2n1
Yield: 72.9 %

Procedure:
15.00 g of 2-amino-5-bromopyridine (3), 16.99 g of ethyl 3-bromo-2-oxopropanoate were dissolved in ethanol (100 mL), and the solution is heated at reflux for 8 hours. The reaction mixture was concentrated, and saturated aqueous NaHCO3 was added to the residue. The resulting precipitate was isolated by filtration, and washed with water to afford 17.01 g of the titled compound as colorless powder (yield: 73%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[CH3:12].C(O)(C)C>Cl.O>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([F:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1c(F)ccc(N)c1Cl
Temperature: 82 °C
Yield: 61.1 %

Procedure:
To a mixture of 2-chloro-6-fluoro-3-nitrotoluene (140 g), isopropanol (560 ml) and water (147 ml), hydrogen reduced iron (172.2 g) was added hydrochloric acid (43 drops) and with vigorous stirring the whole heated to reflux temperature (82° C.) for 4 hours. The cooled mixture was then filtered and the filtrate evaporated under reduced pressure giving an oil which on distillation gave 2-chloro-4-fluoro-3-methylaniline (72 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:12][N:13]=[C:14]=[S:15]>CCO>[I:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:14](=[S:15])[N:13]([CH3:12])[C:4]2=[O:5]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: CN=C=S
Solvent: CCO
Product: Cn1c(=S)[nH]c2c(I)cccc2c1=O
Temperature: 100 °C
Yield: 92.9 %

Procedure:
A sealable flask was charged with 2-amino-3-iodobenzoic acid (Bosche Scientific; 10 g, 38.0 mmol) and methyl isothiocyanate (5.56 g, 76 mmol) in EtOH (120 mL) followed by TEA (7.93 mL, 57.0 mmol). The flask was sealed and heated in an oil bath at 100° C. for 4 h with a blast shield. The mixture was cooled to RT and the solvent was removed in vacuo. The residue was triturated with Et2O (40 mL) and filtered, dried to give 8-iodo-3-methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (11.22 g, 35.3 mmol, 93% yield) as an off white solid. Crude material was used in the next step. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.97 (1H, br.), 8.23 (1H, d, J=8.4 Hz), 8.00 (1H, d, J=8.0 Hz), 7.15 (1H, t, J=7.5 Hz), 3.65 (3H, s).). m/z (ES, +ve) 318.8 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](O)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.ON1C2C=CC=CC=2N=N1.[CH2:31]([C@H:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C1COCC1>[CH2:31]([C@H:33]([NH:40][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[OH:1])=[O:13])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: O=C(O)c1c(O)c(-c2ccccc2)nc2ccccc12
Reactant: CC[C@H](N)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
2.49 g (9.4 mmol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid (CAS [485-89-2]) were suspended in 150 ml of a 7/3 mixture of THF/CH3CH; 1.40 g (10.3 mmol) of 1-hydroxybenzotriazole (HOBT) and 1.27 g (9.4 mmol) of (S)-α-ethylbenzylamine dissolved in 20 ml of CH2Cl2 were added and the reaction mixture was stirred at room temperature for 30 minutes. 2.13 g (10.3 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 20 ml of CH2Cl2 were added dropwise. The reaction was left at room temperature overnight, quenched with 20 ml of H2O, evaporated in-vacuo to dryness and dissolved in EtOAc. The precipitated dicyclohexylurea was filtered off and the organic layer was washed with H2O, 20% citric acid, sat. sol. NaHCO3, sat. sol. NaCl. The organic layer was separated, dried over Na2SO4 and evaporated in-vacuo to dryness; the residue was purified by gradient column chromatography on 60-240 mesh silica gel using a mixture of hexane/EtOAc 9:1 as starting eluent and a mixture of hexane/EtOAc 7:3 as final eluent. The crude product was recrystallized from i-PrOH to yield 1.75 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8].[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[N:10]=2)[N+:7]=1[O-:8]
Reactant: Cc1cccc(-c2cccc(C)[n+]2[O-])n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(-c2cc([N+](=O)[O-])cc(C)[n+]2[O-])n1
Temperature: 0 °C

Procedure:
6,6'-Dimethyl-2,2'-bipyridine-N-oxide (1.50 g, 0.00749 moles) was dissolved in concentrated sulfuric acid (8.0 ml) and fuming nitric acid (6.0 ml) and the mixture was heated at 100° C. for four hours. The solution was poured slowly into ice-water and the pH was adjusted to 5.5 with 10% sodium hydroxide. The product was filtered and dried.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10].[BH4-].[Na+]>[Co](Cl)Cl.CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:14]=1)[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C=CC(CCCCCl)c1cccc(-c2cccnc2)c1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(CCCCCl)c1cccc(-c2cccnc2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 0.422 g (1.2 mmol) methyl 8-chloro-4[m-(3-pyridyl)phenyl]oct-2-enoate, 0.097 g (0.41 mmol) cobalt (II) chloride and 8 mL methanol at 0° C. is added slowly 0.105 g (2.8 mmol) of sodium borohydride. The resulting black suspension is stirred at 0° C. for 30 minutes and then filtered through activated magnesium silicate (Florisil) and the filter cake is washed several times with methanol. The solvent is evaporated to obtain methyl 8-chloro-4-[m-(3-pyridyl)-phenyl]octanoate; IR (CH2Cl2): 1732 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69.6 %

Procedure:
To a suspension of 5.41 g of ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate in 32 ml of ethanol was added dropwise 6.2 ml of a 5 M aqueous sodium hydroxide solution, followed by stirring at 60° C. for 1.5 hours. To the reaction mixture was added dropwise 15.8 ml of 2 M hydrochloric acid at 50° C., and then 1.5 ml of a 2 M hydrochloric acid was added thereto. The insoluble materials were collected by filtration and the solid was washed with ethanol/water=1:1 to obtain 3.46 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: C(OC([NH:8][N:9]([C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([CH3:13])([CH3:12])[CH3:11])=O)(C)(C)C.Cl.C(=O)(O)[O-].[Na+]>CO>[C:10]([N:9]([C:14](=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH2:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NN(C(=O)c1ccccc1)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)N(N)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 112.7 %

Procedure:
To a mechanically stirred solution of N-t-butoxycarbonyl-N'-benzoyl-N'-t-butylhydrazine (52 g, 0.18 mol) in methanol (100 ml) was added concentrated hydrochloric acid (35 ml). The resulting mixture was stirred at room temperature for 4 days and then neutralized with saturated aqueous sodium bicarbonate. The resulting white solid was filtered, washed with water and dried under vacuum to afford N'-t-butyl-N'-benzoylhydrazine (39 g) m.p. 124°-125° C.
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].Cl[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:20]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=1)([CH3:3])[CH3:2]
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2cc3n(c2c1)CCN(c1nccc(C(F)(F)F)n1)C3C(C)C
Temperature: 100 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (50 mg, 0.19 mmol) in iPrOH (2 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (105 mg, 0.58 mmol) and DIEA (185 mg, 0.96 mmol). The mixture was stirred at 100° C. for 4 h. The mixture was concentrated under vacuum and the residue was purified by preparative TLC to afford 1-isopropyl-7-(methylthio)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (45 mg, 57.7% yield) as a yellow oil. LC-MS MS (ESI) m/z 407.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.O1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:27]1[C:28]2[CH:29]=[CH:12][C:13]([C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=4)[CH:3]=3)=[CH:14][C:15]=2[CH2:25][CH2:26]1
Reactant: C1COCCO1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccc4c(c3)CCO4)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 27 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), 3-dihydrobenzofuran-5-ylboronic acid (50 mg, 305 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 45-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (16.8 mg, 27%). Melting point (174.2.0-184.3° C.). 1HNMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 3.32 (t, J=8.59 Hz, 2H) 4.67 (t, J=8.72 Hz, 2H) 6.56 (d, J=2.27 Hz, 1H) 7.01 (d, J=8.59 Hz, 1H) 7.62 (d, J=8.34 Hz, 2H) 7.95 (dd, J=8.46, 1.64 Hz, 1H) 8.00-8.08 (m, 4H) 8.19 (d, J=2.02 Hz, 1H) 11.20 (s, 1H). ESI-MS: m/z 415.3 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[C:14]([NH2:15])=[CH:13][N:12]=[C:11]2[CH:16]=[CH:17][S:18][C:10]=12.[Cl:19][CH2:20][C:21](OCC)(OCC)OCC>C(O)(=O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:9]2=[C:10]3[S:18][CH:17]=[CH:16][C:11]3=[N:12][CH:13]=[C:14]2[N:15]=[C:21]1[CH2:20][Cl:19]
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC2CCC1C2
Reactant: CCOC(CCl)(OCC)OCC
Solvent: CC(=O)O
Product: ClCc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of N7-[(2S)-bicyclo[2.2.1]hept-2-yl]thieno[3,2-b]pyridine-6,7-diamine (0.060 g, 0.23 mmol) and 2-chloro-1,1,1-triethoxyethane (0.134 mL, 0.700 mmol) in acetic acid (0.2 mL) was stirred at 120° C. for 30 min. The solvent was removed and the resultant residue was dissolved in dichloromethane and purified on silica gel (eluting with 0-5% MeOH in dichloromethane) to give the desired product. LCMS calculated for C16H17ClN3S (M+H)+: m/z=318.1. Found: 318.0.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][NH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C>CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CC(O)C>[C:19]1([NH:1][C:2]2[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][NH:4][N:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccccc1
Reactant: NC(=O)c1c[nH]nc1N
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2c(C)c(C)c(C)c(C)c2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: NC(=O)c1c[nH]nc1Nc1ccccc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
3-Amino-1H-pyrazole-4-carboxamide (19.8 g, 157 mmol), K3PO4 (66.7 g, 314 mmol), bromobenzene (23.2 mL, 220 mmol) and 2-propanol (785 mL) were combined in a round bottom flask and purged with a stream of N2 gas for 40 minutes. Pd2(dba)3 (1.80 g, 1.96 mmol) and 2-di-t-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-tri-1-propylbiphenyl (3.77 g, 7.85 mmol) were added and the reaction was purged for an additional 5 minutes. The reaction mixture was then heated to 80° C. and allowed to stir under a N2 atmosphere for 12 hours. The mixture was then allowed to cool to ambient temperature for an additional 16 hours. The reaction mixture was diluted with EtOAc (300 mL) and filtered through celite (slowly). The celite was washed with EtOAc (300 mL) and the filtrate was concentrated in vacuo to afford an oil which was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM). The major, low rf product, was isolated to afford a reddish-brown oily solid. The brown solid was suspended in 40 mL of warm MeOH, cooled to ambient temperature, and water (40 mL) was added. The mixture was stirred for 30 minutes and filtered. The solid was suction dried for 16 hours to afford the title compound as a peach-colored solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:27]3[N:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]4=[N:30][C:26]=3[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:35])=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C>[Br:1][C:22]1[CH:21]=[C:20]2[C:25]([C:26]3[N:30]=[C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][N:28]4[C:27]=3[N:18]([C:15]3[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:17][CH:16]=3)[C:19]2=[O:35])=[CH:24][CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(Br)ccc2c2nc3ccccn3c2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
N-Bromosuccinimide (1.2 equiv., 0.358 mmol, 0.061 g) was added to a solution of 1 (1.0 equiv., 0.295 mmol, 0.105 g) in DMF (3 ml). The reaction mixture was stirred at room temperature for 4 h. Water was added, the resulting precipitate was isolated by filtration and washed with water, isopropanol and isopropyl ether successively to give 3-bromo-6-(4-nitrophenyl)-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (101) (0.050 g, yield=36%, purity (LC)=93%).