Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:28]([CH:38]3[CH2:40][CH2:39]3)CC3C=CC(OC)=CC=3)[C:12]3[N:13]([C:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[CH:22]=4)=[O:19])=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.[Br-].[Li+].[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1.C(O)(C(F)(F)F)=O>CO>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:15]2[N:13]3[N:14]=[C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH2:3][CH2:4]4)[CH:10]=[C:11]([NH:28][CH:38]4[CH2:39][CH2:40]4)[C:12]3=[N:17][CH:16]=2)=[O:19])[CH:26]=[CH:25][N:24]=1
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Reactant: CC1(C)CO1
Agent: [Br-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(O)CN[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4ccnc(Cl)c4)n3n2)CC1
Reaction time: 0.17 h

Procedure:
A solution of 6-((trans)-4-aminocyclohexylamino)-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.178 mmol), lithium bromide (0.774 mg, 8.91 μmol) and 2,2-dimethyloxirane (12.85 mg, 0.178 mmol) in MeOH (5 mL) was stirred at 50° C. for 7 hrs. The reaction mixture was concentrated down, diluted in methanol (1 mL) and treated with TFA (0.824 mL, 10.69 mmol). After 10 minutes, the reaction mixture was concentrated, diluted with methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 30% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA) to isolate N-(2-chloropyridin-4-yl)-8-(cyclopropylamino)-6-((trans)-4-(2-hydroxy-2-methylpropylamino)cyclohexylamino)imidazo[1,2-b]pyridazine-3-carboxamide (41.9 mg, 0.082 mmol, 45.8% yield) as a white solid. LC/MS (BEH C18 2.1×50 mm 1.7u, Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2.2 min with 1 min hold time, Flow rate=2 mL/min, detection at 254 nm, Solvent A: 100% water/0.05% TFA; Solvent B: 100% ACN/0.05% TFA). Rt=0.71 minutes. [M+H]=513.3. 1H NMR (400 MHz, MeOD) δ ppm 8.47 (2H, s), 7.96-8.08 (1H, m), 7.52-7.70 (1H, m), 6.44 (1H, s), 3.69-3.92 (1H, m), 3.15-3.30 (1H, m), 3.05 (2H, s), 2.60-2.77 (1H, m), 2.36-2.48 (2H, m), 2.17-2.37 (2H, m), 1.60-1.80 (2H, m), 1.41-1.62 (2H, m), 1.35 (6H, s), 0.87-1.05 (2H, m), 0.63-0.78 (2H, m)
Reaction SMILES: [F:1][C:2]1([F:37])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[C:24](C(C)(C)C)=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([O-:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.Cl>CC#N>[F:37][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=5)[C:26]([OH:28])=[O:27])[C:20]([CH3:36])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)[O-])c1C(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(=O)O)c1
Temperature: 45 °C
Reaction time: 36 h

Procedure:
To a slurry of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)-t-butylbenzoate (1.0 eq) in MeCN (3.0 vol) was added water (0.83 vol) followed by concentrated aqueous HCl (0.83 vol). The mixture was heated to 45±5° C. After stirring for 24 to 48 h, the reaction was complete, and the mixture was allowed to cool to ambient. Water (1.33 vol) was added and the mixture stirred. The solid was collected by filtration, washed with water (2×0.3 vol), and partially dried on the filter under vacuum. The solid was dried to a constant weight (<1% difference) in a vacuum oven at 60° C. with a slight N2 bleed to afford 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid.HCl as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=O)=[CH:9]2)([O-:3])=[O:2].[N:16]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([NH2:16])=[O:15])=[CH:9]2)([O-:3])=[O:2]
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reaction time: 0.33 h
Yield: 73.3 %

Procedure:
To a mixture of 7-nitro-1H-indole-2-carboxylic acid (4.40 g), 1H-1,2,3-benzotriazol-1-ol (3.45 g) and N,N-dimethylformamide (80 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (4.90 g) at room temperature, and the mixture was stirred for 20 min and 28% aqueous ammonia (7.8 mL) was added. The reaction mixture was stirred at room temperature for 1 hr, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (3.21 g, yield 73%) as yellow crystals. melting point 297-298° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:33])([CH3:32])[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=O)[CH2:14][C:13](=[O:34])[NH:12][C@H:11]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:43])[C@@:10]3([C@@H:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:33])([CH3:32])[CH2:25][NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:14][C:13](=[O:34])[NH:12][C@H:11]3[C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH3:42])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1[C@@H]1NC(=O)C[C@H](c2cc(Cl)ccc2OC(C)(C)CNS(C)(=O)=O)[C@@]12C(=O)Nc1cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
At 0° C., to a solution of chiral (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-dimethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg, 0.03 mmol) prepared in Example 12b in THF (1 mL) was added a toluene solution (1 M) of DIBALH (0.18 mL, 0.18 mmol) in one portion. After stirred for 0.5 h, the mixture was quenched with water. Then the mixture was filtered and the filtrate was concentrated. The residue was purified by Prep-HPLC to give the title compound as a white solid (9 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][S:14]([O:11][CH2:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[CH:6][C:7]=1[F:12])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(F)c(CO)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(F)c(C#N)cc1F
Temperature: 0 °C

Procedure:
To an ice cooled solution of 2,5-difluoro-4-hydroxymethylbenzonitrile (3.10 g, 0.0183 mol; see step (iii) above) and methanesulfonyl chloride (2.21 g, 0.0192 mol) in 60 mL of methylene chloride was added triethyl amine (1.95 g, 0.0192 mol) with stirring. After 1.5 h at 0° C. the mixture was washed with water, dried (Na2SO4) and evaporated. The product could be used without further purification. Yield: 4.5 g (99%).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:31])[CH:28]=2)[CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:31][C:27]4[CH:28]=[C:29]5[C:24](=[CH:25][CH:26]=4)[CH2:23][N:22]([CH3:21])[CH2:30]5)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CN1Cc2ccc(N)cc2C1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2C1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (75.0 mg, 0.244 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (40.0 mg, 0.270 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.049 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 6.98 (s, 1H), 3.94 (s, 2H), 3.88 (s, 2H), 3.09 (s, 3H), 2.61 (s, 3H). MS=420 (MH)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH2:23]([N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:28]=2[CH2:27][CH2:26]1)[CH3:24].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[N:7][C:2]([NH:36][C:33]2[CH:34]=[CH:35][C:28]3[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:31][CH2:30][C:29]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: O=C(N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)C(F)(F)F)n3)cc2CC1
Temperature: 120 °C
Reaction time: 7 h
Yield: 45 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-2,2,2-trifluoro-acetamide (204 mg, 0.571 mmol) was added into a Vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (106 mg, 0.557 mmol) in 2-Methoxyethanol (7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.2 mL) was added and the reaction was heated at 120° C. After 7 h, the reaction was cooled to room temperature, Macroporous carbonate resin (3.16 mmol/g loading; 530 mg, 1.68 mmol) was added and stirred 30 min. The polymer was filtered off, and the solvent removed in vacuo. The residue was dissolved in DCM, then chromatographed (2×12 g SiO2, ISCO, 0-10% MeOH:DCM) to afford N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-2,2,2-trifluoro-acetamide (128 mg, 45%) as a beige solid. m.p.=165° C.; LCMS (m/e) 511 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.94 (s, 1H), 7.32 (m, 2H), 7.08 (d, 1H, J=8.1 Hz), 6.93 (s, 1H), 5.27 (d, 1H, J=7.4 Hz), 3.99 (m, 1H), 3.87 (m, 1H), 3.68 (m, 3H), 3.11 (m, 2H), 2.7-2.9 (m, 4H), 2.30 (d, 1H, J=11.4 Hz), 2.16 (d, 1H, J=11.7 Hz), 1.8-1.9 (m, 2H), 1.2-1.6 (m, 8H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:64][N:65]1[CH2:70][CH2:69][N:68]([CH:71]2[CH2:76][CH2:75][CH:74]([NH2:77])[CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][C@H:74]5[CH2:73][CH2:72][C@H:71]([N:68]6[CH2:67][CH2:66][N:65]([CH3:64])[CH2:70][CH2:69]6)[CH2:76][CH2:75]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(C2CCC(N)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(C)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for min before the addition of 4-(4-methylpiperazin-1-yl)cyclohexanamine (Intermediate 17) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2 and Preparative—3) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide (white solid, 17 mg, 18%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]([CH3:27])[CH3:26])[N:17]=2)=[O:15])[CH2:10][C@H:9]1[CH2:28][C:29](O)=[O:30])=O)(C)(C)C.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:25]([N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]([NH:13][C@H:11]2[CH2:10][C@@H:9]([CH2:28][C:29](=[O:30])[N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[NH:8][CH2:12]2)=[O:15])=[N:17]1)([CH3:27])[CH3:26]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Reactant: C1CCNCC1
Product: CC(C)n1nc(C(=O)N[C@@H]2CN[C@H](CC(=O)N3CCCCC3)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 7 from ((2S,4S)-1-(tert-butoxycarbonyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidin-2-yl)acetic acid (step 1 of Example 13) and piperidine.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][C:22](=[O:28])[NH:23]3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)(C)C>[N:11]1([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH2:20][CH2:21][C:22](=[O:28])[NH:23]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C1CCc2c(cccc2OCCCN2CCN(Cc3ccccc3)CC2)N1
Solvent: CC(C)O
Product: O=C1CCc2c(cccc2OCCCN2CCNCC2)N1

Procedure:
(a)-2 5 Grams of 5-[3-(4-benzylpiperazinyl)propoxy]-3,4-dihydrocarbostyril and 0.8 g of 5%-Pd charcoal are added into 150 ml of isopropanol and catalytically reduced at 60° C. for 5 hours under 3 atm. of hydrogen gas pressure. The catalyst is removed by filtration and the mother liquor thus obtained is concentrated under reduced pressure. The residue is recrystallized from ligroin-benzene to obtain 4.1 g of 5-(3-piperazinylpropoxy)-3,4-dihydrocarbostyril in the form of colorless prism-like crystals having a melting point of 195°-196° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([OH:23])[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:16](=[CH:21][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Yield: 1246.1 %

Procedure:
Methyl N-(benzyloxycarbonyl)-4-aminomethylsalicylate (6.06 g, 19.2 mmoles) was dissolved in acetone (150 mL), and benzyl bromide (2.60 mL, 21.9 mmoles) and anhydrous potassium carbonate (13.28 g, 96.1 mmoles) were added. The mixture was stirred and heated at reflux for 22 hours. The mixture was concentrated to remove most of the acetone, and ethyl acetate (100 mL) was added. Aqueous hydrochloric acid (1N, 200 mL) was added slowly, swirling frequently to dissolve the solid carbonate. The layers were separated, and the aqueous layer was extracted with ethyl acetate (50mL). The ethyl acetate solutions were combined and washed with water (100 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to about 50 mL. This solution was heated to boiling, and hexanes (150 mL) were added. The solution was cooled in ice, and crystals slowly formed. The crystals were collected by filtration, washed with hexanes, and dried in vacuo to afford6.97 g (89% yield) of methyl N-(benzyloxycarbonyl)-4-aminomethyl-2-O-benzylsalicylate (m.p. 106°-107° C., open capillary, uncorrected).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-])=O)=[N:13][CH:14]=2)=[CH:4][CH:3]=1.O>C(O)(=O)C.[Fe]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Br)nc2)cn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Oc2ccc(Br)nc2)cn1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
5-[(6-bromo-3-pyridinyl)oxy]-2-nitropyridine 65 mg, 0.22 mmol) was dissolved in acetic acid (1.5 ml) and water (2 ml) and heated to 50 degrees C. Iron powder (42 mg, 0.75 mmol) was added and the mixture was left for 1 h. Filtration and purification by column chromatography on silica (ethyl acetate/hexane 2:1) gave 57 mg, 97% of desired product.
Reaction SMILES: Br.[N:2]1([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[S:15][CH:16]=[C:17]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=4)[N:18]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH3:28][O:29][C:30]([C:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1([NH:38][C:23]([C:22]2[CH:26]=[CH:27][C:19]([C:17]3[N:18]=[C:14]([N:11]4[CH2:10][CH2:9][N:8]([N:2]5[CH2:3][CH2:4][O:5][CH2:6][CH2:7]5)[CH2:13][CH2:12]4)[S:15][CH:16]=3)=[CH:20][CH:21]=2)=[O:24])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:31]
Reactant: O=C(O)c1ccc(-c2csc(N3CCN(N4CCOCC4)CC3)n2)cc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: Br
Product: COC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(N5CCOCC5)CC4)n3)cc2)CCCCC1

Procedure:
4.50 g (9.90 mmol) of 4-[2-[4-(4-morpholinyl)-1-piperazinyl]-4-thiazolyl]benzoic acid hydrobromide was used instead of 4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]benzoic acid hydrobromide and 1.57 g (9.90 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in the process according to Reference example 201 to obtain 5.08 g (quantitative) of the title compound.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[N:23]=[C:24]=[S:25]>>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][C:16]=1[N:23]=[C:24]1[N:8]([CH2:7][C:6]2[CH:12]=[CH:13][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10][S:25]1
Reactant: N#Cc1ccc(N=C=S)c(Cl)c1
Reactant: ClCC[NH2+]Cc1ccc(Cl)cc1
Agent: [Cl-]
Product: N#Cc1ccc(N=C2SCCN2Cc2ccc(Cl)cc2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.
Reaction SMILES: [O-]CC.[Na+].[Cl:5]/[C:6](=[C:9](\[Cl:12])/[CH:10]=[O:11])/[CH:7]=[O:8].Cl.[CH3:14][NH2:15].O>C(O)(=O)C>[Cl:5][C:6]1[C:7]([N:15]([CH3:14])[C:10](=[O:11])[C:9]=1[Cl:12])=[O:8]
Reactant: O=C/C(Cl)=C(/Cl)C=O
Reactant: CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
Sodium ethoxide (3.56 g, 50 mmol) was added to a solution containing 2,3-dichloromaleic hydride (5.56 g, 33.3 mmol) and methylamine hydrochloride (3.50 g, 55.0 mmol) in 40 mL of acetic acid. The mixture was stirred under a CaCl2 drying tube at 25° C. for 16 hours and then refluxed for 4 hours. The cooled mixture was poured into water (350 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were washed with 100 mL portions of saturated aqueous NaHCO3, water and brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 3.82 g (64%) of 2,3-dichloro N-methylmaleimide as white crystals. Concentration of the mother liquor and chromatography of the residue by radial preparative layer chromatography (Chromatotron, Harrison Research), gave an additional 0.81 g of 2,3-dichloro N-methylmaleimide, raising the yield to 77%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:22])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])#[CH:24].C(N(C(C)C)C(C)C)C.O1CCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][O:20][C:18](=[O:19])[CH2:17][NH:16][C:14]([C:7]1[C:8](=[O:13])[N:9]([CH3:12])[C:10]2[C:5]([C:6]=1[OH:22])=[CH:4][CH:3]=[C:2]([C:24]#[C:23][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:11]=2)=[O:15]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1c(O)c2ccc(C#C[Si](C)(C)C)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
In a sealed tube was combined methyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (0.75 g, 2.0 mmol), Dichlorobis(triphenylphosphine)palladium(II) (0.14 g, 0.20 mmol), copper(I) iodide (0.077 g, 0.41 mmol), ethynyltrimethylsilane (1.4 ml, 10 mmol), and N-ethyl-N-isopropylpropan-2-amine (2.8 ml, 16 mmol) in tetrahydrofuran (20.0 ml, 2.0 mmol). The tube was flushed with Ar, sealed, and placed in an oil bath at 100° C. for 5 hours. The dark mixture was cooled to rt, filtered and washed with ethyl acetate (2×30 mL). The crude mixture was concentrated, adsorbed onto silica and purified by flash chromatography (15% to 40% EtOAc:Hex gradient) to afford the product as a solid (0.59 g, 75% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH3:13])[N:6]([CH3:14])[C:5]2=[O:15].[C-:16]#[N:17].[K+]>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>[CH2:12]([C:7]1[N:6]([CH3:14])[C:5](=[O:15])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:16]#[N:17])[CH:3]=2)[N:8]=1)[CH3:13]
Reactant: [C-]#N
Reactant: CCc1nc2ccc(Br)cc2c(=O)n1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Product: CCc1nc2ccc(C#N)cc2c(=O)n1C
Temperature: 25 °C
Yield: 41.7 %

Procedure:
The substrate of 6-bromo-2-ethyl-3-methyl-3H-quinazolin-4-one (50.0 mg, 0.189 mmol), KCN (23.1 mg, 0.37 mmol), Pd (PPh3)4 (10.0 mg, 0.0094 mmol), and CuI (3.6 mg, 0.019 mmol) was added to a flask, which was flushed with N2. The solvent acetonitrile (2 ml) was added via syringe. The resulting mixture was irradiated at 170° C. for 2 hours in the SmithSynthesizer Microwave Reactor (Personal Chemistry) with vigorous agitation by a magnetic stirrer. The mixture was cooled to room temperature, diluted with ethyl acetate (5 ml), and then filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous MgSO4, and concentrated by rotary evaporation. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 2-Ethyl-3-methyl-4-oxo-3,4-dihydro-quinazoline-6-carbonitrile (Yield 16.8 mg, 46.2%). 1H NMR (400 MHz, CDCl3): δ 1.35 (t, 3H, J=7.30 Hz), 2.85 (q, 2H, J=14.62, 7.30 Hz), 3.54 (s, 3H), 7.68 (d, 1H, J=8.58 Hz), 7.83 (dd, 1H, J=8.58, 2.02 Hz), 8.51 (d, 1H, J=2.02 Hz). MS/M/Z calc. 213.2, Found (ESI); 214.0 (M+1)+. Retention time 2.13 minutes.