Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:34]([C:36](OCC)=[O:37])[NH2:35]>CCOC(C)=O>[O:37]=[C:36]1[NH:34][N:35]=[C:1]([C:3]2[N:4]=[C:5]([O:13][CH2:14][C@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(C#N)cc2ccccc12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (R)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (0.749 g) was added NMP (2 mL) and ethyl hydrazinecarboxylate (0.883 g, 8.48 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with saturated aqueous NH4Cl followed by water. The organic layer was separated and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=1)[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: COc1ccc(CBr)cc1F
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(CN2C(=O)C(C)(C)c3cc(N)c([N+](=O)[O-])cc32)cc1F
Yield: 87.4 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.57 g) is alkylated using 4-bromomethyl-2-fluoro-1-methoxy-benzene (0.5 g; 2.28 mmol) and K2CO3 (0.9 g; 6.52 mmol) at RT for 18 h. After aqueous work-up the crude material is de-acetylated in hydrochloric acid (20 ml; 6 N) at reflux. After aqueous work-up 5-amino-1-(3-fluoro-4-methoxy-benzyl)-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.68 g) is obtained and used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]1[C:15]2[N:16]([N:20]=[C:21]([NH:23][C:24]3[CH:34]=[CH:33][C:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32][C:26]=4[CH:25]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45].[I-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:12])([F:11])[F:13])=[CH:6][C:5]=1[C:14]1[C:15]2[N:16]([N:20]=[C:21]([NH:23][C:24]3[CH:34]=[CH:33][C:27]4[CH2:28][CH2:29][N:30]([CH2:42][CH2:43][S:44]([CH3:47])(=[O:46])=[O:45])[CH2:31][CH2:32][C:26]=4[CH:25]=3)[N:22]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNCC4)nc12
Reactant: CS(=O)(=O)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CCS(C)(=O)=O)CC4)nc12
Temperature: 80 °C
Yield: 57 %

Procedure:
To 2-chloroethyl methyl sulfide (0.891 mL, 9.04 mmol) in methanol (10 mL) was added oxone (11.12 g, 18.08 mmol) in water (5 mL) and the reaction was stirred at room temperature overnight and concentrated. The reaction was partitioned between dichloromethane/1N sodium carbonate, washed with water/brine, dried over sodium sulfate, and concentrated to give 1-chloro-2-methanesulfonyl-ethane (1.17 g, 91%). 320b) To [8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2-yl]-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.200 g, 0.428 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (0.177 g, 1.28 mmol), 1-chloro-2-methanesulfonyl-ethane (0.122 g, 0.856 mmol), followed by sodium iodide (0.0641 g, 0.428 mmol) and was heated at 80° C. overnight and cooled at r.t. The reaction was diluted with ethyl acetate, washed with water several times, dried over sodium sulfate, and concentrated. The product was purified using Prep TLC plates (5% methanol in dichloromethane) and concentrated to give [8-(2-ethoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(2-methanesulfonyl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7yl)-amine (0.140 g, 57%). MP=105-109° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.51 (s, 1H), 8.78 (d, 1H), 7.98 (s, 1H), 7.78 (d, 1H), 7.68 (d, 1H), 7.40 (m, 3H), 7.08 (t, 1H), 6.95 (d, 1H), 4.15 (q, 2H), 3.28 (m, 2H), 3.05 (s, 3H), 2.85 (m, 2H), 2.75 (m, 4H), 2.55 (m, 4H), 1.22 (t, 3H): MS=574 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:28])([F:27])/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Br:1][C:2]1[C:3]2[O:11][CH:20]([C:19]([F:18])([F:28])[F:27])[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][C:4]=2[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: O=Cc1cc(Cl)cc(Br)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(Br)c2OC1C(F)(F)F

Procedure:
A mixture of 3-bromo-5-chlorosalicylaldehyde (1.9 g, 4.2 mmol), potassium carbonate (0.58 g, 4.2 mmol), and ethyl 4,4,4-trifluorocrotonate (0.79 g, 4.7 mmol) was stirred in N,N-dimethylformamide (5 mL) at 95° C. for 18 h. Water (100 mL) was added and the mixture was extracted with ether (3×50 mL). The combined organic extracts were washed with sodium hydroxide (10 mL) and water (2×50 mL). After drying over MgSO4 and concentrating, the mixture filtered through of a pad of silica eluting with ethyl acetate-hexanes (1:4). The eluant was concentrated and a light yellow solid was crystallized from cold hexane (0.43 g, 26%): mp 101.0–102.2° C. 1H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.65 (d, H, J=2.4 Hz), 7.61 (d, H, J=2.4 Hz), 6.03 (qH-F, 1H, J=6.9 Hz), 4.34 (m, 2H), 1.33 (t, 3H, J=7.5 Hz). ESHRMS m/z 384.9435 (M−H, Calc'd 384.9454). Anal. Calc'd for C13H9BrClF3O3: C, 40.50; H, 2.35. Found: C, 40.61; H, 2.40.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[O:26][CH3:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[O:26][CH3:27]
Reactant: CC(C)OC(=O)CBr
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of 4-fluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2-methyl-phenol (94 mg, 0.25 mmol, 1.0 eq) in acetone (4 mL) at room temperature was added Cs2CO3 (124.4 mg, 0.38 mmol, 1.5 eq). The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (55.3 mg, 1.2 mmol, 1.2 eq) was added and stirring continued for a further 2 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brinc, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as a colorless oil (65 mg, 54%).
Reaction SMILES: C([NH:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[CH2:10]O)=[S:7])(C)(C)C.[ClH:22]>>[ClH:22].[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C@@H:9]1[CH2:10][S:7][C:6]([NH2:5])=[N:8]1)([O-:21])=[O:20]
Reactant: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: NC1=N[C@H](Cc2cccc([N+](=O)[O-])c2)CS1
Temperature: 0 °C

Procedure:
1.1 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-nitrobenzyl)ethyl]thiourea in 12 cm3 of 6N hydrochloric acid are heated for 5 hours at a temperature in the region of 100° C. The reaction medium is then cooled to a temperature in the region of 0° C.; a white precipitate forms, which is filtered off on a sinter funnel and then washed with 3 times 20 cm3 of diethyl ether. The filter cake is then dried in a desiccator under vacuum. 0.68 g of (+)-(4R)-4-(3-nitrobenzyl)-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the form of beige-colored crystals melting at 232° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.15 (limiting AB: 2H); from 3.25 to 3.45 (mt: 1H); 3.63 (dd, J=13 and 8 Hz: 1H); 4.62 (mt: 1H); 7.68 (t, J=8 Hz: 1H); 7.81 (broad d, J=8 Hz: 1H); 8.18 (broad d, J=8 Hz: 1H); 8.24 (broad s: 1H); from 9.00 to 10.40 (unres. (a20 mult.: 3H); (αD20=+18.8±0.6 at a concentration of 0.5% in methanol)].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[NH:6][C:7](=[O:19])[C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[OH:21][CH:22]1[CH2:26][CH2:25][NH:24][CH2:23]1>O>[CH2:13]([N:10]1[C:9]2[N:15]=[CH:16][CH:17]=[CH:18][C:8]=2[C:7](=[O:19])[NH:6][C:5]2[C:4]([CH3:20])=[CH:3][C:2]([N:24]3[CH2:25][CH2:26][CH:22]([OH:21])[CH2:23]3)=[N:12][C:11]1=2)[CH3:14]
Reactant: OC1CCNC1
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(Cl)nc21
Solvent: O
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC(O)C3)nc21
Temperature: 170 °C

Procedure:
A suspension of the 2-chloro-5,11-dihydro-11-ethyl-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.14 g) in 3-hydroxypyrrolidine (0.29 g) in an open test tube was heated at 170° C. for 30 minutes. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed, dried, and evaporated. Chromatography over silica gel with ethyl acetate gave the title compound, which crystallized from ethyl acetate. Yield, 0.12 g, m.p. 131°-134° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([O:14]C(=O)C)[C@H:12]([O:18]C(=O)C)[C@@H:11]([CH2:22][O:23]C(=O)C)[O:10][CH:6]1[O:7][CH2:8][CH3:9])(=O)C.C[O-].[Na+]>CO>[O:7]([CH2:8][CH3:9])[C@@H:6]1[O:10][C@H:11]([CH2:22][OH:23])[C@@H:12]([OH:18])[C@H:13]([OH:14])[C@H:5]1[OH:4]
Reactant: CCOC1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
The ethyl 2,3,4,6-tetra-O-acetyl-glucopyranoside was deacetylated with 1M sodium methoxide (2 ml) in Methanol (80 ml) for 20 hours at room temperature. The mixture was neutralized with Amberlite™ IR-120 (H+ -form) and concentrated in vacuo to give the product in quantitative yield as a hygroscopic solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[C:8](/[CH3:13])=[CH:9]/[CH:10]([OH:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:13])[CH2:9][CH:10]([OH:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C/C(=C\C(C)O)c1ccc(-c2ccccc2)c(Cl)c1
Solvent: CCOC(C)=O
Product: CC(O)CC(C)c1ccc(-c2ccccc2)c(Cl)c1

Procedure:
40.0 Gm (0.147 mol) of (E)-4-(2-chloro-4-biphenylyl)-3-pentene-2-ol, dissolved in 800 ml of ethyl acetate, were hydrogenated at room temperature and at a hydrogen pressure of 3 atmospheres in the presence of 15.0 gm of Raney-nickel until hydrogen absorption had ceased. The catalyst was then filtered off, and the filtrate was evaporated in vacuo. The residue, a colorless, non-crystallizing, highly viscous oil, was purified by chromatography on silicagel, first using benzene and then benzene/ethyl acetate (ratio by volume = 9:1) as the eluant. The product, a mixture of both possible diastereomers, was not stable enough for distillation in a high vacuum. The characterization was effected by IR-, UV- and H-NMR-spectra as well as by elemental analysis:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:33])[CH:28]=[CH:29][O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:33])[CH:28]=[CH:29][O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=c1ccoc2cc(O)ccc12
Solvent: c1ccncc1
Solvent: O
Product: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, 0.24 ml of trifluoromethansulfonic anhydride was added at 0° C. to 4 ml of pyridine solution with 180 g of 7-hydroxy-4H-chromen-4-one, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution, and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 83 mg of the above compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][C@H:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:8]=[CH:7][C:6]=2[C:5]([O:19][CH3:20])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:20][O:19][C:5]1[C:6]2[CH2:7][CH2:8][C@@H:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:10][CH2:11][C:12]=2[CH:2]=[CH:3][C:4]=1[NH2:21]
Reactant: COc1c([N+](=O)[O-])cc(Cl)c2c1C=C[C@@H](N1CCOCC1)CC2
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1c(N)ccc2c1CC[C@@H](N1CCOCC1)CC2
Reaction time: 16 h

Procedure:
A mixture of 4-((S)-4-Chloro-1-methoxy-2-nitro-6,7-dihydro-5H-benzocyclohepten-7-yl)-morpholine (12 mg, 0.035 mmol) and 20% Pd(OH)2/C (9 mg) in Methanol (4 mL), was placed under a blanket of Hydrogen at atmospheric pressure. After 16 h, the reaction was filtered and concentrated under reduced pressure to give (S)-1-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([C:14]1[N:19]=[CH:18][C:17]([S:20](Cl)(=O)=[O:21])=[CH:16][CH:15]=1)#[N:13]>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:17]2[CH:18]=[N:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Agent: CN(C)c1ccncc1
Product: N#Cc1ccc(S(=O)Nc2cccc3cccnc23)cn1
Yield: 26.9 %

Procedure:
In a similar fashion using route 18 general procedure 27, 8-aminoquinoline (200 mg, 1.39 mmol), 6-cyanopyridine-3-sulfonyl chloride 19 (337 mg, 1.66 mmol) and DMAP (cat.) gave the title compound (110 mg, 25%) after purification by column chromatography with n-hexane/EtOAc (4:1) as the eluent.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)(=O)=O.[I-:23].[Na+]>>[I:23][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)OCCCc1cccc(OCc2ccccc2)c1
Reactant: [I-]
Agent: [Na+]
Product: ICCCc1cccc(OCc2ccccc2)c1
Yield: 85 %

Procedure:
Using 3-[3-(benzyloxy)phenyl]propyl methanesulfonate (19.7 g) and sodium iodide (29.25 g), the same reaction as Reference Example 9-(v) was carried out to yield the titled compound (18.4 g) as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH2:20][O:21]CC3C=CC=CC=3)=[CH:8][C:7]([C:29]([NH2:31])=[O:30])=[CH:6][N:5]2[C:32]=1[CH3:33].C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH2:20][OH:21])=[CH:8][C:7]([C:29]([NH2:31])=[O:30])=[CH:6][N:5]2[C:32]=1[CH3:33]
Reactant: Cc1cccc(CCOCc2ccccc2)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Cc1cccc(CCO)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Yield: 97.8 %

Procedure:
2,3-dimethyl-8-(2-(2-(benzyloxy)ethyl)-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxamide (0.13 g, 0.29 mmol), cyclohexene (1 ml), Pd(OH)2 cat. (25 mg) were added to ethanol (5 ml) and the mixture was refluxed overnight. An additional amount of cyclohexene (1 ml) and Pd(OH)2 cat. (25 mg) were added and the mixture was refluxed for 4 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (9:1) as eluent. Treating the residue with chloroform and filtration gave 0.1 g (99%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[N:24]1([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OCCCN3CCCCC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1cc(N2CCNCC2)ccc1OCCCN1CCCCC1
Yield: 101.1 %

Procedure:
A solution of 4-[4-(3-piperidin-1-yl-propoxy)phenyl]-piperazine-1-carboxylic acid tert-butyl ester (D10) (1.0 g; 2.48 mM) in trifluoroacetic acid (5 ml) was stirred at room temperature for 60 minutes. The resulting mixture was purified on an SCX ion exchange cartridge to afford the title compound as a colourless crystalline solid (0.76 g)
Reaction SMILES: [CH3:1][N:2]1[N:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.[Al](Cl)(C)C.[CH3:12][C:13]1[O:14][C:15]2[CH:21]=[C:20]([C:22](OCC)=[O:23])[CH:19]=[C:18]([O:27][CH:28]3[CH2:31][N:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29]3)[C:16]=2[CH:17]=1>ClCCl>[CH3:12][C:13]1[O:14][C:15]2[CH:21]=[C:20]([C:22]([NH:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[N:6]=3)=[O:23])[CH:19]=[C:18]([O:27][CH:28]3[CH2:31][N:30]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:29]3)[C:16]=2[CH:17]=1
Reactant: Cn1ncc(N)n1
Reactant: CCOC(=O)c1cc(OC2CN(S(C)(=O)=O)C2)c2cc(C)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCl
Product: Cc1cc2c(OC3CN(S(C)(=O)=O)C3)cc(C(=O)Nc3cnn(C)n3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.5 %

Procedure:
To a solution of 2-methyl-2H-1,2,3-triazol-4-amine (267 mg, 1.98 mmol) in dichloromethane (5 mL) at 0° C. was added Al(CH3)2Cl (1.98 mL, 1.98 mmol, 1M in hexanes) drop-wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-methyl-4-{[1-(methylsulfonyl)azetidin-3-yl]oxy}-1-benzofuran-6-carboxylate (70 mg, 0.198 mmol) was added and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CH2Cl2, washed with brine and dried over Na2SO4. The product was purified by gradient silica gel chromatography using CHCl3/MeOH (95/5 to 85/15) to give the title compound (55 mg, 68%) as a white solid after evaporation of the solvents. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.51 (s, 3 H) 2.94 (s, 3 H) 4.06-4.15 (m, 3 H) 4.16 (d, J=4.80 Hz, 2 H) 4.39 (dd, J=9.60, 6.32 Hz, 2 H) 5.05-5.23 (m, 1 H) 6.54 (s, 1 H) 6.97 (s, 1 H) 7.54 (s, 1 H) 8.12 (s, 1 H) 8.46 (s, 1 H); MS (ESI, pos): 406.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH3:31])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.CCN(C(C)C)C(C)C.Cl[C:42]([O:44][CH3:45])=[O:43]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH3:31])[C:42](=[O:43])[O:44][CH3:45])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: COC(=O)Cl
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 18 h
Yield: 17 %

Procedure:
N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials, 217 mg) and DIPEA (0.2 ml) were stirred in DCM (20 ml). Methyl chloroformate (0.043 ml) was added slowly and the resulting solution was stirred for 18 hours. The solution was evaporated and the residue purified by chromatography, eluting with increasing concentrations of methanol in ethyl acetate (5-10%). The appropriate fractions were evaporated to give an oil, which was triturated with acetonitrile to give the title compound as a solid (43 mg, 17%); NMR spectrum (DMSO-d6 @ 373K) 2.88 (s, 3H), 3.30 (s, 3H), 3.75-3.85 (t, 2H), 4.35-4.55 (bs, 2H), 5.30 (s, 2H), 7.10-7.30 (m, 2H), 7.30-7.40 (m, 2H), 7.50-7.60 (m, 2H), 7.70-7.78 (t, 1H), 7.80-7.95 (m, 2H), 8.43 (bs, 1H), 8.75-8.80 (d, 1H), 9.60-9.80 (bs, 1H); Mass spectrum MH+ 494.0.
Reaction SMILES: CC1NC(C)=CC=1C1C=C[CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH2:32]CC5C=CC=CC=5)[CH2:28][CH2:27]4)=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)[N:8]=1.Cl.NO.O.Cl>C(O)C>[CH2:32]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:9]4[N:8]=[C:9]([NH2:8])[CH:13]=[CH:14][CH:10]=4)=[CH:18][CH:17]=3)=[CH:20][CH:21]=2)[CH2:31][CH2:30]1)[CH2:16][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(-c2cccc(-c3ccc(-c4ccc(CN5CCN(CCc6ccccc6)CC5)cc4)cc3)n2)c(C)[nH]1
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(-c3ccc(CN4CCN(CCc5ccccc5)CC4)cc3)cc2)n1
Yield: 135.8 %

Procedure:
To a 100 mL round-bottomed flask equipped with N2 inlet were added 190 mg (0.361 mmol) 2-(2,5-dimethylpyrrolyl)-6-[4′-(4-phenethyl-piperazin-1-ylmethyl)-biphenyl-4-yl]-pyridine, 126 mg (1.81 mmol) hydroxylamine hydrochloride, 1 mL water, and 5 mL ethanol. The reaction was heated at reflux for 36 hours followed by treatment with an additional 50 mg hydroxylamine hydrochloride and refluxing for 24 hours. The reaction was cooled, poured into dilute aqueous hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 1 N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was converted to the hydrochloride salt using 1 N HCl in ether to afford 110 mg (55%) of a solid, mp 267-269° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]([C:11]2([CH2:21][C:22]#[N:23])[CH2:20][CH2:19][C:14]3(OCC[O:15]3)[CH2:13][CH2:12]2)[N:4]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:2][C:3]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]([C:11]2([CH2:21][C:22]#[N:23])[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]2)[N:4]=1
Reactant: N#CCC1(n2cc(C(N)=O)c(N)n2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCC1(n2cc(C(N)=O)c(N)n2)CCC(=O)CC1
Temperature: 80 °C

Procedure:
Aqueous hydrochloric acid (1 N, 36 mL, 36 mmol) was added to a solution of 3-amino-1-(8-(cyanomethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazole-4-carboxamide (Intermediate 35-5) (5.5 g, 18 mmol) in THF (106 mL). The reaction vessel was capped with a reflux condenser and heated to 80° C. for 2 hours. The reaction mixture was then cooled to ambient temperature, diluted with ethyl acetate, and neutralized with saturated aqueous sodium bicarbonate solution. The organic layer was separated and then washed with brine. The washed solution was dried over sodium sulfate, the dried solution was filtered, and the filtrate was concentrated to afford the title compound, which was used without further purification.