Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH3:24][CH:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:33]2/[C:29]([NH:28][CH:25]([CH3:24])[C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: C#CC(C)NC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CC(C)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 75 °C
Reaction time: 6 h
Yield: 36.3 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.91 g) in 2-propanol (20 mL) were added 4-(but-3-yn-2-ylamino)-1,3-thiazol-2(5H)-one (1.42 g) and piperidinium acetate (834 mg). The reaction mixture was stirred at 75° C. for 6 hr and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.0 g).
Reaction SMILES: COC([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[C:12]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:13]=3[S:14][CH:15]=2)[CH2:7][CH2:6]1)=O.[BrH:24]>>[BrH:24].[F:23][C:20]([F:21])([F:22])[C:17]1[CH:18]=[CH:19][C:12]2[C:11]([CH:8]3[CH2:7][CH2:6][NH:5][CH2:10][CH2:9]3)=[CH:15][S:14][C:13]=2[CH:16]=1
Reactant: COC(=O)N1CCC(c2csc3cc(C(F)(F)F)ccc23)CC1
Agent: Br
Product: FC(F)(F)c1ccc2c(C3CCNCC3)csc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
A mixture of 4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid methyl ester (3.1 g, 9.0 mmol) in HBr (45 mL, 30% in acetic acid) was stirred at room temperature for 20 hours when the volatiles were removed in vacuo. The residue was washed with EtOAc and the product was collected by filtration yielding 3.09 g (94%) of the desired product as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([OH:3])=[O:2].[CH2:12](OS(OCC)(=O)=O)[CH3:13].C(N(CC)CC)C>ClCCl>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O:3][CH2:12][CH3:13])=[O:2]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=Cc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a 3-neck 500 ml round-bottom flask equipped with a magnetic stirrer, reflux condenser and addition funnel was added 2-carboxybenzaldehyde (30.00 g, 0.200 moles), diethylsulfate (33.92 g, 0.220 moles) and 150 ml of dichloromethane under nitrogen. The mixture was heated to reflux and triethylamine (30.36 g, 0.300 moles) was added at such a rate to maintain a brisk reflux. After the addition was complete, the solution was heated at reflux for 1 hour and then allowed to cool to room temperature and stirred overnight. The mixture was then washed with water (1×50 ml), 1.0N hydrochloric and solution (1×50 ml), saturated sodium bicarbonate solution (1×50 ml), saturated sodium chloride solution (1×50 ml), dried over magnesium sulfate and concentrated in vacuo to give 21.0 g of the product as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:11]2[N:6]([C:7]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][C:17]4=[O:22])=[CH:12][C:8]=3[O:9][CH2:10]2)[C:5](=[O:23])[O:4]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:1][CH2:2][C@H:3]2[C@H:11]3[N:6]([C:7]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][O:19][CH2:18][C:17]5=[O:22])=[CH:12][C:8]=4[O:9][CH2:10]3)[C:5](=[O:23])[O:4]2)=[O:33])=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Solvent: ClCCl
Product: O=C(NC[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12)Nc1ccc(Cl)cc1
Yield: 84.4 %

Procedure:
Using compound (3S,3 aS)-3-aminomethyl-7-(3-oxomorpholin-4-yl)-3a,4-dihydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-1(3H)-one (the product of step (e) in Example 1) (60 mg, 0.188 mmol), p-chlorophenylisocyanate (35 mg, 0.225 mmol), and TEA (28 mg, 0.282 mmol) as starting materials, DCM as solvent, preparation following the method as described in Example 21 afforded white compound 75 mg, yield 84.4%.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[CH:17]2>>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH:18]=[CH:17]2
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Brc1ccc2[nH]ccc2c1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1

Procedure:
The title compound was prepared from 4-(tert-butyl)benzyl bromide (180 g, 768 mmol) and 5-bromoindole (152 g, 768 mmol) in substantially the same manner, as described in Step 1 of Example 25. The product (257 g, 97%) was obtained as a yellow solid, mp: 108-109° C. Mass spectrum (ESI, [M+H]+) m/z 342. 1HNMR (400 MHz, DMSO-d6): δ 7.73 (s, 1H), 7.55 (s, 1H), 7.44 (d, 1H, J=8.71 Hz), 7.30 (d, 2H, J=7.96 Hz), 7.19 (d, 1H, J=8.71 Hz), 7.10 (d, 2H, J=7.63 Hz), 6.46 (s, 1H), 5.36 (s, 2H), and 1.21 ppm (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8](/[CH:12]=[CH:13]\[O:14][CH2:15]C)=[CH:7][N:6]=1)=[O:4].CO.[C:19]([O-])(O)=[O:20].[Na+]>Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH2:12][CH:13]([O:14][CH3:15])[O:20][CH3:19])=[CH:7][N:6]=1)=[O:4]
Reactant: O=C([O-])O
Reactant: CCO/C=C\c1cnc(C(=O)OC)c(N)n1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc(CC(OC)OC)nc1N

Procedure:
A solution of 3-amino-5-((Z)-2-ethoxy-vinyl)-pyrazine-2-carboxylic acid methyl ester (220 mg, 0.986 mmol) in 3M HCl in MeOH (210 μl, 6.90 mmol) was heated at 55° C. over night. A solution of 10% of NaHCO3 was added the mixture was extracted with EtOAc. The combined organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a brown solid (141 mg). The crude material was directly used in the next step without further purification.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1>>[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:20][CH2:21][C@H:22]([NH:25][C:36](=[O:37])[CH2:35][CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:23][CH2:24]3)[CH2:15][CH2:16]2)=[N:9][CH:10]=1
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Reactant: O=C(O)CC1CCOCC1
Agent: Cl
Product: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](NC(=O)CC4CCOCC4)CC3)CC2)c2ccoc12

Procedure:
The title compound, white solid (115 mg, 82%), MS (ISP) m/z=469.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and tetrahydropyran-4-yl-acetic acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].BrCCC[CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>CN(C=O)C>[CH3:12][C:9]1[N:10]=[CH:11][C:6]([C:4]2[N:3]=[CH:2][N:1]([CH2:23][N:24]3[C:28](=[O:29])[C:27]4[C:26](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]3=[O:34])[CH:5]=2)=[CH:7][CH:8]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: Cc1ccc(-c2c[nH]cn2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cn(CN3C(=O)c4ccccc4C3=O)cn2)cn1
Temperature: 80 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
To a solution of 5-(1H-imidazol-4-yl)-2-methyl-pyridine (1 eq) in DMF was added potassium carbonate (4 eq) at room temperature under dry conditions. After heating the reaction mixture in a 80° C. oil bath for 1 hour, N-(4-bromobutyl)phtalimide (3.9 eq) was added to the mixture. The solution was left stirring in a 80° C. oil bath for 24 hours. Upon cooling, the reaction was filtered and the solid was washed with ethyl acetate. The filterate was diluted with ethyl acetate and washed with NH4Cl (sat.), H2O, NaCl (sat.), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography using an initial solvent gradient of 97% DCM, 3% MeOH, and 0.1% TEA (1 L) to afford the product (37%). MH+(361)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=O)(=[O:3])[NH2:2].[OH-].[Na+]>CCO>[N+:10]([C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:13]=[C:14]([C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)[NH:2][C:1]2=[O:3])([O-:12])=[O:11]
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)c1cnccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]c(-c2cnccn2)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.1 %

Procedure:
To a mixture of N-(2-carbamoyl-4-nitrophenyl)pyrazine-2-carboxamide (2.42 g, 8.43 mmol, 1.0 eq.) in EtOH (60 mL) was added NaOH (198 g, 49.5 mmol, 5.0 eq.). The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed in vacuo. The residue was partitioned between H2O (50 mL) and ethyl acetate (50 mL). The aqueous layer was neutralized to pH 5 by slow addition of aqueous citric acid. The resulting precipitate was collected and dried to give 2.00 g of 6-nitro-2-(pyrazin-2-yl)quinazolin-4(3H)-one as a yellow solid (88%), LCMS m/z=270.1 (M+1) (Method A) (retention time=1.36 min).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]3[N:11]([C:16]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[F:28])=[O:20])=[CH:17][N:18]=3)[N:12]=[C:13](Cl)[CH:14]=2)[CH:5]=[CH:4][CH:3]=1.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>CN1C(=O)CCC1>[F:28][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:22]=1[NH:21][C:19]([C:16]1[N:11]2[N:12]=[C:13]([NH:29][C@H:30]3[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]3)[CH:14]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]4)[N:7]=3)[C:10]2=[N:18][CH:17]=1)=[O:20]
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(Br)n3)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccncc1F)c1cnc2c(Nc3cccc(N[C@H]4CC[C@H](O)CC4)n3)cc(N[C@H]3CC[C@H](O)CC3)nn12
Temperature: 160 °C

Procedure:
A mixture of 8-(6-bromopyridin-2-ylamino)-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (40 mg, 0.086 mmol) and (trans)-4-aminocyclohexanol (100 mg, 0.868 mmol) in NMP (0.5 mL) was heated at 160° C. in a microwave for 1.5 h (300 W power). The reaction mixture was cooled to room temperature and purified by preparative reversed-phase HPLC to give 45B (39.7 mg, 62%) as yellow solid. HPLC Rt=2.780 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+H]=576.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[C:24]([CH3:35])=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([OH:22])[C:24]=3[CH3:35])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Cc1c(O)cccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(O)c3C)CC2)c(OC)nc1C
Yield: 54 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-hydroxy-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([OH:5])=[O:4].[N+](=[CH2:19])=[N-].C(Cl)(Cl)Cl>CCOCC>[CH3:19][O:4][C:3](=[O:5])[C@H:2]([CH3:1])[CH2:6][CH2:7][CH2:8][C@H:9]([CH3:16])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
2(R),6(R),10-trimethylundecanoic acid (270 mg., [α]D25 -8.64°) was dissolved in ether and treated with an excess of etheral solution of diazomethane at 23° C. for 2.0 hour. The crude product was subjected to evaporative distillation at 98°-101°/0.15 mm Hg to give 247 mg. of 2(R), 6(R),10-trimethylundecanoic acid methyl ester as a colorless oil, [α]D25 -11.30° (c1.1065, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CCCCOC(=O)Cl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 77 μl (2 molar equivalents) of butyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 119 mg of the desired product the desired product (formula shown hereinabove) were isolated as an orange powder (yield=83%) which was characterized as follows:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[OH:5].[Cl:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([C:16]#[N:17])=[C:14](F)[CH:13]=1>>[Cl:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:5][C@@H:4]([C:6]2[CH:10]=[CH:9][S:8][CH:7]=2)[CH2:3][CH2:2][Cl:1])[CH:13]=1
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: O[C@H](CCCl)c1ccsc1
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCCl)c1ccsc1

Procedure:
Using the product of step (d) (322 mg, 1.84 mmol), 4-chloro-2,5-difluorobenzonitrile (320 mg, 1.84 mmol) and the procedure described in Example 72(c), the title compound was prepared (540 mg, 89%).
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:16][CH2:17][CH2:18][C:19]#[CH:20]>C(Cl)Cl>[OH:16][CH2:17][CH2:18][C:19]#[C:20][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Reactant: C#CCCO
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)OC)c(C#CCCO)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
461 mg of dimethyl 5-bromopyridine-2,4-dicarboxylate (from Example 3) and 142 mg of 4-hydroxy-1-butyne are dissolved in methylene chloride in a flask flushed with argon, and 680 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 13 mg of ((C6H5)3P)2PdCl2 and 2 mg of CuI are added and the mixture is boiled under reflux for 2 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After the solvent has been evaporated off, 347 mg of a white solid remain.
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1)C.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]2[NH:18][CH:17]=[CH:16][N:15]=2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Reactant: CN
Product: CNC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Reaction time: 24 h

Procedure:
A solution of 4-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester (1.02 g) in 33% ethanolic methylamine was allowed to stand for 24 hour. The solution was evaporated and the residue was crystallised from ethyl acetate/petrol to give N-methyl-4-(1-imidazolylmethyl)phenoxyacetamide (0.61 g), m.p. 124°-125° C. Found: C, 63.44, H, 6.21, N, 17.25. C13H15N3O2 requires: C, 63.66, H, 6.16, N, 17.13%.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[OH:13][C:14]([CH3:44])([CH3:43])[CH2:15][C@@:16]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:21][C:20](=[O:22])[N:19]([C@H:23]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH3:24])[CH2:18][CH2:17]1>ClCCl>[CH3:12][O:11][C:9]([N:34]1[CH2:35][CH2:36][CH:31]([C:28]2[CH:27]=[CH:26][C:25]([C@@H:23]([N:19]3[CH2:18][CH2:17][C@:16]([CH2:15][C:14]([OH:13])([CH3:43])[CH3:44])([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[O:21][C:20]3=[O:22])[CH3:24])=[CH:30][CH:29]=2)[CH2:32][CH2:33]1)=[O:10]
Reactant: COC(=O)Cl
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.10 mL) and methyl chloroformate (24 μL) were added consecutively to (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (0.12 g) dissolved in dichloromethane (5 mL) at room temperature. The resulting solution was stirred at room temperature overnight and then diluted with dichloromethane. The resulting solution was washed with water and brine and dried (Na2SO4). After removal of the solvent, the residue was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1→90:10) to afford the title compound as a foam-like solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].C([BH3-])#N.[Na+]>>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccccc1F
Yield: 74 %

Procedure:
Reduction of 2-fluorobenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil (74% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.52 (3H, s, OCH3), 4.11 (2H, s, NCH2), 5.78 (1H, broad s, NH), 7.05 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.27 (1H, m, aromatic), 7.38 (1H, m, aromatic). The hydrochloride salt was obtained as a white solid: mp 138-143° C. (dec.). Anal. calcd. for C8H10FNO—HCl: C, 50.14; H, 5.78; N, 7.31. Found: C, 50.37; H, 5.71; N, 7.18.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:20]#[N:21])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(Br)cc2C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Temperature: 90 °C
Yield: 67 %

Procedure:
A solution of 1B (250 mg, 0.76 mmol) and zinc cyanide (88 mg, 0.75 mmol) in DMF (2.5 mL) was bubbled with argon for 10 min, then tetrakis-(triphenylphosphine)palladium(0) (65 mg, 0.057 mmol) was added and the solution was deoxygenated. The reaction mixture was then heated at 90° C. for 4 h, cooled to RT, and partitioned between EtOAc and water. The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined EtOAc extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (0 to 60%) in hexane to give the title compound (140 mg, 67% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:14][CH2:15][N:16]([CH2:24][CH2:25]Cl)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20]>CS(C)=O.C1COCC1>[C:19]([O:18][C:17]([N:16]1[CH2:24][CH2:25][C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)([C:11]#[N:12])[CH2:14][CH2:15]1)=[O:23])([CH3:22])([CH3:21])[CH3:20]
Reactant: N#CCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)c2)CC1
Temperature: 0 °C

Procedure:
A suspension of 15.8 g of sodium hydride of a concentration of 60% in oil in 400 ml of DMSO is admixed dropwise at AT under an inert atmosphere with a solution of 30 g of 3-chlorophenylacetonitrile in 200 ml of THF and then with a solution of 45.5 g of tert-butyl bis(2-chloroethyl)carbamate in 200 ml of DMSO and is heated at 60° C. overnight. The reaction mixture is poured into an ice/water mixture and extracted with ether, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM. This gives 33 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](Cl)[CH2:10][C:4]=2[CH:3]=1.[C:18]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]>C(Cl)(Cl)Cl.O>[C:18]([N:23]1[CH2:28][CH2:27][N:26]([CH:9]2[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=3[CH2:10]2)[CH2:25][CH2:24]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)N1CCNCC1
Reactant: Clc1ccc2c(c1)CC(Cl)c1ccccc1S2
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
100 g of 2,10-dichloro-10,11-dihydro-dibenzo[b,f]thiepin in 300 ml of chloroform are heated at reflux for 24 hours together with 182 g of 1-carbethoxy-piperazine. The mixture is then diluted with chloroform and water. The organic phase is washed several times with water and dried over magnesium sulphate. After filtration, the filtrate is concentrated under reduced pressure and the residue crystallised from acetone/hexane. There is obtained 1-carbethoxy-4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine of melting point 92°-93° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[CH3:13].[Cl:27][C:28]1[CH:33]=[C:32](Cl)[N:31]=[CH:30][N:29]=1.C(N(CC)C(C)C)(C)C>CC(O)CC>[Cl:27][C:28]1[N:29]=[CH:30][N:31]=[C:32]([N:1]2[CH:5]=[CH:4][N:3]=[C:2]2[NH:6][C:7]2[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[CH:10]=[CH:11][C:12]=2[CH3:13])[CH:33]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1ncc[nH]1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC(C)O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1nccn1-c1cc(Cl)ncn1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of N-[3-(1H-Imidazol-2-ylamino)-4-methyl-phenyl]-3-trifluoromethyl-benzamide (330 mg, 0.92 mmol), 4,6-dichloropyrimidine (409 mg, 2.75 mmol), N,N-diisopropylethyl amine (500 μL, 2.87 mmol) in 2-butanol (20 mL) is heated at 110° C. After 16 hours, the reaction mixture is concentrated. The solid is washed with saturated sodium carbonate, water, ethyl acetate, and dried to give the title compound. 1H NMR 600 MHz (DMSO-d6) δ 10.71 (s, 1H), 10.50 (s, 1H), 9.09 (s, 1H), 8.80 (s, 1H), 8.33 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.17 (s, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.84 (s, 1H), 7.77 (t, J=8.4 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.95 (s, 1H), 2.38 (s, 3H); MS m/z 473.3 (M+1).