Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH2:22][CH3:23])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:25]([CH3:35])[C:26](=O)[C:27]([O:29][CH2:30][CH2:31]CC)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:25]([CH3:35])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH2:22][CH3:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCOC(=O)C(=O)C(C)Br
Reactant: CCO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCC)C2)oc1C
Yield: 88.8 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-ethoxypiperidin-4-yl)carbamate obtained in Example (112f) (0.88 g, 2.74 mmol), butyl 3-bromo-2-oxobutanoate obtained in Example (106a) (4 g, 15.8 mmol), sodium bicarbonate (0.7 g, 8.33 mmol) and THF (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 1.05 g of the title compound as a light brown oily substance (83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1([CH3:22])[CH2:12][C:11](=O)[C:10]2[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:9]=2[O:8]1)[CH3:2].B.B(F)(F)F.CCOCC>O1CCCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1([CH3:22])[CH2:12][CH2:11][C:10]2[CH:14]=[CH:15][C:16]([OH:21])=[C:17]([CH2:18][CH2:19][CH3:20])[C:9]=2[O:8]1)[CH3:2]
Reactant: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2=O
Agent: B
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1c(O)ccc2c1OC(C)(CCC(=O)OCC)CC2
Yield: 79.3 %

Procedure:
Using the procedure of Example 2, 257 mg of racemic-3,4-dihydro-7-hydroxy-2-methyl-4-oxo-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester was reduced with borane.tetrahydrofuran and boron trifluoride etherate. There was obtained 195 mg of racemic-3,4-dihydro-7-hydroxy-2-methyl-8-n-propyl-2H-1-benzopyran-2-propanoic acid ethyl ester as a pale yellow oil, after chromatographic purification on silica gel.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:19][C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:9]([NH:8][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[O:10][CH2:11][C:12]=2[CH:18]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Product: c1ccc(CNc2ccc3c(c2)COC(NC2CCCCCC2)=N3)cc1
Yield: 96.2 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and benzaldehyde (90 mg, 0.85 mmol) according to the procedure described for example 88. Obtained the title compound as a yellow oil (259 mg, 96%), MS (ISP) m/e=350.5 [(M+H)+].
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O)C([O-])=O>>[C:15]([O:14][C:12]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:7])=[O:8])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1CCCCN1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCCCC1=O

Procedure:
In another process, described in J. Org. Chem. Vol. 48, pp. 2424 to 2426 (1983), δ-valerolactam is reacted with tert-butyl oxydiformate in a first stage to form N-tert-butoxycarbonylvalerolactam, which is then broken down in a second stage with 1.1 equivalents of sodium methylate to form methyl 5-(O-tert.-butylurethano)valerate.
Reaction SMILES: [O:1]=[C:2]1[O:8][CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:9]([O:11][CH2:12][CH3:13])=[O:10].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[OH:1][CH:2]1[O:8][CH2:7][CH2:6][CH:5]2[CH:3]1[CH:4]2[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1C2CCOC(=O)C21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1C2CCOC(O)C21
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of ethyl (1SR,6SR,7SR)-2-oxo-3-oxa-bicyclo[4.1.0]heptane-7-carboxylate (15.2 g, 82.8 mmol) in anhydrous tetrahydrofuran (300 mL) at −78° C. and under argon, a 1.5 M solution of diisobutylaluminium hydride in toluene (82.8 mL, 124.2 mmol) in anhydrous tetrahydrofuran (150 mL) at −78° C. under an argon atmosphere was added dropwise via cannula. The solution was stirred for six hours at this temperature and then diluted with ethyl acetate (200 mL) and quenched with a saturated aqueous solution of sodium tartrate (200 mL). The resulting mixture was stirred at room temperature overnight. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified by column chromatography using ethyl acetate and hexane 1:2 as eluent to afford 12.3 g (85% yield) of (2RS) and (2SR) ethyl (1SR,6RS,7SR)-2hydroxy-3-oxa-bicyclo[4.1.0]heptane-7-carboxylate as a colorless oil, which exist with their corresponding open hydroxyaldehyde forms.
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].CCN=C=NCCCN(C)C>CC#N>[C:1]([NH:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:24])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (1 mmol) was taken up in CH3CN (5 mL) along with tert-butyl 2-aminoethylcarbamate (1 mmol) and EDCI (1.1 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. It was then washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (CH2Cl2) afforded tert-butyl 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylcarbamate.
Reaction SMILES: COC=CC1C=CC=CC=1[C:11]1[C:12]2[C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH:24]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(=O)([O-])[O-].[K+].[K+]>CS(O)(=O)=O.ClCCl>[CH:20]1[C:19]2[C:24]3[C:11]([C:12]4[C:17]([C:18]=2[CH:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:14][CH:13]=[C:12]1[C:11]=3[CH:24]=[CH:23][CH:18]=[CH:17]1
Reactant: COC=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: c1ccc2c(c1)ccc1c3ccccc3c3ccccc3c21
Yield: 25 %

Procedure:
A reaction vessel was charged with 24.0 g of 9-[2-(2-methoxyvinyl)phenyl]phenanthrene and 100 mL of dichloromethane. 6 drops of methanesulfonic acid were added to the mixture using a Pasteur pipette at room temperature with stirring. The mixture was stirred at room temperature for 8 hours. After completion of the reaction, 100 mL of a 10% potassium carbonate aqueous solution was added to the mixture. After removing the aqueous phase, the organic phase was washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic phase was concentrated. The residue was purified by silica gel column chromatography to obtain 5.21 g of the target benzo[g]chrysene (yield: 25%).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][OH:27])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]1([C:7]2[C:15]([CH:16]=[CH:17][C:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[CH2:26][O:27][C:28](=[O:30])[CH3:29])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(C=Cc1c(-c2ccccc2)nn2ccccc12)N1CCCCC1CO
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCCCN1C(=O)C=Cc1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
1-[3-(2-Phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-hydroxymethylpiperidine (trans isomer) (0.50 g) was added to a stirred solution of acetic anhydride (0.16 g) in pyridine (5 ml) at room temperature, and stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture and washed with 1N aqueous sodium hydroxide solution, water and saturated sodium chloride aqueous solution, then dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (50 g) with a mixture of chloroform and acetone (20:1) as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give 1-[3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acryloyl]-2-acetoxymethylpiperidine (trans isomer) (0.35 g) as an oil.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][Si](C(C)(C)C)(C)C)[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23]([NH2:24])=[N:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:19]2[CH:26]=[C:25]([I:27])[C:23]([NH2:24])=[N:22][C:20]2=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO
Reaction time: 1 h

Procedure:
To a solution of the starting nucleoside (40) (323 mg, 0.64 mmol) in THF (15 ml) under N2 protected atmosphere was added at room temperature tetrabutylammonium fluoride (TBAF) 1M in THF (0.7 ml, 0.7 mmol). Mixture stirred for one hour and then quenched by addition of H2O (5 ml). THF was evaporated and aqueous residue extracted into EtOAc (3×25 ml). Combined organic extracts were dried (MgSO4), filtered and the volatiles evaporated under reduced pressure giving a crude material which was purified by flash chromatography on a pre-packed silica column eluted with EtOAc. The product (41) was obtained as a white solid (233 mg, 93%). 1H NMR (d6 DMSO) δ 1.96-2.05 (m, 1H, H-2′) 2.24 (ddd, J=13.5, 5.8 and 2.8 Hz, 1H, H-2′), 3.50-3.62 (m, 2H, H5′), 3.91-3.97 (m, 2H, H3′, H4′), 4.03-4.07 (m, 2H, HHC—CH═), 5.11-5.16 (m, 2H, OH, CH═CHH), 5.24 (dd, J=17.2, 1.6 Hz, 1H, CH═CHH), 5.82-5.91 (m, 1H, CH═CHH), 6.02 (dd, J=7.6, 6.0 Hz, 1H, H-1′), 6.60 (s, 1H, NHH), 7.79 (s, 1H, NHH), 8.21 (s, 1H, H-6). MS (ES): m/z (%) (M−H) 392 (100%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]1([C:18]2[N:19]=[C:20]([SH:29])[NH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[C:12]1([C:18]2[N:19]=[C:20]([S:29][CH2:4][CH2:5][CH2:6][CH2:11][CH2:10][O:3][CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[NH:21][C:22]=2[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCCc1ccccn1
Reactant: Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CS(C)=O
Product: c1ccc(-c2nc(SCCCCCOCCc3ccccn3)[nH]c2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 9.5 %

Procedure:
Sodium hydride (2.24 g of 50% w/w slurry in mineral oil, 46.7 mmol) was washed in hexane and dried under vacuum. Dimethylsulfoxide (30 mL) was added, followed by a solution of 2-(2-hydroxyethyl)pyridine (5.00 mL, 44.4 mmol) in dimethylsulfoxide (20 mL) dropwise. After stirring for 2 hours, the mixture was treated with 1H-bromo-5-chloropentane (6.00 mL, 45.5 mmol), and was heated to 80° C. for 18 hours. The resulting mixture was cooled, treated with 4,5-diphenyl-2-mercapto-1H-imidazole (7.00 g, 27.7 mmol), potassium carbonate (7.00 g, 50.6 mmol) and sodium iodide (1 g), and heated again to 80° C. for an additional 24 hours. The mixture was cooled, poured into 400 mL ethyl acetate, and washed with water (4×400 mL). The ethyl acetate layer was washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was separated by flash chromatography, and the product was further purified by preparative thin-layer chromatography to afford the title compound as an oil (940 mg, 2.12 mmol, 8%). 1H NMR (CDCl3): 11.53 (1H, br s); 8.48 (1H, dt, J=5.1, 0.9 Hz); 7.61-7.06 (13H, m); 3.70 (2H, t, J=6.6 Hz); 3.37 (2H, t, J=6.0 Hz); 2.97 (2H, t, J=7.3 Hz); 2.94 (2H, t, J=6.6 Hz); 1.68-1.30 (6H, m). High-resolution mass spectrum: calculated for C27H30N3OS 444.2110, observed 444.2101, difference 1.9 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=[O:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:47]1COCC1>C[Mg]Br.CCOC(C)=O.Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34][C:35](=[O:44])[O:36][CH2:37][C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]([OH:46])[CH3:47])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a mixture of benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.200 g, 0.320 mmol) in THF (5.0 mL), methylmagnesium bromide in THF (3.0 M, 0.43 mL, 1.3 mmol) was added slowly at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature. The reaction mixture was then diluted with EtOAc (10 mL), and 1 M HCl was slowly added to adjust the pH to 7. The aqueous layer was extracted twice with EtOAc. The organic extracts were combined, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (201 mg, 98%). LCMS calc. for C35H41N6O6 (M+H)+: m/z=641.2. Found: 641.1.
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH2:6][SiH:7]([Cl:9])[Cl:8])[Cl:5]>C1C=CC=CC=1>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH2:6]1
Reactant: C#C
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Solvent: c1ccccc1
Product: Cl[Si]1(Cl)C=C[Si](Cl)(Cl)C1
Yield: 3.7 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)methane in the presence of RhCl(PPh3)3. Into the same apparatus as described in Example 1 were placed 1.02 g of bis(dichlorosilyl)methane, 0.102 g of RhCl(PPh3)3, and 20 ml of dried benzene. Acetylene gas was blown into the flask at 90 ml/min for 2 hours. The products were vacuum distilled at 67 Pa to yield a mixture comprising 0.61 g of 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-ene (TCD-GC area 3.7%) and 1,1,3,3-tetrachloro-1,3-disilacyclopentane (TCD-GC area 35.6%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19].[Cl-].[NH4+]>C(Cl)Cl>[CH2:1]([NH:8][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: NCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNCc1ccccc1)c1ccc(F)cc1
Yield: 62.8 %

Procedure:
To a solution of benzylamine (1.29 g, 12.1 mmol) in methylene chloride was added triethylamine (7.6 g, 75.0 mmol), and then 2-bromo-1-(4-fluorophenyl)ethanone (3.27 g, 15.1 mmol) was added thereto. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was partitioned. The organic layer was dried over sodium sulfate and concentrated to give crude 2-(benzylamino)-1-(4-fluorophenyl)ethanone (1.85 g) as an oil. The oil (1.50 g) was dissolved in a mixed solvent of methanol (9 mL) and water (1 mL), and sodium borohydrogen (0.8 g) was added at room temperature. The reaction mixture was concentrated and extracted with tert-butyl methyl ether, and the organic layer was concentrated. Isopropyl acetate (4 mL) and heptane (4 mL) were added to the residue, and the mixture was refluxed. The precipitated crystals were collected by filtration and dried to give racemic 1-(4-fluorophenyl)-2-(benzylamino)ethanol (0.21 g). 1-(4-fluorophenyl)-2-(benzylamino)ethanol: 1H-NMR (CDCl3) δ: 2.70-2.73 (1H, m), 2.91-2.94 (1H, m), 3.80-3.88 (2H, m), 4.68-4.71 (1H, m), 7.00-7.52 (9H, m)
Reaction SMILES: ClC1C=C(OC2C=CC=CC2(N)F)N=CN=1.[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31]C(NC(=O)CC3C=CC(F)=CC=3)=S)=[CH:27][C:26]=2[F:45])[CH:19]=1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=[O:59])[CH2:55][C:56]([OH:58])=O)=[CH:49][CH:48]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:56](=[O:58])[CH2:55][C:54]([NH:53][C:50]3[CH:49]=[CH:48][C:47]([F:46])=[CH:52][CH:51]=3)=[O:59])=[CH:27][C:26]=2[F:45])[CH:19]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1
Reactant: O=C(O)CC(=O)Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1(F)C=CC=CC1Oc1cc(Cl)ncn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(CC(=O)Nc1ccc(Oc2cc(Cl)ncn2)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 4-chloro-6-(2-amino-2-fluorophenoxy)pyrimidine (29 mg, 0.12 mmol, Compound B of Example 2), 3-(4-fluorophenylamino)-3-oxopropanoic acid (26 mg, 0.13 mmol, Compound B of Example 1) in DMF (1.5 mL) was treated with DIPEA (24 μl, 0.14 mmol) and TBTU (46 mg, 0.14 mmol). The reaction mixture was stirred at RT overnight, diluted with EtOAc (25 mL), and the organic phase was washed with brine (3×20 mL), dried (MgSO4) and concentrated. The product was purified by flash chromatography using 1-3% MeOH in CH2Cl2 as the eluent to give the title compound as a white solid (35 mg, 78%). 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.25 (s, 1H), 8.65 (s, 1H), 7.78 (d, 1H, J=12.1 Hz), 7.63-7.57 (m, 3H), 7.40-7.34 (m, 2H), 7.16 (t, 2H, J=8.8 Hz), 3.48 (s, 2H); MS(ESI+) m/z 419.21 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:10][Si:11]([CH3:30])([CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[O:12][Si:13]([CH3:23])([CH3:22])[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH:19]1[CH2:21][O:20]1>C(O)C>[OH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([CH2:21][CH:19]([OH:20])[CH2:18][O:17][CH2:16][CH2:15][CH2:14][Si:13]([CH3:22])([CH3:23])[O:12][Si:11]([CH3:30])([CH3:10])[CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH2:3][CH2:2]1
Reactant: OCCN1CCNCC1
Reactant: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC(O)CN1CCN(CCO)CC1
Temperature: 70 °C

Procedure:
2-piperazin-1-yl ethanol (0.74 g) and 20 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,1,3,3-Tetramethyl-3-(3-oxiranylmethoxy-propyl)-1-(2-trimethylsilanyl-ethyl)-disiloxane (2.0 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, ethanol was removed under vacuum, and the mixture was vacuum distilled to remove impurities.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C#CCCCCCCO
Solvent: ClCCl
Product: C#CCCCCCCOC(=O)CCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 111 %

Procedure:
Chloroacetyl chloride (0.16 ml, 2.0 mmol, 1 equiv.) was added to a stirred solution of 7-Octyn-1-ol (300 mg, 2.4 mmol, 1.2 equiv.) in CH2Cl2 (6 m-) at −5° C. The reaction mixture was allowed to warm-up to r.t., were it was stirred for 4 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica eluting with EtOAc/hexane (10%) to give the desired compound as a pale yellow liquid (450 mg, 100%).
Reaction SMILES: Cl[CH:2]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]1[CH:17]=[O:18].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[C:11]1([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]([CH:17]=[O:18])[CH:2]2[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C1CNCCN1
Reactant: O=CC1c2cccnc2N(c2ccccc2)C1Cl
Product: O=CC1c2cccnc2N(c2ccccc2)C1N1CCNCC1
Yield: 63 %

Procedure:
2-Chloro-1-phenyl-1,3-dihydropyrrolo[2,3-b]pyridine-3-carboxaldehyde is reacted with piperazine as described in Example 2 to give 1-phenyl-2-(piperazin-1-yl)-1,3-dihydropyrrolo[2,3-b]pyridine-3-carboxaldehyde (63% yield).
Reaction SMILES: Cl[C:2]1([C:8]([O:10][CH3:11])=[O:9])[C:6](=[O:7])[CH:5]=[CH:4][S:3]1.S(=O)(=O)(O)O.[C:17](O)(=O)C>>[OH:7][C:6]1[CH:5]=[C:4]([CH3:17])[S:3][C:2]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1sc(C)cc1O

Procedure:
To a stirred suspension of 2-chloro-2-methoxycarbonylthiophen-3(2H)-one (6.35 g, 33 mmol) in acetic acid (20 ml) was added sulphuric acid (1.8 ml) in acetic acid (20 ml). The mixture was stirred until dissolved then methyl mercaptan was bubbled through for 0.5 hours (total approximately 2 g). The mixture was stirred at room temperature for 18 hours, poured onto ice-water and the oily precipitate extracted into dichloromethane. After evaporation of solvent the crude oil was used in the following preparation.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=2)[N:21]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C:25]([Cl:28])([F:27])[F:26])=[N:23][N:24]=3)[N:21]=2)[CH:10]([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Reactant: CC1CN(Cc2ccccc2)CCN1
Product: CC1CN(Cc2ccccc2)CCN1c1ccc2nnc(C(F)(F)Cl)n2n1
Yield: 41 %

Procedure:
A mixture of 1-benzyl-3-methyl-piperazine and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 339 to give 6-(4-benzyl-2-methylpiperazin-1-yl)-3-[chloro(difluoro)methyl][1,2,4]triazolo[4,3-b]pyridazine in 41% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11]CCC)[CH:3]=1.CC1C=C(O)C(=CC=1)C(OC)=O.N>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([NH2:8])=[O:7]
Reactant: CCCOc1cc(C)ccc1C(N)=O
Agent: COC(=O)c1ccc(C)cc1O
Agent: N
Product: Cc1ccc(C(N)=O)c(O)c1

Procedure:
The starting-material, 4-methyl-2-propoxybenzamide, was prepared by reacting methyl 4-methylsalicylate (25.75 g) with ethanolic ammonia to yield 4-methylsalicylamide (12.54 g) which was then reacted with bromopropane, potassium iodide and potassium carbonate in acetone.