Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH:13]/[N:14]=[CH:15]/[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[N:23]=2)=[CH:18][CH:17]=1)=[S:12])([CH3:3])[CH3:2].Cl[CH2:39][C:40](=[O:42])[CH3:41].C(N(CC)CC)C.O>CC(=O)CC>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:40]([CH3:41])([OH:42])[CH2:39][S:12]/[C:11]/1=[N:13]/[N:14]=[CH:15]\[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:26]=[CH:25][N:24]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=3)[N:23]=2)=[CH:20][CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)c1ccccc1N1/C(=N\N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)SCC1(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (134 mg, 0.26 mmol) in butanone (1.9 mL) was added chloroacetone (0.03 mL, 0.33 mmol) and triethylamine (0.04 mL, 0.28 mmol), and the reaction was stirred at room temperature for 16 hours. The mixture was transferred to a separatory funnel containing water (5 mL) and extracted twice with dichloromethane. The organic extracts were filtered through a phase separator, adsorbed onto silica gel, and purified by flash chromatography (0-25% ethyl acetate/B, where B=1:1 dichloromethane/hexanes) to provide the title compound as a yellow solid (117 mg, 79%): mp 114-116° C.; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.19 (dd, J=10.1, 6.2 Hz, 3H), 7.79 (dd, J=11.5, 4.7 Hz, 4H), 7.50-7.44 (m, 1H), 7.44-7.36 (m, 4H), 7.29-7.25 (m, 1H), 3.55 (d, J=11.5 Hz, 1H), 3.45 (s, 1H), 3.34 (d, J=11.5 Hz, 1H), 2.98 (dt, J=13.8, 6.9 Hz, 1H), 1.43 (s, 3H), 1.27-1.16 (m, 6H); 19F NMR (376 MHz, CDCl3) δ −58.02; ESIMS m/z 582 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15]>CCO>[Br:1][C:2]1[C:3]([OH:15])=[C:4]([NH2:12])[C:5](=[C:9]([Br:11])[CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c(Br)cc(Br)c(O)c1[N+](=O)[O-]
Solvent: CCO
Product: Nc1c(O)c(Br)cc(Br)c1C(=O)O
Yield: 67.3 %

Procedure:
4,6-Dibromo-3-hydroxy-2-nitrobenzoic acid (4.09 g, 12 mmol) and PtS2 (160 mg, 0.62 mmol) in EtOH (150 mL) was hydrogenated at atmospheric pressure and room temperature for 45 h. Filtration and evaporation of the filtrate gave a crude product (3.69 g) which was purified by flash chromatography (SiO2, toluene-EtOAc). Treatment with activated charcoal in MeOH and crystallization from MeOH/H2O gave the title compound (2.51 g). Mp: 162°-164.5° C. 1H NMP (DMSO-d6): δ 6.96 (s, 1 H). 13C NMR (DMSO-d6): δ 167.69, 140.56, 139.95, 121.81, 117.23, 112.53, 110.45. MS(EI, 70ev): m/z (rel. int.) 309, 311, 313 (M+, 36, 72, 34).
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].O>ClCCl>[Cl:19][C:20]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:21]=1[C:22]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:23]
Reactant: c1cnc2c(c1)NCCCC2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2ncccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a mixture of 2.90 g of 6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine, 2.37 g of triethylamine in 40 ml of dichloromethane is added 5.16 g of 2-chloro-4-nitrobenzoyl chloride in 50 ml of dichloromethane. The mixture is stirred at room temperature under argon for 3 hours and then poured into water. The organic layer is separated and washed with 1N NaHCO3, H2O, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate, the pad washed with CH2Cl2 and ethyl acetate and the filtrate concentrated to dryness. The residual solid (7.13 g) is triturated with ethyl acetate to give 4.41 g of off-white crystals, m.p. 143°-145° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCCCCCCCCCc1ccccc1
Reactant: COc1ccc(C=O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OCCCCCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a solution of 3-hydroxy-4-methoxybenzaldehyde (2.5 grams), 11-phenylundecylalcohol (4.6 grams) and triphenylphosphine (4.9 grams) in tetrahydrofuran at 0° C. is slowly added diethyl azodicarboxylate (2.9 ml). After stirring for 2 hours at room temperature the mixture is concentrated under reduced pressure and purified by column chromatography on a silica gel column using a 9:1 mixture of hexane and ethyl acetate as eluent to give 2.4 grams of a yellow oil. 1H NMR (CDCl3) δ 1H NMR (CDCl3) δ 0.82-1.89 (m, 18H), 2.35-2.70 (m, 2H), 3.95 (s, 3H), 4.00-4.08 (m, 2H), 6.95-7.45 (m, 8H), 9.84 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=O)[CH2:14][CH3:15].O>C(C(C)=O)C>[CH2:14]([C:13]1[N:1]=[C:2]2[N:6]([CH:12]=1)[C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[S:3]2)[CH3:15]
Reactant: Nc1nc2ccccc2s1
Reactant: CCC(=O)CBr
Solvent: CCC(C)=O
Solvent: O
Product: CCc1cn2c(n1)sc1ccccc12
Yield: 110 %

Procedure:
After 5.40 g of 2-aminobenzothiazole and 7.52 g of 1-bromo-2-butanone were allowed to stand in 40 ml of methyl ethyl ketone at room temperature overnight, 40 ml of water was added to the reaction mixture. Methyl ethyl ketone was distilled off on a water bath of 50° C. under reduced pressure. The residue was crystallized with ether and the crystals were then taken out by filtration to give 8.0 g of 2-ethylimidazo[2,1-b]benzothiazole.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35]N)=[CH:31][CH:30]=1)([CH3:28])[CH3:27]>>[CH:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:31][CH:30]=1)([CH3:28])[CH3:27]
Reactant: CC(C)c1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: CC(C)c1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (4-isopropyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=441.0 (M+H)+
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](OC)=[O:22])[CH:17]=[CH:18][CH:19]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH:17]=[CH:18][CH:19]=1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)Cc1cccc(Cl)c1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a solution of dimethyl methylphosphonate (4.32 mL, 40 mmol) in anhydrous THF (40 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 27.5 mL, 44 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl 3-chlorophenylacetate (3.69 mL, 20 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH/CH2Cl2 1.5/98.5) to give the product (1.43 g) with colorless oil in 26% yield. 1H-NMR (CDCl3) δ 3.07 (d, J=21 Hz, 2H), 3.750 (s, 3H), 3.775 (s, 3H), 3.873 (s, 2H), 7.01 (t, J=8.0 Hz, 1H), 7.19 (s, 1H), 7.28 (d, J=8.0 Hz, 2H).
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:8])[CH2:6][OH:7].Cl[C:10]1[C:11]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[NH:38][N:39]=[CH:40][CH:41]=3)=[CH:33][CH:32]=2)=[CH:12][C:13]2[N:17]=[C:16](S(C)(=O)=O)[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[CH:30]=1>C1COCC1.C(#N)C>[N:39]1[NH:38][C:37]([C:34]2[CH:35]=[CH:36][C:31]([C:11]3[CH:10]=[CH:30][C:14]4[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:16]([O:7][CH2:6][C:5]([OH:4])=[O:8])=[N:17][C:13]=4[CH:12]=3)=[CH:32][CH:33]=2)=[CH:41][CH:40]=1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)c(Cl)cc21
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(OCC(=O)O)nc2cc(-c3ccc(-c4ccn[nH]4)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A 20 mL scintillation vial equipped with a septum cap and a magnetic stirring bar was charged under N2 with NaH (18.0 mg, 60% suspension in mineral oil, 0.45 mmol). A solution of hydroxyacetic acid methyl ester (81.0 mg, 0.90 mmol) in THF (1.5 mL) was added dropwise to the vial. Immediately after the addition was complete, a solution of 6-chloro-2-methanesulfonyl-5-[4-(2H-pyrazol-3-yl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole (compound 45-1, 75.0 mg, 0.150 mmol) in THF (1 mL) was added. The resulting suspension was stirred at rt for 5 min, then diluted with ACN (2 mL) and quenched by slow addition of water (2 mL). The resulting solution was stirred at rt for 5 min, and then additional 15 min at 65° C. The solution was acidified with 5% aqueous HCl and extracted with EtOAc (three times, 3 mL). The organic layers were combined and washed with 5% aqueous HCl and water and evaporated to dryness in vacuo to give the title compound as yellowish oil. LR-MS (API-ES): mixture of two N-SEM isomers, calculated for C24H27ClN4O4Si 498.2, observed m/e 499.0 (M+H)+ (Rt 3.01, 3.15 min). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:17]1[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Product: COc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 5-methoxyindole (5.0 g, 34 mmol) and 4-piperidone hydrochloride hydrate (10.0 g, 65 mmol). The product was isolated as a yellow solid. Yield 6.1 g (79%). mp 191°-195° C. FDMS m/e=228 (M+ of free base).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:20]([CH2:19][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH3:11])[C:21]([NH2:22])=[N:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1CCC#N
Reactant: Nc1cc(F)ccc1C=O
Product: COc1ccccc1Cc1cc2ccc(F)cc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-4-fluorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]([CH3:19])([CH2:17][CH3:18])[CH2:13][CH2:14][C:15]#N.[OH2:20].Cl>C(OCC)C.O1CCOCC1>[CH3:11][C:12]([CH3:19])([CH2:17][CH3:18])[CH2:13][CH2:14][CH:15]=[O:20]
Reactant: CCC(C)(C)CCC#N
Reactant: O
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC(C)(C)CCC=O

Procedure:
Diisobutylaluminium hydride (1M solution in toluene, 18.5 ml.) was added to a solution of 4,4-dimethylhexanenitrile (2.0 g.) in dry diethyl ether (100 ml.) stirred under nitrogen. The mixture was refluxed for 3 hours and cooled. A solution of water (2 ml.) and dioxane (10 ml.) was added dropwise followed by dilute hydrochloric acid (80 ml.) and the solution stirred for 1 hour. Diethyl ether was added and the ethereal extracts separated. The ethereal extracts were dried (anhydrous magnesium sulphate) and evaporated to give 4,4-dimethylhexanal (1.3 g.). Nuclear Magnetic Resonance Spectrum (NMR) was as follows: 0.9,6H,s; 1.4,7H,m; 2.4,2H,m; 9.7,1H,t.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[N:5]2.[C:19]1([C:25]2[N:26]=[C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O.C(OCC)(=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([NH:10][C:11]([N:33]1[CH2:34][CH2:35][N:30]([C:27]3[S:28][CH:29]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=3)[CH2:31][CH2:32]1)=[O:18])=[N:5]2
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc2nccn2n1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Nc1ccc2nccn2n1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 66.5 %

Procedure:
A mixture of 2,2,2-trichloroethyl imidazo[1,2-b]pyridazin-6-ylcarbamate (198 mg, 0.408 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.815 mmol) and diisopropylethylamine (0.076 ml, 0.408 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction solution, and the mixture was exacted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 110 mg (66.5%) of the desired product as a solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:25]=[CH:24][C:14]([NH:15]C(=O)C3C=CC=CC=3)=[N:13][C:11]2=[O:12])[C@H:7]([OH:26])[C@@H:6]1[OH:27])=[N+]=[N-]>N>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:25]=[CH:24][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[C@H:7]([OH:26])[C@@H:6]1[OH:27]
Reactant: [N-]=[N+]=NC[C@H]1O[C@@H](n2ccc(NC(=O)c3ccccc3)nc2=O)[C@H](O)[C@@H]1O
Agent: N
Product: NC[C@H]1O[C@@H](n2ccc(N)nc2=O)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.1 %

Procedure:
Then, the thus-obtained 5′-amino-5′-deoxy-N4-benzoylcytidine (8.5 g, 24.5 mmol) was dissolved in 28% aqueous ammonia (200 ml), and the mixture was stirred at room temperature for 24 hours. The solution was evaporated to dryness, and acetone was added to recover 5′-amino-5′-deoxycytidine (5.76 g, yield 97%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH2:3]1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.ClCCl>[CH3:45][S:46]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[CH2:3]1)(=[O:48])=[O:47]
Reactant: O=C(NCCOC[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCNC(=O)OCc2ccc([N+](=O)[O-])cc2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.87 g) and triethylamine (0.35 ml) in a mixture of tetrahydrofuran (5 ml) and dichloromethane (10 ml) was dropwise added a solution of methanesulfonyl chloride (0.16 ml) in dichloromethane (2 ml) with stirring at 0°-5° C. and the mixture was stirred at 0°-5° C. for 30 minutes. The reaction mixture was washed with water (20 ml), dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (20 g) and eluted with a mixture of methanol and chloroform (1:99 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)2-[2-(4-nitrobenzyloxycarbonylamino)ethyloxymethyl]pyrrolidine (0.92 g).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:14][CH2:13][CH2:12][O:11]1)C1C=CC=CC=1.[H][H]>O1CCCC1.[Pd]>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[O:16][C@@H:15]1[CH2:14][CH2:13][CH2:12][O:11][C@H:10]1[CH2:9][OH:8]
Reactant: [H][H]
Reactant: c1ccc(COC[C@@H]2OCCC[C@H]2OC2CCCCO2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: OC[C@@H]1OCCC[C@H]1OC1CCCCO1

Procedure:
2.93 g of dl-trans-2-benzyloxymethyl-3-(tetrahydropyran-2-yloxy)tetrahydropyran (prepared as described in Preparation 35) were dissolved in 130 ml of tetrahydrofuran and were then hydrogenated at room temperature for 8 hours in the presence of 1.30 g of a 10% w/w palladium on activated carbon catalyst and of hydrogen at an initial pressure of 4 atmospheres (about 4 bars). The catalyst was removed by filtration, and then the solvent was distilled off. The resulting residue was purified by column chromatography through 50 g of silica gel. Those fractions eluted with mixtures of hexane and diethyl ether ranging from 2:1 to 1:1 by volume were worked up to give 1.87 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[C:4](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)/[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>C(OCC)(=O)C.[Pt]>[CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: COC(=O)/C(=C\c1ccc(-c2ccccc2)cc1)CC(=O)OC(C)(C)C
Agent: [Pt]
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1

Procedure:
A solution of 2-[1-biphenyl-4-yl-meth-(Z)-ylidene]-succinic acid 4-tert-butyl ester 1-methyl ester (410 mg, 1.163 mmol) in ethyl acetate (20 mL) is hydrogenated over Pt/C (40 mg) at 1 atm for 18 hours. The catalyst is filtered through Celite and the solvent is removed under reduced pressure to give 2-biphenyl-4-ylmethyl-succinic acid 4-tert-butyl ester 1-methyl ester. The enantiomers are separated by chiral HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH2:8][OH:9])#[N:2]>ClCCl.[O-2].[O-2].[Mn+4]>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH:6]=[CH:7][CH:8]=[O:9])#[N:2]
Reactant: N#Cc1cccc(C=CCO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: N#Cc1cccc(C=CC=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of active manganese dioxide (20 g) in a solution of 3-cyanocinnamyl alcohol (Example 10(d), 4.0 g) in dichloromethane (100 ml) was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was evaporated to give the title product as a white solid, m.p. 100° C.
Reaction SMILES: [CH:1]1([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:16]([NH:23][CH2:24][CH2:25][OH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([NH:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][N:23]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25][OH:26])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCNCc1ccccc1
Reactant: O=C(CCCCBr)NC1CCCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCCN(CCO)Cc1ccccc1)NC1CCCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
N-cycloheptyl-5-bromopentanamide (4.15 g, 15 mmole) in solution in dimethylformamide (20 ml) is added dropwise to a hot solution (60° C.) of N-benzylethanolamine (2.27 g, 2.13 ml, 15 mmole) in dimethylformamide (25 ml) in the presence of potassium carbonate (4.15 g, 3 mmole). The reaction mixture is agitated for 2 hours at 60° C. then the solvent is evaporated under reduced pressure. The residue is taken up in dichloromethane (50 ml) and washed with water (3×30 ml). The organic phase is collected, dried over magnesium sulfate; the solvent is evaporated under reduced pressure. The product obtained is purified by flash chromatography over silica gel in a mixture of dichloromethane/methanol (90/10) to give 3.04 g (50%) of the expected compound in the form of an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1OC
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)c(Cl)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][OH:32])=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:25][CH2:24][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH:21]([CH3:23])[CH3:22])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:7][CH2:6]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[CH:28][C:27]([CH2:30][CH:31]=[O:32])=[CH:26][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][C:8]2([O:13][CH2:12][CH2:11][N:10]([C:14]([C:16]3[N:17]=[C:18]([CH:21]([CH3:22])[CH3:23])[S:19][CH:20]=3)=[O:15])[CH2:9]2)[CH2:24][CH2:25]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4Cl)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CC=O)ccc4Cl)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(2-chloro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 61, step d) (0.230 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.074 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.313 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 40 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a yellow foam. Yield 0.274 g.