Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[S:29][CH:30]=[CH:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1nccs1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1nccs1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-aminothiazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(thiazol-2-yl)terephthalamide. MS (Q1) 469 (M)+.
Reaction SMILES: [BH4-].[Na+].[NH2:3][C:4]1[C:9]([C:10](=[O:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:8][C:7]([Br:17])=[CH:6][N:5]=1>CO>[NH2:3][C:4]1[C:9]([CH:10]([OH:16])[C:11]([N:13]([CH3:14])[CH3:15])=[O:12])=[CH:8][C:7]([Br:17])=[CH:6][N:5]=1
Reactant: CN(C)C(=O)C(=O)c1cc(Br)cnc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C(=O)C(O)c1cc(Br)cnc1N
Reaction time: 0.08 h
Yield: 56.9 %

Procedure:
Sodium borohydride (85.5 mg, 2.25 mmol) was added to methanol (5 mL) at 0° C. After 5 min., 2-(2-amino-5-bromo-pyridin-3-yl)-N,N-dimethyl-2-oxo-acetamide (408 mg, 1.50 mmol) in MeOH (15 mL) was added. After 1 h, the reaction was quenched by addition of saturated NH4Cl and the mixture was concentrated in vacuo. The residue was extracted with ethyl acetate, dried over Na2SO4 and purified by silica gel chromatography using DCM and MeOH to afford 2-(2-amino-5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (234 mg, 57.1%) as a brown oily solid. The material was used in the next step. MS: m/z 274 (M+H+).
Reaction SMILES: [Na][Na].[O:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[C:5]([OH:7])=[O:6].[CH:12]([O-])=O.[Na+].Cl.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.SC[C@H]([C@@H](CS)O)O.C([O-])=O.COC(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C(N)(CO)CO.CO>[OH:3][C@H:4]([CH2:8][C:9](=[O:11])[CH3:10])[C:5]([O:7][CH3:12])=[O:6]
Reactant: O=C[O-]
Reactant: CC(=O)CC(=O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Solvent: CO
Solvent: COC(OC)OC
Product: COC(=O)[C@H](O)CC(C)=O
Reaction time: 1.5 h

Procedure:
A solution of the disodium salt of 2,4-dioxopentanoic acid (0.52 g, 3 mmol) and sodium formate (0.24 g, 3.5 mmol) in Tris buffer (5 mM; pH corrected to 7.5 with 2M HCl; 20 ml) was de-oxygenated by bubbling through nitrogen for 30 minutes. NADH (28 mg, 0.04 mmol), dithiothreitol (2 ml of a 1M aqueous solution), formate dehydrogenase (20 U) and R-lactate dehydrogenase (Staphylococcus epidermidis, Sigma, 500 U) were added successively at room temperature under nitrogen. The mixture was stirred under nitrogen for 69 hours, with periodic addition of dilute HCl (0.5M; 2.6 ml) from a burette to maintain the pH in the range 6.0-6.2. After acidification to pH2, water was removed by rotary evaporation at 40° C., followed by evacuation to 0.5 mm Hg (~0.65 mbar). The residue was subject to methanolysis using methanol (15 ml), trimethylorthoformate (15 ml) and TsOH (100 mg, 0.53 mmol) over 5.5 hours. The mixture was concentrated under a stream of nitrogen and transacetylated with PPTS (10 mg) and acetone (20 ml) over 1.5 hours. The title compound was obtained as pale yellow oil (0.23 g, 53%), having identical spectroscopic properties to the (S)-enantiomer (compound 6). 1H-NMR analysis of the corresponding Mosher derivative indicated that homochiral (>0.99% ee) product had been obtained with an [α]D24 of +11.3° (c=2.2, Me2CO).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17](=[O:19])[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a mixture of para-fluorophenol (15 g) and K2CO3 (18.5 g) in 100 mL acetone were added chloroacetone (10.4 mL) and of Kl (22 g). After heating at reflux for 18 h the reaction mixture was cooled down and left at RT overnight. The reaction mixture was filtered, washed with acetone, and evaporated to dryness. The residue was partitioned between dichloromethane and water, the organic layer was separated and washed with water, dried over MgSO4, and evaporated to yield 15 g of 1-(4-fluoro-phenoxy)-propan-2-one as a yellow liquid.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]=[C:6]([CH3:29])[CH:7]=[CH:8][CH:9]=[C:10]([C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[C:15]([CH:22]([CH3:24])[CH3:23])[C:14]=1[O:25][CH2:26][CH2:27][CH3:28])[CH2:11][CH3:12])C.[OH-].[Na+].Cl>CCO>[CH:22]([C:15]1[C:14]([O:25][CH2:26][CH2:27][CH3:28])=[C:13]([C:10]([CH2:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]([CH3:29])=[CH:5][C:4]([OH:30])=[O:3])[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=1)([CH3:23])[CH3:24]
Reactant: CCCOc1c(C(=CC=CC(C)=CC(=O)OCC)CC)cc(C(C)C)cc1C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1c(C(=CC=CC(C)=CC(=O)O)CC)cc(C(C)C)cc1C(C)C
Temperature: 80 °C
Yield: 71 %

Procedure:
A solution of 7-(3,5-diisopropyl-2-propoxy-phenyl)-3-methyl-nona-2,4,6-trienoic acid ethyl ester (Compound 7, 11.4 g, 27.7 mmol) in EtOH (220 mL) was treated with 1M NaOH (111 mL, 111 mmol) and was heated to 80 ° C. for 3 h. The mixture was cooled to room temperature, acidified with 1M HCl (115 mL), and was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by recrystallization from CH3CN to yield the title compound as an off-white solid (7.56 g, 71%).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[N:5]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1)=[C:1]=[S:2]
Reactant: Nc1ccc(C(CC(=O)O)CC(=O)O)cc1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)CC(CC(=O)O)c1ccc(N=C=S)cc1
Temperature: 40 °C

Procedure:
11.5 g (100 mmol) of thiophosgene is added to 22.12 g (100 mmol) of 3-(4-aminophenyl)-glutaric acid in 300 ml chloroform and heated for 50 minutes at 40° C. It is evaporated to dryness and the residue is crystallized from a little isopropanol/ether.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.Cl.Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[CH:17]=[CH:16]4)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: ClCc1ccccn1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccccn3)ccc2c1

Procedure:
The title compound was prepared according to the method of Example 123 using the product of Example 11 and 2-(chloromethyl)pyridine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1n[nH]c2cc(Br)ccc12
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1n[nH]c2cc(Br)ccc12)N1CCOCC1
Temperature: 45 °C
Reaction time: 0.67 h

Procedure:
To a solution of 6-bromo-1H-indazole-3-carboxylic acid (500 mg, 2.07 mmol) in DMF (10 mL) was added CDI (403.62 mg, 2.49 mmol) and the reaction mixture stirred at 45° C. for 40 minutes. Morpholine (0.36 ml, 4.16 mmol) was then added and the reaction mixture stirred at RT. The reaction mixture was quenched by diluting with water. The product was extracted into EtOAc (×2) and the combined organic extracts were then washed with water and brine and dried (Na2SO4), filtered and concentrated in vacuo to give the crude (78% pure) title compound: 1H NMR (500 MHz, DMSO) delta 3.58-3.79 (6H, m), 3.96-4.13 (2H, m), 7.36 (1H, dd, J=8.59, 1.66 Hz), 7.86 (1H, d, J=1.10 Hz), 7.93 (1H, s), 13.66 (1H, br. s.); LC-MS: m/z=+311.70 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1)([O-])=O.CO>[Zn].C(O)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13]([C:15]3([OH:21])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[N:12][CH:11]=2)=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(-c2cnc(C3(O)CCOCC3)s2)nc1
Temperature: 50 °C

Procedure:
To a solution of Example 7A (0.106 g, 0.344 mmol) in a solvent mixture of methanol (2 mL) and acetic acid (2 mL) was added Zn powder (0.067 g, 1.03 mmol). The reaction was heated to 50° C. for 5 h, and was then cooled to room temperature. The reaction was quenched by the addition of saturated aqueous NaHCO3 (5 mL) and ethyl acetate (5 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×5 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the title compound, which was used without further purification. MS (ESI) m/z 278 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:23]=[CH:22][C:11]2[N:12]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13](=[O:16])[N:14]([CH3:15])[C:10]=2[CH:9]=1.[OH:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>O.C1COCC1>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:12]1[C:11]2[CH:22]=[CH:23][C:8]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:24])[CH:30]=3)=[CH:9][C:10]=2[N:14]([CH3:15])[C:13]1=[O:16]
Reactant: OB(O)c1cccc(O)c1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Br)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(-c3cccc(O)c3)cc21
Reaction time: 0.25 h

Procedure:
A solution of Cesium carbonate (3.66 g, 11.2 mmol, 3.0 eq) in Water (1 ml) was charged with a solution of 5-bromo-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1-5, 1.37 g, 3.74 mmol) dissolved in anhydrous THF (19 ml). 3-Hydroxyphenyl boronic acid was introduced and the solution was deoxygenated. The 1,1′-Bis(diphenylphosphino) ferrocene-palladium(II)dichloride dichloromethane complex (153 mg, 0.19 mmol, 0.05 eq) was introduced and the mixture was irradiated in a microwave at 125 deg C. for 15 min. LC/MS analysis showed ˜50% conversion, so more of each reagent was added and the reaction was irradiated again at 120 deg C. for 30 min. The completed reaction was partitioned between EtOAc (2×25 ml) and saturated aqueous NaHCO3 (25 ml), and the combined organic layers were dried over Na2SO4 and concentrated. The crude product was purified via flash column chromatography (SiO2: 100% Hex to 60:40 EtOAc/Hex), affording 1-(2,2-dimethylpropyl)-5-(3-hydroxyphenyl)-3-methyl-1,3-dihydro-2H-benzimidazol-2-one (1479) as a pink-orange solid. 1H NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 2H), 7.21-7.15 (m, 2H), 7.11-7.06 (m, 2H), 6.81 (d, 1H, J=5.4 Hz), 3.68 (s, 2H), 3.47 (s, 3H), 1.07 (s, 9H). LRMS m/z: Calc'd for C19H22N2O2 (M+H) 311.4, found 311.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:3]=1>[OH-].[OH-].[Pd+2].CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([NH:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NC2CCOCC2)c1F)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NC2CCOCC2)c1F
Reaction time: 4 h
Yield: 9 %

Procedure:
[(2R)-3-{2-[2-Chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.321 g, 0.58 mmol), Pd(OH)2 (0.064 g) and MeOH (10 mL) were combined and treated as described in General Procedure E, Part D, for 4 hours. The reaction was not complete, and therefore the contents were filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The resulting residue was redissolved in MeOH (10 mL), Pd(OH)2 (0.080 g) was, and the contents were again stirred under hydrogenation conditions as described in General Procedure E, Part D, for 2.5 hours. The contents were then filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The resulting crude product was purified by RP-HPLC to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(tetrahydro-2H-pyran-4-ylamino)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as an off-white solid (0.024 g, 9%). LCMS: (M+H)+=459.5.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.O>C(Cl)Cl>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH:2]([S:17]([CH3:16])(=[O:19])=[O:18])[NH2:1])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(N)S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To a solution of t-butyl 4-(aminomethyl)tetrahydropyridine-1(2H)-carboxylate (1.50 g, 7.0 mmol, 1 eq) in DCM (anhydrous) (20 mL) is added methanesulfonyl chloride (569 μL, 7.35 mmol, 1.05 eq). To this add triethylamine (2.05 ml, 14.7 mmol, 2.1 eq), dropwise over 15 min. Stir at room temperature for 3 hr. and then add water (20 mL) with stirring. The organic phase is isolated then washed with 2 M aqueous hydrochloric acid (20 mL), and saturated aqueous sodium hydrogen carbonate solution (20 mL). Dry the organic layer (magnesium sulphate) and concentrate to give 4-(methanesulfonyl-aminomethyl)-piperidine-1-carboxylic acid t-butyl ester (2.1 g, 102%). MS (ES): m/z=315.1 [M+Na]+. To a solution of this compound (2.1 g, 7.2 mmol, 1 eq) in 1,4-dioxane (25 mL) add 4 M hydrogen chloride in dioxane (17.95 mL, 72 mmol, 10 eq). Stir at room temperature for 29 hr., basify with 2 M aqueous sodium hydroxide, and then add DCM (20 mL). Separate the layers and extract the aqueous twice with DCM (20 mL), dry the combined organics over magnesium sulphate, filter and concentrate. Extract the aqueous layer a further four times with 3:1 chloroform:isopropanol (25 mL). Concentrate the aqueous layer to less than 10 mL volume and extract again with four times with 3:1 chloroform:isopropanol (25 mL). Combine with all the previous organic extracts to give N-piperidin-4-ylmethyl-methanesulfonamide (703 mg, 50%). MS (m/z): 193 (M+1).
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[N:4][CH:3]=[N:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>ClCCl>[Cl:14][CH2:15][C:16]([NH:6][C:5]1[S:1][N:2]=[CH:3][N:4]=1)=[O:17]
Reactant: Nc1ncns1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ncns1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of [1,2,4]-thiadiazol-5-ylamine (3.0 g) in dry dichloromethane (30 mL) under nitrogen at 0° C. was treated with triethylamine (4.6 mL) followed by slow addition of chloroacetyl chloride (2.6 mL). The reaction mixture was allowed to warm up to room temperature. After 2 h, the mixture was partitioned between dichloromethane and water. The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 50-75% EtOAc/cyclohexane to give the title compound (1.00 g) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]1([OH:31])[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C>ClCCl.C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][C:21]2([OH:31])[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: Nc1cnc2ccccc2c1NCC1(O)CCC2(CC1)OCCO2
Reactant: CCOCC(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
A solution of ethoxyacetyl chloride (4.38 g, 35.7 mmol) in dichloromethane (50 mL) was added to a 0° C. solution of 8-{[(3-aminoquinolin-4-yl)amino]methyl}-1,4-dioxaspiro[4.5]decan-8-ol (10.7 g, 32.5 mmol) and triethylamine (4.98 mL, 35.7 mmol) in dichloromethane (250 mL). After one hour, the solution was allowed to warm to rt and stir for 2 d. More ethoxyacetyl chloride (0.15 equivalent) was added. After two hours, the solution was transferred to a separatory funnel and washed with water (200 mL). The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to yield an orange solid. The solid was dissolved in ethanol (150 mL) and triethylamine (13.6 mL, 97.4 mmol) was added. The solution was heated at reflux for 16 h. The volatiles were removed under reduced pressure to yield a brown oil that was crystallized from isopropanol to yield 8-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1,4-dioxaspiro[4.5]decan-8-ol as off-white crystals (2.50 g) and a second crop (1.50 g) of crystals. A third crop (4.91 g) was isolated after recrystallization of the mother liquor from ethyl acetate. A total of 8.91 g (69%) of 8-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-1,4-dioxaspiro[4.5]decan-8-ol was isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:6]([NH2:8])=[O:5])[CH2:26][CH2:25]1.[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCNCC1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Product: CN1CCN(C(N)=O)CC1

Procedure:
Prepare by the method of Example 20.9 using 1-tert-butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (1.6 g, 5.2 mmol) and 4-methylpiperazine (1.2 mL, 10.5 mmol) to give the title compound: Rf =0.54 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH3:10])=[CH:5][N:4]=1.[CH3:11][N:12]([CH2:14][C:15]1[O:19][C:18]([CH2:20][S:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1)[CH3:13]>N1C=CC=CC=1>[CH3:13][N:12]([CH2:14][C:15]1[O:19][C:18]([CH2:20][S:21][CH2:22][CH2:23][NH:24][C:3]2[NH:8][C:7](=[O:9])[C:6]([CH3:10])=[CH:5][N:4]=2)=[CH:17][CH:16]=1)[CH3:11]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSc1ncc(C)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cnc(NCCSCc2ccc(CN(C)C)o2)[nH]c1=O

Procedure:
Reaction of 2-methylthio-5-methyl-4-pyrimidone with one equivalent of 2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamine by boiling under reflux in pyridine for 48 hours gives 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-methyl-4-pyrimidone.
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N.CO>C(O)(=O)C.C1(C)C=CC=CC=1>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=CC=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C=Cc1ccccc1
Yield: 98 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of acetic acid (5 drops) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate is isolated in 98% yield whose NMR values are found matching with reported values as in example 1.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)[C:3]([NH2:5])=[O:4]>[Pd].C(OCC)(=O)C.CO>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:2]([CH3:1])[C:3]([NH2:5])=[O:4])=[CH:7][CH:8]=1
Reactant: CN(C(N)=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C(N)=O)c1ccc(N)cc1
Reaction time: 5 h
Yield: 100.3 %

Procedure:
A 100-mL round bottom flask was charged with 1-methyl-1-(4-nitrophenyl)urea (0.63 g, 3.26 mmol) and 10% palladium on carbon (0.15 g) in 1:1 ethyl acetate/methanol (20 mL). This mixture was vigorously stirred under H2 (1 atm) for 5 h. After this time, the mixture was filtered through celite to afford the title compound (0.54 g, 100%) as a white solid. MW=165.19. 1H NMR (DMSO-d6, 500 MHz) δ 6.90-6.86 (m, 2H), 6.57-6.53 (m, 2H), 5.29 (br s, 2H), 5.11 (s, 2H), 3.00 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:36])[CH2:15][N:16](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].C1(S)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:36])[CH2:15][NH:16][CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)=[O:4]
Reactant: C=C1CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C1CNCCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Reaction time: 8 h
Yield: 56.7 %

Procedure:
2-(4-Fluoro-phenyl)-10-methanesulfonyl-5-methylene-7-(2-nitro-benzenesulfonyl)-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (4 mg, 7.94 umol) is dissolved in anhydrous THF (0.5 mL) and to this solution Cs2CO3 (25.9 mg, 0.08 mmol) followed by PS-thiophenol (Cardullo et. al Synlett 2005) (100 mg of resin with a 2 mmol/g of loading). This amount of resin is previously treated by shaking for 30 min in a sealed vial with 2 mL of a 0.7M solution of PPh3 in dry deoxygenated THF. The resin is filtered on a sintered glass, washed with dry THF and then used immediately without drying. The mixture is then stirred slowly overnight. The solid is filtered then washed several times with THF (25 mL) and CH2Cl2 (20 mL). The combined organic is evaporated to afford 2-(4-Fluoro-phenyl)-10-methanesulfonyl-5-methylene-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (2 mg, 56%). MS-ES [M+H]+=444.9.