Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:15][CH3:16])=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C(CC)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC(CC)c1ccc(F)cc1
Yield: 126.8 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)pentenoate (45.65 g,0.137 mol) and 10% palladium on carbon (0.86 g, Aldrich) in 95 % ethanol was shaken under 4 atm hydrogen pressure in a Parr hydrogenator for 1.5 hr. The mixture was filtered and concentrated by spin evaporation in vacuo. Fractional distillation gave 38.95 g (63%) of ethyl 3-(4-fluorophenyl)valerate as a clear oil contaminated with 29% triethyl phosphonoacetate. b.p., 133°-142° C. at 17 mm Hg;
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23])C)(C)(C)C.FC(F)(F)S(O)(=O)=O>>[CH3:6][NH:7][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22]
Reactant: CN(CCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: O=S(=O)(O)C(F)(F)F
Product: CNCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.6 g (1.8 mmol) of tert-butyl[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]methylcarbamate is solubilized in 865 ml (10.8 mmol; 6 equivalents) of trifluoromethanesulphonic acid and the reaction mixture is maintained under stirring for 2 hours at ambient temperature. The solvents are evaporated off, then the excess acid is coevaporated with 3 times 50 ml of dichloromethane. The expected product is used without other purification in the following stage.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]3[CH:10]=[C:11](I)[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.[CH3:24][CH2:25]OC(C)=O>CN(C=O)C.[F-].[K+]>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:9]3[CH:10]=[C:11]([CH:24]=[CH2:25])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1
Reactant: CCOC(C)=O
Reactant: Fc1cccc(F)c1-c1nc2c(Br)n[nH]c2c2ccc(I)cc12
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 2.22 g of 3-bromo-5-(2,6-difluorophenyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline in 11 ml of DMF. After argon has been bubbled through the mixture for 10 min, 1.47 ml of tributylvinylstannane and 481 mg of bis(triphenylphosphene)palladium(II) dichloride are added. The mixture is heated at 100° C. for 1 h and then after cooling is evaporated to dryness under vacuum. This gives an oil which is taken up in 350 ml of AcOEt and 300 ml of 20% aqueous KF solution. The mixture is stirred at RT for 30 min and then the suspension is filtered on a glass frit bearing a bed of Clarcel Flo. The organic phase is extracted with AcOEt and then washed with saturated aqueous NaCl solution, dried over MgSO4 and evaporated to dryness under RP. This gives 3.1 g of a crude product, which is purified by chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (95/5 by vol.), to give 1.44 g of 3-bromo-5-(2,6-difluorophenyl)-7-vinyl-1H-pyrazolo[4,3-c]isoquinoline (light yellow solid). MS (E/I): m/z=386 (M+); 1H NMR: 5.43 (d, J=11.2 Hz, 1H); 6.00 (d, J=17.6 Hz, 1H); 6.92 (dd, J=17.6, 11.2 Hz, 1H); 7.37 (t, J=7.9 Hz, 2H); 7.65 (broad s, 1H); 7.73 (m, 1H); 8.33 (dd, J=8.8, 1.5 Hz, 1H); 8.51 (d, J=8.8 Hz, 1H); 14.59 (broad m, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(=O)([O-])[OH:19].[Na+].C(OCC)(=O)C>S(=O)(=O)(O)O.O1CCCC1.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]=[C:9]([C:12](=[O:19])[CH3:13])[CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC=C(C#C[Si](C)(C)C)C1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1CC=C(C(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-allyloxycarbonyl-3-trimethylsilylethynyl-3-pyrroline (7.60 g), mercuric sulfate (0.9 g) and sulfuric acid (5 drops) in a mixture of tetrahydrofuran (76 ml) and water (23 ml) was stirred at room temperature overnight. After confirming the disappearance of the starting material, to the mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate twice, and the combined organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, water and brine successively, dried over magnesium sulfate. Evaporation of the solvent gave 1-allyloxycarbonyl-3-acetyl-3-pyrroline (2.3 g).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][C@@H:28](O)[CH2:29][C@H:30]([OH:32])[CH3:31].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[O:7]([C@@H:28]([CH3:27])[CH2:29][C@H:30]([OH:32])[CH3:31])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](O)C[C@H](C)Oc1ccccc1
Reaction time: 21 h

Procedure:
After phenol (300 mg, 3.19 mmol), triphenylphosphine (1008 mg, 3.83 mmol), (2R,4R)-2,4-pentanediol (399 mg, 3.83 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (896 mg, 3.83 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 21 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml, ×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-phenoxypentane-2-ol as a colorless oily substance (481 mg, yield: 84%/phenol).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([NH:23][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C1CCc2cc(-c3ccccc3)ccc2O1
Reactant: C=CCN
Product: C=CCNC(=O)C1CCc2cc(-c3ccccc3)ccc2O1

Procedure:
4 Was prepared as a white solid, mp: 123°-124° C. from the ethyl ester of 3,4-dihydro-6-phenyl-2H-1-benzopyran-2-carboxylic acid (Witiak et al. (1975)) and 2-propenamine by the procedure described in the last paragraph of Example 2.
Reaction SMILES: [C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15](C(N3C4C=CC=CC=4C(=O)CCC3)=O)=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:36].N1C=CC=C(CC(N)=S)C=1>>[ClH:36].[C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Agent: Cl
Agent: NC(=S)Cc1cccnc1
Product: O=C(Nc1ccccc1)c1ccccc1-c1ccccc1

Procedure:
Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide and 400 mg of 3-pyridylthioacetamide hydrochloride, the procedure of Example 5 was repeated to obtain 100 mg of 4'-[[2-(3-pyridylmethyl)-5,6-dihydro-4H-thiazolof5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide hydrochloride as an amorphous solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: O=S(=O)(O)c1cccnc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 525.5 %

Procedure:
A mixture of 3-pyridinesulfonic acid (1.0 g, 6.3 mmol), phosphorous pentachloride (1.6 g, 1.2 mmol), and phosphorous oxychloride (2.0 mL, 3.3 mmol) was combined and stirred at 100° C. for 18 h. The reaction was cooled to 25° C., diluted with CHCl3, and bubbled with HCl gas. The resulting precipitate was collected by filtration, washed with CHCl3, and dried in vacuo to yield 1.12 g of the title compound (84%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[S:15][C:14]([NH2:16])=[N:13][CH:12]=1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:16][C:14]1[S:15][C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:12][N:13]=1)=[O:21]
Reactant: Cn1c(-c2cnc(N)s2)cc2ccccc21
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-c2cnc(NC(=O)c3ccccc3Cl)s2)cc2ccccc21
Reaction time: 8 h
Yield: 97 %

Procedure:
To a mixture of 5-(1-methylindol-2-yl)-1,3-thiazole-2-ylamine (53, 10 mg, 0.043 mmol) in 1 ml DCM were added 2-chlorobenzoyl chloride (11 μl, 2 eq), DIEA (37 μl, 3 eq) and DMAP (2 mg). After stirred at r.t for overnight, the reaction mixture was worked up with DCM/aq. NaCO3, the DCM phase was concentrated to dryness. The solid residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1). 0.1 ml of 1N NaOH were added and mixture was stirred at r.t for 1 h before worked up DCM//aq. NaCO3. DCM phase was concentrated and subjected to silica gel flash column to give 15.3 mg of (2-chlorophenyl)-N-[5-(1-methylindol-2-yl)(1,3-thiazol-2-yl)]carboxamide (54) as yellow solid (yield: 97%; purity>95%). LC-MS: calcd. for C18H14ClN3OS: 368 (M+1).
Reaction SMILES: C1COCC1.C(O)(=O)C(O)=O.C[O:13][CH:14](OC)[CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>O>[CH2:20]([O:19][C:17]([NH:16][CH2:15][CH:14]=[O:13])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(CNC(=O)OCc1ccccc1)OC
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=CCNC(=O)OCc1ccccc1
Yield: 50 %

Procedure:
To a solution of 80 ml THF, 40 ml water, and 800 mg oxalic acid was added 9.6 g (40 mmol) of N-benzyloxycarbonyl aminoacetaldehyde dimethyl acetal, and refluxed for 4 days. The THF was removed under reduced pressure and the remaining solution was extracted with ether (3×100 ml), the ether fractions were combined and dried over anhydrous sodium sulfate. The ether was removed under reduced pressure and the remaining solution was purified by flash chromatography (hexane and ethyl acetate 3:1 then 1:1) to yield 3.88 g, 50% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][OH:9].C1(OC)C(=CC=CC=1)O.BrCCCO.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[S:41](Cl)(=[O:44])(=[O:43])[NH2:42]>CC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][O:9][S:41](=[O:44])(=[O:43])[NH2:42]
Reactant: NS(=O)(=O)Cl
Reactant: COc1ccccc1OCCCO
Agent: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: OCCCBr
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccccc1OCCCOS(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A solution of 13.0 g (0.071 mole) of 3-(2-methoxyphenoxy)-1-propanol (prepared in 68% yield from guaiacol (43.2 g, 0.35 mole), 3-bromo-1-propanol (89.3 g, 0.61 mole) and potassium carbonate (112.0 g, 0.81 mole) in 1 l of acetone and 9.0 g (0.089 mole) of triethylamine in 50 ml of methylene chloride was added dropwise (20 min.) to a stirred, cooled (ice-acetone bath) solution of 22 ml (0.0786 mole) of sulfamoyl chloride (3.57M solution in acetonitrile, Preparation 20) in 30 ml methylene chloride at such a rate the temperature was maintained at ≤12° C. The reaction mixture was stirred at ambient temperature for 3 hr. The solvents were evaporated under reduced pressure and the viscous residue was triturated with 300 ml of ethyl acetate and the solids removed by filtration. The filtrate was washed with three 300 ml portions of water, dried (magnesium sulfate) and the solvent evaporated under reduced pressure to yield 11.7 g (63%) of a colorless, viscous oil that solidified upon standing. The solid was recrystallized from methylene chloride-petroleum ether (30°-60° C.) to give 6.9 g (37%) of the title compound as a white solid, mp 80°-83° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([O:18][CH2:19][CH2:20][NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:15]=[N:16][CH:17]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:27].[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH3:30][N:21]([CH2:20][CH2:19][O:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:27])[CH2:4][CH2:5]3)[CH:13]=1)[S:22]([CH2:25][CH3:26])(=[O:24])=[O:23]
Reactant: CCS(=O)(=O)NCCOc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)CCOc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Reaction time: 0.25 h
Yield: 80.5 %

Procedure:
To a solution of ethanesulfonic acid {2-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-ethyl}-amide (example 151, 0.06 g, 0.154 mmol) in DMF (1.5 mL) cooled at 0° C. with an ice bath was added 60% NaH in mineral oil (0.008 g, 0.2 mmol) and the reaction mixture was stirred for 15 min. Then, MeI (0.026 g, 0.185 mmol) was added and the reaction mixture was stirred at 0° C. for another 30 min. The mixture was quenched with aq. ammonia (1 mL), diluted with brine (5 mL) and then extracted with EtOAc (2×20 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.050 g, 80%) as a light yellow amorphous solid. MS: 404.4 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][C@H:4]([CH3:8])[NH:3]1.[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH3:8][C@H:4]1[NH:3][C@@H:2]([CH3:1])[CH2:7][N:6]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(N)(=O)=O)C[C@H](C)N1
Yield: 70 %

Procedure:
To a solution of (2R,6S)-2,6-Dimethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 3 d. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected dried and reduced in vacuo to yield (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide as a white solid (1.05 g). A mixture of (3R,5S)-3,5-dimethylpiperazine-1-sulfonamide (0.541 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.731 g) and (2R,3R)-3-({6-chloro-2-[(2,3-difluorobenzyl)thio]pyrimidin-4-yl}oxy)butan-2-ol ((the product of example 4 step i), 0.541 g) in dioxane (40 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 20 min. The reaction mixture was then reduced in vacuo and the residue separated between DCM (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by prep HPLC to give the title compound as a white solid. Yield: 80 mg
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][C@@H:6]([OH:9])[CH2:5]1.[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22](OCC(Cl)(Cl)Cl)=[O:23])([CH3:12])[CH3:11]>C1COCC1>[CH:10]([CH:13]1[C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH2:16][CH2:15][N:14]1[C:22]([O:9][C@@H:6]1[CH2:7][CH2:8][N:4]([CH3:3])[CH2:5]1)=[O:23])([CH3:12])[CH3:11]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: CN1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)O[C@@H]1CCN(C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 2.8 %

Procedure:
NaH (0.19 g, 5.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL) at 0° C. and (R)-1-methylpyrrolidin-3-ol (0.47 mL, 4.00 mmol) was added. The suspension was stirred at 0° C. for 30 min and added to a solution of Intermediate 2 (1.33 g, 4.00 mmol) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and (R)-1-methylpyrrolidin-3-ol in THF were added after 18 and 26 h, respectively. After 44 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 ml) followed by 2%, 4%, 5%, 10% and 20% MeOH in DCM (200 mL)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 30% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid]). The residue was de-salted using K2CO3 in DCM to give (3R)-1-methylpyrrolidin-3-yl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo-[4,5-c]pyridine-5-carboxylate (32.3 mg, 2.7%) as a colourless gum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8](=[O:29])[C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[C:11]([NH:17][C:18](=O)[CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=1>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:9]1[CH:14]=[CH:13][C:12]2[N:15]([CH3:16])[C:18]([CH2:19][NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[N:17][C:11]=2[CH:10]=1)=[O:29]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(NC(=O)CNC(=O)OC(C)(C)C)c1)c1ccccn1
Solvent: CC(=O)O
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNC(=O)OC(C)(C)C)n2C)c1ccccn1

Procedure:
10.0 g (0.02 mol) of 3-[(N-tert-butoxycarbonylamino)acetylamino]-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide were dissolved in 50 mL of glacial acetic acid and refluxed for one hour. Then the solvent was distilled off, the residue was mixed with ice water and adjusted to pH 8 by the addition of 2N ammonia. After extraction three times with ethyl acetate, the combined organic phases were washed with saline solution and dried over sodium sulfate. After evaporation of the solvent, the crude product was chromatographed on silica gel, eluting first with methylene chloride, then with methylene chloride/ethanol (50:1) and (25:1). The desired fractions were combined and evaporated down. Yield: 5.85 g (61% of theory), C25H31N5O5 (481.6); Rf value: 0.70 (silica gel; methylene chloride/ethanol=9:1).
Reaction SMILES: [CH:1]1([C:7]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C([Cl:24])=O)CCCCC1.O.Cl.N1CCC(=O)CC1>>[Cl:24][C:4]1[CH:5]=[CH:6][C:1]([C:7]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[O:8])=[CH:2][CH:3]=1
Reactant: O=C1CCN(C(=O)C2CCCCC2)CC1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: O=C1CCNCC1
Solvent: O
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2)CC1

Procedure:
N-cyclohexanecarbonyl-4-piperidone from cyclohexanecarbonyl chloride and 4-piperidone hydrochloride hydrate. Colourless crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.I[CH3:19].[H-].[Na+]>C1COCC1>[CH3:19][O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COC(=O)c1cc(CCO)cc2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cc(C(=O)OC)c2ccccc2c1

Procedure:
Methyl 3-(2-hydroxyethyl)-1-naphthalenecarboxylate (1 eq.) from the previous step and iodomethane (19 eq.) were taken up in THF (0.3 M). To this solution was then added sodium hydride (60% w/w dispersion in oil, 1 eq.) and the resulting suspension was stirred at RT in darkness for 18 h. The volatiles were then removed in vacuo and the resulting residue partitioned between ether and 1 N aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were then washed further with 1 N aq. NaOH, water and brine. This was then dried over Na2SO4, filtered and the filtrate concentrated in vacuo to afford a yellow oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 19:1 (v/v) Hex:EtOAc→1:1 (v/v) EtOAc:Hex) afforded the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:27])[NH:9][C:10]2[S:14][N:13]=[C:12]([S:15]CC3C=CC(OC)=CC=3)[C:11]=2[C:25]#[N:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:1]1([O:7][C:8](=[O:27])[NH:9][C:10]2[S:14][N:13]=[C:12]([SH:15])[C:11]=2[C:25]#[N:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CSc2nsc(NC(=O)Oc3ccccc3)c2C#N)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(S)nsc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 101 %

Procedure:
To a mixture of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl]-carbamic acid phenyl ester (1.0 g, 2.5 mmol), trifluoracetic acid (26 mL) and anisole (2.7 g, 25 mmol) at 0° C. was added mercuric acetate (0.80 g, 2.5 mmol). The mixture was allowed to warm to room temperature overnight. After concentration in vacuo, the mixture was diluted with 100 mL of water and 100 mL of ethyl acetate. Hydrogen sulfide was bubbled in slowly until precipitation of the mercury salts was complete. The mixture was diluted with brine, extracted 3× with 200 mL of ethyl acetate, and the combined organic layers were filtered through celite, dried over Na2SO4, filtered and concentrated in vacuo, affording 0.70 g (100%) of (4-cyano-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester as a colorless solid. 1H NMR (400 MHz, acetone-d6) δ 7.47 (t, 2H, J=7.6 Hz), 7.35-7.30 (m, 3H) ppm; MS (APCl, m/z): 276 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:11]([OH:13])=[O:12])[N:3]=1.C(O)(=O)C(O)=O>C(O)(=O)C.[Zn]>[O:1]=[C:2]1[NH:3][C:4]([C:11]([OH:13])=[O:12])=[CH:5][CH:6]([C:8]([OH:10])=[O:9])[NH:7]1
Reactant: O=C(O)c1cc(C(=O)O)nc(O)n1
Agent: O=C(O)C(=O)O
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1NC(C(=O)O)=CC(C(=O)O)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-Hydroxypyrimidine-4,6-dicarboxylic acid (239 mg. 1.30 mmol) was suspended in acetic acid (17M, 60 ml) at 70° with stirring. Zinc dust (600 mg. 9.17 mmol) was added portionwise over a period of 30 min and the mixture was stirred for 1 h at 70° then cooled to room temperature. A solution of oxalic acid (200 mg. 2.22 mmol) in acetic acid (10 ml) was added and the reaction mixture allowed to stand for 5 h. The mixture was filtered and the filtrate evaporated to dryness. The residue was dissolved in hot water (5 ml), filtered and cooled to 4° to 4 days. 2-Oxo-1,2,3,6-tetrahydropyrimidine-4,6-dicarboxylic acid was obtained as off-white crystals (58 mg, 24%).