Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=2)[C:3]=1[C:32]#[N:33].[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1.O>O1CCCC1>[C:20]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[C:3]([C:32]#[N:33])[C:4]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=1)#[N:21]
Reactant: O[C@@H]1CCNC1
Reactant: CNC(=O)c1cccc(CSc2nc(Cl)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cccc(CSc2nc(N3CC[C@@H](O)C3)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
73 mg (0.15 mmol) of 3-[({6-chloro-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]pyridin-2-yl}sulfanyl)methyl]-N-methylbenzenecarboxamide Example 84A were initially charged in 1.5 ml of tetrahydrofuran. After addition of 26.6 mg (0.31 mmol) of (R)-3-pyrrolidinol, the mixture was stirred at RT for 30 min. Water was added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:4]=1[CH2:23][C:24]([OH:26])=[O:25].S(=O)(=O)(O)O.[CH3:32]O>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[S:9][C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:6]2=[C:5]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:4]=1[CH2:23][C:24]([O:26][CH3:32])=[O:25]
Reactant: COc1nc2sc3c(c2c(-c2ccc(C)cc2)c1CC(=O)O)CCCC3
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(OC)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3

Procedure:
The compound is prepared from the [2-methoxy-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetic acid following standard esterification procedures known to the skilled in the art. As an example, the transformation is achieved using a catalytic amount of sulphuric acid in methanol.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C1(C)C(C)=CC=CC=1>[ClH:1].[Cl:1][CH2:2][C:3]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=1
Reactant: COc1cccc(CC(NC(=O)CCl)c2ccccc2)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Cc1ccccc1C
Product: COc1ccc2c(c1)CC(c1ccccc1)N=C2CCl
Product: Cl
Temperature: 25 °C
Yield: 131.7 %

Procedure:
Solid N-chloroacetyl-1-phenyl-2-(3-methoxyphenyl)ethylamine (72.0 g, 0.23 mol) was added with stirring to a suspension of phosphorus pentoxide (261.1 g, 1.84 mol) in xylene (6 L) maintained under nitrogen at reflux, and the resulting mixture was refluxed for 1 hr, after which it was allowed to cool to ambient temperature. The xylene was decanted off and the residue was cooled to 0° C. Ice cold water (4 L) was added to the residue, and the resulting solution was then basified to pH 11 with 50% NaOH, and then extracted, first with ether (1 L) and then with chloroform (2×750 ml). The combined organic extracts were dried over MgSO4, evaporated to a dark oil which was dissolved in a mixture of acetone (200 ml) and ether (100 ml) and then acidified with HCl gas. Upon standing, the treated extracts yielded yellowish solid crystals, which were collected by filtration to give 48.8 g (64%) of 1-chloromethyl-3,4-dihydro-6-methoxy-3-phenylisoquinoline hydrochloride. An analyticl sample recrystallized from acetone had a mp. 174°-175° C.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[O:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[C:25](Cl)=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:11])=[CH:6][CH:5]=1.C([O-])=O.[NH4+]>C(O)C.CCCCCC.[C].[Pd]>[F:47][C:2]([F:1])([F:46])[O:3][C:4]1[CH:45]=[CH:44][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:18]3[S:19][C:20]4[CH:25]=[N:24][C:23]([C:27]([F:30])([F:29])[F:28])=[N:22][C:21]=4[N:31]=3)[CH2:15][CH2:14][N:13]2[S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)(=[O:34])=[O:33])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCCCCC
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C(F)(F)F)ncc3s2)CCN1S(=O)(=O)c1ccc(C2CC2)cc1
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
To a mixed solution of the compound (66 mg) obtained in Step 5, ammonium formate (28 mg) and ethanol (1.3 ml) was added 10% palladium carbon (33 mg) with heating under reflux. The mixture was stirred at the same temperature for 10 min and ammonium formate (28 mg) and 10% palladium carbon (33 mg) were added and the mixture was stirred for 10 min. Ammonium formate (28 mg) and 10% palladium carbon (33 mg) were further added. The reaction mixture was allowed to return to room temperature, and diluted with ethanol. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), and the obtained crude product was suspended in hexane, collected by filtration, and dried to give the title compound (31 mg).
Reaction SMILES: Cl.NO.C([N:6]([CH2:9][CH3:10])CC)C.[Br:11][C:12]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16]C=1C=O.CS(Cl)(=O)=O>C(#N)C>[Br:11][C:12]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:10]=1[C:9]#[N:6]
Reactant: COc1ccc(C=O)c(Br)c1OC
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: NO
Solvent: CC#N
Product: COc1ccc(C#N)c(Br)c1OC
Reaction time: 8 h
Yield: 18.2 %

Procedure:
A mixture of hydroxylamine hydrochloride (1.42 g, 20. 4 mmol) and triethylamine (5.7 ml, 40.8 mmol) in acetonitrile (10 ml) was stirred at room temperature for 15 minutes before a solution of 2-bromo-3,4-dimethoxybenzaldehyde (5.0 g, 20.4 mmol) in acetonitrile (40 ml) was added over 40 minutes. The resulting mixture was stirred overnight before a fifth of the resulting solution was charged with methanesulfonyl chloride (0.74 ml, 10 mmol total) and triethylamine (0.6 ml, 4.3 mmol total) portionwise over 6 hours. The mixture was stirred overnight, quenched with water, extracted with ethyl acetate, dried over MgSO4 and concentrated in-vacuo to give 0.90 g of the subtitle product (93%).
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([CH2:41][OH:42])[S:39][CH:40]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:42][CH2:41][C:38]1[S:39][CH:40]=[C:36]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:12][CH:11]=2)=[O:8])[CH:37]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Reactant: CC1(C)OB(c2csc(CO)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2csc(CO)c2)c1
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.1, 50 mg, 0.124 mmol), (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methanol (45 mg, 0.187 mmol), 2 M Na2CO3 (0.124 mL, 0.249 mmol) and DME (2.5 mL) were added to a MW vial, which was sealed and evacuated/purged with argon. PdCl2(dppf)-(CH2Cl2) was added (10 mg, 0.012 mmol) and the mixture was stirred at 140° C. for 30 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 5) tR 1.55 min, m/z=479.9 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC.[CH2:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH3:37]>C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:41]2[CH2:42][CH2:43][N:38]([CH2:36][CH3:37])[CH2:39][CH2:40]2)=[O:8])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CCN(C(=O)c2ccc(N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A mixture of 4-amino-2-trifluoromethyl-benzoic acid (15 g, 73.1 mmol), HOBT (14.56 g, 95 mmol), EDC (16.82 g, 88 mmol), Et3N (20.38 mL, 146 mmol), 1-ethyl-piperazine (8.35 g, 73.1 mmol) in DCM (200 mL) was stirred at 25° C. for 2 h. To the mixture was added DCM (200 mL) and then washed with H2O, 2 mol/L NaOH (2×150 mL) and brine. The organic layer was dried over Na2SO4 and concentrated to give a off white solid of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 65.2 mmol, 89.0% yield): 1H NMR (400 MHz, CDCl3) δ: 7.07 (d, J=8.0 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.79 (dd, J=2.0, 8.0 Hz, 1H), 3.99 (s, 2H), 3.84-3.76 (m, 2H), 3.25-3.23 (m, 2H), 2.50-2.39 (m, 4H), 2.33-2.31 (m, 2H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 302 (M+H).
Reaction SMILES: FC(F)(F)C=CC(OCC)=O.[F:12][C:13]([F:28])([F:27])[CH:14]([C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][C:16](O)=[O:17].O.[NH2:30][NH2:31]>>[C:20]1([C:19]2[CH:14]([C:13]([F:28])([F:27])[F:12])[CH2:15][C:16](=[O:17])[NH:30][N:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: O=C(O)CC(C(=O)c1ccccc1)C(F)(F)F
Agent: CCOC(=O)C=CC(F)(F)F
Solvent: O
Product: O=C1CC(C(F)(F)F)C(c2ccccc2)=NN1

Procedure:
In the same manner, reaction of α-phenyl-4-morpholinoacetonitrile with ethyl 3-trifluoromethylacrylate, followed by treatment of the resulting 3-trifluoromethyl-3-(benzoyl)propionic acid with hydrazine hydrate gives 6-phenyl-5-trifluoromethyl-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][C:4]=1[O:21][CH2:22][CH2:23][NH:24][C:25](=O)[CH3:26].P(Cl)(Cl)(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[C:5]2[C:25]([CH3:26])=[N:24][CH2:23][CH2:22][O:21][C:4]=12
Reactant: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)cc1OCCNC(C)=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(ccn2S(=O)(=O)c2ccccc2)c2c1OCCN=C2C
Yield: 1 %

Procedure:
To N-(2-{[6-methoxy-1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)acetamide (Intermediate 33, 0.10 g, 2.7 mmol) dissolved in acetonitrile (150 mL), phosphoryl chloride (2 mL) was added and the reaction mixture was heated at reflux for 5 days. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (0.010 g). MS m/z 371 [M+H]+.
Reaction SMILES: N[CH2:2][CH2:3][O:4][C:5]1[CH:30]=[C:29]([S:31][CH3:32])[CH:28]=[CH:27][C:6]=1[C:7]([NH:9][C:10]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:11]=1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13])=[O:8].C=O.[C:35]([BH3-])#[N:36].[Na+].Cl.[C:40](=O)([O-])[O-].[Na+].[Na+]>CO.C(Cl)Cl.C(O)(=O)C.CO>[ClH:21].[Cl:26][C:23]1[CH:24]=[CH:25][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:27]=[CH:28][C:29]([S:31][CH3:32])=[CH:30][C:5]=2[O:4][CH2:3][CH2:2][N:36]([CH3:35])[CH3:40])=[C:11]([CH:22]=1)[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:13]
Reactant: CSc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCN)c1
Reactant: O=C([O-])[O-]
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CSc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCN(C)C)c1
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of 2-[2-(2-aminoethoxy)-4-(methylthio)benzoylamino]-5-chloro-N-(5-chloropyridin-2-yl)benzamide (1.25 g, 2.47 mmol), paraformaldehyde (312 mg, 10.4 mmol) and methanol (30 mL) was added acetic acid to obtain a pH of 4.0. Sodium cyanoborohydride (311 mg, 4.95 mmol) was added to this mixture. After stirring overnight, the reaction was concentrated, dissolved in 10% MeOH/CHCl3, and passed through an SCX column. The eluent was concentrated and chromatographed on silica gel (1:10 EtOAc:CH2Cl2 to 1:10 MeOH:CH2Cl2) to give impure product. The impure product was dissolved in 5% MeOH/CH2Cl2 and 1 N HCl and stirred for one hour. The mixture was basified with 50% satd sodium carbonate and extracted with CH2Cl2. The organic layer was concentrated and purified by HPLC on a Vydac C18 column [preparative: gradient 20% CH3 CN/(0.01% HCl in H2O) to 80% CH3 CN/(0.01% HCl in H2O) over 6 h on a 5×25 cm column; analytical: 5% CH3 CN/(0.1% TFA in H2O) to 70% CH3 CN/(0.1% TFA in H2O) on a 0.46×25 cm column] to give the title product as a white solid (329 mg, 62%).
Reaction SMILES: C([NH:11][C@:12]([CH3:25])([C:22]([OH:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=1)(OCC1C=CC=CC=1)=O.[CH2:26](N(CC)CC)C.[Cl:33]C[CH2:35][C:36]([CH3:41])([CH3:40])[C:37]([O-:39])=[O:38]>CN(C)C=O>[ClH:33].[OH:21][C:16]1[CH:15]=[C:14]([CH2:13][C@@:12]([CH3:25])([C:22]([O:24][CH2:26][O:39][C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])=[O:23])[NH2:11])[CH:19]=[CH:18][C:17]=1[OH:20]
Reactant: C[C@@](Cc1ccc(O)c(O)c1)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Reactant: CC(C)(CCCl)C(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)[C@@](C)(N)Cc1ccc(O)c(O)c1
Product: Cl

Procedure:
A solution of 4.2 g. (0.012 mole) of racemic N-carbobenzyloxy-3-(3,4-dihydroxyphenyl)-2-methylalanine, 1.3 g. (0.013 mole) of triethylamine and 1.26 g. (0.013 mole) of chloromethylpivalate in 20 ml. dimethylformamide is stirred at 90°C. for 20 hours and then poured into 200 ml. The product is extracted into 100 ml. of ethyl acetate and washed with 25 ml. of a saturated sodium bicarbonate solution and 25 ml. of water. After drying over anhydrous magnesium sulfate and filtering, the filtrate is concentrated under reduced pressure to give the N-carbobenzyloxy derivative of the desired ester. This material is dissolved in 100 ml. of absolute ethanol containing 10 ml. of a 9.6 N ethanolic-anhydrous hydrogen chloride solution and hydrogenated with 3 g. of a 10% palladium-on-carbon catalyst at an initial pressure of 35 p.s.i. for 24 hours. After removing catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue is dissolved in 25 ml. of water, made basic with a saturated sodium carbonate solution to pH 8 and the insoluble product extracted with 100 ml. of ethyl acetate. After drying over anhydrous magnesium sulfate and filtering, 5 ml. of 9.6 N ethanolic anhydrous hydrogen chloride solution is added and the solution concentrated under reduced pressure to given 1.5 g. (22.6%) of the hydrochloride of the racemic pivaloyloxymethyl 3-(3,4-dihydroxyphenyl)-2-methylalaninate, homogeneous upon thin layer chromatography [fluorescent silica gel plate developed with a 5-2-3 (by volume) mixture of n-butanol-acetic acid-water] Rf = 0.86.
Reaction SMILES: Cl.[NH2:2][OH:3].[O-]CC.[Na+].[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:11]=1)#[N:9]>C(O)C>[C:20]([O:19][C:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:8](=[N:2][OH:3])[NH2:9])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#N)c1
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(C(N)=NO)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (3.16 g, 0.045 mol) was added to a stirred solution of sodium ethoxide in ethanol [prepared by dissolving 1.17 g of sodium in 70 ml of ethanol]. The mixture was stirred at room temperature for 15 min then 1-cyano-3-tert-butyloxycarbonylaminobenzene (3.00 g, 0.014 mol) was added. The mixture was heated at 50° C. overnight then cooled to ambient temperature. The mixture was then filtered and the filtrate evaporated in vacuo. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×20 ml). The organic layers were combined, washed with brine (50 ml) then dried (Na2SO4). The solvent was evaporated to leave a pink fo.m. The foam was left at 0° C. overnight, then triturated with 1:1 petrol:ethyl acetate. The title compound was collected as a white solid (2.52 g, 73%). 1H NMR (360 MHz, D6 -DMSO)δ1.47 (9H, s), 5.69 (2H, brs), 7.24 (2H, m), 7.41 (1H, brd, J=6.5 Hz), 7.82 (1H, s), 9.35 (1H, s), 9.58 (1H, s). MS (CI, NH3) 252 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[N:9]=[C:8]([CH:10]([OH:13])CO)[CH:7]=[C:6]([CH3:14])[CH:5]=1)[CH3:2]>C1COCC1.O.CC(=O)OCC>[CH2:15]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([CH:10]=[O:13])[CH:7]=[C:6]([CH3:14])[CH:5]=1)[CH3:16]
Reactant: CCN(CC)c1cc(C)cc(C(O)CO)n1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cc(C)cc(C=O)n1
Reaction time: 16 h
Yield: 90.7 %

Procedure:
A solution of diethyl-(4-methyl-6-vinyl-pyridin-2-yl)-amine (457 mg, 2.40 mmol), N-methyl-morpholine-N-oxide (885 mg), and OsO4 (5 mg, 20 μmol, 200 μL of a 2.5% solution in tert.-butanol) in acetone (16 mL) and water (2 mL) is stirred at rt for 18 h. The mixture is diluted with EA (200 mL) and washed with water (50 mL). The org. extract is dried over MgSO4, filtered and concentrated to give crude 1-(6-diethylamino-4-methyl-pyridin-2-yl)ethane-1,2-diol (550 mg) as a brown oil; LC-MS: tR=0.55 min, [M+1]+=225.03. 1H NMR (CDCl3): δ 1.20 (t, J=7.0 Hz, 6H), 2.27 (s, 3H), 3.51 (q, J=7.0 Hz, 4H), 3.71 (dd, J=11.3, 5.8 Hz, 1H), 3.75 (s br, 1H), 3.88 (dd, J=11.0, 3.8 Hz, 1H), 4.62 (t, J=4.8 Hz, 1H), 6.22 (s, 1H), 6.33 (s, 1H). A solution of the above crude 1-(6-diethylamino-4-methyl-pyridin-2-yl)-ethane-1,2-diol (550 mg, 2.45 mmol) and NaIO4 (857 mg, 4.01 mmol) in THF (18 mL) and water (3 mL) is stirred at rt for 7 h before another portion of NaIO4 (524 mg, 2.45 mmol) is added. Stirring is continued for 16 h. The mixture is diluted with EA, washed with water, dried over MgSO4, filtered and concentrated to give crude 6-diethylamino-4-methyl-pyridine-2-carbaldehyde (427 mg) as a green oil; LC-MS: tR=0.55 min, [M+1]+=193.01; 1H NMR (CDCl3): δ 1.22 (t, J=7.0 Hz, 6H), 2.34 (s, 3H), 3.60 (q, J=7.0 Hz, 4H), 6.49 (s, 1H), 7.04 (s, 1H), 9.89 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].O.[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>C(O)C.C(O)(=O)C>[NH:15]1[C:14]([NH:13][CH2:7][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[CH:10][CH:9]=2)=[N:18][N:17]=[N:16]1
Reactant: Nc1nnn[nH]1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1cccc(CNc2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 19.1 %

Procedure:
A mixture of 3-nitrobenzaldehyde (1.51 g) and 5-aminotetrazole monohydrate (1.03 g)in absolute ethanol (30 ml) and glacial acetic acid (0.57 ml) was stirred at room temperature for 40 minutes and then refluxed under nitrogen for 5 hours 30 minutes. Solvents were removed under high vacuum and the remaining solid was suspended in absolute ethanol (50 ml) and treated at room temperature with solid sodium borohydride (1.2 g) over 20 minutes. After a further 15 hours of stirring, the solvent was removed under vacuum and the residue was dissolved in water (100 ml) and extracted with diethyl ether (2×30 ml). The basic aqueous phase was acidified to pH 2 with 2N hydrochloric acid and the precipitated solid was collected by filtration, washed with water, diethyl ether, and finally recrystallized from absolute ethanol to give the title compound (420 mg) as white needles; mp 208°-210° C.; δH (250 MHz, DMSO-d6) 8.21 (1H, br s, Ar--H), 8.12 (1H, br d, J=9 Hz, Ar--H), 7.80 (1H, d, J=8 Hz, Ar--H), 7.70 (1H, br t, J=6.3 Hz, --NH--), 7.64 (1H, t, J=8 Hz, Ar--H), 4.53 (2H, d, J=6.3 Hz, --CH2 --); m/z (CI) 220 (M-).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[CH2:31](N(CC)CC)[CH3:32].Cl.C([NH:41][CH2:42][C:43]([OH:45])=[O:44])C.C(OCC)(=O)C>CN1C(=O)CCC1>[CH2:31]([O:45][C:43](=[O:44])[CH2:42][NH:41][C:2]1[N:3]([CH2:28][CH2:29][CH3:30])[C:4](=[O:27])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=4)[CH:15]=3)=[N:8][C:9]=2[N:10]=1)[CH3:32]
Reactant: CCN(CC)CC
Reactant: CCNCC(=O)O
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCCn1c(NCC(=O)OCC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 100 °C
Yield: 72.2 %

Procedure:
To a solution of 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (0.1 g, 0.22 mmol) in NMP (1.5 ml) under argon was added triethyl amine (0.113 g, 1.118 mmol) and ethyl glycine hydrochloride (0.096 g, 0.68 mmol). The reaction mixture was heated at 100° C. for 16 hours. To the reaction mixture ethyl acetate was added and it was washed with water and brine. Ethyl acetate layer was dried over sodium sulphate, filtered and concentrated under reduced pressure and residue obtained was purified by column chromatography to obtain {6-Oxo-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-6,7-dihydro-1H-purin-2-ylamino}-acetic acid ethyl ester (0.080 g, 69%) as an off white solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[O:19]=[C:20]1[C:25](C(Cl)=O)=[CH:24][CH:23]=[C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[O:21]1.[O:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[CH2:39][NH2:40]>>[C:14]([CH:13]=[C:11]1[CH2:12][N:8]([C:6]([C:25]2[C:20](=[O:19])[O:21][C:22]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=2)=[O:7])[C@H:9]([C:16]([NH:40][CH2:39][C:35]2[O:34][CH:38]=[CH:37][CH:36]=2)=[O:18])[CH2:10]1)#[N:15]
Reactant: NCc1ccco1
Reactant: CCCCCc1ccc(C(=O)Cl)c(=O)o1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Product: CCCCCc1ccc(C(=O)N2CC(=CC#N)C[C@H]2C(=O)NCc2ccco2)c(=O)o1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, 2-oxo-6-pentyl-2H-pyran-3-carbonyl chloride, and 2-furylmethylamine the title compound was obtained in 34% purity by LC/MS. MS(ESI+): m/z=424.4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11](O)[CH2:12][OH:13].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:9][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[O:13][CH2:12][CH2:11][O:10]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(c2ccc(N)cc2)OCCO1
Yield: 34.9 %

Procedure:
A mixture of 4′-aminoacetophenone (1.45 g, 10.7 mmol), ethylene glycol (2.00 g, 32.2 mmol), and p-TsOH.H2O (2.45 g, 12.9 mmol) in toluene (30 mL) were heated to reflux under a Dean-Stark trap for 3.5 h. Basic work-up and purification gave 4-(2-methyl-[1,3]dioxolan-2-yl)-phenylamine as colourless crystals (0.67 g, 35%).