Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([CH:9]2[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1ncccc1I
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1ncccc1C1CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-chloro-3-iodopyridine (2.39 g, 9.98 mmol), cyclopropylboronic acid (860 mg, 10 mmol) and potassium carbonate (4.14 g, 30.0 mmol) in 1,4-dioxane (50 mL) was added tetrakis(triphenylphosphine)palladium(0) (1.16 g, 1.00 mmol). The reaction mixture was stirred at 120° C. for 4 hours, then diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (Gradient: 10% to 30% ethyl acetate in petroleum ether) to afford the product as a colorless oil. Yield: 1 g, 6 mmol, 60%. 1H NMR (400 MHz, CDCl3) δ 8.20 (dd, J=4.7, 1.8 Hz, 1H), 7.24-7.28 (m, 1H), 7.14 (br dd, J=7.6, 4.8 Hz, 1H), 2.12-2.21 (m, 1H), 1.04-1.11 (m, 2H), 0.67-0.72 (m, 2H).
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([N:15]2[C:19]([C:20]([O:22]C)=[O:21])=[CH:18][N:17]=[CH:16]2)[CH2:7]1.[OH-].[Na+]>C(O)(=O)C>[CH3:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]([N:15]2[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]=[CH:16]2)[CH2:7]1
Reactant: COC(=O)c1cncn1C1CC(C)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC1CC(n2cncc2C(=O)O)c2ccccc21
Yield: 90 %

Procedure:
A solution of 3.6 parts of methyl 1-(2,3-dihydro-3-methyl-1H-inden-1-yl)-1H-imidazole-5-carboxylate mononitrate in 50 parts of a sodium hydroxide solution 20% is stirred for 1.5 hours at reflux temperature. After cooling, the reaction mixture is neutralized with acetic acid. The product is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 2.4 parts (90.0%) of 1-(2,3-dihydro-3-methyl-1H-inden-1-yl)-1H-imidazole-5-carboxylic acid; mp. 209.3° C. (compound 2.36).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1O.[Cl:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:13]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:14]([C:12](=[O:13])[CH2:11][Cl:10])[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1
Reactant: Oc1c(Cl)cccc1Cl
Reactant: Cc1ccc(NC(=O)CCl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(C(=O)CCl)c2c(Cl)cccc2Cl)cc1

Procedure:
Same procedure as example 6a starting from 2,6-dichlorophenol and 2-chloro-N-(4-methylphenyl)acetamide. At the end of the acetylation reaction the mixture was diluted with a small amount of toluene (0.2 part) to prevent solidification.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28]C)=[O:27])[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:10]=1)[CH:2]=[CH2:3].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH2:1]([NH:4][C:5]1[N:6]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([OH:28])=[O:27])[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)OC)ccc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1C
Temperature: 0 °C
Yield: 84.3 %

Procedure:
To a suspension of methyl 3-[2-(allylamino)-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 2) (1.59 g, 3.34 mmol) in dioxane (7 mL) was added 2N NaOH (2.51 mL, 5.01 mmol). Stirred at ambient temperature for 1h, cooled (0° C.), added 5% citric acid to precipitate the product, filtered precipitate, and dried in vacuo to give the desired compound as a white solid (1.30 g, 84%). 1H NMR (CD3OD/400 MHz) δ8.08 (m, 1H), 7.81 (s, 1H), 7.56 (m, 2H), 7.00 (t, 2H, J=8.4 Hz), 5.80 (m, 1H), 5.51 (s, 2H), 5.07 (m, 2H), 3.93 (m, 2H), 2.14 (s, 3H). ESHRMS m/z 462.1006 (M+H calculated for C22H19ClF2N3O4 requires 462.1027).
Reaction SMILES: CN(C)C=O.[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:11][CH3:12])[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(OCC)(=O)C>[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: CCOC(=O)CCl
Reactant: COC(OC)C(O)c1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C)c(C(O)C(OC)OC)cc1C
Yield: 77.1 %

Procedure:
To N,N-dimethylformamide (81 g) were added 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (20.0 g), potassium carbonate (15.8 g) and ethyl chloroacetate (12.4 g) at room temperature with stirring. The mixture was stirred at room temperature for an hour, and then stirred at 71° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and a mixture of ethyl acetate and hexane was added to the residue. The precipitated crystals were collected by filtration to give ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenoxy]acetate (21.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:15]=1[NH:14][C:13]1[CH:12]=[N:11][CH:10]=[CH:9][C:8]2=1.[Cl:16]N1C(=O)CCC1=O>C1COCC1>[Cl:16][C:4]1[C:3]([O:2][CH3:1])=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][N:11]=[CH:12][C:13]=3[NH:14]2)=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc2c1[nH]c1cnccc12
Solvent: C1CCOC1
Product: COc1c(Cl)ccc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a mixture of 8-methoxy-β-carboline (1.0 g, 5 mmol) in THF (100 ml) was added N-chlorosuccinimide (0.70 g, 5.2 mmol). The reaction was stirred at RT for 4 h before concentrating and washing the residue with 1:1:1 mixture of 10% Na2CO3, hexane, and EtOAc (400 ml). The resulting residue was triturated with xylenes to provide 677 mg of 7-chloro-8-methoxy-β-carboline.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.Cl>N1C=CC=CC=1.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]#[C:10][CH3:11])[CH2:12][C:13]([OH:21])=[O:14])=[CH:6][CH:7]=1
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC#CC(CC(=O)O)c1ccc(O)cc1
Yield: 95.2 %

Procedure:
A solution of 5-[1-(4-hydroxyphenyl)but-2-ynyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (20 g, 69.44 mmol) in pyridine-water (5:1, 390 mL) is heated at reflux for 16 hours and after cooling is acidified to pH ˜2 with 5 N HCl and extracted with EtOAc (2×300 mL). The combined extracts are washed with saturated brine, dried over MgSO4, filtered, and concentrated to give an off-white solid (13.5 g, 96%). ESI/MS m/z 203 (M−H)−.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[O:7]([CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccccc1
Reaction time: 12 h
Yield: 61.5 %

Procedure:
A mixture consisting of 34.8 gm (0.37 mol) of phenol, 111 gm (0.81 mol) of potassium carbonate, 89 ml (0.69 mol) of ethyl 2-bromo-propionate and 200 ml of ethanol was boiled for 12 hours, while stirring. Thereafter, the reaction mixture was filtered, and the filtrate was distilled, yielding 44.2 gm of ethyl 2-phenoxy-propionate, b.p. 93°-94° C. at 0.1 mm Hg.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22]([NH:25]S(C(C)(C)C)=O)([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CO.Cl.O1CCOCC1>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([C:22]([NH2:25])([CH3:24])[CH3:23])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(NS(=O)C(C)(C)C)c1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reaction time: 8 h

Procedure:
2-Methyl-propane-2-sulfinic acid {1-[6-(4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-1-methyl-ethyl}-amide (76.3 mg, 0.172 mmol) in Methanol (1.9 mL, 48 mmol) was added 4.0 M of Hydrogen chloride in 1,4-Dioxane (0.97 mL, 3.9 mmol) and was stirred overnight. After removal of solvent, the residue was dissolved in DMSO, then HPLC give product as a gel (53 mg, 91%). LCMS Rf=1.58 min m/z 341.20 ([M+1], 100%). 1H NMR (400 MHz, CHLOROFORM-d) Shift=8.22 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.45 (dd, J=2.6, 9.2 Hz, 1H), 7.15 (s, 1H), 4.38-4.24 (m, 1H), 2.28 (d, J=10.4 Hz, 2H), 1.93 (d, J=12.9 Hz, 2H), 1.88 (s, 6H), 1.58-1.40 (m, 2H), 1.31-1.01 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[F:19][C:20]([F:32])([F:31])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH2:17]([O:16][C:14]([C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:4]2[CH:3]=[C:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][C:20]([F:19])([F:32])[F:31])[CH:7]=[CH:6][CH:5]=2)[N:9]=1)=[O:15])[CH3:18]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CCOC(=O)c1cc(C)n(-c2cccc(Br)c2)n1
Product: CCOC(=O)c1cc(C)n(-c2cccc(-c3ccccc3OC(F)(F)F)c2)n1

Procedure:
The titled compound was prepared by reacting ethyl 1-(3-bromophenyl)-5-methyl-1H-pyrazole-3-carboxylate (from Step 1 of EXAMPLE 1) with 2-(Trifluoromethoxy)phenylboronic acid (from Step 3 of EXAMPLE 1) under the reaction condition described in Step 4 of EXAMPLE 1.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(C(C)C)CC)(C)C.Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>C(Cl)Cl>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[CH2:1][N:2]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6c(c5)CNC6)sc4n3)CC2)cc1
Reactant: COC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)cc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(Isoindolin-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (97 mg, 0.263 mmol) was dissolved in DCM (2.625 mL) and diisopropylethylamine (91 μL, 0.525 mmol) before methyl bromoacetate (48.5 μL, 0.525 mmol) was added and stirred at ambient temperature for 3 h. Methyl 2-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)isoindolin-2-yl)acetate was obtained after purification via flash chromatograpy. MS (ESI) m/z: Calculated: 441.2; Observed: 442.4 (M++H).
Reaction SMILES: [CH2:1]([C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[CH2:5]1)C=C.I([O-])(=O)(=O)=O.[Na+].[CH3:28][OH:29]>O.[Os](=O)(=O)(=O)=O>[O:29]=[CH:28][CH2:1][C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[CH2:5]1
Reactant: C=CCC1(C(=O)OC)CCc2cc(C(=O)OC)ccc2C1
Reactant: CO
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCC(CC=O)(C(=O)OC)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-dimethyl 2-allyl-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate from Step B (433 mg, 1.50 mmol) in MeOH (20 mL) and H2O (7 mL) was added osmium tetroxide (2.5 wt. % in t-BuOH, 1.07 mL, 0.105 mmol) and sodium periodate (964 mg, 4.51 mmol). The resulting mixture was stirred for 1 h at ambient temperature and a thick white precipitate quickly formed. After 70 min, the mixture was partitioned between dilute aqueous NaCl (100 mL) and EtOAc (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=291 (M+1).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[S:7][CH:8]=1)(=O)[NH2:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:1]([C:4]1[N:5]=[C:6]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[N:11]2)[S:7][CH:8]=1)(=[S:29])[NH2:2]
Reactant: CCOC(=O)c1cnn(Cc2nc(C(N)=O)cs2)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(Cc2nc(C(N)=S)cs2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a solution (10 mL) of the compound (524 mg, 1.87 mmol) obtained in Example 33b in toluene was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson reagent, 756 mg, 1.87 mmol), and the mixture was heated under reflux overnight. The reaction mixture was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 30 min, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=1/1) and recrystallization (ethyl acetate-hexane) to give the title compound (200 mg, 36%) as pale-yellow crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][N:6]=1)(=[O:3])[CH3:2].C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16]>N1C=CC=CC=1.C(O)C>[C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CC(=O)Nc1ccc(C=O)cn1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(/C=C/C(=O)O)cn1
Yield: 81.9 %

Procedure:
A mixture of 2-acetylamino-5-formylpyridine (241 mg) and malonic acid (168 mg) in pyridine (0.12 ml) and ethanol (0.36 ml) was refluxed for 2 hours. After cooling the mixture, the precipitate was collected by filtration, and washed ethyl acetate to give (E)-3-(6-acetylamino-3-pyridyl)acrylic acid (248 mg) as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1)[CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:32]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCSCCCN(CCO)CCCCc1ccc(C#N)cc1
Product: CCCS(=O)CCCN(CCO)CCCCc1ccc(C#N)cc1
Yield: 24.6 %

Procedure:
3.1 g of 4-[4- [(2-hydroxyethyl)[3-(propylthio)propyl]amino]butyl]benzonitrile was oxidized with 2.2 g of m-chloroperbenzoic acid in analogy with example 2. The yield was 0.8 g of the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:24][O:23][CH2:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[O:23]1[CH2:24][CH:21]([N:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CN(C2COC2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TFA (2 mL) was added to a solution of 4-oxetan-3-ylpiperazine-1-carboxylic acid tert-butyl ester (150 mg, 0.62 mmol) in DCM (10 mL) and the mixture was stirred at ambient temperature for 30 min, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to give 1-oxetan-3-ylpiperazine as a colourless oil. A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.51 mmol), 1-oxetan-3-ylpiperazine (88 mg, 0.62 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (10 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 99:1 to 98:2 to 95:5) to afford 513 as a white solid (98 mg, 37%). LCMS (Method I): RT=2.43 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.01 (dd, J=6.9, 2.4 Hz, 1 H); 7.78 (m, 1 H); 7.33-7.23 (m, 2 H); 4.70-4.60 (m, 4 H); 4.35 (m, 4 H); 3.97-3.75 (m, 7 H); 3.79 (s, 2 H); 3.57-3.49 (m, 1 H); 3.37 (q, J=7.5 Hz, 2 H); 2.66 (m, 4 H); 2.42 (m, 4 H); 1.46 (t, J=7.5 Hz, 3 H)
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[CH:19][N:18]=[C:17]3[N:24](C(OC(C)(C)C)=O)[CH:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)[C:16]=23)[CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:50]>CCOCC>[ClH:50].[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([CH:21]3[CH2:22][CH2:23]3)=[CH:19][N:18]=[C:17]3[NH:24][CH:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)[C:16]=23)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(C3CC3)cnc3c2c(NC(=O)c2cccnc2)cn3C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCCN(c2c(C3CC3)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Yield: 48 %

Procedure:
(R)-tert-Butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (81 mg, 0.14 mmol) was treated with TFA followed by 2M HCl in ether as described in Example 1, Step K, to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (33 mg, 48% yield). 1H NMR (400 MHz, D2O) δ 9.16 (d, 1H), 8.82 (dd, 1H), 8.72 (dt, 1H), 7.95 (s, 1H), 7.92 (dd, 1H), 7.41 (s, 1H), 3.98-3.93 (m, 1H), 3.61-3.53 (m, 1H), 3.32-3.25 (m, 2H), 3.15-3.06 (m, 1H), 1.96-1.85 (m, 2H), 1.64-1.56 (m, 1H), 1.52-1.41 (m, 1H), 1.39-1.27 (m, 1H), 0.98-0.92 (m, 2H), 0.70-0.61 (m, 2H); LCMS (APCI+) m/z 377.2 (M+H)+, Retention time=2.12 minutes (Method 2).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].O>CN(C)C=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:13]
Reactant: ClCCCBr
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2ccccc2N1CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A suspension of NaH in mineral oil (55-60%) (712 mg) was added to a solution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) in N,N-dimethylformamide (50 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. then 1-bromo-3-chloropropane (1.34 mL, 13.6 mmol) was added. The slurry was stirred for additional 16 h. at ambient temperature then water (50 mL) was added and the product was extracted with diethyl ether (2×50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by flash-chromatography (eluent: dichloromethane) to give 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI (2.5 g, 15 mmol), K2CO3 (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL, 15 mmol) were added to a solution of 1-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 60° C. for 16 h. The acetonitrile was evaporated in vacuo, water (50 mL) was added and the product was extracted with ethyl acetate (2×50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash-chromatography (eluent: ethyl acetate) gave the title product. Yield: 2.06 g, 58%. Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+1+=329.5 (UV/MS(%)=100/100). 1H NMR (400 MHz, CD3OD): δ=0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d), 7.20 (1H, broad d), 7.25 (1H, broad t). 13C NMR (CD3OD): δ 13.2, 22.8, 24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9, 115.2, 123.2, 127.0, 127.4, 127.9, 139.1, 171.5
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(O)(=O)C.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)CCC>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[NH:22][N:3]=[N:2][N:1]=2)=[CH:23][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CCCCO
Solvent: CC(=O)O
Product: c1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Yield: 85 %

Procedure:
6.6×10-2 mol of sodium azide and 6.6×10-2 mol of acetic acid were added to a solution of 5×10-2 mol of 4-benzyloxy benzonitrile (VIII) in 20 ml butanol. The reaction medium was then reflux-heated for 4 hours. 1 g sodium azide, 2 g acetic acid and 10 ml butanol were added and the reaction medium was again reflux-heated for 2 days. After concentration by evaporation of the solvent, the residue was dissolved in 20 ml of 10% aqueous NaOH. After filtration, the aqueous phase was extracted with ether. The alkaline solution was acidified with 2N HCl to obtain the expected compound, which was isolated with an 85% yield (M.P.=228° C.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]([CH3:35])[S:33][C:32](=[O:36])[NH:31][N:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:18].C(N(CC)CC)C>ClCCl>[CH2:8]([N:7]([CH2:6][CH2:5][O:4][C:2]([N:31]1[N:30]=[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[N:19]([C:17](=[O:18])[C:16]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:20][CH2:21][CH2:22]3)[CH:34]([CH3:35])[S:33][C:32]1=[O:36])=[O:3])[CH2:10][CH3:11])[CH3:9]
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Reactant: CCN(CC)CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6 g of 2-(N,N-diethylamino)ethyl chloroformate dissolved in 50 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3,6-dihydro-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-2H-1,3,4-thiadiazin-2-one ("A") and 9.8 ml of triethylamine in 100 ml of dichloromethane, and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed, and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; hydrochloride.