Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:16]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:10][N:11]=2)[CH2:16][NH:3]1
Reactant: C=O
Reactant: CN(N)C(=O)Nc1nnc(C2CCC2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1NCN(c2nnc(C3CCC3)s2)C1=O
Reaction time: 0.33 h

Procedure:
2-Methyl-4-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-methyl-4-(5-cyclobutyl-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3-one.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][CH:7]([CH:12]([CH3:14])[CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][CH:7]([CH:12]([CH3:13])[CH3:14])[C:6]=3[CH:15]=2)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CC(C)C1OC(=O)Nc2ccc(O)cc21
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Product: CC(C)C1OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4-isopropyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][C:20](=[CH2:27])[CH2:21][O:22][CH:23]1[CH2:26][NH:25][CH2:24]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][C:20](=[CH2:19])[CH2:21][O:22][CH:23]1[CH2:26][N:25]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:24]1
Reactant: C=C(C)COC1CNC1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C(C)COC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 3-[(2-methylprop-2-en-1-yl)oxy]azetidine hydrochloride (78 mg, 0.48 mmol; which may be prepared as described in Step 2), DIPEA (119 μL, 0.72 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was precipitated in methanol/water and then filtered. The resulting solid was dissolved in chloroform and washed with water to give a beige solid. This solid was triturated in diethyl ether to give the title compound (13 mg, 16%) as a white solid.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10])C1C=CC=CC=1.[Li+].[OH-]>C1COCC1>[C:9]([C:11]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c2ccccc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.8 %

Procedure:
2-carboxy-4-hydroxyquinoline (5 g, 1.0 eq) was dissolved in 50 mL DMF. Cesium carbonate (20 g, 2.3 eq) was added to the solution and the resulting reaction mixture was heated at 50° C. for 20 minutes. Benzyl bromide (10 g, 2.1 eq) was added. The resulting reaction mixture was stirred at 50° C. for 1 hour. Then the reaction mixture was poured into 500 mL ice-water, the precipitate was collected by filtration, and dried in vacuo to afford 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.1 g). 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.0 g) was dissolved in 50 mL THF, and 2 N LiOH solution (20 mL) was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was then removed in vacuo, and the residue acidified by the addition of 2N NaHSO4 to pH 3–4. The white precipitate was collected to afford 2-carboxy-4-benzyloxyquinoline (7.2 g), which was used without further purification.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.O>C1COCC1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CCOC(C)=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:3][CH2:2][CH2:1][OH:4])=[CH:10][CH:11]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: OCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCOCc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
Ethylene glycol (0.084 mL, 1.5 mmol) was added to NaH (38 mg, 1.52 mmol, 95% in oil) in THF (3 mL). 1-(Bromomethyl)-4-chlorobenzene (310 mg, 1.5 mmol) was added to the reaction, and the residual 1-(bromomethyl)-4-chlorobenzene was transferred to the reaction tube with additional THF (1 mL). (Bu)4NI (55 mg, 0.15 mmol) was then added, and the reaction was heated at 60° C. for 18 h and then rt for 4 h. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (1×1 mL), and the combined organic layers were concentrated. The crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes (fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the title compound (129 mg, 46%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:17]([CH2:18][CH2:19][OH:20])[N:16]=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[O-:23][C:24]#[N:25].[Na+].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.C([O-])(O)=O.[Na+]>[C:24]([O:20][CH2:19][CH2:18][N:17]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[CH:14][CH:15]=[N:16]1)(=[O:23])[NH2:25]
Reactant: N#C[O-]
Reactant: OCCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)OCCn1nccc1-c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
A solution of 2-[5-[4-(4-fluorophenoxy)phenyl]-pyrazol-1-yl]ethanol (118 mg, 0.40 mmol) in 1 mL of toluene was treated with solid sodium cyanate (2 eq.; 53 mg, 0.82 mmol) added in one portion. The resulting mixture was cooled in an ice-water bath and neat trifluoroacetic acid (60 μL, 89 mg, 0.78 mmol) was added dropwise via syringe. The reaction was stirred at room temperature. After 2 hours, the reaction had completely solidified and an additional 1 mL of toluene was added. After stirring overnight, the reaction was recooled to 0° C. and diluted with 3 mL of a saturated aqueous NaHCO3 solution. The aqueous layer was separated and extracted with EtOAc (3×5 mL). The organic layers were combined, washed with brine, dried (Na2SO4), filtered and concentrated. Column chromatography (13 cm of flash silica in a 2 cm diameter column eluted with 600 mL of 3:2 CH2Cl2/EtOAc) afforded 21 mg (15%) of the carbamate as a solid, mp 120-125° C. 1H NMR (CDCl3): δ7.57 (d, 1H, J=2 Hz), 7.35 (d, 2H, J=9 Hz), 7.10-7.05 (m, 4H), 7.02 (d, 2H, J=9 Hz), 6.26 (d, 1H, J=2 Hz), 4.60 (br s, 2H), 4.43 (t, 2H), 4.35 (t, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](C=CN(C)C)=[CH:7][N:6]=1)=[O:4].I([O-])(=O)(=O)=O.[Na+].O.CO[CH:25]([O:28][CH3:29])[O:26][CH3:27]>CO.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH:25]([O:26][CH3:27])[O:28][CH3:29])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(C=CN(C)C)cn1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cnc(C(OC)OC)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A mixture of 5-(2-dimethylamino-vinyl)-pyrazine-2-carboxylic acid methyl ester (3.00 g, 14.5 mmol) and sodium periodate (9.09 g, 43.5 mmol) in methanol (40 mL) at 0° C. was treated dropwise with water (80 mL). The mixture was stirred at 0° C. for 30 min and then at 25° C. for 30 min. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The aqueous later was separated and saturated with sodium chloride. The aqueous layer was then extracted with ethyl acetate (4×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford a red solid. The resulting solid was combined with trimethylorthoformate (15 mL) and methanol (40 mL) and then was treated with p-toluenesulfonic acid monohydrate (191 mg, 1 mmol). The reaction mixture was heated under reflux for 1.5 h and then cooled to 25° C. The reaction was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 5-dimethoxymethyl-pyrazine-2-carboxylic acid methyl ester (2.26 g, 73%) as a yellow oil which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:10](O)(=[O:14])[C:11]([CH3:13])=[CH2:12]>ClCCl>[CH3:12][CH:11]1[CH2:13][C:4]2[C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[S:1][C:5]=2[C:10]1=[O:14]
Reactant: c1ccc2sccc2c1
Reactant: C=C(C)C(=O)O
Solvent: ClCCl
Product: CC1Cc2c(sc3ccccc23)C1=O
Temperature: 67.5 °C
Yield: 78.9 %

Procedure:
A solution of 66.9 g of benzo[b]thiophene (0.5 mol) and 46.3 g of methacrylic acid (0.537 mol) in 60 ml of dichloromethane was added dropwise starting at 70° C. within 20 minutes to 1000 g of super-PPA. The temperature was maintained at 65-70° C. during the addition. Methylene chloride was distilled off. After 2 h of reaction time, the reaction mixture was poured onto crushed ice and stirred until the polyphosphoric acid had completely dissolved. The aqueous phase was extracted with a dichloromethane/hexane solvent mixture (30 parts by volume/70 parts by volume). The combined organic phases were washed with a saturated aqueous solution of sodium hydrogen-carbonate and with water and dried over magnesium sulfate. After removing the solvents under reduced pressure, 79.8 g of a dark orange oil (71%) were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([NH:6][C:7]2[S:8][C:9]([CH2:17][CH3:18])=[CH:10][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([N+:21]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>O.[Zn]>[NH2:21][C:4]1[CH:3]=[C:2]([Br:1])[CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[S:8][C:9]([CH2:17][CH3:18])=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc(CC)sc1Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Product: CCOC(=O)c1cc(CC)sc1Nc1ccc(Br)cc1N
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl 2-(4-bromo-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate (0.4 g, 0.001 mol) was added to powdered zinc (0.4 g) and ammonium chloride (0.4 g) in water (10 ml) and stirred at 50° C. for 24 hours. The reaction mixture was filtered and the recovered solid washed successively with water and ethyl acetate. The organic phase was separated, washed with water, dried (MgSO4) and evaporated in vacuo to give the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].F[C:24](F)(F)[C:25](O)=O.C1(OC2NC(N)=C3C(N=2)=NC(OC)=N3)CCCCC1.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:22][CH2:25][CH2:24][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: O=C(O)C(F)(F)F
Agent: COc1nc2nc(OC3CCCCC3)[nH]c(N)c-2n1
Agent: ClCCCCBr
Product: COc1nc2c(N)nc(OC3CCCCC3)nc2n1CCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-(cyclohexyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]2=[O:21])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]([F:38])([F:37])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>N1C=CC=CC=1>[F:23][C:2]([F:1])([F:22])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:16][CH2:17][N:18]([S:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][C:25]([F:24])([F:37])[F:38])(=[O:35])=[O:34])[CH2:19][CH2:20]3)[C:12]2=[O:21])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Solvent: c1ccncc1
Product: O=C1N(c2ccc(C(O)C(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2
Temperature: 25 °C

Procedure:
Crude 2-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one from step A) (0.327 g) dissolved in pyridine at RT and under an argon atmosphere was treated with 2-trifluoromethoxy-benzenesulfonyl chloride (0.286 g) and the mixture was then stirred at RT over night. Then the most of pyridine was evaporated off in vacuo, the residue was dissolved in AcOEt which was then washed with 1M aqueous HCl and brine, dried over magnesium sulphate and concentrated in vacuo. The crude product was chromatographed over silica gel (eluent: AcOEt/Heptane, gradient from 0 to 30%) to give the desired product as a light brown solid. MS (ESI): 553.12 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].C([Cl:19])(=O)C=C>CCOCC>[ClH:19].[NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13][CH3:14])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11]
Reactant: C=CC(=O)Cl
Agent: CCO[Si](CCCN)(OCC)OCC
Solvent: CCOCC
Product: Cl

Procedure:
To a solution of 66.3 g of aminopropyl triethoxy silane in 200 ccs of ether, a solution of 13.6 g of acryloyl chloride in 100 ccs of ether was added dropwise at 0° C. The white precipitate of aminopropyl triethoxy silane hydrochloride formed was filtered off by suction whereupon the ether filtrate was concentrated by evaporation and the residue was distilled.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=O)[CH3:13])[CH2:3]1.[NH2:33][CH2:34][CH2:35][OH:36].C1(C)C=CC=CC=1>O>[OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[N:33][CH2:34][CH2:35][OH:36])[CH3:13])[CH2:3]1
Reactant: NCCO
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=NCCO)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
The (2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione (8.0 g), 2-aminoethanol (40 ml), toluene (200 ml) and Dowex 50-W resin (0.8 g) were added to a flask fitted with a water separator. The mixture was heated under reflux for 10 h, by which time approximately 15 ml of a distillate had collected in the water separator. The contents of the flask were filtered while still hot and the residue was rinsed with hot toluene. The filtrate was washed with water, dried over sodium sulfate and the solvent was removed under reduced pressure to give (2β,3α,5α)-3-hydroxy-20-[(2-hydroxyethyl)imino]-2-(2,2-dimethyl-4-morpholinyl)pregnan-11-one. δ (CDCl3) 0.50 (s,3H), 1.05 (s,3H), 1.21 (s,3H), 1.23 (s,3H) and 2.36 (s,2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[I:11]N1C(=O)CCC1=O.CN(C=O)C.CC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([I:11])[C:3]=12
Reactant: Clc1ncnc2[nH]ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Clc1ncnc2[nH]nc(I)c12
Temperature: 50 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
Charge 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (6.1 g, 1.0 eq), N-iodosuccinimide (NIS) (21.55 g, 2.0 eq) and DMF (213.5 mL) in a round bottom flask. Stir the reaction mass at 50° C. for 16 h. Monitor the reaction by TLC (10% acetone in DCM). Concentrate the reaction mass under reduced pressure. Charge ethyl acetate and wash with water and saturated aq. sodium chloride. Dry the organic layer over anhydrous sodium sulfate and concentrate the organic layer under reduced pressure to give 4-chloro-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (6.8 g, 61.43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:21]([C:27]#[N:28])[C:22]([O:24]CC)=[O:23])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>C(O)C>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C:8]([CH:21]([C:27]#[N:28])[C:22]([OH:24])=[O:23])([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(C#N)C1(c2cccc(Cl)c2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Cl)c2)(C(C#N)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 77.3 %

Procedure:
A solution of 16b (5.2 g, 12.8 mmol) was dissolved in ethanol (30 ml) and 4 M aqueous sodium hydroxide (30 ml, 120 mmol) was added. The resulting solution was stirred at room temperature for 6.5 hours and then stored at 0° C. overnight. Concentrated hydrochloric acid (10 ml) was added dropwise at 0° C. and the mixture was then adjusted to pH˜4 with 1 M hydrochloric acid. The solution was extracted with ethyl acetate (500 ml) and the aqueous phase was acidified to pH˜3 and re-extracted with ethyl acetate. Both ethyl acetate layers were combined and washed with water and brine and then dried and concentrated to afford [1-(tert-butoxycarbonyl)-4-(3-chlorophenyl) piperidin-4-yl](cyano)acetic acid (16c) as a rigid foam (3.75 g, 77%). This material was used without further purification.
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]3)=[CH:21][CH:20]=2)[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=4[CH2:3][C:2]([NH2:1])=[O:42])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=3)=[CH:20][CH:21]=2)[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
tert-Butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I28) (0.184 g, 0.315 mmol) was dissolved in DCM (10 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (1.21 mL, 15.8 mmol) was added to the solution and the reaction was stirred at room temperature for 1 hour. Volatiles were removed in vacuo, EtOAc (100 mL) and 2 M aq. NaOH (70 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (70 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give a white solid. The solid was taken up in DCM (˜7 mL) and methanol (˜1 mL) and concentrated in vacuo. The process was repeated with only DCM twice to give the title compound (4) (0.110 g, 72% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.69-7.62 (m, 2H), 7.44 (s, 1H), 7.26-7.12 (m, 6H), 6.93 (s, 1H), 3.50 (s, 2H), 3.15-3.06 (m, 2H), 3.06-2.90 (m, 4H), 2.60-2.43 (m, 3H), 1.85 (d, J=11.1 Hz, 1H), 1.69-1.61 (m, 1H), 1.61-1.41 (m, 2H). 3 Aliphatic protons obscured by residual DMSO. LCMS Method C: rt 4.81 min; m/z 484.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[H-].[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([CH3:33])[O:32][CH2:31][CH2:30][O:29]2)=[CH:24][CH:23]=1.O>O1CCOCC1>[CH3:33][C:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][O:16][N:15]=[CH:14][C:5]3[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=3[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:23][CH:24]=2)[O:29][CH2:30][CH2:31][O:32]1
Reactant: CC1(c2ccc(CBr)cc2)OCCO1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C)c(Oc2ccccc2)c1C=NOCc1ccc(C2(C)OCCO2)cc1
Yield: 74.2 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dioxane, and 0.14 g (0.0058 mole) of sodium hydride was added. Thereafter, 1.1 g (0.0043 mole) of 2-(4-bromomethylphenyl)-2-methyl-1,3-dioxolane was added to this solution which was then heated under reflux for 3 hours. After completion of the reaction, the reaction solution was poured into 200 ml of cold water and extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.3 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:16][C:15]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[N:14][C:13]=1[C:28]([NH2:30])=[O:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[S:16][C:15]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[N:14][C:13]=2[C:28]([NH2:30])=[O:29])=[O:7])=[CH:4][CH:3]=1
Reactant: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1N
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1NC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.9 %

Procedure:
To a mixture of 4-fluorobenzoylchloride (0.16 g, 1 mmol) and a catalytic amount of DMAP in pyridine (5 mL) was added dropwise a solution of 5-amino-2-(quinolin-4-ylamino)thiazole-4-carboxamide (0.25 g, 0.87 mmol) in pyridine (5 mL), and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filteration and washed successively with water, ether, and MeOH to give 0.12 g (33% yield) of the titled compound. LCMS m/z [M+H]+408.2 .