Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(CC)CC.[CH3:22][CH2:23][OH:24]>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([O:24][CH2:23][CH3:22])=[O:5]
Reactant: CCO
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
To a solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (5.0 g, 22.0 mmol) in THF (25 mL) was added Et3N (3.1 mL, 22.0 mmol) followed by EtOH (1.3 mL, 22.0 mmol). This mixture was stirred at ambient temperature for 1 h and quenched with saturated, aqueous NH4Cl (10 mL). The layers were separated and the aqueous layer was extracted with 3×10 mL EtOAc and the combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 60% hexanes in EtOAc) to give the title compound (4.8 g, 20.3 mmol, 92% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.42 (t, J=7.1 Hz, 3H), 4.43 (q, J=7.1 Hz, 2H), 7.23-7.34 (m, 1H), 7.74-7.82 (m, 1H), 8.23 (dd, J=6.3, 2.4 Hz, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13]([O-:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K+].[I-].[Na+]>CN(C=O)C.CCOCC>[C:21]([O:20][P:13]([O:25][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl 4-(bromomethyl)benzoate (1200 mg, 5.24 mmol), potassium di-tert-butyl phosphate (1431 mg, 5.76 mmol) and sodium iodide (785 mg, 5.24 mmol) were combined in DMF (3.00 mL) under nitrogen. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ether, washed with 10% LiCl solution and brine, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane/EtOAc) to provide Preparation 55A (571 mg, 1.593 mmol, 30%): 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.4 Hz, 2H), 7.53-7.37 (m, 2H), 5.05 (d, J=7.5 Hz, 2H), 3.92 (s, 3H), 1.48 (d, J=0.4 Hz, 18H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9](OCCOC)=[O:10].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH3:19])=[C:8]([CH2:9][OH:10])[CH:16]=[CH:17][CH:18]=1
Reactant: COCCOC(=O)c1cccc(OCCOC)c1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COCCOc1cccc(CO)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methoxyethyl 3-(2-methoxyethoxy)-2-methylbenzoate (0.83 g, 3.1 mmol) in DCM (50 mL) at 0° C. was added DIBAL (1M in THF, 13.6 mL, 4.4 eq) dropwise under inert atmosphere. After stirring for 24 h at rt, the reaction was quenched with saturated ammonium chloride until dissolution of the jelly precipitate. The aqueous phase was extracted with DCM, and the combined organic phases dried over sodium sulfate and concentrated in vacuo to afford (3-(2-methoxyethoxy)-2-methylphenyl)methanol in a quantitative yield.
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]2[C:5]([CH2:6][CH2:7][CH2:8][C@@:9]32[C:14]([F:16])([F:15])[CH2:13][O:12][C:11]([NH2:17])=[N:10]3)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[N:30][CH:31]=[C:32]([CH:35]=2)[C:33]#[N:34])O1>>[NH2:17][C:11]1[O:12][CH2:13][C:14]([F:16])([F:15])[C@@:9]2([C:18]3[C:5](=[CH:4][CH:3]=[C:2]([C:28]4[CH:29]=[N:30][CH:31]=[C:32]([CH:35]=4)[C:33]#[N:34])[CH:19]=3)[CH2:6][CH2:7][CH2:8]2)[N:10]=1
Reactant: NC1=N[C@@]2(CCCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2ccc3c(c2)[C@@]2(CCC3)N=C(N)OCC2(F)F)c1
Yield: 72 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-7-bromo-5′,5′-difluoro-3,4,5′,6′-tetrahydro-2H-spiro[naphthalene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.1) with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile yielded the title compound (72% yield) as an off-white solid. MS (ISP): m/z=355.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[C:11](C(O)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:27](C=O)C.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.[Cl-].[Na+].O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[C:11]([NH2:27])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn(-c2ccc(Cl)cc2)c1C1CCC1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Nc1cnn(-c2ccc(Cl)cc2)c1C1CCC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a mixture of 1-(4-chlorophenyl)-5-cyclobutyl-pyrazole-4-carboxylic acid (4.0 g, 14.4 mmol) in CH2Cl2 (100 mL) was added oxalyl chloride (3.78 mL, 43.4 mmol) and DMF (0.06 mL). After 2 h at room temperature, the reaction mixture was concentrated in vacuo, re-dissolved in 40 mL of acetone, and added to a 0° C. solution of NaN3 (3.75 g, 57.8 mmol) in H2O (40 mL). Brine (150 mL) and EtOAc (350 mL) were then added. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was stirred in 100 mL of toluene at 95° C. for 1 h, cooled to room temperature, and then treated with 150 mL of 6 M aqueous HCl at 110° C. for 1 h. After cooling to room temperature the mixture was basified with dilute NH4OH and extracted with EtOAc (500 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-100% EtOAc/CH2Cl2 gradient elution) to yield 1-(4-chlorophenyl)-5-cyclobutyl-pyrazol-4-amine (2.9 g, 81% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](/[CH:10]=[CH:11]/[C:12]2[N:13]([CH3:23])[N:14]=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[S:5][C:6]=1[C:7]([OH:9])=O.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:7]([C:6]2[S:5][C:4](/[CH:10]=[CH:11]/[C:12]3[N:13]([CH3:23])[N:14]=[N:15][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:3][C:2]=2[CH3:1])=[O:9])[CH2:26][CH2:27]1
Reactant: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)O
Reactant: NC1CCOCC1
Product: Cc1nc(/C=C/c2c(-c3ccccn3)nnn2C)sc1C(=O)NC1CCOCC1
Yield: 66 %

Procedure:
As described for example 10 g, 4-methyl-2-[(E)-2-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-vinyl]-thiazole-5-carboxylic acid (56 mg, 0.17 mmol), was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (46 mg, 66%) which was obtained as a light yellow solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: COc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 4-chloro-3-nitropyridine (Kruger J, Mann F. G, J. Chem. Soc., 1955, 2755) (700 mg, 4.41 mmol) in ethanol (10 ml) was added 4-methoxyaniline (1.087 g, 8.82 mmol), followed by sodium acetate (362 mg, 4.41 mmol). The mixture was heated under reflux for 16 hours, cooled to room temperature and diluted with water (30 ml). The resulting precipitate was collected by filtration, washed with water (×3) and dried in vacuo to afford the title compound (800 mg, 74%); MS (ES+) m/e 309 [M+H]+.
Reaction SMILES: C12(C)C(C)(C)C(CC1)CC2C(Cl)=O.N[CH:15]1[CH2:21][CH2:20][C:19](=[O:22])[NH:18][C:16]1=[O:17].C(OC1C=CC=CC=1C([NH:31]C1CCC(=O)NC1=O)=O)(=O)C>C(Cl)(Cl)Cl>[NH2:31][N:18]1[C:19](=[O:22])[CH2:20][CH2:21][CH2:15][C:16]1=[O:17]
Reactant: NC1CCC(=O)NC1=O
Reactant: CC(=O)Oc1ccccc1C(=O)NC1CCC(=O)NC1=O
Agent: CC1(C)C2CCC1(C)C(C(=O)Cl)C2
Solvent: ClC(Cl)Cl
Product: NN1C(=O)CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A mixture of (+)-camphanic chloride (19 mg, 00868 mmol), aminoglutarimide (21 mg, 0.0868 mmol) and Et3N (24) in CHCl3 (1 ml) was stirred at room temperature for 16 hours. The solution was diluted with CHCl3, washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, concentrated and purified by chromatography (silica gel, CH2Cl2; EtOAc=10:1) to give product (16 mg, 60.0% yield) as a colorless gel: 13CNMR (CDCl3) δ 172.6, 169.4, 168.6, 165.5, 90.3, 58.3, 53.3, 48.2, 47.6, 29.2, 28.2, 26.9, 22.7, 14.6, 7.6; MS (CI/CH4) m/z 308 (M+). This compound exhibited angiogenic activity in the assay of Example 13.
Reaction SMILES: [Cl-].[CH2:2]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([NH:15][NH3+:16])=[O:14])[C:8](=[O:23])[C:7]1=[O:24])[CH2:3][CH2:4][CH3:5].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH2:35][CH:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:33]1[C:44](O)=[O:45])=[O:31])([CH3:28])([CH3:27])[CH3:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:2]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:13]([NH:15][NH:16][C:44]([CH:33]2[CH:34]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:35][CH2:36][CH2:37][N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[O:45])=[O:14])[C:8](=[O:23])[C:7]1=[O:24])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1CCN(C(C(=O)N[NH3+])c2ccccc2)C(=O)C1=O
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccccc2)C1C(=O)O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1CCN(C(C(=O)NNC(=O)C2C(c3ccccc3)CCCN2C(=O)OC(C)(C)C)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 11 %

Procedure:
To a solution of 2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazinium chloride (94.0 mg, 0.27 mmol) in 1,2-dichloroethane (2 ml) were added 1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (71.0 mg, 0.23 mmol), 1-hydroxybenzotriazole (44.5 mg, 0.26 mmol), diisopropylethylamine (0.050 ml, 0.27 mmol), and polystyrene bound carbodiimide (353 mg, 0.46 mmol, 1.34 mmol/g). The reaction was allowed to stir gently at room temperature for 24 h. The reaction was filtered, concentrated, and purified via reverse phase HPLC to yield tert-butyl 2-({2-[(4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetyl]hydrazino}carbonyl)-3-phenylpiperidine-1-carboxylate (11%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Br[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:17])[C@@H:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OC
Product: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(C)c1)OC

Procedure:
A mixture of 3-(4-Hydroxy-3-methyl-phenyl)-2-methoxy-propionic acid ethyl ester and from Step E and 4-(3-bromopropoxy)biphenyl were treated under standard condition I to give the title product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:38])[CH:36]=[CH2:37]>ClCCl>[C:35]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:27])[C:9]1[CH:26]=[CH:25][C:12]([CH:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)(=[O:38])[CH:36]=[CH2:37]
Reactant: C=CC(=O)Cl
Reactant: CN(CCCCCCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCN(C)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 23 °C
Reaction time: 72 h
Yield: 67.5 %

Procedure:
A stirred mixture of 4'-[(6-hydroxyhexyl)methylamino]-4-methylsulfonylstilbene (Example 7, 20.0 g, 52 mmol), triethylamine (6.3 g, 62 mmol) and dry dichloromethane (DCM) was treated dropwise with acryloyl chloride (5.6 g, 62 mmol) in 50 mL of DCM at 23° C. under nitrogen. The resulting solution was stirred at 23° C. for 72 hours, and then filtered. The filtrate was washed successively with saturated NaCl, with saturated NHCO3, and with water. The organic layer was dried (MgSO4), and the solvent was removed at reduced pressure to deposit a yellow oil which gradually crystallized. The product was recrystallized from tetrahydrofuran (THF)/hexanes to yield 15.5 g (68%) of a yellow solid, mp 88°-90° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)[CH3:2].[I-:12].[Na+].ClN>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([I:12])[C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])[CH3:2]
Reactant: CCc1ccc(O)c(C=O)c1
Reactant: [I-]
Agent: NCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc(I)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 30.0 g of 5-ethyl-salicylaldehyde (Reg.No. 52411-35-5) in 500 ml of DMF was treated with 36.0 g of sodium iodide and 67.6 g of Chloroamine T and stirred for one hour at room temperature. The reaction mixture was concentrated in a high vacuum, poured into ice-water, made acid with 2N hydrochloric acid and extracted with ethyl acetate. The organic phases were washed with aqueous sodium thiosulphate solution, saturated sodium chloride solution and ice-water, dried over sodium sulphate and concentrated. The residue was taken up in ether-hexane (1:1) and filtered. The filtrate was concentrated and gave 45.8 g of 5-ethyl-2-hydroxy-3-iodo-benzaldehyde; MS (EI) m/z 276 M+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[CH:34]=[CH:33][C:27]([CH2:28][NH:29][C:30](=O)[CH3:31])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[F:23][C:24]1[CH:34]=[CH:33][C:27]([CH2:28][NH:29][C:30](=[S:10])[CH3:31])=[CH:26][CH:25]=1
Reactant: CC(=O)NCc1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(=S)NCc1ccc(F)cc1
Temperature: 80 °C
Yield: 106.1 %

Procedure:
Step c) Add Lawesson reagent (1.8 g, 3.6 mmol) to N-(4-fluorobenzyl)acetamide (0.9 g, 5.4 mmol) in 50 mL of toluene and heat to 80° C. for 12 hours. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, Acetone: Hexane=20:80) to give a mixture. Wash with ether and discard insoluble solid impurities by filtration. Remove solvent under reduced pressure to give N-(4-fluorobenzyl)-thioacetamide (0.7 gm) in 71% as a yellow solid: MS 184 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.F[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1c(F)cc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
To a solution of 4-chloro-2,6-difluorophenol (5.0 g, 30.4 mmol), 4-fluorobenzaldehyde (3.1 mL, 28.9 mmol) in DMF (30 mL), was added K2CO3 (5.0 g, 36.2 mmol). The mixture was heated at 100° C. overnight. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated, purified by flash chromatography to afford the title compound (5.4 g, 20.10 mmol, 66.1% yield) as a colorless oil. LCMS: rt=3.52 min, [M+H+]=269
Reaction SMILES: ClC1C=CC(C(C2C=CC=CC=2C2C(C)=NOC=2/C=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=O)=CC=1.[Cl:30][C:31]1[CH:52]=[CH:51][C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[C:44]([CH:49]=O)=[N:45][O:46][C:47]=2[CH3:48])=[O:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:52]=[CH:51][C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[C:44](/[CH:49]=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[N:45][O:46][C:47]=2[CH3:48])=[O:36])=[CH:33][CH:32]=1
Reactant: Cc1noc(/C=N/[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1onc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Product: Cc1onc(/C=N/[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
This material can be made in a similar manner as (R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide starting from 4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde (1.10 g, 3.38 mmol). LC/MS m/z 429 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]([C:23]#[N:24])([CH2:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O.O1CCOCC1>[CH2:1]([CH:8]([CH2:12][C:13]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=1)=[O:22])[C:23]#[N:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(CC(=O)c1ccc(Cl)c(Cl)c1)(Cc1ccccc1)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: N#CC(CC(=O)c1ccc(Cl)c(Cl)c1)Cc1ccccc1

Procedure:
A solution of 2-benzyl-2-cyano-4-oxo-4-(3,4-dichlorophenyl)-butanoic acid (5 g, 13.8 mmol) in 10% water/1,4-dioxane (250 ml) was refluxed for about 24 hours. The solvents were removed under reduced pressure and the residue was purified by flash chromatography, using cyclohexane/ethyl acetate 0÷15 as eluent. The title compound was obtained as a colourless solid (2.7 g, 62%) (m.p. 101°-102° C.)
Reaction SMILES: [CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH2:19][CH2:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].Cl>O>[CH2:1]([S:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)[CH:15]=2)[CH2:10]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: CCCCS(=O)(=O)NC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Yield: 66.5 %

Procedure:
In 55 ml of water were dissolved 2.45 g of 2-n-butylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 1.40 g of sodium hydroxide, and 2.66 g of sodium 3-nitrobenzenesulfonate was added thereto. The mixture was refluxed under heating for 5 hours. After cooling, the reaction mixture was made acidic with 10% hydrochloric acid and extracted with ethyl acetate, the extract was dried, and then the solvent was removed. The resulting crystals were recrystallized from methanol to obtain 1.62 g of 2-n-butylsulfonylamino-5-[pyridazin-3(2H)-on-6-yl]-indane.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11](Br)=[CH:12][N:13]=2)[CH2:3]1.[CH2:25]([Sn](CCCC)(CCCC)C#CC)[CH2:26][CH2:27]C>O1CCOCC1.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>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[C:19]#[N:20])[C:10](=[O:15])[C:11]([C:25]#[C:26][CH3:27])=[CH:12][N:13]=2)[CH2:3]1
Reactant: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)ncc(Br)c1=O
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Temperature: 96 °C
Reaction time: 40 h
Yield: 76.1 %

Procedure:
2-[2-(3-(R)-Amino-piperidin-1-yl)-5-bromo-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (Example 1) (120 mg, 0.31 mmol) and tributyl(1-propynyl)tin (140 μL, 0.46 mmol) were stirred in dioxane (5 mL) in a flask purged with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.046 mmol) was added, and the solution stirred at 96° C. for 40 h. Concentration in vacuo and purification by silica gel chromatography (16% MeOH/CHCl3) gave 82 mg (76%) of the title compound as a clear oil. 1H NMR (400 MHz, MeOD-d4): δ 7.82 (s, 1H), 7.64 (d, 1H, 7.6 Hz), 7.53 (t, 1H, J=7.6 Hz), 7.36 (t, 1H, J=7.6 Hz), 7.16 (d, 1H, J=7.6 Hz), 5.30 (s, 2H), 3.40-3.48 (m, 1H), 3.21-3.30 (m, 1H), 2.78-2.89 (m, 2H), 2.58-2.66 (m, 1H), 1.91 (s, 3H), 1.85-1.93 (m, 1H), 1.52-1.74 (m, 2H), 1.18-1.27 (m, 1H). MS (ES) [m+H] calc'd for C20H21N5O, 348; found 348.
Reaction SMILES: [C:1]1([C:6]([NH:8][CH2:9][C:10]([O:12]C)=[O:11])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:15]>CO>[C:1]1([C:6]([NH:8][CH2:9][C:10]([O-:12])=[O:11])=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na+:15]
Reactant: COC(=O)CNC(=O)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CNC(=O)c1cccs1
Yield: 103.8 %

Procedure:
To 200 ml of a solution of 16.70 g of methyl 2-(2-thenoylamino)acetate in methanol, 20 ml of aqueous solution of 4.02 g sodium hydroxide was added, and heated to reflux for 30 minutes. The solvent was distilled off under reduced pressure. The residue was crystallized by addition of isopropanol to provide 18.03 g of the objective compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[SH:8].[CH:15](O)=O>>[CH2:13]([N:10]([CH2:11][CH3:12])[C:3]1[C:2]2[N:1]=[CH:15][S:8][C:7]=2[N:6]=[C:5]([CH3:9])[N:4]=1)[CH3:14]
Reactant: CCN(CC)c1nc(C)nc(S)c1N
Reactant: O=CO
Product: CCN(CC)c1nc(C)nc2scnc12

Procedure:
3 g of 5-amino-4-diethylamino-6-mercapto-2-methylpyrimidine was dissolved in 50 ml of 90% formic acid and refluxed for 2 hours. After the completion of the reaction, formic acid was distilled off under reduced pressure. The residue was added with 30 ml of water, and neutralized with ammonium hydroxide. This aqueous solution was extracted with 200 ml of ethyl acetate and the organic layer was dried over sodium sulphate anhydride. Then the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica-gel to obtain 7-diethylamino-5-methylthiazolo[5,4-d]pyrimidine (1.6 g).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 70 °C
Yield: 61.7 %

Procedure:
A mixture of Intermediate 148e (313 mg, 0.7 mmol), Intermediate 186b (262 mg, 0.7 mmol) and DIPEA (182 μL, 1.05 mmol) in dioxane (4 mL) was heated at 70° C. for 20 h. The reaction mixture was cooled to RT and eluted directly on SCX-2 using MeOH and 2M NH3 in MeOH. The basic fractions were evaporated under reduced pressure. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound as a yellow glass (293 mg). LCMS (Method 3): Rt 3.63 min, m/z 679 [MH+].