Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].Br[C:12]1[CH:13]=[C:14]([C:22]#[N:23])[C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu](I)I.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:12]2[CH:13]=[C:14]([C:22]#[N:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]n1
Reactant: N#Cc1cc(Br)cc2ccccc12
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccn(-c2cc(C#N)c3ccccc3c2)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
A suspension of 1H-pyrazole-3-carboxylic acid ethyl ester (0.1 g), 3-bromonaphthalene-1-carbonitrile (0.17 g), copper iodide (0.0068 g), (1R,2R)-(−)-N, N′-dimethylcyclohexane-1,2-diamine (0.010 g) and potassium carbonate (0.21 g) in toluene (3 mL) was stirred at 90° C. overnight. After cooling to room temperature, ethyl acetate was added to the reaction mixture. The resulting mixture was filtered through a Celite pad. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 1-(4-cyanonaphthalene-2-yl)-1H-pyrazole-3-carboxylic acid ethyl ester (0.040 g). To a solution of this compound (0.040 g) in a mixed solvent of tetrahydrofuran (0.2 mL), ethanol (0.08 mL) and water (0.08 mL) was added lithium hydroxide monohydrate (0.017 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (0.35 mL). The precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give the title compound (0.026 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25](OS(C)(=O)=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (30.0 g, 154 mmol), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butylester (52.5 g, 200 mmol) and cesium carbonate (80.1 g, 246 mmol) in anhydrous DMF (400 mL) was heated to 100° C. for 24 h. DMF was removed under high vacuum. The residue was then diluted with water (200 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were washed with water (3×50 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the orange-brown oily residue was added diisopropyl ether (300 mL), and the mixture was stirred at 0° C. for 2 h. Colorless crystals separated out that were filtered off and dried in vacuo to give a 1st crop of the title compound. The filtrate was then concentrated in vacuo, the residue was mixed with diisopropyl ether (100 mL), a small amount of the 1st crop was added as a seed, and the mixture was stirred overnight. The resulting white precipitate was filtered and dried in vacuo as 2nd crop of the title compound. 1H NMR (300 MHz, CDCl3): δ=1.33 (s, 12H), 1.48 (s, 9H), 1.85-1.93 (m, 2H), 2.15-2.18 (m, 2H), 2.83-2.92 (m, 2H), 4.23-4.39 (m, 3H), 7.76 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:32]=[CH:31][C:11]([CH2:12][O:13][C:14]3[CH:15]=[C:16]4[N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21][N:17]4[C:18](=[O:20])[N:19]=3)=[CH:10][C:9]=2[F:33])=[CH:5][C:4]=1[C:36]([F:39])([F:38])[F:37])#[N:2]>CN(C=O)C>[F:33][C:9]1[CH:10]=[C:11]([CH2:12][O:13][C:14]2[CH:15]=[C:16]3[NH:23][CH2:22][CH2:21][N:17]3[C:18](=[O:20])[N:19]=2)[CH:31]=[CH:32][C:8]=1[O:7][C:6]1[CH:34]=[CH:35][C:3]([C:1]#[N:2])=[C:4]([C:36]([F:37])([F:38])[F:39])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)c(F)c1)nc2=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(COc3cc4n(c(=O)n3)CCN4)cc2F)cc1C(F)(F)F

Procedure:
Prepared in a manner similar to that described for E71 using tert-butyl 7-((4-(4-cyano-3-(trifluoromethyl)phenoxy)-3-fluorobenzyl)oxy)-5-oxo-2,3-dihydroimidazo[1,2-c]pyrim-idine-1-(5H)-carboxylate (75 mg, 0.137 immol) in DMF (2 mL) and silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[N:8]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[N:6]=[CH:5]2.C[S-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)=[CH:17][CH:16]=1)[N:6]=[CH:5]2
Reactant: COc1cc2nc(Nc3ccc(N4CCOCC4)cc3)ncc2cc1Br
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1cc2nc(Nc3ccc(N4CCOCC4)cc3)ncc2cc1Br

Procedure:
A 0.32M suspension of 6-bromo-7-methoxy-N-(4-morpholinophenyl)quinazolin-2-amine (1.0 eq) and sodium thiomethoxide (4.0 eq) in DMF was heated to 80° C. in an oil bath for 12 h. LCMS data indicated the reaction was complete. The mixture was partitioned between ethyl acetate and water. The insoluble solid was filtered off and was rinsed with ether and air dried to give product. ES/MS m/z 401/403 (MH+).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH:5]=[N:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[SH-:17].[Na+].Cl>CN(C)C=O>[CH2:15]([O:14][C:12]([C:3]1[N:4]=[CH:5][N:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[C:2]=1[SH:17])=[O:13])[CH3:16]
Reactant: CCOC(=O)c1ncn(-c2nccs2)c1Cl
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(-c2nccs2)c1S
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
8.0 g of 5-chloro-4-ethoxycarbonyl-1-(thiazol-2-yl)imidazole was dissolved in 30 ml of dimethylformamide. To the resulting solution was added 6.2 g of sodium hydrosulfide (content of 70%), followed by stirring of the resulting mixture at 60° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water and the resulting solution was made weakly acidic with conc. hydrochloric acid. Crystals precipitated were filtered out, washed and dried to give 7.5 g of the desired compound. m.p.: 155° to 158° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH2:20][N:21]3[CH2:26][CH2:25][N:24](C(OCC4C=CC=CC=4)=O)[CH2:23][CH2:22]3)[CH2:15]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:15]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(CCCN2CCC[C@@H](CN3CCN(C(=O)OCc4ccccc4)CC3)C2)cc1
Solvent: CO
Product: CS(=O)(=O)c1ccc(CCCN2CCC[C@@H](CN3CCNCC3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
Benzyl 4-[((3R)-1-{3-[4-(methylsulfonyl)phenyl]propyl}piperidin-3-yl)methyl]piperazine-1-carboxylate (5.00 g, 9.70 mmol) was dissolved in methanol (30 ml) in a three-necked flask. The air was removed under reduced pressure and replaced with argon before the addition of 10% Pd/C (1.00 g). A balloon of hydrogen was then added and the reaction stirred at room temperature for 18 h. The hydrogen was evacuated and replaced with argon. The catalyst was then filtered using a nylon whatman autocup and the solvent removed under reduced pressure to afford the desired product as a yellow gum (3.50 g, 95% crude yield).
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[C:13]([O:20][CH3:21])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][O:20][C:13]1[CH:12]=[C:11]([N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)[CH:16]=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
To a solution of 4-piperidone hydrochloride monohydrate (10.0 g, 0.065 mol) in DMF (80 mL) are added 4-Fluoro-2-methoxy-1-nitro-benzene (10.0 g, 0.058 mol) and potassium carbonate (20.2 g), and the mixture is stirred at 70° C. for 20 h. After a filtration, the filtrate is poured into H2O (ca. 300 mL), and the resulting precipitates are collected by a filtration followed by washing with H2O for several times to give title compound (8.98 g) in 61% yield. Orange solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[CH:41]=[CH:40][C:19]([C:20]([NH:22][C@@H:23]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)[CH2:24][NH:25]C(=O)OC(C)(C)C)=[O:21])=[C:18]([F:42])[CH:17]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.O1CCOCC1>>[NH2:25][CH2:24][C@@H:23]([NH:22][C:20](=[O:21])[C:19]1[CH:40]=[CH:41][C:16]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][C:11]([F:14])([F:15])[CH2:12][CH2:13]3)[N:4]=2)=[CH:17][C:18]=1[F:42])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCC(F)(F)CC3)cnc2N)cc1F)c1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCC(F)(F)CC3)cnc2N)cc1F)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To (S)-tert-butyl (2-(4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzamido)-2-(3-chlorophenyl)ethyl)carbamate (11 mg, 0.018 mmol) was added HCl 4M in dioxane (1 mL, 4.00 mmol). The reaction was stirred for 1 h at room temperature. The solvent was removed and concentrated to residue, which was dissolved in 1:1 acetonitrile/water, filtered and lyophilized to HCl salt. The crude salt residue was dissolved in 1 mL of DMSO, purified by prep HPLC and lyophilized to give 3.8 mg of the desired product (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-4-(3-amino-6-(4,4-difluorocyclohexyl)pyrazin-2-yl)-2-fluorobenzamide as a TFA salt (33%). LCMS (m/z): 504.2 (MH+), 0.74 min; 1H NMR (CD3OD) δ ppm 7.85-7.73 (m, 2H), 7.62 (dd, J=8.0, 1.4 Hz, 1H), 7.54 (dd, J=12.1, 1.2 Hz, 1H), 7.46 (s, 1H), 7.38-7.28 (m, 3H), 5.39 (dd, J=9.0, 5.9 Hz, 1H), 3.40-3.33 (m, 2H), 2.72 (br. s., 1H), 2.12-1.98 (m, 2H), 1.96-1.73 (m, 6H).
Reaction SMILES: C(O)C(N)(CO)C[OH:4].Cl.[C@@H:10]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21](N)[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[CH2:12][CH2:11]1>>[C@@H:10]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([OH:4])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[CH2:12][CH2:11]1
Reactant: NC(CO)(CO)CO
Reactant: Nc1ncnc2c1ncn2[C@H]1CC[C@@H](CO)O1
Agent: Cl
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Reaction time: 2 h

Procedure:
The washed cells described above were added to 0.05M Tris-HCl buffer (pH 7.2) containing 1 g/dl of 2',3'-dideoxyadenosine in a concentration of 5 g/dl followed by reacting at 30° C. for 2 hours. The amount of 2',3'-dideoxyinosine produced at this stage is shown in Table 2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:16][CH2:8][C:5]1[N:4]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)c(-c2cccc(F)c2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(-c2nc(CBr)ccc2Cl)c1
Temperature: 74 °C

Procedure:
To a solution of 3-chloro-2-(3-fluorophenyl)-6-methylpyridine (0.435 g, 2.0 mmol) in CCl4 (40 mL) was added N-bromosuccinimide (0.350 g, 2.0 mmol). The reaction mixture was heated to 74° C. and AIBN (0.027 g, 0.16 mmol) was added. The reaction mixture was heated to reflux for 1 d, diluted with EtOAc, washed with H2O (1×), brine (1×), dried over MgSO4, filtered through a pad of silica (1.5 cm), and concentrated. The product, 6-(bromomethyl)-3-chloro-2-(3-fluorophenyl)pyridine, was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[OH-].[K+].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]>O.[Cu]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C(O)Cc1ccccc1I
Reactant: COc1ccccc1S
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccccc1Sc1ccccc1CC(=O)O

Procedure:
2-Methoxythiophenol (2.8 g, 20 mmol) was added to a solution of potassium hydroxide (4.6 g, 80 mmol) in water (50 ml) and the mixture was degassed for 15 minutes. 2-Iodophenylacetic acid (5.24 g, 20 mmol) and copper bronze (64 mg, 1 mmol) were then added to the reaction mixture, which was refluxed overnight. The solution was cooled down, filtered and the precipitate washed with water (50 ml). The filtrate was acidified with conc HCl (pH 1), extracted with dichloromethane (3×100 ml). The organics were combined, extracted with saturated brine, dried over sodium sulphate and evaporated in vacuo to give the title compound as a pale brown oil which solidified overnight. The compound was used without any further purification (5.10 g, 93%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11]([C:33]2[C:28]([Cl:27])=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1cccnc1Cl
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2cccnc2Cl)nc1

Procedure:
By carrying out the operation analogously to example 1, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 2-chloro-3-pyridineboronic acid, the desired product is obtained in the form of an ecru solid (yield=43%).
Reaction SMILES: CN(C)C=O.[CH2:6]([C:12]1[CH:27]=[CH:26][C:15]([CH2:16][S:17][C@@H:18]2[CH2:22][NH:21][C@H:20]([C:23]([OH:25])=[O:24])[CH2:19]2)=[CH:14][CH:13]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:28]([S:36][CH2:37][C@@H:38]([CH3:51])[C:39](OC1C=CC([N+]([O-])=O)=CC=1)=[O:40])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[C:28]([S:36][CH2:37][C@@H:38]([CH3:51])[C:39]([N:21]1[CH2:22][C@@H:18]([S:17][CH2:16][C:15]2[CH:26]=[CH:27][C:12]([CH:6]3[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:13][CH:14]=2)[CH2:19][C@H:20]1[C:23]([OH:25])=[O:24])=[O:40])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C[C@@H](SCc2ccc(C3CCCCC3)cc2)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Dimethylformamide (4.5 ml) is added to (4S)-4-(4-hexylbenzylthio)-L-proline (430 mg), and the mixture is cooled to 0° C. To the mixture are added successively triethylamine (0.21 ml) and 4-nitrophenyl (2S)-3-(benzoylthio)-2-methylpropionate, and the obtained mixture is stirred at room temperature overnight. To the reaction mixture is added 10% citric acid, and the whole is extracted with ethyl acetate. The organic layer is washed with water and a saturated sodium chloride aqueous solution successively and dried over sodium sulfate. The residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to give 580 mg (81%) of the titled compound as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:33])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[S:5][CH:6]=1.[OH-].[Li+]>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:33])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:31][CH3:32])=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[S:5][CH:6]=1
Reactant: COC(=O)c1cc2c(Oc3ccc(CC(=O)Nc4nc(C)cs4)cc3)ccnc2cc1OC
Agent: [Li+]
Agent: [OH-]
Product: COc1cc2nccc(Oc3ccc(CC(=O)Nc4nc(C)cs4)cc3)c2cc1C(=O)O
Yield: 97 %

Procedure:
Using an analogous procedure to that described in Example 8, N-(4-methylthiazol-2-yl)-2-[4-(7-methoxy-6-methoxycarbonylquinolin-4-yloxy)phenyl]acetamide was reacted with lithium hydroxide to give the title compound in 97% yield; 1H NMR: (DMSOd6) 2.26 (d, 3H), 3.83 (s, 2H), 4.01 (s, 3H), 6.63 (d, 1H), 6.76 (s, 1H), 7.34 (d, 2H), 7.51 (d, 2H), 7.57 (s, 1H), 8.62 (s, 1H), 8.78 (d, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: OB(O)c1ccc(O)cc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)cc3)c(F)cn2c1=O
Yield: 61.7 %

Procedure:
Ethyl 8-(4-hydroxyphenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and (4-hydroxyphenyl)boronic acid (55.4 mg, 0.40 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (80 mg, 68%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[N:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.O.CCO[C:24]([CH3:26])=[O:25]>CN1C(=O)CCC1>[N:11]1([C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH:11][C@H:15]3[CH2:16][CH2:26][C@H:24]([OH:25])[CH2:19][CH2:14]3)[N:10]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[N:12]1
Reactant: CS(=O)(=O)c1nccc(-n2nnc3ccccc32)n1
Reactant: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: O[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-methanesulfonyl-pyrimidin-4-yl)-1H-benzotriazole (1.59 g, 6 mmol) in 15 mL of NMP was added trans-4-aminocyclohexane (3.11 g, 27 mmol) and the resulting mixture was stirred at 120° C. for 2 hours. It was then cooled, poured onto 100 mL of water, stirred and allowed to stand overnight. The resulting suspension was filtered, the collected solids were washed with water and dissolved with CH2Cl2; the solvent was removed under reduced pressure. The solid residue formed was taken up with EtOAc, filtered and dried to give trans-4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexanol as a white solid (910 mg, 51% yield), mp=224.8-228.1° C.; MS=311 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28]Cl)[CH2:22][CH2:21]1>>[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([CH3:30])[CH2:28][O:1][C:2]2[C:11]3[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=3)[O:5][C:4](=[O:13])[C:3]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:22][CH2:21]1
Reactant: CC(CCl)CN1CCOCC1
Reactant: Cc1cccc2c(O)c(-c3ccccc3)c(=O)oc12
Product: Cc1cccc2c(OCC(C)CN3CCOCC3)c(-c3ccccc3)c(=O)oc12
Yield: 65 %

Procedure:
Prepared according to the method of Example 8 from 4-hydroxy-8-methyl-3-phenyl-coumarin and 3-morpholino-2-methyl-1-chloropropane. An oil is obtained which cannot be crystallised. Yield 65%.
Reaction SMILES: ClC(OC(C)C)=O.[CH3:8][O:9][C:10]1[N:15]=[C:14](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:13]=[CH:12][C:11]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1.C([N:30](CC)C(C)C)(C)C.ClC(OCC)=O.N>CN(C=O)C.O.C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[N:15]=[C:14](/[CH:16]=[CH:17]/[C:18]([NH2:30])=[O:19])[CH:13]=[CH:12][C:11]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1nc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Agent: CC(C)OC(=O)Cl
Agent: CCOC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Reaction time: 0.33 h

Procedure:
Isopropyl chloroformate (3.99 mL) was added dropwise to a solution of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid (5.2 g) and N,N-diisopropylethylamine (7.44 mL) in DMF (52 mL) under ice-cooling, and the reaction solution was stirred for 20 minutes. Aqueous ammonic (5.2 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. Similarly, ethyl chloroformate (3.76 mL) was added dropwise to a solution of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid (4.8 g) and N,N-diisopropylethylamine (6.87 mL) in DMF (48 mL) under ice-cooling, and the reaction solution was stirred for 10 minutes. Then, aqueous ammonia (5.2 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solutions were mixed and diluted with water and chloroform, and then the organic layer was separated. The aqueous layer was extracted with chloroform five times. The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-2-propanol system) to obtain 3.54 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.O.CCOC(C)=O.[CH3:44][N:45](C=O)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2]>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]2)[C:5]2[C:10]([C:44]#[N:45])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(N4CCC(CNC(=O)OC(C)(C)C)CC4)nc(Cl)nc32)cc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of tert-butyl (1-(2-chloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (418 mg, 0.647 mmol), Pd2 dba3 (60 mg, 0.065 mmol) and dppf (72 mg, 0.13 mmol) in DMF (5 mL) was degassed with Ar before being charged with Zn(CN)2 (91 mg, 0.78 mmol). The mixture was stirred at 70° C. for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a flash silica gel column, eluted with EtOAc/hexane (10-30%) to give tert-butyl (1-(2-chloro-5-cyano-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)methylcarbamate (180 mg).