Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:10]=1[SH:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)C=O>C(#N)C>[CH2:24]([S:11][C:10]1[N:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:8]=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ncn(-c2nc(C)cs2)c1S
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2nc(C)cs2)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture consisting of 4.2 g of 4-ethoxycarbonyl-1-(4-methylthiazol-2-yl)imidazole-5-thiol, 3.2 g of anhydrous potassium carbonate, 2.2 g of benzyl chloride, 20 ml of dimethylformamide and 100 ml of acetonitrile was stirred at room temperature for 2 hours. After the reaction, solid materials were separated by filtration, and the filtrate was condensed under reduced pressure to obtain crude 5-benzylthio-4-ethoxycarbonyl-1-(4-methylthiazol-2-yl)imidazole as oily product. The resulting oily product was dissolved in 100 ml of chloroform and after addition of 13 g of conc. hydrochloric acid and 30 ml of water, 28 g of a 10% sodium hypochlorite solution was added dropwise to the mixture at -10° C. to -5° C. over 15 minutes. After the reaction mixture was stirred at 0° C. or lower for 20 minutes, an organic layer was separated and an aqueous layer was extracted with chloroform. After the organic layers were combined and washed with water, 60 ml of tetrahydrofuran was added to the organic layer and then 20 ml of a 28% aqueous ammonia was added dropwise under icc-cooling, and the mixture was stirred at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, an organic layer was separated and an aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried, and then concentrated under reduced pressure to obtain oily product. The resulting oily product was identified as 5-benzylsulfinyl-4-ethoxycarbonyl-1-(5-chloro-4-methylthiazol-2-yl)imidazole by NMR and MS analyses.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:21])[CH3:20]>O1CCCC1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:21][CH2:19][CH3:20])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(-c2cccc(Br)c2)nc1C#N
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(C#N)c(C#N)nc1-c1cccc(Br)c1
Temperature: 0 °C
Yield: 80 %

Procedure:
2,3-Dicyano-5-chloro-6-(m-bromophenyl)pyrazine (1.15 g; 0.0036 mole) was dissolved in 20 ml of tetrahydrofuran. The solution was cooled to 0° C., and 0.50 g of a 70% aqueous solution of ethylamine was added. The mixture was worked up in the same way as in Example 13, and recrystallized from ethanol to afford 0.95 g (yield 80%) of 2,3-dicyano-5-ethylamino-6-(m-bromophenyl)pyrazine.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].O>ClCCl>[C:1]([NH:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[C:8]([N+:17]([O-:19])=[O:18])[CH:9]=1)(=[O:14])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butylamine (5.1 g, 70 mmol) in dichloromethane (200 mL) was added dropwise a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (17.9 g, 70 mmol) in dichloromethane (100 mL) at room temperature over a period of 30 min, and then the reaction mixture was stirred for 2 h. The reaction mixture was poured into water (100 mL), the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried (Na2SO4), and concentrated to give 21.3 g (quant.) of the title compound as yellow solids: 1H-NMR (CDCl3) δ 8.38 (1H, d, J=2.0 Hz), 8.02 (1H, dd, J=2.0, 8.6 Hz), 7.70 (1H, d, J=8.6 Hz), 4.95 (1H, br.s), 1.28 (9H, s).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=1.[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[C:35]([NH2:45])[CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:38]=2)[CH2:29][CH2:28]1)(=[O:26])=[O:25]>O1CCOCC1.C(OCC)(=O)C>[CH3:23][S:24]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:34]=[C:35]([NH:45][C:13]3[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=3)[CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:38]=2)[CH2:31][CH2:32]1)(=[O:25])=[O:26]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)N1CCN(c2cc(N)cc(-c3ccccc3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CCN(c2cc(Nc3nccc(C(F)(F)F)n3)cc(-c3ccccc3)c2)CC1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
p-Toluenesulfonic acid (21.46 mg, 0.113 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (22.5 mg, 0.123 mmol) were added to a solution of 5-[4-(methylsulfonyl)piperazin-1-yl]biphenyl-3-amine (34 mg, 0.103 mmol) in dioxane (1 mL) and the reaction mixture was stirred for 14 hours at 100° C., then allowed to cool to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL), then washed with saturated aqueous NaHCO3 (30 mL) followed by brine (30 mL). The aqueous layers were extracted with ethyl acetate (30 mL), then the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided N-{5-[4-(methylsulfonyl)piperazin-1-yl]biphenyl-3-yl}-4-(trifluoromethyl)pyrimidin-2-amine MS ESI calc'd. for C22H23F3N5O2S [M+H]+ 478, found 478. 1H NMR (400 MHz, Acetone): δ 9.18 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 7.71-7.66 (m, 4H); 7.47 (t, J=7.5 Hz, 2H); 7.37 (t, J=7.3 Hz, 1H); 7.23 (d, J=4.9 Hz, 1H); 7.02 (s, 1H); 3.43 (d, J=10.6 Hz, 8H); 2.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].[Br:28]Br>C(O)(=O)C>[Br:28][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:5]([CH3:27])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=3)[C:12]=2[CH:11]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(Cl)cc3C2C)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccc(Cl)cc3C2C)cc1
Yield: 61.3 %

Procedure:
The title compound was prepared from 8-chloro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.95 g, 2.38 mmol), bromine (0.12 mL, 9.50 mmol), and glacial acetic acid (24 mL) according to the procedure and in the same manner as described in Example 4, step a. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:3 to 1:1 gradient) to yield 2-bromo-8-chloro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.70 g, 1.46 mmol, 61%) as a white solid;
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C:4](=O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:39](O)(=[S:41])[CH3:40]>O1CCCC1>[C:2]([C@@H:3]1[CH2:4][NH:5][C:39](=[S:41])[CH2:40]1)(=[O:1])[CH3:6]
Reactant: O=C1C[C@@H](O)CN1
Reactant: CC(O)=S
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1CNC(=S)C1
Reaction time: 0.17 h

Procedure:
In 300 ml of tetrahydrofuran was suspended 4.5 g of (4R)-4-hydroxy-2-pyrrolidone, 23.4 g of triphenylphosphine was added thereto, and the mixture was stirred for 10 minutes. Subsequently, 14 ml of diethyl azodicarboxylate was added dropwise to the reaction mixture at -10° C., and the mixture was stirred at the same temperature for 10 minutes. After 6.3 ml of thioacetic acid was added drop-wise to the reaction mixture at -10° C. or lower, the mixture was stirred at the same temperature for 2 hours and the solvent was removed. The residue was crystallized from diisopropyl ether. After the crystals were removed by filtration, the filtrate was condensed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; chloroform:ethanol=98:2)to obtain 3.8 g of (4S)-4-acetylthio-2-pyrrolidone as an oily product. NMR (CDCl3) δ: 2.29 (dd, 1H), 2.35 (s, 3H), 2.81 (dd, 1 H), 3.31 (dd, 1H), 3.88 (dd, 1H), 4.10 to 4.23 (m, 1H), 7.02 to 7.17 (b, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:40]1CCOCC1.N>C1COCC1.C(Cl)Cl>[NH2:40][C:36]([C@@H:9]1[CH2:10][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[O:38]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Reactant: CN1CCOCC1
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 100 %

Procedure:
A stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (3) (5 g, 9.16 mmol) in THF (50 ml) was cooled to −15° C. (acetone/ice). NMM (1.5 ml, 13.7 mmol) was added to the solution followed by IBCF (1.54 ml, 11.9 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with concentrated aqueous ammonia (3 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2×20 ml) and concentrated to give tert-butyl (2S,4S)-2-(aminocarbonyl)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-1-carboxylate (4) (5 g, 100%) as a pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 546.1.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH:3]1[O:5][CH2:4]1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][CH2:4][CH:3]([OH:5])[CH:2]([CH3:1])[CH2:6][CH3:7])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][CH2:4][CH:3]([OH:5])[CH:2]([CH3:1])[CH2:6][CH3:7]
Reactant: CCC(C)C1CO1
Reactant: NCCCCCCN
Product: CCC(C)C(O)CNCCCCCCNCC(O)C(C)CC

Procedure:
Condensation of 3-methyl-1-pentene oxide and hexamethylenediamine affords N,N'-(1,6-hexylene)-bis[2-hydroxy-3-methylpentylamine] (I: R= CH3CH2 (CH3)C, R' = H, X= (CH2)6, Z= H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14](Br)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.[Br-].[CH2:29]([Zn+])[CH2:30][CH3:31]>C1COCC1.[Cu]I>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC[Zn+]
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: [Cu]I
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OCC)c1OC
Temperature: 160 °C

Procedure:
A mixture of ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61, 0.1 g), palladium chloride dppf adduct with DCM (0.01 g), copper (I) iodide (0.003 g) and n-propyl zinc bromide (0.5M solution in THF, 0.96 ml) in THF (0.5 ml) was stirred and heated in the microwave at 160° C. for 10 minutes. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-60% to give ethyl 6-(benzenesulphonylmethyl)-2-methoxy-3-propylbenzoate (0.034 g) as a clear gum.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=1>CN(C)C=O>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:13]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Oc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
To a solution of phenol (1.97 g, 20.9 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (1.00 g, 20.9 mmol) at 0° C., which was stirred for 5 minutes at 0° C. 2,5-Dibromopyridine (4.50 g, 19.0 mmol) was then added to this reaction solution at 0° C., and stirred for 40 minutes at room temperature. The reaction solution was then stirred for further 3 hours at 120° C. After allowing to room temperature, the reaction solution was partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=6:1) to obtain the title compound (3.85 g, 81%).
Reaction SMILES: [C:1]([C:4]1[C:5]([F:23])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38]Cl>C(Cl)Cl>[C:1]([C:4]1[C:5]([F:23])=[C:6]([N:11]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[S:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:14])=[O:13])[CH:7]=[CH:8][C:9]=1[F:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCN(c1ccc(F)c(C(C)=O)c1F)S(=O)(=O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-benzenesulfonamide (2.88 g, 8.293 mmol) was dissolved in dry DCM (75 mL) under nitrogen atmosphere. DIPEA (1.55 mL, 9.12 mmol, 1.1 eq) was then added, followed by 2-methoxyethoxymethyl chloride (0.98 mL, 9.12 mmol, 1.1 eq) and the mixture was stirred at room temperature for 1 h. It was then diluted with DCM and washed with water and brine, dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (n-hexane/ethyl acetate 7:3) to give 2.25 g (62%) of N-(3-acetyl-2,4-difluoro-phenyl)-2,5-difluoro-N-(2-methoxy-ethoxymethyl)-benzene-sulfonamide as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].CCCC[Sn]([C:25]1[N:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(CCCC)CCCC>C1COCC1.CN(C=O)C>[F:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[CH:25][N:30]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1

Procedure:
A mixture of 2-bromo-1-fluoro-4-nitrobenzene (2.0 g, 9.1 mmol) and 2-(1,1,1-tributylstannyl)pyridine (3.36 g, 9.11 mmol) in THF (80 ml) and DMF (10 ml) was degassed with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (200 mg, 3 mol %) was added, and the mixture was heated at reflux for 24 h. More 2-bromo-1-fluoro-4-nitrobenzene (0.60 g, 2.7 mmol) and catalyst (100 mg, 1.5 mol %) were added, and the mixture was heated as before for another 24 h. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel, eluting with 50% dichloromethane in isohexane, then 100% dichloromethane, then 100% ethyl acetate (UV detection). 2-(2-Fluoro-5-nitrophenyl)pyridine was isolated as a colourless solid (2.11 g, 100%): 1H NMR (400 MHz, CDCl3) δ 7.30-7.37 (2H, m), 7.80-7.87 (2H, m), 8.27 (1H, m), 8.78 (1H, m), 9.01 (1H, dd, J 3.1, 6.7 Hz); MS (ES+) m/z 219 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH:17]=[O:18])[CH:7]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:19])=[C:6]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][OH:18])[CH:7]=1
Reactant: O=Cc1c(-c2cc(Br)ccc2O)nc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(-c2cc(Br)ccc2O)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
2-(5-bromo-2-hydroxyphenyl)imidazo[1,2-a]pyridine-3-carbaldehyde (0.19 g, 0.63 mmol) was dissolved in MeOH (2 mL) at 0° C. NaBH4 (0.072 g, 1.9 mmol) was added portionwise. After addition, the mixture was stirred at 25° C. for 30 minutes, and then H2O (20 mL) was added by dropwise. Extracted with EtOAc (3*50 mL), washed by brine (50 mL). After concentrated, the resulting residue was purified using Prep-TLC (petroleum ether:EtOAc=3:1) to provide 4-bromo-2-(3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)phenol (150 mg, yield: 85%). 1H-NMR (CDCl3, 400 MHz) δ 8.33˜8.35 (m, 1H), 7.72 (s, 1H), 7.62˜7.64 (m, 1H), 7.31˜7.37 (m, 2H), 6.92˜7.01 (m, 2H), 5.20 (s, 2H). MS (M+H)+: 319/321.
Reaction SMILES: [CH3:1][C:2]1([Li])[CH:6]=[C:5]([CH3:7])[C:4]([CH3:8])=[C:3]1[CH3:9].[CH3:11][Si:12]([CH3:15])(Cl)Cl>>[CH3:11][Si:12]([CH3:15])([CH:6]1[C:5]([CH3:7])=[C:4]([CH3:8])[C:3]([CH3:9])=[C:2]1[CH3:1])[CH:6]1[C:2]([CH3:1])=[C:3]([CH3:9])[C:4]([CH3:8])=[C:5]1[CH3:7]
Reactant: [Li]C1(C)C=C(C)C(C)=C1C
Reactant: C[Si](C)(Cl)Cl
Product: CC1=C(C)C([Si](C)(C)C2C(C)=C(C)C(C)=C2C)C(C)=C1C
Yield: 65 %

Procedure:
In "Chem. Berichte" 119 1750 (1986) , a solution containing 1,2,3,4-tetramethylcyclopentadienyl lithium and dimethyldichlorosilane is heated for 5 days to obtain dimethylbis(2,3,4,5-tetramethylcyclopentadienyl)silane in a 65% yield.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=[O:18])=[N:15][CH:16]=1.[O:20]1[C@H:22]2[CH2:23][C@@:24]3([CH3:46])[CH:28]([CH:29]4[CH2:30][C@H:31]([F:40])[C:32]5[C@@:37]([CH3:38])([C@:21]124)[CH:36]=[CH:35][C:34](=[O:39])[CH:33]=5)[CH2:27][C@@H:26]([CH3:41])[C@:25]3(O)[C:42]([OH:44])=[O:43].Cl>CN(C=O)C>[O:20]1[C@H:22]2[CH2:23][C@@:24]3([CH3:46])[CH:28]([CH:29]4[CH2:30][C@H:31]([F:40])[C:32]5[C@@:37]([CH3:38])([C@:21]124)[CH:36]=[CH:35][C:34](=[O:39])[CH:33]=5)[CH2:27][C@@H:26]([CH3:41])[C@:25]3([O:18][C:17]([C:14]1[CH:13]=[N:12][C:11]([CH3:10])=[CH:16][N:15]=1)=[O:19])[C:42]([OH:44])=[O:43]
Reactant: Cc1cnc(C(=O)O)cn1
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N,N-Diisopropylethylamine (2.3 mL) is added to a cooled (0° C.) solution of 5-methylpyrazine-2-carboxylic acid (736 mg) in DMF (7 mL), followed by O-(7-azabenzotriazo-1-lyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 2.26 g). The suspension is stirred at room temperature for 10 minutes, then a solution of (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (2 g) in DMF (7 ml) is added. After 2 hours, the reaction mixture is added dropwise to a solution of 1M HCl. The product is collected by filtration, washed repeatedly with water and dried to yield 5-methyl-pyrazine-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-carboxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected H-NMR signals (CDCl3) δ 0.95 (3H, d), 1.10 (3H, s) 1.40 (3H, s), 2.65 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:29])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]#[N:28])=[N:19]3)[C@@H:12]([CH3:30])[CH2:11]2)=[C:4]([F:31])[CH:3]=1.[NH2:32][OH:33].Cl>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:29])[CH2:17][N:18]3[C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20]([C:27]([NH:32][OH:33])=[NH:28])=[N:19]3)[CH:12]([CH3:30])[CH2:11]2)=[C:4]([F:31])[CH:3]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(C#N)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(=N)NO)c4cccnc43)C(C)C2)c(F)cc1Cl
Temperature: 65 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-oxo-ethyl}-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.6 g, 3.6 mmol, 1 eq), NH2OH.HCl (0.84 g, 10.8 mmol, 3 eq), TEA (1.5 ml), and ethanol (10 ml) was stirred at 65° C. overnight. The reaction solution was concentrated in vacuo, and dissolved in ethyl acetate, washed with brine, and concentrated to provide 1-{2-[4-(4-Chloro-2-fluoro-5-methoxy-phenyl)-2-methyl-piperazin-1-yl]-2-oxo-ethyl}-N-hydroxy-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine (1.2 g).
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13]N(S(C)(=O)=O)C)=[O:12])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].N[C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)=[O:12])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CN(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)S(C)(=O)=O
Solvent: Clc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 80 °C
Yield: 103.2 %

Procedure:
32.3 g of 1-[(N-methylsulfonyl-N-methylamino)-sulfonyl]-3-(N-methylsulfonyl-N-methylamino)urea are slurried in 500 ml of chlorobenzene, 15.5 g of 2-amino-4,6-di-methoxypyrimidine are added at 80° C. with stirring, and the mixture is heated for 3 hours at 80° C. After cooling to 20° C., the precipitate is filtered off and washed with 100 ml of chlorobenzene. 36.4 g of the desired product are obtained with a purity of 98.1%, corresponding to a yield of 96.8% of theory. The melting point for the product is 183°-185° C. 5.1 g of N-methylmethanesulfonamide are recovered from the liltrate by distillation, corresponding to a yield of 92.7% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:4]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[CH:7][CH:6]=[C:5]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1nc(OCC(F)(F)F)ccc1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc(OCC(F)(F)F)ccc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 36.4 %

Procedure:
A mixture of (2-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methanol (1.19 g, 5.02 mmol, Step-2), phthalimide (0.74 g, 5.02 mmol), di-tert-butyl azodicarboxylate (1.05 g, 6.02 mmol) and triphenylphosphine (1.97 g, 7.53 mmol) in tetrahydrofuran (50 mL) is stirred at room temperature for 20 hours. The reaction mixture is concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (6:1) to give 0.67 g (37% yield) of the title compound as a white solid.