Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:21].C(=O)(O)[O-].[Na+]>ClCCl.O1CCCC1>[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:23][CH2:24][N:25]([CH:3]2[CH2:2][O:1][CH2:4]2)[CH2:26][CH2:27]1)#[N:21]
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(C4COC4)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 6 h
Yield: 44.5 %

Procedure:
3-Oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature to a solution of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg) described in Reference Example 169 in dichloromethane (20 ml) and tetrahydrofuran (20 ml), and stirred at the same temperature for eight hours. Further 3-oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature and stirred at the same temperature for six hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:34][CH2:35][F:36]>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([CH2:34][CH2:35][F:36])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: FCCBr
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(CCF)CC4)cn3)nc2n1C1CCCC1
Yield: 46.3 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.229 mmol) and 1-bromo-2-fluoroethane (88 mg, 0.687 mmol) gave 7-cyclopentyl-2-{5-[4-(2-fluoro-ethyl)-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (51 mg, 80%). MS (ESI) m/z 481.3 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:10])=[O:9].[H-].[Na+].[CH3:33][O:34][CH2:35]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]([CH2:33][O:34][CH3:35])[C:12]1[C:13]([C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])=[N:14][N:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=1)(=[O:9])=[O:10]
Reactant: COCCl
Reactant: O=C(c1nn(-c2ccccc2)cc1NS(=O)(=O)c1ccccc1Br)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cn(-c2ccccc2)nc1C(=O)N1CCOCC1)S(=O)(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-N-[3-(morpholin-4-ylcarbonyl)-1-phenyl-1H-pyrazol-4-yl]benzenesulfonamide (200 mg; 0.41 mmol; 1.00 eq.) in THF (30 mL) is added NaH (24 mg; 0.61 mmol; 1.50 eq.) in a portionwise manner and the resulting mixture is stirred at room temperature for 15 minutes whereupon Chloromethyl methyl ether (82 μl; 0.81 mmol; 2.00 eq.) is added dropwise. The reaction mixture is stirred at room temperature for 2 hours then quenched with sat. aq. NaHCO3. Extraction with ethyl acetate (2×), ishing with brine, drying over magnesium sulfate and concentration in vacuo gives 240 mg (quant) of the title compound as a colourless oil. 1H NMR (DMSO) δ 8.82 (s, 1H), 7.93-7.8 (m, 4H), 7.64-7.46 (m, 4H), 7.39 (t, J=7.4 Hz, 1H), 5.32 (s, 2H), 3.59-3.51 (m, 2H), 3.42 (s, 3H), 3.46-3.37 (m, 4H), 3.15-3.06 (m, 2H). MS (ESI+): 505.2.
Reaction SMILES: [Br:1]Br.[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:7]=1[OH:15])([CH3:5])[CH3:4].O>C(O)(=O)C>[Br:1][C:10]1[CH:11]=[C:6]([CH:3]([CH3:5])[CH3:4])[C:7]([OH:15])=[C:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=1
Reactant: BrBr
Reactant: CC(C)c1cccc(C(C)C)c1O
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(Br)cc(C(C)C)c1O
Reaction time: 6 h
Yield: 64.9 %

Procedure:
This is a modification of the procedure of Schuster, Ingeborg I.; Parvez, Masood; Freyer, Alan J. J. Org. Chem. 1988, 53, 5819. A solution of bromine (6.3 mL, 119 mmol) in acetic acid (40 mL) was added dropwise to a stirred, room temperature solution of 2,6-diisopropylphenol (20 mL, 97.1 mmol of 90% tech. grade) in acetic acid (280 mL). After 6 h, water was added and the mixture was extracted with ether. The ether phase was dried and concentrated and the residue was flash chromatographed (petroleum ether: eluent) to provide 4-bromo-2,6-diisopropylphenol (16.2 g, 65%) as a red oil. This oil was dissolved in DMF (50 mL), iodomethane (11.7 mL, 189 mmol) and potassium carbonate (26.3 g, 117 mL) were added to it. This reaction mixture was stirred for 5 h and diluted with water. This mixture was extracted with ether and the ether extracts were dried, concentrated and flash chromatographed (petroleum ether: eluent) to provide the title compound as a colorless oil (15.4 g, 90%): NMR (CDCl3); δ 7.17 (s, 2H), 3.70 (s, 3H), 3.29 (septet, 1H), 1.20 (d, 12 H).
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10](C3C=NC=C(C(F)(F)F)C=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:48]3[CH:53]=[CH:52][N:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[N:9]=[C:8]2[CH:22]2[CH2:23][CH2:24][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:26][CH2:27]2)[CH2:2][CH2:3][CH2:4]1
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-2-(trifluoromethyl)pyridine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=501, obsd.=501).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>>[C:42]([O:41][C:39]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: CC(C)(C)OC(=O)CCCCCCCBr
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCCCC(=O)OC(C)(C)C)C(C)(C)CCC2(C)C
Yield: 80.7 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 3.82 g (9.34 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]-4-methoxyphenyl}acrylate obtained in Example 13(f) with 3 g (10.7 mmol) of tert-butyl 8-bromooctanoate obtained above, 4.36 g (77%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[O:34][C:33]([CH3:36])([CH3:35])[O:32][CH:31]5[C:37]([O:39]CC)=[O:38])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CO>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]5[O:34][C:33]([CH3:36])([CH3:35])[O:32][CH:31]5[C:37]([OH:39])=[O:38])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1OC(C)(C)OC1c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)OC(C(=O)O)C(c2ccc(-c3cccc(-n4cc(C(=O)NC5CC5)c(=O)c5cccnc54)c3)cc2)O1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
To a solution of ester from step 3 in THF-MeOH (1:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 15 min. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The combined organic extract was washed with brine, dried and solvent evaporated, the residue triturated in hexane/ether then isolated by filtration to afford the title acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[H-].[Na+].[CH3:12]OS(OC)(=O)=O.O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:12]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cccc1Br
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 2-bromo-6-methylphenol (34.6 g, 0.18 mol) in THF (300 mL) was added NaH (9.6 g, 0.24 mol, 60%) in several portions. After the mixture was stirred for 1 h, Me2SO4 (28.0 g, 0.22 mol) was added dropwise. Then the mixture was stirred over night. Water (50 mL) was added, and the solvent was removed under reduced pressure. Then the residue was dissolved in Et2O (250 mL) and the organic layer was washed with NaOH (5%, 100 mL), brine (100 mL), and dried with Na2SO4. After removing the solvent, 35.3 g of the crude product was obtained (yield: 95%). 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.81 (s, 3H), 6.88 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=O)[NH:10][N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][N:10]=1
Reactant: COc1ccc2c(-c3ccc(Cl)cc3)n[nH]c(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(-c3ccc(Cl)cc3)nnc(Cl)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-chlorophenyl)-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][N:13]1CCCC1=O>C(OCC)(=O)C>[Cl:11][C:4]1[N:3]=[C:2]([C:12]#[N:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C

Procedure:
2,6-Dichloro-3-nitropyridine (5.18 mmol, 1 g) is mixed with 5 ml of N-methyl-2-pyrrolidinone in a microwave reactor. The reaction mixture is heated at 180° C. for 15 minutes (6 bars). The crude reaction product is dissolved in ethyl acetate, filtered and washed several times using an aqueous phase. The organic phase is collected, dried on magnesium sulfate and dry concentrated. The crude product thus obtained is purified by silica gel chromatography (heptane/AcOEt) to yield, after concentration, 0.62 g (65%) of a brown oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([O:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.[Cl:16]Cl.O>C(O)(=O)C>[Cl:16][C:4]1[C:3](=[O:15])[CH:2]=[CH:1][C:14]2[C:5]=1[O:6][C:7]1[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=1)[N:13]=2
Reactant: O=c1ccc2nc3ccccc3oc-2c1
Reactant: ClCl
Solvent: CC(=O)O
Solvent: O
Product: O=c1ccc2nc3ccccc3oc-2c1Cl

Procedure:
To a solution of 1.2 g of 3H-phenoxazin-3-one in acetic acid (25 ml) was added K2Cr2O7 (3.7 g). A solution of chlorine in acetic acid was added dropwise to the resulting suspension. After disappearance of the starting material, as monitored by TLC, the reaction mixture was poured into 200 ml of H2O and the resulting precipitate was filtered (1.2 g) and chromatographed on silica gel to yield the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH:35]1([CH2:41]Br)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>COCCO>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCC1CCCCC1
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(SCC2CCCCC2)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
A mixture of 147 mg (0.42 mmole) of 5-n-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (from Example 15, Step C), 146 μl (108 mg, 0.84 mmole) of N,N-diisopropylethylamine, 117 μl (148 mg, 0.84 mmole) of cyclohexylmethyl bromide, and 1.5 ml of 2-methoxyethanol was stirred under N2 at 70° C. overnight and then at reflux for an additional 4 hours. The solution was concentrated in vacuo, and the residue was partitioned between 25 ml of ethyl acetate and 25 ml of 0.2 N HCl. The ethyl acetate layer was washed with saturated NACl, then dried over anhydrous MgSO4, filtered, and rotary evaporated in vacuo. Column chromatography of the residue on silica gel (elution with a gradient of 0-0.8% methanol in CH2Cl2) afforded 111 mg (59%) title compound as an oil, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 445 (M+1)+.
Reaction SMILES: [SH:1][C:2]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14].ON1C2N=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH2:11]([O:15][C:16](=[O:35])[C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[NH:18][C:19]([C:21]1([NH:26][C:7]([C:2]2([SH:1])[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:9])[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)C1(S)CCCC1
Reactant: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)C2(S)CCCC2)CCCC1
Reaction time: 14 h

Procedure:
To a stirred solution of 1-mercapto-1-cyclopentanecarboxylic acid (1.74 g, 4.54 mmol) in dichloromethane (50 mL) and triethylamine (0.63 mL) is added [(1-amino-(1-cyclopentyl)carbonyl]-L-tyrosine butyl ester hydrochloride (0.66 g). To this solution is added 1-hydroxy-7-azabenzotriazole (0.68 g, 4.55 mmol) and 1,3-dicyclohexylcarbodiimide (1.03 g, 4.99 mmol). The mixture is stirred for 14 hours and then the solid precipitate is removed by filtration. The organic phase is washed with a saturated solution of sodium bicarbonate (10 mL), brine (10 mL), dried over magnesium sulfate and the solvent is removed to give a clear oil. The oil is purified by flash chromatography (SiO2, hexane/ethyl acetate, 6:4) to give a clear foam. The foam is crystallized from ethyl ether to yield N-[[1-[[(1-mercapto- 1-cyclopentyl)carbonyl]amino]- 1-cyclopentyl]carbonyl]-L-tyrosine butyl ester, m.p. 106°-107° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:28]([CH3:30])[CH3:29])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]([O-:34])(=[S:33])[CH3:32].[K+]>CN(C)C=O>[C:31]([S:33][CH:21]1[CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:12](=[O:13])[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH:28]([CH3:30])[CH3:29])[N:15]=2)[CH2:22]1)(=[O:34])[CH3:32]
Reactant: CC([O-])=S
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (649 mg, 1.35 mmol) (obtained as described in Reference Example 59(4)) in dimethylformamide (19 ml) was added potassium thioacetate (930 mg, 8.14 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1) ethyl acetate as the eluant to afford 3-acetylthio-1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)azetidine (618 mg, yield 100%) as a pale brown solid.
Reaction SMILES: [CH3:1][P:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.[OH:11]O>C(Cl)Cl>[CH3:1][P:2]([CH3:10])([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)=[O:11]
Reactant: Cc1ccc(P(C)C)cc1
Reactant: OO
Solvent: ClCCl
Product: Cc1ccc(P(C)(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl-p-tolyl phosphane (25 g, 0.165 mol) (1a) in diclholoromethane (DCM) (50 mL) was added an aqueous solution of hydrogen peroxide (10%, 60 mL, 0.176 mol) in drops. This is an exothermic reaction so the flask was cooled in ice water during the addition. After the addition the reaction was allowed to stir at rt overnight until the HPLC showed no starting material (18 h). From the resulting reaction mixture the organic phase was separated and the aqueous phase was extracted with additional dichloromethane (3×60 mL) until the aqueous layer showed little or no evidence of product by HPLC. The combined organics were washed with a solution of sodium bisulfite (10 mL) followed by water (10 mL) and dried over Na2SO4 and concentrated on a rotary evaporator. The desired product was purified by Crystallization from ethyl acetate/hexane (18.8 g). m.p. 90-92° C. 1H NMR (300 MHz, CDCl3) δ (ppm)) 1.469 (d, J=13 Hz, 6H), 2.169 (s, 3H), 7.04 (d, J=5.5 Hz, 2H), 7.38 (m, 2H). 31P NMR (121 MHz, CDCl3) δ 34.327.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:13](OCC)=[O:14]>C1COCC1>[CH:13]([CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[C:3]([O:10][CH2:11][CH3:12])=[O:9])=[O:14]
Reactant: CCCCCC(=O)OCC
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(C=O)C(=O)OCC
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
First, 60 g of 60% NaH was suspended in 600 ml of THF and 72.1 g of ethyl hexanoate was added dropwise to the suspension solution thus prepared at room temperature. After the suspension solution was raised in temperature to 40° C. and stirred for 15 minutes, 185.2 g of ethyl formate was added dropwise for 6 hours. Furthermore, 30 g of 60% NaH and 92.6 g of ethyl formate were divided into four parts and each part was added separately. Afterward, the solution mixture was stirred at 40° C. for 3 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1.[C:48](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10](=[O:47])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[N:18]=[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH:40]4[CH2:45][CH2:44][N:43]([CH3:48])[CH2:42][CH2:41]4)=[CH:35][C:34]=3[CH3:46])[N:27]=2)[CH:12]=1
Reactant: Cc1cc(OC2CCNCC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(OC2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Yield: 43.7 %

Procedure:
To N-(2,6-difluorophenyl)-3-[3-(2-{[2-methyl-4-(4-piperidinyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzamide (Example 6) (0.098 g, 0.16 mmol) in DCM (4 mL) and MeOH (2 mL) was added acetic acid (0.20 mL, 1M in DCM, 0.20 mmol) and formaldehyde (0.024 mL, 37% weight in H2O, 0.32 mmol). Sodium triacetoxyborohydride (0.053 g, 0.25 mmol) in one portion and the reaction was stirred at rt until complete by MS. Purification by flash chromatography, followed by preparative HPLC chromatography (prep-HPLC) provided the title compound (0.044 g, 0.070 mmol, 43%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58-1.67 (m, 2H), 1.88-1.95 (m, 2H), 2.11-2.21 (m, 8H), 2.55-2.65 (m, 2H), 4.33 (s, 1H), 6.45 (d, J=5.1 Hz, 1H), 6.81 (d, J=8.1 Hz, 2H), 6.87 (s, 2H), 7.17-7.26 (m, 3H), 7.36-7.47 (m, 2H), 7.62 (t, J=7.8 Hz, 1H), 7.71 (d, J=9.1 Hz, 1H), 7.77-7.85 (m, 1H), 8.06 (d, J=9.5 Hz, 1H), 8.18 (d, J=5.3 Hz, 1H), 8.31 (s, 1H), 8.89 (s, 1H), 9.32 (br. s., 1H). MS (M+H, ES+) 646.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:10]([N+:13]([O-:15])=[O:14])=[C:9]([F:11])[C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(C(=O)O)c(Cl)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C(=O)O)c(Cl)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2-Chloro-4-fluoro-5-methylbenzoic acid (2.0 g) was added to concentrated sulfuric acid (20 ml) to dissolve it, and potassium nitrate (1.07 g) was added portionwise to the solution under ice cooling. After the addition, the temperature of the reaction mixture was given back to room temperature to conduct stirring overnight. The reaction mixture was poured into ice water and extracted with diethyl ether. After an organic layer was collected and dried over anhydrous magnesium sulfate, the solvent was distilled off to obtain the title compound (2.25 g) as a reddish brown oil.