Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][CH:11]([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][CH:18](O)[CH2:19][CH3:20].C1(C)C=CC=CC=1.OS(O)(=O)=O>O>[CH:18]([O:14][C:13](=[O:15])[CH2:12][CH:11]([NH:10][S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:9])=[O:8])[CH3:16])([CH2:19][CH3:20])[CH3:17]
Reactant: CCC(C)O
Reactant: CC(CC(=O)O)NS(=O)(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)OC(=O)CC(C)NS(=O)(=O)c1ccccc1

Procedure:
The mixture of 2.0 gr DL-N benzensulfonyl-3 aminobutyric acid (I), 1.0 gr 2-butanol, 30 ml toluene and 0.04 gr H2SO4 (conc) was heated under reflux for ca 6 hr. The water formed in the reaction was separated by azeotropic distillation. The cooled reaction mixture was washed twice with bicarbonate 2%, and dried over magnesium sulfate. Distillation of the solvent and alcohol yield 1.8 gr procuct, confirmed by spectroscopy.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:54][C:55]([F:64])([F:63])[C:56]1[N:60]=[C:59]([CH2:61][NH2:62])[O:58][N:57]=1>CN(C=O)C>[CH:1]1([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([NH:62][CH2:61][C:59]2[O:58][N:57]=[C:56]([C:55]([F:64])([F:63])[F:54])[N:60]=2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Reactant: NCc1nc(C(F)(F)F)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 9c) (124 mg, 0.43 mmol) in DMF (4 mL) were added DIPEA (0.1 mL, 1.08 mmol) and HATU (204 mg, 0.54 mmol) at 25° C. The reaction mixture was stirred for 30 min at 25° C. To this was added C-(3-trifluoromethyl-1,2,4-oxadiazol-5-yl)-methylamine (CAN 944905-93-5) (60 mg, 0.36 mmol) and the reaction mixture was stirred for 12 h at 25° C. Volatiles were removed in vacuo and the resultant residue was purified by prep-HPLC to get 5-cyclopentyl-6-(2,2,2-trifluoro-ethoxy)-N-(3-trifluoromethyl-1,2,4-oxadiazol-5-ylmethyl)-nicotinamide (61 mg, 38.7%) as off-white solid; MS (ESI): 439 (M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:21]([CH2:1][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1ccc(COc2cccc(C=O)c2)cc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COc2cccc(CNc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a stirred solution of methyl 4-((3-formylphenoxy)methyl)benzoate (464 mg, 1.72 mmol) in anhydrous DCM (8 mL) was added aniline (0.63 mL, 6.87 mmol) followed by glacial acetic acid (0.46 mL, 6.87 mmol). The reaction was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (1.52 g, 6.87 mmol) was added and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with DCM (100 mL). The organic layer was washed with 1 N HCl (3×30 mL) and saturated aqueous NaHCO3 (30 mL) and passed through a hydrophobic fit. The solvent was removed in vacuo to afford the title compound as an oil that solidifies on standing (380 mg, 64% yield).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH2:13][PH:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][PH:14](=[O:18])[O:15][CH2:16][CH3:17])[CH:10]=[CH:11][CH:12]=1
Reactant: CCO[PH](=O)Cc1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCO[PH](=O)Cc1cccc(O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
BBr3 (3.16 mL, 1 M solution in DCM) was added to a solution of ethyl (3-methoxyphenyl)methylphosphinate (0.169 g, 0.789 mmol) in DCM at 0° C. The reaction was stirred at rt for 15 h, then partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.35-7.40 (m, 1H), 7.19-7.26 (m, 2H), 7.05 (dd, 1H, J=8.3, 2.6 Hz), 3.85 4.05 (m, 2H), 1.69 (d, 3H, J=14.6 Hz), 1.29 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=[O:3].[H][H]>[Ni]>[C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:2]([CH3:1])[OH:3])=[CH:5][CH:6]=1)(=[O:12])[CH3:13]
Reactant: [H][H]
Reactant: CC(=O)Oc1ccc(C(C)=O)cc1
Agent: [Ni]
Product: CC(=O)Oc1ccc(C(C)O)cc1
Temperature: 60 °C
Yield: 80.4 %

Procedure:
102 g of 4-acetoxyacetophenone and 10 g of Raney nickel catalyst are charged in a 300-ml stirred reactor. The reactor is then charged with hydrogen at 500 psig and heated to 60° C. for 270 minutes. The reactor is then cooled down and the product analyzed by gas chromatography. The analysis gives 80.4% 4-acetoxyphenyl methylcarbinol.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([F:32])([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1>C1COCC1>[F:32][C:11]([F:10])([C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]3=[N:24][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:20]3[CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(F)(F)c2ccc(-c3cccnc3N)cc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)c2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 362 mg) in THF (dry) (20 mL) was added 2-chloroethanesulfonyl chloride (0.571 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(difluoro(4-methylphenyl)methyl)phenyl)pyridin-2-amine obtained by step C of Example 136 in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with water/THF then water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo and washed with IPE to give the title compound (197 mg) as an off-white powder. A part of product was recrystallized from MeCN/IPE.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:43](=[O:44])[C:42]4[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-c2cn(C3CCN(C(=O)c4ccc(F)cc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and p-fluorobenzoyl chloride (475.5 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=15:1) to yield the target product as white solid powder.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:13]([F:24])[CH:12]=2)[CH2:6]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([F:24])[C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:15]([F:17])[CH:16]=2)[CH2:6]1
Reactant: [N-]=[N+]=NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: CO
Product: NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Reaction time: 16 h

Procedure:
(±)-5-(Azidomethyl)-3-[4-(3-pyridyl)-3,5-difluorophenyl]-2-oxazolidinone (PREPARATION 6, 354 mg, ~1.07 mmol) in methanol (40 ml) and palladium on carbon (10%, 50 mg) are mixed. The mixture is purged with nitrogen and then placed under an atmosphere of hydrogen (1 atm). The reaction is allowed to stir at 20-25° for 16 hrs. After this time, the reaction is filtered and concentrated under reduced pressure to a solid amine. The crude amine is suitable for acetylation without further purification. An analytical sample is prepared by preparative TLC (SG) methanol/chloroform (10/90). The title compound is recovered as a solid, mp 143-145°; FTIR (neat) cm-1 3368, 1757, 1646, 1412, 1244, 1025 and 714; MS (EI, m/z) 305, 276, 233, 219, 44 and 29; NMR (CDCl3) 8.71, 8.62, 7.79, 7.39, 7.33, 4.79-4.70, 4.06, 3.92, 3.18, 2.98 and 1.52 δ.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:21]1([C@@H:27]2[CH2:29][C@H:28]2[N:30]=[C:31]=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:31]([NH:30][CH:28]3[CH2:29][CH:27]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)NC1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
To 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl amine (165 mg, 0.61 mmol, 1 equiv.) dissolved in 2.5 mL anhydrous THF was added, via syringe, trans-2-phenyl-cyclopropyl-isocyanate (90 uL, 0.60 mmol, 1 equiv.). The mixture was left stirring at room temperature for 18 h under inert atmosphere, then the solvent was removed in vacuo. The product was purified by column chromatography on SiO2, using 2-4% MeOH in EtOAc as eluent. A taupe foam was isolated, which recrystallized from hot acetonitrile to afford the title compound as a white solid (60 mg), mp 156-157° C.
Reaction SMILES: O=[CH:2][CH2:3][C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[CH2:5]1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.CC(O)=O.C([BH3-])#N.[Na+]>CO>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][CH2:2][CH2:3][C:4]2([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=3)[CH2:5]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc2c(c1)CCC(CC=O)(C(=O)OC)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCC(CCNCc1ccc(OC)cc1)(C(=O)OC)C2
Reaction time: 18 h

Procedure:
A solution of (1)-dimethyl 2-(2-oxoethyl)-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate from Step C (436 mg, 1.50 mmol), 4-methoxybenzylamine (247 mg, 1.80 mmol), and AcOH (0.206 mL, 3.60 mmol) was stirred in MeOH (10 mL) at ambient temperature for 5 min, then sodium cyanoborohydride (113 mg, 1.80 mmol) was added. After 18 h, the mixture was concentrated in vacuo, and the residue was partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted further with CH2Cl2 (10 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=412 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([C:13]#[N:14])[CH:5]=1.[OH-].[Li+]>O1CCCC1>[C:13]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=1)[C:3]([OH:15])=[O:2])#[N:14]
Reactant: COC(=O)c1cc(C#N)cc(N(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)c1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 101.2 %

Procedure:
A solution of methyl-3-cyano-5-dimethylaminobenzoate (318 mg, 1.6 mmol) in tetrahydrofuran (5 mL) was treated with 0.5 N lithium hydroxide (3.7 mL, 1.9 mmol). The reaction was stirred at 70° C. for 30 minutes and then the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified by the dropwise addition of 2 N hydrogen chloride until a white precipitate no longer formed. Following extraction of the aqueous layer with diethyl ether, the organic layer was then washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 308 mg (quantitative) of 3-cyano-5-dimethylaminobenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][C:18]([OH:20])=O)[CH2:15][N:16]=1)=[CH:8]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:54][CH2:55][C@H:56]([OH:58])[CH3:57]>O.CN(C)C=O>[OH:58][C@H:56]([CH3:57])[CH2:55][NH:54][C:18](=[O:20])[CH2:17][CH:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:21][C:22]2[CH:23]=[N:24][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:26][CH:27]=2)=[CH:4][C:3]=3[O:2][CH3:1])=[N:16][CH2:15]1
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: C[C@@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)NC[C@@H](C)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.3 %

Procedure:
A mixture of [2-(7-methoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetic acid (300 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (190 mg), 1-hydroxybenzotriazole (130 mg), (2R)-1-aminopropan-2-ol (100 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was washed with ethyl acetate-diethyl ether to give pale yellow crystals. The crystals were recrystallized from acetone-methanol to give the title compound (220 mg, 65%) as colorless prisms. MS 519 (MH+). mp 185-186° C.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH:8]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:9]([OH:11])[CH3:10])([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[CH3:1][C:2]([Si:5]([CH3:21])([CH3:22])[O:6][CH2:7][C@H:8]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:9](=[O:11])[CH3:10])([CH3:3])[CH3:4]
Reactant: CCCCCCC(=O)NC(CO[Si](C)(C)C(C)(C)C)C(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)C(C)=O
Reaction time: 18 h

Procedure:
A mixture of (10c), (2.30.g, 6.94 mmol) and pyridinium dichromate (10.62 g, 28.2 mmol) in 20 mL of N,N-dimethylformamide is stirred under argon for 18 h. The reaction mixture is diluted with 100 mL of water and extracted with ethyl acetate (3×40 mL). The organic layer is separated, washed with water and brine, dried and evaporated to give 1.87 g of a residual brown liquid. The liquid is purified by chromatography using 1:6 ethyl acetate/hexane to give 997 mg of the desired product as an oil. NMR δ 0.83 (s, 9H), 1.61 (m, 2H), 2.22 (t, 2H), 2.23 (s, 3H), 3.82 (dd, 1H), 4.09 (dd, 1H), 4.57 (m, 1H), 6.42 (brd, 1H); MS (FAB) m/z 330 (M+H calc'd. for C17H36NO3Si 330).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([OH:26])=O)[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[NH2:36].O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:36][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][N:30]=4)=[O:26])[CH2:19]3)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(N3CCCC(C(=O)O)C3)nc3scnc23)cc1OC
Reactant: Nc1cnccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2nc(N3CCCC(C(=O)Nc4cnccn4)C3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a solution of 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-3-carboxylic acid (30 mg, 0.07 mmol) and pyrazin-2-amine (7 mg, 0.07 mmol) in pyridine (6 mL) was added POCl3 (0.2 mL, 2.19 mmol) at 0° C., the reaction mixture was stirred at room temperature for 15 hours, a sat. NaHCO3 solution was added slowly, the solvent was removed in vacuo, and water (5 mL) and methanol (3 mL) were added. The precipitate was collected by filtration and washed with water (3 mL) and methanol (3 mL) to afford 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(pyrazin-2-yl)piperidine-3-carboxamide (30 mg, 87.2%) as a brown solid. 1H NMR (300 MHz, DMSO): δ 10.87 (s, 1H), 9.62 (s, 1H), 9.30 (s, 1H), 8.83 (s, 1H), 8.39-8.33 (m, 2H), 7.61 (d, 1H, J=2.1 Hz), 7.31 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 6.82 (d, 1H, J=8.4 Hz), 4.76 (d, 1H, J=11.4 Hz), 4.60 (d, 1H, J=12.3 Hz), 3.68 (s, 3H), 3.64 (s, 3H), 3.13 (t, 1H, J=10.8 Hz), 3.01-2.93 (m, 1H), 2.79-2.71 (m, 1H), 2.04-2.00 (m, 1H), 1.81-1.67 (m, 2H), 1.46-1.42 (m, 1H). LC-MS: 493 [M+H]+, tR=1.50 min. HPLC: 95.75% at 214 nm, 96.29% at 254 nm, tR=5.38 min.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32]>>[Cl:28][C:29]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:30]=1[C:31]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:9]3[N:10]=[CH:11][CH:12]=[C:7]4[CH2:6][CH2:5][O:4][C:8]=34)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:32]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, white solid (119 mg, 95%), MS (ISP) m/z=503.2 [(M+H)+], mp 243.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10]12(O)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2.CS(O)(=O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[C:10]12([C:6]3[CH:7]=[C:2]([Br:1])[C:3]([CH3:9])=[CH:4][C:5]=3[OH:8])[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: Cc1cc(O)ccc1Br
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)c(C23CC4CC(CC(C4)C2)C3)cc1Br
Temperature: 54 °C
Yield: 84.3 %

Procedure:
A mixture of 4-bromo-3-methylphenol (4.68 g, 25 mmol), 1-adamantanol (3.81 g, 25 mmol), and MeSO3H (1.2 mL) in CH2Cl2 (18 mL) was stirred and heated at 54° C. (oil-bath) for 28.8 h. The resulting solution was diluted with CHCl3 (150 mL), washed with H2O, 5% NaHCO3, and brine and dried. The residue obtained on concentration was washed with hot hexane to give 6.77 g (85%) of 2-(1-adamantyl)-4-bromo-5-methylphenol as a white solid, mp 155-156° C. IR 3541, 2905, 2845, 1147 cm−1; 1H NMR δ (CDCl3) 1.77 (bs, 6H, AdCH2), 2.07 (bs, 9H, AdCH and AdCH2), 2.28 (s, 3H, CH3), 4.67 (s, 1H, OH), 6.54 (s, 1H, 6-ArH), 7.30 (s, 1H, 3-ArH).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([CH2:36][OH:37])=[C:5]([F:35])[C:6]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH:18]C(=O)C(C)(C)C)=[C:14]([F:25])[CH:13]=3)=[CH:9][C:8](=[O:26])[C:7]=2[C:27]=1[NH:28]C(=O)C(C)(C)C.[OH-].[Na+]>C(O)C>[NH2:28][C:27]1[C:7]2[C:8](=[O:26])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:25])[CH:13]=3)[O:11][C:6]=2[C:5]([F:35])=[C:4]([CH2:36][OH:37])[C:3]=1[F:2]
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c3o2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(CO)c(F)c3o2)cc1F
Yield: 60.5 %

Procedure:
40 mL of ethanol and 20 mL of concentrated hydrochloric acid were added to 903 mg (1.79 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-hydroxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one and the mixture was heated at reflux for 6.5 hours. The reaction solution was cooled on ice and adjusted to pH 7 to 8 by addition of a 10N aqueous solution of sodium hydroxide thereto, and the precipitated crystals were collected by filtration. The crystals were purified by silica gel column chromatography (chloroform:methanol=40:1-9:1) and triturated with ethyl acetate to give 364 mg of Compound 118 (yield: 60%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)(Cl)Cl>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2Co3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143°-144° C.; 1H NMR (CD3OD, 400 MHz) β 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H), 1.90-2.00 (m, 4H), 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H), 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: [CH2:1]([NH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH2:9].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O=[Pt]=O.C(O)C>[C:12]1([CH2:11][NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCCCCCCN
Reactant: O=Cc1ccccc1
Agent: O=[Pt]=O
Solvent: CCO
Product: c1ccc(CNCCCCCCCCNCc2ccccc2)cc1

Procedure:
Combine 14.4 g (0.1 mol) of 1,8-octanediamine, 20.3 ml (0.2 mol) of benzaldehyde, 0.3 g PtO2 and 150 ml ethanol and treat the mixture with H2 at 45 lb/in2 in a shaker flask until no more gas is taken up. Remove the catalyst by filtration and remove the solvent at reduced pressure to yield the title compound.