Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)=[CH:13][CH:12]=1)#[N:10]>CS(C)=O>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][C:22]3([CH2:4][O:25]3)[CH2:21][CH2:20]2)=[CH:15][CH:16]=1)#[N:10]
Reactant: C[S+](C)(C)=O
Reactant: N#Cc1ccc(CCN2CCC(=O)CC2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1ccc(CCN2CCC3(CC2)CO3)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
60% sodium hydride (1.89 g) was added to anhydrous dimethylsulfoxide (42 mL) and the mixture was stirred at room temperature for ten minutes under nitrogen atmosphere. After gradually adding trimethylsulfoxonium iodide (10.4 g) to the mixture at 10 to 19° C., the mixture was stirred at 8 to 10° C. for thirty minutes and at room temperature for sixty minutes. An anhydrous dimethylsulfoxide solution (42 mL) of the compound (9.00 g) obtained in Step 2 was added dropwise to the mixture. After stirring the resulting mixture at room temperature for one and half hours, the reaction mixture was poured into an ice water (250 mL) gradually with stirring. The mixture was extracted with ethyl acetate, and the organic layer was combined and washed with water and brine successively. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was crystallized from hexane and collected by filtration to obtain the titled compound (8.61 g) as crystals.
Reaction SMILES: Cl.[Si]([O:19][CH2:20][CH2:21][O:22][CH2:23][C@H:24]([O:35][C:36]1[C:37]2[N:44]=[N:43][N:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])[C:38]=2[N:39]=[CH:40][N:41]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][N:29]=1)=[O:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:25](=[O:26])[C@@H:24]([O:35][C:36]2[C:37]3[N:44]=[N:43][N:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[CH3:51])[C:38]=3[N:39]=[CH:40][N:41]=2)[CH2:23][O:22][CH2:21][CH2:20][OH:19])=[N:29][CH:30]=1
Reactant: Cc1ccccc1-n1nnc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Agent: Cl
Solvent: CO
Product: Cc1ccccc1-n1nnc2c(O[C@@H](COCCO)C(=O)Nc3ccc(Cl)cn3)ncnc21
Reaction time: 4 h
Yield: 49.3 %

Procedure:
Hydrochloric acid (10%, 1 mL) was added dropwise to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy)propanamide (Intermediate AP7) (250 mg, 0.35 mmol) in methanol (20.00 mL) at room temperature. The resulting solution was stirred for 4 hours. Most of the methanol was evaporated and the remaining aq. soln was diluted with saturated NH4Cl and extracted with EtOAc (2×30 mL). The organic layers were combined, dried (MgSO4) and evaporated to give crude product. The crude product was purified by flash silica chromatography, eluting with 0 to 100% EtOAc in isohexane to afford the product (81 mg, 48.8%). 1H NMR (400 MHz, CDCl3) δ2.20 (s, 3H), 2.60-2.66 (m, 1H), 3.73-3.83 (m, 4H), 4.20-4.32 (m, 2H), 6.15 (t, 1H), 7.41-7.54 (m, 4H), 8.17-8.21 (m, 1H), 8.23-8.25 (m, 1H), 8.70 (s, 1H), 9.20 (s, 1H), OH not observed; m/z (ESI+) (M+H)+=470.43; HPLC tR=2.25 min
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7])=O.Cl.[NH2:19][OH:20].N1C=CC=CC=1.Cl>CO>[OH:20][N:19]=[CH:1][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(c1cc(C)no1)c1ccccc1C=O
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COC(c1cc(C)no1)c1ccccc1C=NO
Yield: 81.2 %

Procedure:
To 1.39 g (6 mmol) of 5-(2-formyl-α-methoxybenzyl)-3-methylisoxazole in 12 ml of methanol was added 0.83 g (12 mmol) of hydroxylamine hydrochloride and 1.07 ml (13.2 mmol) of pyridine and stirred under reflux for 2 hours. After completion of the reaction, 200 ml of 0.1 N hydrochloric acid was added and extracted twice with 100 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylisoxazole (1.20 g, 81.2%) as oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11]C(C)=O.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:11][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[C:3]([CH3:10])[CH:4]=1
Reactant: CC(C)=O
Reactant: Cc1cc(O)cc(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1cc(C)c(Cl)c(C)c1
Yield: 77 %

Procedure:
To a 1 L round-bottom flask 4-chloro-3,5-dimethylphenol 63 (20 g, 127.7 mmol) and acetone (500 mL, 0.2 M) was placed. To this solution were added potassium carbonate (35.3 g, 255.4 mmol) and iodomethane (63.44 g, 447 mmol). The reaction was stirred and heated to reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 4-chloro-3,5-dimethylphenyl methyl ether 64 (16.88 g, 77%). 1HNMR (300 MHz, CDCl3): δ 2.41 (s, 3H), 2.59 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 3.82 (s, 3H), 4.06 (s, 3H), 4.11 (s, 2H), 5.97 (d, 1H), 6.44 (s, 1H), 6.70 (s, 1H), 7.15 (d, 1H), 8.41 (brd, 1H), 10.31 (brd, 1H), APCI-MS m/z 468.2 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:6]([CH2:7]O)[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2].C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[CH2:1]([C@H:3]1[C@@H:6]([CH2:7][F:26])[N:5]([S:9]([C:12]2[C:13]([CH3:18])=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:4]1=[O:19])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CO
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(S(=O)(=O)c2ccccc2C)[C@@H]1CF
Reaction time: 8 h

Procedure:
To (±)-cis-3-Ethyl-4-hydroxymethyl-N-toluenesulfonyl-2-azetidinone (3.9 mg) in CH2Cl2 (0.5 ml) was added diethylaminosulfur trifluoride (DAST) (15μl). The mixture was stirred overnight under nitrogen. The mixture was purified by preparative TLC on a silica gel plate (1000μ) and developed with CH2Cl2 to give the titled compound. NMR(CDCl3): δ1.06(3H, t), 1.6-2.0(2H, m), 2.45(3H, s), 3.26(1H, dt), 4.27(1H, dm), 4.65(1H, m), 4.88(1H, m), 7.37(2H, d), 7.88(2H, d)
Reaction SMILES: [OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][NH:10][CH2:9]3.C(N(C(C)C)CC)(C)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)Cl>[OH:1][C:2]1[C:14](=[O:15])[N:6]2[CH2:7][CH:8]3[CH2:13][CH:12]([C:5]2=[N:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][N:10]([C:38]([O:37][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:39])[CH2:9]3
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CNCC2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC1CC2CN(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 16 h
Yield: 13.2 %

Procedure:
To ethyl 3-hydroxy-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,11-methanopyrimido[1,2-a][1,5]diazocine-2-carboxylate (0.26 g, 0.661 mmol) in CH2Cl2 (5 mL) was added diisopropylethylamine (0.576 mL, 3.31 mmol) and benzylchloroformate (0.102 mL, 0.727 mmol). The reaction mixture was stirred at 23° C. for 16 hours. HCl (1N, 15 mL) was then added to the reaction mixture and the organic material extracted with CH2Cl2 (3×15 mL) and ethyl acetate (3×15 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The organic material was purified by Silica gel column chromatography (Biotage flash chromatography system) eluting with gradient of ethyl acetate 100% to ethyl acetate methanol (1:9) to afford 0.036 g (13% yield) of the title compound. 1H NMR (400 MHz, MeOD) δ ppm 7.36 (5 H, s), 4.95-5.10 (2 H, m) 3.95-4.40 (2 H, br m), 2.75-3.30 (5 H, br m), 1.75-2.50 (4 H, m), 0.95-1.45 (4 H, m). LCMS (+ESI, M+H+) m/z: 414.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1>C(O)C.O=[Mn]=O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1)=[O:1]
Reactant: O=C(O)CCc1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: CCO
Product: O=Cc1ccc(CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 70.2 %

Procedure:
A solution of 3-(4-hydroxymethyl-phenyl)-propionic acid (720 mg, 4.0 mmol, Example 2a) in ethanol (20 mL) is treated with MnO2 (350 mg, 4.0 mmol) and the resulting suspension is stirred at 80° C. for 18 h. Another portion of MnO2 (500 mg, 5.7 mmol) is added and stirring is continued at 80° C. for 2 days. The mixture is filtered and the filtrate is evaporated to give 3-(4-formyl-phenyl)-propionic acid (500 mg) as a brown solid; LC-MS: tR=0.72 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[C:37]([CH3:39])[CH:38]=1)[C:32]([O:34][CH3:35])=[O:33].CCN=C=NCCCN(C)C.Cl>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:36]=[C:37]([CH3:39])[CH:38]=3)[C:32]([O:34][CH3:35])=[O:33])=[O:21])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: COC(=O)c1cc(C)cc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C)cc(C(=O)OC)c3)cn2)C1

Procedure:
Methyl (R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-5-methylbenzoate was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-5-methylbenzoate hydrochloride using Amidation Method 2 (EDCl).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.CN(C)C1C=CC=CC=1.Cl[C:23]([N:25]=[C:26]=[O:27])=[O:24]>ClCCl>[C:7]1([CH:5]2[N:6]3[C:23](=[O:24])[NH:25][C:26](=[O:27])[CH:1]=[C:2]3[O:3][CH2:4]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC1=NC(c2ccccc2)CO1
Reactant: O=C=NC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: O=c1cc2n(c(=O)[nH]1)C(c1ccccc1)CO2
Temperature: 25 °C
Reaction time: 14 h
Yield: 99 %

Procedure:
To 2-methyl-4-phenyl-4,5-dihydrooxazole (5.70 g, 35.4 mmol) and N,N-dimethylaniline (4.68 g, 6.83 mmol) in dichloromethane (25 mL) at 0° C. was added dropwise chlorocarbonyl isocyanate (3.80 g, 35.4 mmol). The mixture was allowed to warm to room temperature and was stirred for 14 h, during which time a thick white precipitate formed. The suspension was filtered, and the solid was triturated with diethyl ether (3×10 mL) to give a white powder (8.07 g, 99%). 1H NMR (TMS/CDCl3, 300 MHz): 7.44-7.24 (m, 5H); 5.57 (dd, J=3.3, 8.1 Hz, 1H), 5.12 (s, 1H); 5.00 (dd, J=8.1, 8.7 Hz, 1H); 4.54 (dd, J=3.3, 8.7 Hz, 1H); 3.04 (s, 1H). MS=231.0 ((M+H)+).
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][CH:35]1[CH2:37][CH2:36]1.O>CN(C)C=O>[CH:35]1([CH2:34][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[N:9]=3)[CH2:3][CH2:4]2)[CH2:37][CH2:36]1
Reactant: ClCC1CC1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-n2nc(N3CCN(CC4CC4)CC3)c3ccccc32)cc1
Yield: 51.6 %

Procedure:
A stirred mixture of 5.0 g of 3-(1-piperazinyl)-1-[4(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.2 g of potassium carbonate, and 1.4 g of chloromethylcyclopropane in 50 ml of dimethylformamide was heated at 85°-90° for 20 hours. The reaction mixture was poured into water and the aqueous suspension extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was flash chromatographed on silica gel utilizing ethyl acetate as the eluent. Concentration of the appropriate fractions gave 2.7 g (48%) of 3-[4-(cyclopropyl)methyl-1piperazinyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 98°-100°.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([C:7](=[O:14])[C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH3:10])[C:3]([O:5]C)=O.[OH-].[Na+].O.Cl>CS(C)=O>[CH3:15][C:2]1([CH3:1])[C:7](=[O:14])[C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH2:10][C:3]1=[O:5]
Reactant: COC(=O)C(C)(C)C(=O)C(C)(C)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
106 g (495 mmol) of methyl 2,2,4,4-tetramethyl-3,5-dioxohexanoate were added dropwise to a suspension of 19.8 g (495 mmol) of sodium hydroxide in 500 ml of dimethyl sulfoxide. The mixture was stirred at room temperature, treated with 500 ml of water and adjusted to pH 1 using hydrochloric acid, and the deposited precipitate was then filtered off with suction. After drying, 70 g (95%) of 2,2,4,4-tetramethyl-1,3,5-cyclohexanetrione were obtained.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[N:6]=[N:5][CH:4]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[N:6]=[N:5][CH:4]=1)=[O:1]
Reactant: N#Cc1ccc(-n2nncc2CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc(-n2nncc2C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
A mixture of 4-[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]benzonitrile (225 mg, 1.12 mmol, 1.00 equiv) and MnO2 (1958 mg, 22.52 mmol, 20.04 equiv) in dichloromethane (20 mL) was stirred at room temperature overnight. The solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with 0-50% of ethyl acetate in petroleum ether to give 110 mg (49%) of 4-(5-formyl-1H-1,2,3-triazol-1-yl)benzonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.96 (s, 1H), 8.70 (s, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.97 (d, J=8.0 Hz, 2H) ppm.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[NH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCN(CC)CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:6]([N:8]([CH2:14][C:15]([F:18])([F:16])[F:17])[CH2:9][C:10]([F:12])([F:11])[F:13])=[O:7])([O-:23])=[O:22]
Reactant: NCC1CCOCC1
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (75 mg, 0.215 mmol) and 4-aminomethyltetrahydropyran (27 mg, 0.236 mmol) in 3 mL of EtOH containing Et3N (0.045 mL, 0.323 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 87 mg (91%); 1H NMR (CDCl3) 1.47 (m, 2H), 1.75 (m, 2H), 1.98 (m, 1H), 3.27 (t, J=5.47 Hz, 2H), 3.43 (m, 2H), 4.03 (m, 2H), 4.24 (q, J=8.33 Hz, 6H), 6.93 (d, J=8.98 Hz, 1H), 7.54 (d, J=8.98 Hz, 1H), 8.30 (s, 1H), 8.40 (brs, 1H); MS (ESI) 444.31 (MH+).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32]([CH2:36][OH:37])([OH:35])[CH2:31][CH2:30]2)[C:9]=1[Br:38].C(O)(C(F)(F)F)=O.O>>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:34][CH2:33][C:32]([CH2:36][OH:37])([OH:35])[CH2:31][CH2:30]2)[C:9]=1[Br:38]
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(C2CCC(O)(CO)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1c(Br)c(C2CCC(O)(CO)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn12
Yield: 39.3 %

Procedure:
4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol (385 mg, 0.510 mmol) was treated with a mixture of TFA/H2O (2/2 mL) at rt overnight. The reaction mixture was evaporated to dryness and purified by a reverse phase HPLC to afford 4-(7-amino-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanol as a pale yellow solid (99 mg). HPLC-MS TR=3.27 min (isomer 1) and 3.32 min (isomer 2) (UV 254 nm, 10 min method); mass calculated for formula C24H24BrN5O2 493.1, observed LCMS m/z 494 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O.O>[OH:19][CH2:18][C@@H:15]1[CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]2[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](CO)CC[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: OC[C@H]1CC[C@H]2CNCCN2C1
Yield: 92.2 %

Procedure:
A solution of 5.84 g (21.6 mmol) of (7S,9aS)-N-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (WO 93/25552) in 140 mL of trifluoroacetic acid and 60 mL of water was stirred at room temperature for 16 h. The mixture was concentrated and the residue dissolved in water. The aqueous phase saturated with solid sodium carbonate and extracted with chloroform (3×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated to give 3.39 g (92%) of the title compound. This material was used without further purification for subsequent reactions. 13C NMR (base, d-6 DMSO): δ24.8, 25.1, 36.0, 45.7, 51.9, 56.1, 56.7, 62.0, 62.7.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
3.0 mL of trifluoroacetic acid solution containing 40 mg of tert-butyl 2-(benzamido)-4-(4-nitrophenyl)benzoate was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and ethyl acetate and methanol were added to she obtained residue and a solid substance was separated by filtration to obtain 15 mg of 2-(benzamido)-4-(4-nitrophenyl)benzoic acid as white solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(OC([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O)(C)(C)C.CC(C)([O-])C.[Na+]>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].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1(C)C=CC=CC=1>[N:22]1([C:2]2[CH:14]=[CH:13][C:5]([CH2:6][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: Brc1ccc(CN2CCOCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: c1cc(N2CCNCC2)ccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
4-Bromobenzyl bromide (Aldrich Co., 2.0 g) and morpholine (0.73 ml) were dissolved in acetonitrile (15 ml), potassium carbonate (1.3 g) was added, and the mixture was heated under reflux for 4 hr. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate (5:1)) to give 4-(4-bromobenzyl)morpholine (1.55 g). 4-(4-Bromobenzyl)morpholine (1.55 g), 1-(tert-butoxycarbonyl)piperazine (1.27 g), 2-(di-tert-butylphosphino)biphenyl (37 mg), tris(dibenzylideneacetone)dipalladium (57 mg) and sodium tert-butoxide (1.2 g) were added to toluene (13 ml), and the mixture was heated under reflux for 5 hr. The insoluble material was filtered through a Celite (trademark) filter, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography. The obtained 4-[4-(morpholine-4-ylmethyl)phenyl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in dichloromethane, trifluoroacetic acid was added and the mixture was stirred overnight at room temperature. The mixture was neutralized with an aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(4-piperazin-1-ylbenzyl)morpholine (1.06 g, yield 51%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2=CC=CC=C2C1=O.O.NN>CO>[NH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCO
Agent: NN
Solvent: CO
Solvent: O
Product: NCCCCCCCCCCCCO
Yield: 74.1 %

Procedure:
In 600 ml of methanol was dissolved while warming 48.0 g of N-(12-hydroxydodecyl)phthalimide, 50 ml of hydrazine monohydrate was added at room temperature with stirring and the mixture was stirred overnight. The crystal thus separated out was filtered off and the solvent was distilled off. The residue was extracted with hot chloroform and insolubles were filtered off. The filtrate was distilled, the residue was extracted with hot chloroform (100 ml×3) and then the solvent was distilled off. The residue was dissolved in methanol and recrystallization from methanol-ethyl acetate gave 21.6 g of the title compound as a crystal.