Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C(=[N:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.[C:27]([NH:35][CH:36]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH2:38][CH:39]=[O:40])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[NH4+].[Cl-]>C1COCC1>[NH2:20][CH:21]([CH:39]([OH:40])[CH2:38][CH2:37][CH:36]([NH:35][C:27](=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(CCC=O)NC(=O)c1ccccc1
Reactant: CCOC(=O)CN=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(CCC(O)C(N)C(=O)OCC)NC(=O)c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
Diisopropylamine (2.34 ml, 16.7 mmoles) is added to anhydrous THF (75 ml) and cooled to -10° C. At this point 2.24M n-BuLi (6.8 ml, 15.2 mmoles) is added slowly. After complete addition the reaction mixture is stirred for 10 minutes before being cooled to -78° C. At that temperature ethyl N-benzylideneglycinate (4) (2.9 g, 15.2 mmoles) is added and stirring is allowed to proceed for 15 minutes before aldehyde (8) (4.0 g, 15.2 mmoles), dissolved in anhydrous THF (25 ml), is added dropwise to the yellow anion. After complete addition the reaction is stirred another 11/2 hours before being poured into cold 5% aqueous NH4Cl. This mixture is extracted with CHCl3 (3×100 ml). The combined extracts are washed with saturated aqueous NaCl, dried over MgSO4, filtered and evaporated to dryness. The oily residue is taken up in THF (300 ml) and shaken with 5% aqueous HCl (200 ml) in a separatory funnel. This mixture is washed with Et2O (3×100 ml), basified with solid NaHCO3 and extracted with CHCl3 (3×150 ml). The combined extracts are washed with saturated aqueous NaCl (1×150 ml), dried over MgSO4, filtered and evaporated to dryness in vacuo to yield 4.0 g (72% yield) of the desired compound as a yellow glass. 'H-N.M.R. (CHCl3 /TMS): δ=1.20 (t, 3H, --CH2CH3); 1.28 (t, 3H, --CH2CH3 ); 1.45-2.20 (m, 4H, --CH2CH2 --); 2.46 (broad s, 2H, --NH2); 3.18-4.00 (m, 2H, >CH--NH2, CHOH); 4.19 (q, 2H, --CH2CH3); 4.25 (q, 2H, --CH2CH3); 4.53-5.08 (m, 1H, >CH--NH--); 7.05-7.97 ppm (m, 5H, Ph).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][C@H:8]([NH:10][S:11]([C:14]3[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH2:9][C@H:5]2[CH2:4][N:3]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1.C([O-])(O)=[O:33].[Na+]>Cl>[O:1]=[C:2]1[N:6]2[CH2:7][C@H:8]([NH:10][S:11]([C:14]3[C:15]([OH:33])=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[CH2:9][C@H:5]2[CH2:4][N:3]1[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1
Reactant: O=C([O-])O
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)c3cccnc3Cl)CN12
Agent: Cl
Agent: [Na+]
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)C[C@@H]2C[C@@H](NS(=O)(=O)c3cccnc3O)CN12
Temperature: 100 °C
Reaction time: 24 h
Yield: 21 %

Procedure:
2-Chloro-pyridine-3-sulfonic acid [(6R,7aS)-3-oxo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-6-yl]-amide (example 15) (100 mg, 0.21 mmol) was added to concentrated hydrochloric acid (10 mL, 12 M), the mixture was stirred for 24 h at 100° C. To the mixture was added sat. NaHCO3 to adjust to pH=8. Then extracted with ethyl acetate (15 mL×2), dried over anhydrous sodium sulfate and concentrated. The residue was directly purified by pre-TLC (dichloromethane:MeOH=100:1) to yield 20 mg (21%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 12.0 (bs, 1H) 8.22-8.19 (m, 1 Hz), 7.85-7.80 (m, 1H), 7.46-7.41 (m, 2H), 7.11-7.08 (m, 2 Hz), 6.49-6.41 (m, 2H), 4.09-3.91 (m, 4H), 3.63-3.61 (m, 1H), 3.04-3.01 (m, 1H), 2.22-2.20 (m, 1H), 1.64-1.62 (m, 1H); LC-MS: 459.0 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][NH:33][C:32]3=[O:36])=[CH:27][CH:26]=2)[CH:23]=[CH:22][N:21]=[N:20]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:33]1[C:32](=[O:36])[N:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)=[CH:26][CH:27]=2)[CH:35]=[N:34]1)[CH3:12]
Reactant: O=c1[nH]ncn1-c1ccc(Cn2ccnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](n1ncn(-c2ccc(Cn3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane was reacted with 4-[4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-3(2H,4H)-1,2,4-triazolone in the same manner as in Working Example 2 to give 2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(1H-1,2,3-triazol-1-ylmethyl)-phenyl]-3(2H,4H)-1,2,4-triazolone (Compound 29).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C[S-:11].[Na+]>CN1CCCC1=O>[SH:11][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[S-]
Reactant: N#Cc1ncccc1Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ncccc1S
Temperature: 140 °C
Yield: 42.7 %

Procedure:
A mixture of 3-chloro-2-cyanopyridine (2.50 g, 18.05 mmol), and sodium thiomethoxide (3.60 g, 51.40 mmol) in 1-methyl-2-pyrrolidinone (25 mL) was heated at 140° C. overnight. The reaction mixture was cooled to 0° C. and quenched with 50% aqueous HCl. A light brown precipitate formed and the reaction was cooled for 1 h while stirring. The light brown solid was collected by vacuum filtration and dried under reduced pressure overnight to provide 3-mercaptopicolinonitrile (1.05 g). The crude product was used carried forward without further purification. MW=136 confirmed by LC-MS, tr=1.85 min (Method E) MH+=137.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5](=O)[CH2:6][CH2:7][CH3:8].O.[NH2:18]N>C(O)C>[C:10]1([C:4]2[CH:3]=[N:2][NH:18][C:5]=2[CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: CCCC(=O)C(=CN(C)C)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCc1[nH]ncc1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of 1-(dimethylamino)-2-phenylhex-1-en-3-one (3.51 g, 16.2 mmol) in ethanol (80.0 mL), was added hydrazine hydrate (1.57 mL, 32.4 mmol). The reaction mixture was stirred at 80° C. After 3 h, the reaction mixture was cooled to room temperature, concentrated under reduced pressure and crystallized in 20% ethanol/H2O to give the title compound as a white solid (3.01 g). LCMS m/z=187.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.92-1.00 (m, 3H), 1.64-1.76 (m, 2H), 2.75-2.84 (m, 2H), 7.36-7.41 (m, 5H), 7.65 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)([O:6]CC)=[O:5])[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([O:3][P:4]([CH2:9][O:10][CH2:11][CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:23])=[N:15][C:14]1=2)([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(COCCn1cnc2c(=O)[nH]c(N)nc21)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOP(=O)(O)COCCn1cnc2c(=O)[nH]c(N)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
9-(2-(diethylphosphonomethoxy)ethyl)guanine (0.198 g, 0.57 mmol) was dissolved in 15 mL of 1N sodium hydroxide solution and the mixture was stirred at room temperature for 1 hour. The solution was then acidified with 10% aqueous hydrochloric acid to pH 1 and concentrated in vacuo. Residual salts were removed by reverse phase column chromatography (C18 adsorbent, elution with water) to provide 0.150 g of 9-(2-(ethylphosphonomethoxy)ethyl)-guanine as a white crystalline solid, mp=192.5°-193.5° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[C:5]([Cl:19])[CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.N.C(#[N:23])C>O>[NH2:23][C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[C:5]([Cl:19])[CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1
Reactant: CC#N
Reactant: Clc1cc(Cl)c2nc(Cl)nc(-c3ccccc3)c2c1
Agent: N
Solvent: O
Product: Nc1nc(-c2ccccc2)c2cc(Cl)cc(Cl)c2n1

Procedure:
A mixture of 300 mg of 2,6,8-trichloro-4-phenylquinazoline (compound No. II-5), 30 g of an aqueous 28% ammonia solution and 6 ml of acetonitrile was reacted in a pressure-resistant reaction vessel at 105° C. for 1.5 hours. The resulting reaction solution was cooled and then poured into 100 ml of water. The mixture was extracted with 60 ml of ethyl acetate and the resultant extract was concentrated. The resulting residue was purified by silica gel column chromatography (chloroform) to obtain 230 mg of the titled compound. Mp. 212.7° C. 1H NMR (CDCl3): 5.56 (2H, br. s), 7.54-7.60 (3H, m), 7.63-7.68 (2H, m), 7.74 (1H, d, J=2.3 Hz), 7.79 (1H, d, J=2.3 Hz).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([Cl:19])=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=O)=O.[F:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:24]=[C:25]([F:28])[C:26]=1O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:19][C:8]1[C:7]([CH2:6][O:5][C:26]2[C:25]([F:28])=[CH:24][C:23]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:22][C:21]=2[F:20])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:10][N:9]=1
Reactant: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Reactant: CS(=O)(=O)OCc1c(Cl)nsc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(F)c(OCc2c(Cl)nsc2-c2ccc(Cl)cc2)c(F)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methyl methanesulfonate (320 mg, 0.95 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (230 mg, 1.00 mmol, 1.06 equiv), potassium carbonate (420 mg, 3.04 mmol, 3.21 equiv), N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at 30° C. The resulting solution was diluted with of H2O. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (17/83). The collected fractions were combined and concentrated under vacuum. This resulted in 340 mg (68%) of ethyl 3-(4-[[3-chloro-5-(4-chlorophenyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate as colorless oil. Mass spectrum (ESI, m/z): Calcd. for C21H17C12F2NO3S, 472.0 (M+H). found 472.0.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH3:31]>O1CCOCC1>[NH2:31][C:22]1[N:21]=[C:20]([CH2:19][N:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=3)[C:12]2=[O:30])[CH:25]=[CH:24][N:23]=1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(S(C)(=O)=O)n3)C(C)(C)C2=O)cc1
Reactant: N
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)n3)C(C)(C)C2=O)cc1

Procedure:
A solution of 0.45 g of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-{[2-(methylsulphonyl)pyrimidin-4-yl]methyl}imidazolidine-2,4-dione obtained in stage e) in 2.1 mL of dioxane and 2.1 mL of 30% aqueous ammonia is heated in a sealed microwave tube at 120° C. for 1 hour. After evaporating off the solvents, 0.38 g of 1-[(2-aminopyrimidin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione is obtained, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:29][C:30]([F:33])([F:32])[F:31]>C1COCC1>[F:31][C:30]([F:33])([F:32])[CH2:29][N:23]1[CH2:24][CH2:25][N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:19]3)[CH2:21][CH2:22]1
Reactant: FC(F)(F)CBr
Reactant: O=S(=O)(c1ccccc1)c1cnc2c(N3CCNCC3)cccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CCN(CC(F)(F)F)CC3)cccc2c1
Temperature: 100 °C

Procedure:
A solution of 3-phenylsulfonyl-8-piperazin-1-yl-quinoline (D12) (200 mg, 0.55 mmol) in dry THF (2 ml) was treated with sodium hydride (24 mg, 0.6 mmol, 60% oil dispersion), and 1-bromo-2,2,2-trifluoroethane (815 mg, 5 mmol). The mixture was heated to 100° C. for 4 days then cooled, evaporated and the residue subjected to purification by flash chromatography on silica gel (eluting with dichloromethane-methanol-aq. NH3) to give the free base form of the title compound. This was treated with 1M HCl in ether then crystallised from isopropanol to give the title compound (E8) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][C:24]=2[F:31])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CO.[NH2:34][OH:35]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29](=[N:34][OH:35])[NH2:30])=[CH:25][C:24]=2[F:31])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Solvent: O
Solvent: CO
Product: NC(=O)[C@@H](CCC(F)(F)F)N(Cc1ccc(C(N)=NO)cc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 47.5 °C
Yield: 96 %

Procedure:
(2R)-2-[[(4-Chlorophenyl)sulfonyl][(4-cyano-2-fluorophenyl)methyl]amino]-5,5,5-trifluoropentanamide (399 g) and methanol (1.6 L) were charged to a reactor followed by hydroxylamine (50% solution in water, 93 mL, 1.8 eq). The mixture was heated to 45-50° C. until complete reaction by HPLC (<0.15 relative AP starting material). Water (0.5 L) was charged slowly, keeping the batch temperature between 30-50° C. The batch was allowed to stand until crystallization started and then water (2.7 L) was charged. The batch was cooled to 15-20° C. and filtered. The cake was washed with 2:1 MeOH:water (2 L) and then dried under vacuum at 50° C. to give the title compound as white solid (415 g, 96% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.43-1.64 (m, 1 H) 1.77-1.93 (m, 1 H) 1.93-2.17 (m, 2 H) 4.41 (dd, J=8.48, 6.03 Hz, 1 H) 4.60 (d, J=17.14 Hz, 1 H) 4.94 (d, J=16.77 Hz, 1 H) 5.81-5.98 (m, 2 H) 7.19-7.27 (m, 1 H) 7.37-7.47 (m, 2 H) 7.52 (d, J=4.14 Hz, 2 H) 7.64 (d, J=8.67, Hz, 2 H) 7.85 (d, J=8.85 Hz, 2 H) 9.71-9.83 (m, 1 H). IR (KBr): 3491, 3379, 1680, 1651, 1592, 1433, 1343. Anal. Calcd. for Cr19H19ClF4N4O4S Calc. C, 44.66; H, 3.74; N, 10.96; S, 6.27; F, 14.87; Cl, 6.94. Found: C, 44.90; H, 3.91; N, 10.91; S, 6.41; F, 15.21; Cl, 6.95.
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12]C)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Cl.[OH-:15].[Na+]>>[OH:15][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: [OH-]
Reactant: COC(=O)C12CCC(Br)(CC1)CC2
Agent: Cl
Agent: [Na+]
Product: O=C(O)C12CCC(O)(CC1)CC2
Yield: 89 %

Procedure:
Methyl 4-bromobicyclo[2.2.2]octane-1-carboxylate (17.0 g, 69.0 mol) was refluxed in aqueous sodium hydroxide solution (1500 mL, 1%) for 24 h. After cooling, the reaction solution was acidified with hydrochloric acid (6 N, 100 mL) and extracted with diethyl ether (6×500 mL). The combined ether layers were dried over magnesium sulfate and concentrated to afford the title compound (10.4 g, 61.1 mmol, 89% yield), which was used in the next step without further purification. MS (ESI) m/z 169.2 [M+H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].[CH2:12]([NH2:14])[CH3:13].O.[OH-].[Na+]>O1CCCC1>[CH2:12]([NH:14][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:13]
Reactant: CCN
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCNCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2-Nitrobenzylbromide (0.23 mol) in tetrahydrofuran (500 ml) was added to a stirred mixture (4.35M) of 70% aqueous ethylamine (350 ml) and water (350 ml) over a 20 minutes. The reaction stood at ambient temperature for 1 hour, was reduced to low volume, treated with ice/water to 800 ml and basified with an aqueous solution of sodium hydroxide (ION, 23 ml). It was extracted with ether (2×) and the combined extracts dried (MgSO4) and evaporated to give N-ethyl-2-nitrobenzylamine as a yellow oil (44 g, 100%).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH:16]([NH:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:18])[CH3:15]
Reactant: CC(C)=O
Reactant: Nc1ccccc1Oc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Nc1ccccc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of 2-phenoxyaniline (0.93 g, 5.0 mmol) in dichloroethane (50 ml) was added anhydrous acetone (0.73 ml, 10.0 mmol) and acetic acid (0.1 ml, 2.0 mmol). The mixture was stirred for 30 min, and sodium triacetoxyborohydride (3.18 g, 15.0 mmol) was added in one portion. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched by slow addition of MeOH (10 ml) and concentrated under reduced pressure. The residue was poured into water (50 ml) and extracted with ethyl acetate (3×100 ml). Organic extracts were combined and washed with brine (2×100 ml) and dried (Na2SO4), concentrated under reduced pressure to give N-isopropyl-2-phenoxyaniline (1.05 g, 91%) as colorless oil.
Reaction SMILES: C(N(CC)CC)C.Cl[Si:9]([CH3:12])([CH3:11])[CH3:10].[NH2:13][C:14]1[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=[C:16]([CH2:23][CH2:24][CH:25]([OH:27])[CH3:26])[CH:15]=1.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:13][C:14]1[N:19]2[N:20]=[CH:21][CH:22]=[C:18]2[N:17]=[C:16]([CH2:23][CH2:24][CH:25]([O:27][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH3:26])[CH:15]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC(O)CCc1cc(N)n2nccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CCc1cc(N)n2nccc2n1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Triethylamine (400 μl) and chlorotrimethylsilane (680 μl ) were added to 5 ml of a THF solution containing 500 mg of the crystals obtained in step (6), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted with dichloromethane. The organic layer was collected, washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. n-Hexane was added to the residue. The crystals precipitated were collected by filtration to provide 520 mg of 7-amino-5-(3-trimethylsilyloxybutyl) pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH:11](OCC)OCC.C(O)C>ClC1C=CC=CC=1>[Br:1][C:2]1[C:3]2[O:9][CH:10]=[CH:11][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(COc1ccc(F)cc1Br)OCC
Solvent: CCO
Solvent: Clc1ccccc1
Product: Fc1cc(Br)c2occc2c1
Reaction time: 2 h
Yield: 29.6 %

Procedure:
2-Bromo-1-(2,2-diethoxy-ethoxy)-4-fluoro-benzene (60 g, 0.22 mol, Step A) was combined with Amberlyst-15 (20 g, Aldrich) in chlorobenzene (500 mL, Aldrich) and stirred with a paddle stirrer while the temperature was maintained at very gentle reflux. At the same time an azeotrope containing ethanol and chlorobenzene was removed via downward distillation. After 2 hours, more chlorobenzene was added (200 mL) and additional azeotrope was collected. The content of the flask was filtered and excess chlorobenzene was distilled (45° C., at ˜1 mm). The residue was purified by silica gel chromatography (5–10% ethyl ether/hexane) to give 7-bromo-5-fluoro-benzofuran (14 g, ˜33%) and taken to the next step. H1NMR (300 MHz, DMSOd6), ppm: 8.20 (d), 1H, 7.52 (m), 2H, 7.10 (d), 1H.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH2:3].[O-][CH2:31]C.[Na+].CI>CCOCC>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH:23]([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:31])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccccc1C(C(OCC)OCC)C(C(=O)OCC)C(=O)OCC
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: C=CCOc1ccccc1C(C(OCC)OCC)C(C)(C(=O)OCC)C(=O)OCC

Procedure:
A solution of ethyl 3-(2-allyloxyphenyl)-4,4-diethoxy-2-ethoxycarbonylbutanoate (described in Example 1(i)), in ether is treated with sodium ethoxide and subsequently with methyl iodide to give ethyl 3-(2-allyloxyphenyl)-4,4-diethoxy-2-ethoxycarbonyl-2-methylbutanoate, which is subsequently reacted in a manner similar to that described in Example 1(i) to give 4-(2-allyloxyphenyl)-5-ethoxy-3-methyl-2-oxotetrahydrofuran.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C@H:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O.C(N(CC)CC)C>ClC(Cl)C>[OH:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:25]1=[O:26]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2O)C1=O)C(C)(C)C
Yield: 67.3 %

Procedure:
A solution of Example 145A (180 mg, 0.521 mmol) and disuccinimidyl carbonate (0.16 g, 0.625 mmol) in dichloroethane (5 mL) was treated with triethylamine (87 μL, 0.625 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered, and the solvents were evaporated to give the crude residue which was purified using silica gel chromatography eluting with a gradient of 100% hexanes to 60% hexanes in ethyl acetate to give the title compound (0.127 g, 67%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[BrH:34]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:34][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CO)c2)cc1
Reactant: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CBr)c2)cc1

Procedure:
A mixture of 10.0 g of N-[3-(hydroxymethyl)phenyl]-N'-[4-(tetradecyloxy)phenyl]urea, 70 ml of hydrogen bromide in acetic acid and 40 ml of chloroform is refluxed for 2.5 hours, then cooled. The solid is collected and washed with carbon tetrachloride and two times with water. The collected solid is crystallized from ethyl alcohol:tetrahydrofuran followed by recrystallization from tetrahydrofuran to give 7.4 g of the desired product as a white powder, m.p. 164°-169° C.