Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([OH:17])=O)[CH2:10][O:11][C:12]#[C:13][CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH:23][C:15](=[O:17])[C@H:9]([CH2:10][O:11][C:12]#[C:13][CH3:14])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC#COC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
N-tert-butoxycarbonyl O-propynyl L-serine (14.55 g, 59.82 mmol) was dissolved in DMF (60 mL) and the solution cooled to 0° C. (icebath). Glycine methyl ester hydrochloride (7.51 g, 59.8 mmol) was suspended in DMF (40 mL) and N,N-diisopropylethylamine (7.73 g, 59.8 mmol) added. The resulting suspension was added to the solution of N-tert-butoxycarbonyl O-propynyl L-serine in one portion. HOBt hydrate (9.16 g, 59.8 mmol) dissolved in DMF (20 mL) was added. Finally, EDC hydrochloride (12.61 g, 65.8 mmol) was added in small portions. The reaction mixture was stirred for 1 h at 0° C. after which the icebath was removed and stirring continued for 25 h at room temperature before the solvent was evaporated. The residue was taken up in EtOAc (400 mL) and the solution washed with 1 M aqueous H2SO4 (3×200 mL), 7.5% (w/w) K2CO3 solution (3×200 mL) and saturated brine (200 mL). The solution was dried with anhydrous MgSO4 and the solvent evaporated affording a yellow/orange oil (17.23 g, 92%); δH (300 MHz; d6-DMSO) 8.31 (1H, t, J 6, NH(Gly)), 6.85 (1H, d, J 8, NH(propSer)), 4.26-4.15 (1H, m, CαH(propSer)), 4.13 (2H, t, J 2, CH2CCH), 3.88 (1H, dd, J 17 and 6, CαHH(Gly)), 3.81 (1H, dd, J 17 and 6, CαHH(Gly)), 3.65 (1H, dd, J 10 and 5, CHH), 3.62 (3H, s, OCH3), 3.52 (1H, dd, J 10 and 8, CHH), 3.41 (1H, t, J 2, CCH), 1.39 (9H, s, (CH3)3); δC (75 MHz; d6-DMSO) 170.2, 170.0, 155.1, 79.9, 78.3, 77.2, 69.2, 59.7, 57.6, 54.0, 51.6, 40.6, 28.1, 20.7, 14.0
Reaction SMILES: [Br:1][CH:2]([CH2:14][Br:15])[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1.[CH3:16][C:17]1[C:26]([CH3:27])=[C:25]2[C:20]([CH2:21][CH2:22][C:23]([CH2:29][CH2:30][CH2:31][CH:32]([CH2:34][CH2:35][CH2:36][CH:37]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH3:38])[CH3:33])([CH3:28])[O:24]2)=[C:19]([CH3:45])[C:18]=1O.C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[CH3:27][C:26]1[C:17]([CH3:16])=[C:18]([O:12][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH:2]([Br:1])[CH2:14][Br:15])=[CH:10][N:9]=2)=[O:13])[C:19]([CH3:45])=[C:20]2[CH2:21][CH2:22][C:23]([CH2:29][CH2:30][CH2:31][CH:32]([CH2:34][CH2:35][CH2:36][CH:37]([CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH3:38])[CH3:33])([CH3:28])[O:24][C:25]=12
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1OC(=O)c1ccc(CCC(Br)CBr)cn1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 81 %

Procedure:
2.42 g of 5-(3,4-dibromobutyl)picolinic acid, 2.15 g of dl-α-tocopherol and 4.0 ml of triethylamine were dissolved in 15 ml of methylene chloride, and with stirring under ice cooling, a solution of 1.0 ml of phosphorus oxychloride in 5 ml of methylene chloride was added dropwise. The reaction was performed at this temperature for 3 hours. The reaction mixture was washed with 2 N hydrochloric acid, and then with water, and dried. Then, methylene chloride was distilled off. The residue was chromatographed on a column of silica gel using benzene/ethyl acetate (4:1) as an eluent to give 3.03 g of dl-α-tocopheryl 5-(3,4-dibromobutyl)picolinate as a slightly yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH3:14])[C:10]#[N:11].[CH3:15][O:16][C:17]([NH:19]N)=[O:18].C(O)(=O)C.[H][H]>[Ni].C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][CH2:13][CH3:14])[CH:10]=[N:11][NH:19][C:17]([O:16][CH3:15])=[O:18]
Reactant: COC(=O)NN
Reactant: CCCC(C#N)c1ccc(Cl)cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCC(C=NNC(=O)OC)c1ccc(Cl)cc1Cl

Procedure:
11.0 g of Raney nickel are added to a solution of 22.8 g (0.1 mol) of 2-(2,4-dichlorophenyl)-valeronitrile, 9.0 g (0.1 mol) of hydrazinecarboxylic acid methyl ester and 6.0 g (0.1 mol) of acetic acid in 200 ml of 95% aqueous ethanol, and the mixture is hydrogenated at room temperature under a normal pressure of hydrogen for 6.5 hours. Filtration and crystallisation yield 23.3 g (77% of theory) of the above product, which after recrystallisation from methanol has a melting point of 165°-166° C. and gives the following analytical data: IR spectrum (CHCl3) in cm-1 : 1750, 1718; 1H-NMR spectrum (250 MHz, CDCl3) 8.0 (bs, 1H, HN); 7.41 (d, J=2, 1H, H--Ar); 7.28 (s, 1H, HC=N--); 7.23 (dAB xd, JAB =8, J=2, 1H, H--Ar); 7.16 (dAB, JAB =8, 1H, H--Ar); 4.11 (q, J=7, 1H, HC(2)); 3.80 (s, 3H, H3CO--); 2.02-1.68 (m, 2H, H2C(3)); 1.40-1.10 (m, 2H, H2C (4)); 0.88 (t, J=7, 3H, H3C); mass spectrum: 304/302 (M+).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3C(C)=NO[N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CC[C@H](OC(=O)C(F)(F)F)C2)C2[N:39]=[N:38][NH:37][C:35]=2N=1)(C)(C)C.ClCC1N(C)N=NN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:21]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[N:37]([CH3:35])[N:38]=[N:39][N:16]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as yellow gum. MS (m/e): 359.3 (MH+).
Reaction SMILES: [Na+].[Cl-].[OH2:3].[OH-:4].[K+].[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9](Cl)=[O:10])[CH3:7]>CCCCCCCCCC>[CH2:6]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([O:3][O:4][C:13]([O:4][O:3][C:9](=[O:10])[CH:8]([CH2:6][CH3:7])[CH2:12][CH2:13][CH2:14][CH3:15])([CH2:12][CH:8]([CH3:9])[CH3:6])[CH3:14])=[O:10])[CH3:7]
Reactant: O
Reactant: [OH-]
Reactant: CCCCC(CC)C(=O)Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCCCCCCCCC
Product: CCCCC(CC)C(=O)OOC(C)(CC(C)C)OOC(=O)C(CC)CCCC
Temperature: 6.5 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Into a 200 ml beaker were charged 50 g of 1-hydroperoxy-1,3-dimethyl butyl peroxy-2-ethyl hexanoate (0.06 mole) in n-decane, 10 g of NaCl-25%, and 20 g of demi-water. The pH was adjusted with KOH-45% to 13.5 at a temperature of 8-12° C. Then 9.8 g of 2-ethylhexanoyl chloride were dosed in 20 minutes simultaneously with the lye, with the pH kept at >13.5. The mixture was stirred for another 60 minutes at 5-8° C. After separation of the water layer, the remaining hydroperoxide was reduced with a sulphite reduction. The organic layer was washed with NaHCO3-6%. The product was dried over magnesium sulphate. Yield: 47.4 g of product with an active oxygen content of 3.77% (chemical yield:93%). Ratio mono:bis=1:99.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH3:16])=[C:12]([OH:14])[CH:13]=1.Cl>CCO>[CH3:16][O:15][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:13][C:12]=1[OH:14]
Reactant: Brc1nccs1
Reactant: COc1ccc(N)cc1O
Agent: Cl
Solvent: CCO
Product: COc1ccc(Nc2nccs2)cc1O
Yield: 62 %

Procedure:
Following the general procedure for the synthesis of 2-R-5-(thiazol-2-ylamino)phenol; 2-bromothiazole (0.27 mL, 3.05 mmol), 5-amino-2-methoxyphenol (212 mg, 1.52 mmol) and 37% HCl solution (0.26 mL, 3.05 mmol) in 10% aqueous EtOH solution (5 mL) was stirred at 90° C. for 24 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 1/1) in 62% yield (210 mg).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogen carbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-1-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.45 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.77 g, 70%).
Reaction SMILES: COC(=O)C1C=C(O)C=C(O)C=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21](=[O:66])[C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)[CH:25]=[C:24]([O:47]CCCOC2C=CC(OCC3C=CC=CC=3)=CC=2)[CH:23]=1>CC(C)=O.CN(C=O)C>[CH3:19][O:20][C:21](=[O:66])[C:22]1[CH:27]=[C:26]([O:28][CH2:29][CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)[CH:25]=[C:24]([OH:47])[CH:23]=1
Reactant: COC(=O)c1cc(OCCCOc2ccc(OCc3ccccc3)cc2)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Agent: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(OCCCOc2ccc(OCc3ccccc3)cc2)c1
Yield: 30 %

Procedure:
A mixture of 2.0 g (11.9 mmol) of 3,5-dihydroxybenzoic acid methyl ester, 3.8 g (11.9 mmol) of 3-[(4-phenylmethoxy)phenoxy]propyl bromide and 1.7 g (12.3 mmol) of potassium carbonate in 40 ml of acetone and 2 ml of DMF was stirred at reflux for 24 hours. The solvents were removed at reduced pressure, the residue was stirred with methylene chloride and filtered. The filtrate was concentrated to a solid which was recrystallized from methylene chloride-methanol to give 1.77 g, mp 134°-136°, of 3,5-bis[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester. The filtrate was concentrated to a solid which was purified by chromatography on 20 g of silica gel (230-400 mesh) using 10% ethyl acetate-hexane to give 1.47 g (30% yield, mp 120°-122°) of 3-hydroxy-5-[3-[4-(phenylmethoxy)phenoxy]propoxy]benzoic acid methyl ester.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=O.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1.N12CCCN=C1CCCCC2>ClCCl>[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([NH:34][S:31]([C:28]1[CH:29]=[N:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:32])=[O:33])=[O:18]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: NS(=O)(=O)c1ccc(Cl)nc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(Cl)nc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
1,1′-Carbonyl-diimidazole (4.22 g, 26 mmol) was added to a solution of 2,4-dichlorobenzoic acid (4.73 g, 24.8 mmol) in 100 ml dichloromethane the mixture was stirred for 30 minutes at room temperature and subsequently refluxed for 30 minutes. Then 6-chloro-pyridine-3-sulfonic acid amide (5.00 g, 26 mmol) and 1,8-diazabicylo[5.4.0]undec-7-en (3.96 g, 26 mmol) were added and the mixture was stirred at room temperature overnight. After evaporation to dryness the residue was taken up with 100 ml ethyl acetate and washed with 1 M HCl and 1 M NaOH and the organic phase was dried over sodium sulphate and concentrated in vacuo. Flash chromatography (SiO2, heptane-ethyl acetate gradient) yielded 6.72 g of the title compound as a white solid, m/z=365 (ES+), 363 (ES−).
Reaction SMILES: [CH:1]1([C:4]#[C:5][CH2:6][OH:7])[CH2:3][CH2:2]1.[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:6][C:5]#[C:4][CH:1]2[CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC#CC1CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC#CC2CC2)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of crude 3-cyclopropylprop-2-yn-1-ol (intermediate AT) (0.55 mg) in 10 mL of CH2Cl2 was added TsCl (1.33 g, 6.87 mmol) and DMAP (0.035 g, 0.2865 mmol) at 0° C. Triethylamine (0.96 mL, 6.87 mmol) was added dropwise to the mixture and the reaction temperature was held so as not to exceed 0° C. After stirring for 3 h, the mixture was quenched with 10 mL of water. The aqueous layer was extracted twice with 20 mL each of CH2Cl2. The organic layer was washed with 20% HCl and water prior to drying over anhydrous Na2SO4. The organic phase was concentrated and the crude product was purified by gel column chromatography to obtain intermediate AU (0.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12]3[C:17]([NH:18][C:10]=2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.N1C2C(=CC=CC=2)C(=O)C1=O.[OH:30][CH2:31][CH2:32][NH:33][CH2:34][CH2:35][NH2:36].Cl>C(OCCO)C.CC(=O)OCC.CO>[ClH:1].[CH:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]1[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=1[C:2]([NH:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31][OH:30])=[N:3]2
Reactant: Clc1nc2ccccc2c2[nH]c3ccccc3c12
Reactant: NCCNCCO
Agent: Cl
Agent: O=C1Nc2ccccc2C1=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCCO
Product: OCCNCCNc1nc2ccccc2c2[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of compound 4a as obtained from the above Synthesis Ex. 1 (0.50 g, 2 mmol) and N-(2-hydroxyethyl)ethylenediamine (0.63 g, 6 mmol) in 2-ethoxyethanol (5 mL) was heated at 140-150° C. for 24 hrs (by TLC monitoring). After cooling, the reaction mixture was evaporated in vacuo to give a residue, which was dissolved in EA (50 mL). The EA layer was washed with H2O and brine and then dried (MgSO4). Concentration of the EA layer gave a residue, which was dissolved in MeOH (10 mL) and then added with a solution of 6N HCl at 0° C., followed by stirring at room temperature for 8 hrs. The resultant precipitate was filtered off, washed with MeOH, and dried at 90° C. under reduced pressure for 24 hrs to give the title compound 9 (0.50 g, 70% yield).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH2:12]([O:14][CH2:15][C:16]1[N:17]([CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[C:18]2[C:27]3[CH:26]=[C:25]([NH:28][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:34]=1)[CH3:13].[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:41][C:20]1[C:19]2[N:34]=[C:16]([CH2:15][O:14][CH2:12][CH3:13])[N:17]([CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])[C:18]=2[C:27]2[CH:26]=[C:25]([NH:28][C:29](=[O:33])[CH:30]([CH3:31])[CH3:32])[CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccc(NC(=O)C(C)C)cc3c2n1CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccc(NC(=O)C(C)C)cc3c2n1CC(C)(C)O
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (60% pure, 0.283 g, 1.0 mmol) was added to a solution of N-[2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]-2-methylpropanamide (0.380 g, 1.0 mmol) in chloroform (10 mL) and the reaction was stirred for 1 hour. The mixture was cooled in an ice bath and ammonium hydroxide (3 mL) was added. After 15 minutes of stirring, p-toluenesulfonyl chloride (0.190 g, 1.0 mmol) was added and the reaction mixture was stirred for 72 hours. The fractions were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were washed with brine and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a linear gradient of 2-20% CMA in chloroform). Recrystallization from acetonitrile provided 0.231 g of N-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-8-yl]-2-methylpropanamide as an off-white solid, mp 259-261° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([O:34]C)=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:23][CH2:22][C:21]([C:32]([OH:34])=[O:33])=[CH:20][C:19]=3[CH:36]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2cnn(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2cnn(C)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.7 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylate (321 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutralize, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-[(1-methylpyrazol-4-yl)methyl]-2,3-dihydro-1-benzazepine-4-carboxylic acid (239 mg) as yellow crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:22][N:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:51][CH2:52][C:53]([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[CH2:57][CH2:56]1)=[O:54]>CN(C=O)C.O>[O:54]=[C:53]([N:55]1[CH2:56][CH2:57][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:69])[F:70])[CH:63]=2)[CH2:59][CH2:60]1)[CH2:52][NH:51][C:23]([C:20]1[CH:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([F:10])([F:27])[F:26])[NH:22][N:21]=1)=[O:25]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2C(F)(F)F)[nH]n1
Reaction time: 8 h
Yield: 56 %

Procedure:
DIPEA (76 mg, 0.59 mmol) was added to a stirred solution of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid (43 mg, 0.167 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from (o-trifluoromethyl)acetophenone) in DMF (2 mL) followed by HOBt (24 mg, 0.176 mmol) and EDCI.HCl (34 mg, 0.176 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (0.057 mg, 0.167 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by washing with chloroform to afford 51 mg (56% Yield) of 5-(2-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 541, 87.52%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (d, 1H), 8.1 (m, 1H), 7.6 (m, 4H), 7.5 (t, 1H), 7.3 (t, 3H), 6.76 (s, 1H), 4.8 (m, 1H), 4.1 (d, 2H), 3.7 (m, 2H), 3.4 (m, 1H), 3.2 (m, 1H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH3:13][C:14]([CH3:25])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](OC)=[O:16].C(O)(=O)C>C1COCC1.O>[CH3:13][C:14]([CH3:25])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:15](=[O:16])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: CCCCCCC(C)(C)C(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Dimethyl methylphosphonate (7.6 g, 0.061 mol) was dissolved in 70 ml anhydrous THF under argon atmosphere. To the mixture stirred at -78° C. was added dropwise n-butyl lithium (1.44N, 42.4 ml, 0.061 mol). After 30 minutes, methyl 2,2-dimethyloctanoate (4.5 g, 0.024 mol) was further added dropwise. After being stirred for 30 minutes the mixture was warmed to room temperature. To the mixture cooled with ice bath were added 3.8 ml of acetic acid and 10 ml of water. After concentration of the reaction mixture, 20 ml of water was added to the residue and the mixture was extracted with ethyl acetate (50 ml×2). The ethyl acetate layers were washed with water (20 ml×1) and with brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. Distillation of the residue gave dimethyl 3,3-dimethyl-2-oxononanylphosphonate (5.34 g, 0.0192 mol, 79%, b.p. 137° -140° C./0.6 mmHg). The structure of this product was confirmed by the following data.