Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.C(O)(=O)C.C(O)(=O)C(O)=O.[CH2:15]([NH:17][NH2:18])[CH3:16].[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](=O)[C:29]([O:31]C)=O)=[CH:20]1>C(O)C>[CH2:15]([N:17]1[CH:20]=[C:21]2[C:28]([C:29](=[O:31])[NH:19][C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=32)=[N:18]1)[CH3:16]
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Solvent: CCO
Solvent: CC(=O)Cl
Product: CCn1cc2c(n1)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Yield: 67.7 %

Procedure:
Acetyl chloride (19 mL, 273 mmol), acetic acid (30 mL), and ethylhydrazine oxalate (41 g, 272 mmol) were added sequentially to a suspension of methyl 1H-indol-3-yl(oxo)acetate (37 g, 180 mmol) in ethanol (910 mL). The reaction mixture was heated at reflux for 18 hours, cooled to ambient temperature, and concentrated under reduced pressure to a small volume. Dichloromethane (100 mL) and ice were added, and the mixture was adjusted to pH 14 with the addition of 50% w/w sodium hydroxide. A precipitate formed. The dichloromethane was removed under reduced pressure, and the precipitate was isolated by filtration, triturated with hot acetonitrile, and isolated by filtration to provide 26 g of 2-ethyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a tan solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[K+].O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:24]([CH3:27])([CH3:25])[CH3:23])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
[Reference: European Patent Application 87-109919.8 example 85a, page 148 line 22]To a solution of 4'-methyl[1,1'-biphenyl]-2-carboxylic acid (25.0 g, 0.118 mol) in dichloromethane (120 mL) at 0° C. was added oxalyl chloride (2.0 M solution in methylene chloride (470 mL, 0.236 mol) over 30 minutes. The solution was warmed to 25° C., stirred for three hours and concentrated in vacuo to remove excess oxalyl chloride. The remaining residue was suspended in diethyl ether (300 mL), cooled to 0° C. and potassium t-butoxide (26.44 g, 0.236 mol) was added over 15 minutes keeping the temperature of the mixture between 15°-25° C. The mixture was allowed to warm to 25° C. and was stirred for one hour, poured into water (200 mL), and extracted with diethyl ether. The ether extract was then washed with aqueous sodium bicarbonate (saturated solution), dried (magnesium sulfate) and concentrated in vacuo to an amber oil. Subsequent distillation (124°-130° C., 0.6 mm Hg) yielded the title compound as a colorless liquid (27.7 g, 92%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[C:23](O)=[O:24].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:23]([C:14]3[CH:15]=[N:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:13]=3)=[O:24])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cnc2ccccc2n1
Reaction time: 15 h
Yield: 89.3 %

Procedure:
5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.160 g, 0.696 mmol, Example 1, Step H), quinoxaline-2-carboxylic acid (0.254 g, 1.46 mmol), BOP-Cl (0.372 g; 1.46 mmol), and triethylamine (0.352 g, 3.48 mmol) were placed in DCM (5 mL) at room temperature and stirred for 15 hours. 3M aqueous LiOH (3 mL) was then added, and the reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added, and the reaction was filtered. The resulting solid was slurried with 10:1 DCM:MeOH and filtered to give solid N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide (0.240 g, 89% yield).
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:8]1[C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=1)(=O)=O.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[N:37][NH:38][N:39]=2)=[CH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([N:9]2[C@@H:8]([C:20]3[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=3)[C@H:7]([CH2:6][N:37]3[N:38]=[N:39][C:35]([C:32]4[CH:31]=[N:30][C:29]([CH3:28])=[CH:34][CH:33]=4)=[N:36]3)[O:11][C:10]2=[O:12])=[CH:18][CH:17]=1
Reactant: Cc1ccc(-c2nn[nH]n2)cn1
Reactant: CS(=O)(=O)OC[C@@H]1OC(=O)N(c2ccc(Cl)cc2)[C@H]1c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-c2nnn(C[C@@H]3OC(=O)N(c4ccc(Cl)cc4)[C@H]3c3cc(F)cc(F)c3)n2)cn1
Temperature: 90 °C

Procedure:
To a small reaction tube is placed ((4S,5R)-3-(4-chlorophenyl)-4-(3,5-difluorophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate (50 mg, 0.12 mmol), ACN (1 mL), 2-methyl-5-(2H-tetrazol-5-yl)pyridine (39 mg, 0.24 mmol), and potassium carbonate (33 mg, 0.24 mmol). The tube is capped and the reaction is heated to 90° C. for 4 h. The reaction is then quenched with water (2 mL), and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The product is purified by flash chromatography (12 g Redisep, 0-10% MeOH/DCM) to give the title compound. 1H NMR (acetone-d6, 400 MHz) δ 9.18 (br s, 1H), 8.39 (d, J=8.1 Hz, 1H), 7.58 (br s, 1H), 7.47-7.44 (m, 2H), 7.29-7.23 (m, 2H), 7.02 (dddd, J=9.1, 9.1, 2.3, 2.3 Hz, 1H), 5.87 (d, J=5.0 Hz, 1H), 5.54 (dd, J=14.7, 5.8 Hz, 1H), 5.46 (dd, J=14.7, 4.0 Hz, 1H), 5.12 (ddd, J=5.7, 5.1, 4.0 Hz, 1H), 2.65 (s, 3H); HPLC-MS calculated C23H17ClF2N6O2 (M+H+) 483.1, found 483.0.
Reaction SMILES: [C:1]([C:4]([CH3:21])([CH3:20])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8])([OH:3])=[O:2].CC1(C)CCC(=O)OC1=O.[N+](C1C=CC(CO)=CC=1)([O-])=O.[CH3:43][O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49]Cl)=[CH:47][CH:46]=1>CN(C)C=O.O.C(N(CC)CC)C>[CH3:43][O:44][C:45]1[CH:52]=[CH:51][C:48]([CH2:49][O:2][C:1]([C:4]([CH3:21])([CH3:20])[CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])=[O:3])=[CH:47][CH:46]=1
Reactant: CC(C)(CCC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: COc1ccc(CCl)cc1
Agent: CC1(C)CCC(=O)OC1=O
Agent: O=[N+]([O-])c1ccc(CO)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)C(C)(C)CCC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 80 °C
Reaction time: 9.5 h

Procedure:
To a solution of p-nitrobenzyl 4-carboxy-4-methylvalerate (17.26 g) in dry dimethylformamide (100 ml), prepared by the procedure similar to that described in Example 174 from 2,2-dimethylglutaric anhydride and p-nitrobenzyl alcohol, was added p-methoxybenzyl chloride (9.16 g) and triethylamine (5.91 g). The reaction mixture was stirred at 80° C. for 9.5 hours, diluted with water and extracted with diethyl ether. The extract was washed successively with aqueous potassium carbonate, water, dilute hydrochloric acid and again water, dried over anhydrous sodium sulfate and evaporated to give p-nitrobenzyl 4-p-methoxybenzyloxycarbonyl-4-methylvalerate.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]([C:15]([F:21])([F:20])C(F)(F)F)=[N:4]1)C.[F:22]C(F)(F)C1C(C(F)(F)F)=C(C(OCC)=O)NN=1.IC>>[CH3:1][N:3]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([C:11]([F:12])([F:13])[F:14])[C:5]([C:15]([F:20])([F:21])[F:22])=[N:4]1
Reactant: CCn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(F)(F)F
Solvent: CI
Product: Cn1nc(C(F)(F)F)c(C(F)(F)F)c1C(=O)O

Procedure:
1-Methyl-3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylic acid is synthesized analogously to the preparation of 1-ethyl-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid from ethyl 3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylate and iodomethane.
Reaction SMILES: C[C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=C[CH:23]=1>ClCCl>[CH3:23][O:6][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)[CH:2]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(Oc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
A suspension of methyl 3-hydroxybenzoic acid (5.4 g, 35.5 mmol), 3-fluorophenylboronic acid (5.5 g, 35.5 mmol), cupric acetate (7.1 g, 35.5 mmol), 3 A molecular sieves (9 g), pyridine (12 mL, 145 mmol) in dichloromethane (220 mL) was stirred at ambient temperature under ambient atmosphere. After 11 days, the mixture was filtered through Celite® and the volatiles were removed from the filtrate. The 3-(3-fluorophenoxy)benzoic acid methyl ester (3.68 g) was eluted from silica gel column with 5:1 hexane:ethyl acetate and taken onto the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([Sn](C)(C)C)=[CH:22][N:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1ccc([Sn](C)(C)C)cn1
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccc(C)nc3)cccc2c1N
Yield: 76.5 %

Procedure:
Using method C, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.500 mmol) and 2-methyl-5-(trimethylstannyl)pyridine (270 mg, 1.058 mmol) were reacted to afford the title compound (123 mg, 76% yield). 1H NMR (300 MHz, CDCl3) δ 8.75 (bs, 1H), 8.55 (br, 1H), 8.03 (m, 1H), 7.91 (m, 1H), 7.84-7.70 (m, 2H), 7.30 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 2.64 (s, 3H), 1.67 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[OH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:34][C@H:31]3[CH2:32][CH2:33][C@H:28]([OH:27])[CH2:29][CH2:30]3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
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: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1Cl
Reaction time: 8 h

Procedure:
In THF (20 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (180 mg, 0.48 mmol), trans-4-hydroxycyclohexylamine (66 mg, 0.58 mmol) and HATU (220 mg, 0.58 mmol). The solution was cooled in an ice bath and DIEA (0.25 mL, 1.44 mmol) was added then. The reaction was conducted at ambient temperature for 8 h, followed by concentration, addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated and purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(trans-4-hydroxycyclohexanyl)pyrimidine-5-formamide (141 mg, 62% yield).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:10])[CH2:6][C:7](=[NH:9])[NH2:8])[CH3:3].C([O-])C.[Na+].Br[CH2:16][C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=O>C(O)C>[NH2:9][C:7]1[NH:8][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)=[CH:16][C:6]=1[C:5]([O:4][CH2:2][CH3:3])=[O:10]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc3ccccc3c2)[nH]c1N
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, 834 mg (5 mmol) of 2-amidino-acetic acid ethyl ester hydrochloride [for preparation see: Liebigs Ann. Chem., 1895 (1977)] are introduced into 10 ml of ethanol and, at 0-5° C., 358 mg (5 mmol) of sodium ethanolate are added thereto. The bright yellow suspension is stirred for 15 min and then 623 mg (2.5 mmol) of 2-bromo-1-(naphth-2-yl)-ethan-1-one (2-bromo-2'-acetonaphthone; Aldrich; Milwaukee/USA) are added thereto. After 3 days' stirring at RT, the reaction mixture is concentrated by evaporation. The residue is taken up in ethyl acetate/water and filtered and the organic phase is separated off and washed with 3 portions of water and brine. The aqueous phases are extracted with ethyl acetate and the organic phases are dried over MgSO4 and concentrated by evaporation. Column chromatography (SiO2 ; ethyl acetate/hexane [1:1]) and stirring in diethyl ether/hexane yield the title compound; m.p. 149-151° C.; TLC-Rf =0.5 (ethyl acetate/hexane [1:1]); FAB-MS: (M+H)+ =281.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:13]=[CH2:14])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+]>O1CCOCC1.O>[O:12]=[C:9]1[CH2:8][CH2:7][C:6]([CH:13]=[CH2:14])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1
Reactant: C=CC1(C(=O)OCC)CCC(=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CC1(C(=O)O)CCC(=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A solution of the commercially available 4-oxo-1-vinyl-cyclohexanecarboxylic acid ethyl ester (provided by Small Molecules Inc.), (1.20 g, 6.11 mmol) in 1,4-dioxane (20 mL) was treated with a solution of lithium hydroxide monohydrate (734 mg, 30.6 mmol) in water (10 mL). After stirring at 50° C. for 2 h, the volatiles were removed in vacuo. The residue was partitioned between water and diethyl ether. The aqueous layer was acidified to pH 1 by addition of saturated potassium hydrogen sulfate solution and was extracted with ethyl acetate (3×). The organic layer was dried over anhydrous magnesium sulfate, filtered and the volatiles were removed in vacuo to afford the title compound (1.00 g, 97%) as a clear gum. 1H NMR (300 MHz, CDCl3) δ 1.92-2.08 (m, 2H), 2.36-2.59 (m, 6H), 5.34 (d, J=17.5 Hz, 1H), 5.35 (d, J=10.5 Hz, 1H), 5.97 (dd, J=17.5, 10.5 Hz, 1H), 11.30 (br s, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:38])[C@H:31]2[C:46]2[CH:60]=[CH:59][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56](O)=[O:57])=[O:53])=[CH:48][CH:47]=2)=[CH:26][CH:25]=1.CN1CCOCC1.[NH2:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71]>C(Cl)Cl>[F:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:33](=[O:34])[C@H:32]([S:35][CH2:36][CH:37]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)[OH:38])[C@H:31]2[C:46]2[CH:47]=[CH:48][C:49]([O:50][CH2:51][C:52]([NH:54][CH2:55][C:56]([NH:68][C@@H:69]([C:74]([OH:76])=[O:75])[C:70]([CH3:73])([CH3:72])[CH3:71])=[O:57])=[O:53])=[CH:59][CH:60]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
TBTU (0.021 g, 0.067 mmol) was added to a solution of N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycine (0.030 g, 0.056 mmol) and N-methyl morpholine (0.017 g, 0.166 mmol) in CH2Cl2 (5 ml) at 30° C. After 1.5 h, D-tert-leucine (0.011 g, 0.083 mmol) was added. Full conversion to the corresponding amide was obtained after 30 minutes. The reaction was quenched by the addition of water (1 ml). After 10 minutes, MeOH (3 ml) and NaBH (0.042 g, 1.11 mmol) were added. After 5 minutes, the reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). The reaction mixture was concentrated and purified by preparative HPLC using an eluent of 0-50% CH3CN in 0.1M N4OAc buffer. The title compound (0.025 g, 69%) was obtained as a colourless solid. M/z: 654.0 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 0.86 (s, 9H), 2.82-2.98 (m, 2H), 3.76-3.81 (m, 2H), 3.92-3.96 (m, 1H), 4.26-4.33 (m, 1H), 4.52 (s, 2H), 4.68-4.76 (m, 1H), 5.02-5.07 (m, 1H), 6.97-7.37 (m, 12H), 7.58-7.63 (m, 1H), 8.29-8.34 (m, 1H).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)C=CC=CC=1.C([Li])CCC.CCCCCC.[CH3:43][C:44]1([CH3:52])[CH2:49][CH:48]([CH:50]=O)[CH2:47][CH2:46][O:45]1>C1COCC1.CCOCC>[CH3:43][C:44]1([CH3:52])[CH2:49][CH:48](/[CH:50]=[CH:9]/[CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:47][CH2:46][O:45]1
Reactant: c1ccc(COCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC1(C)CC(C=O)CCO1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)CC(/C=C/CCOCc2ccccc2)CCO1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a stirred suspension of triphenyl{3-[(phenylmethyl)oxy]propyl}phosphonium bromide (20.74 g, 42.2 mmol) in THF (60 ml) at −15° C. under a nitrogen atmosphere was added n-butyl lithium, 1.6M in hexane (26.4 ml, 42.2 mmol) dropwise over 30 mins. The orange/red solution was stirred at −10° C. for 30 mins. A solution of 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (6 g, 42.2 mmol) in THF (10 ml) was added dropwise at −10° C. over 25 mins. The reaction mixture was then stirred at −10° C. for 15 mins and then gradually allowed to warm up to room temperature while stirring under nitrogen atmosphere for 16 hours. Ether (10 ml) was added and the suspension was filtered on Celite. The Celite was washed with ether (2×40 mL). The filtrate was concentrated under vacuum. The residue was purified by chromatography on silica (2×100 g) using a cyclohexane:ethyl acetate 0->25% gradient over 40 mins on a Flashmaster II. The fractions were analysed by TLC (revealed with a permanganate dip). The desired fractions were combined and concentrated under vacuum to yield the title compound as a colourless oil (7.46 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A solution of 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) and triethylamine (500 μL, 3.59 mmol) in dichloromethane (30 mL) was cooled to 0° C. Benzoyl chloride (380 μL, 3.26 mmol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature. After several hours the reaction mixture was washed with distilled water (1×50 mL) and brine (2×50 mL), dried over sodium sulfate and then concentrated under reduced pressure to provide 1.5 g of crude orange gooey material. This material was purified by column chromatography (65 g of silica gel, eluting with 7.5% methanol in dichloromethane). The purified material was dissolved in a small amount of dichloromethane and the solution was diluted with hexane to precipitate a white powder. This material was isolated by filtration, washed with hexanes and then dried in a vacuum oven at 60° C. overnight to provide 0.72 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide as a white powder, m.p. 149.5-151.3° C. Analysis: Calculated for C29H37N5O: % C, 73.85; % H, 7.91; % N, 14.85;
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([F:39])([F:38])([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:37][S:34]([F:35])([F:36])([F:38])([F:39])[C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(COCCn2ccnn2)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(C=Cc2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(COCCn4ccnn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
14 mg (0.50 mmol) 95% sodium hydride were given to a solution of 110 mg (0.50 mmol) 4-(2-[1,2,3]Triazol-1-yl-ethoxymethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 173 mg (0.50 mmol) 4-chloromethyl-2-[2-(4-pentafluorosulfanyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 155 mg (59%) colorless powder.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C(N(C(C)C)C(C)C)C.N1(C(N2C=CN=C2)=O)C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]([C@@H:34]2[C@@H:39]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)[N:38]([C@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:37](=[O:55])[C@@H:36]([CH2:56][C:57](O)=[O:58])[CH2:35]2)[CH:31]=[CH:32][CH:33]=1.[NH4+].[Cl-]>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:30]([C@H:34]2[CH2:35][C@H:36]([CH2:56][C:57]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:58])[C:37](=[O:55])[N:38]([C@@H:47]([CH2:53][CH3:54])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C@@H:39]2[C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CS(N)(=O)=O
Reactant: CCOC(=O)[C@@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)NS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanesulfonamide (0.02 g, 0.2 mmol), N-ethyl-N-isopropylpropan-2-amine (0.05 ml, 0.3 mmol), di(1H-imidazol-1-yl)methanone (0.04 g, 0.2 mmol) and 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3, 0.030 g, 0.06 mmol) were combined in 2 mL of THF. After being stirred at 25° C. for 12 h, sat. NH4Cl solution was added and the reaction mixture was extracted with EtOAc. The combined organic layers were successively washed with sat. aq. NaHCO3 solution and sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reversed phase HPLC (10 to 90% AcCN/H2O with 0.1% TFA in 45 min) to give the title compound as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[O:8][C:9](=O)[C:4]=2[CH:3]=1.O.[NH3:18]>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:15][CH:16]=1)[N:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:18][C:9]2=[O:8]
Reactant: O=c1oc(C(F)(F)F)nc2ccc(I)cc12
Reactant: N
Solvent: O
Product: O=c1[nH]c(C(F)(F)F)nc2ccc(I)cc12

Procedure:
6-iodo-2-trifluoromethyl-benzo[d][1,3]oxazin-4-one (0.6 g, 1.76 mmole) was stirred with 25 mL of concentrated ammonia water at 40° C. for 5 h, cooled to 0C, the precipitate was filtered and dried under vacuo. The product was recrystallized from ethyl acetate and haxanes to give 0.58 g, mp >255° C. (sub), MS (CI) m/z 341 (MH)+.