Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].Br[CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1.O>O1CCCC1>[CH2:3]([O:7][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C=CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCOCc1ccc(C(=O)O)cc1

Procedure:
To the suspension of sodium hydride (1.390 g, 95%, 55 mmol) in tetrahydrofuran (150 ml), But-3-en-1-ol (3.966 g, 4.7 ml, 55 mmol) was added. After the reaction mixture was refluxed for 30 min, 4-Bromomethyl-benzoic acid (5.376 g, 25 mmol) was added and the reaction was kept to reflux for additional 10 h. After cooling down, water (100 ml) was added and the tetrahydrofuran was removed under vacuum. This resulting aqueous solution was adjusted with 6N HCl to pH 2 at 5° C. to generate white precipitate, which was then collected by filtration. The recrystallization of this crude product from hexane/ether yielded pure 4-But-3-enyloxymethyl-benzoic acid as colorless crystal (4.15 g, 80.5%). 1H-NMR (400 MHz, d6-DMSO): 7.91 (d, J=8.2, 2 arom. H); 7.41 (J=8, 2 arom. H); 5.81 (m, —CH═CH2); 5.10 (2 d-like, —CH═CH2); 4.53 (s, —OCH2—C6H4); 3.49 (m, CH2═CH—CH2CH2O); 2.32 (m, CH2═CH—CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.14 (—C═O); 143.72; 135.49; 129.73; 129.28 (2 arom. C); 127.08 (2 arom. C); 116.46; 71.13; 69.18.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21]1([C@H:27]([N:29]2[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]2)[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]2([OH:35])[CH2:33][CH2:34][N:29]([C@@H:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:28])[CH2:30][CH2:31]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: C[C@H](c1ccccc1)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@H](c1ccccc1)N1CCC(O)(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: -75 °C
Reaction time: 1 h
Yield: 121.8 %

Procedure:
175.2 g (666 mmol) 4-benzyloxybromobenzene was dissolved in 1.4 L dry THF (MS 4 A) under argon. The solution was cooled to −75° C. and a solution of 416 mL 1.6 M butyllithium (666 mmol) in hexane was added during 40 minutes. After stirring for 1 hour a solution of 113 g (555 mmol) (R)-1-(1-phenyl-ethyl)-piperidin-4-one in 400 mL THF was added during 1hour at −75° C. The mixture was stirred for another 1 hour and, after heating to room temperature, poured into 1.5 L of ice-water. The mixture was extracted with 1 L ethyl acetate. The organic phase was washed with 1 L of a half-saturated NaCl solution, dried over Na2SO4 and concentrated to yield 262 g of (R)-4-(4-benzyloxy-phenyl)-1-(1-phenyl-ethyl)-piperidin-4-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[O:16][CH2:15][C@@H:14]([S:17]C(=O)C)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C@@H:12]2[O:16][CH2:15][C@@H:14]([SH:17])[CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)S[C@@H]1CO[C@@H](CS(=O)(=O)c2ccc(F)cc2)C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=S(=O)(C[C@H]1C[C@H](S)CO1)c1ccc(F)cc1
Yield: 63.1 %

Procedure:
The title compound is prepared by the procedure of Example 16 using 0.955 g of product from Example 31, 0.72 ml of 25% sodium methoxide/methyl alcohol and 10 ml of tetrahydrofuran to give 0.523 g of the desired product.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36]([NH2:39])[CH2:37][CH3:38]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:39][CH2:36][CH2:37][CH3:38])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCN
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CCCNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 1.00 mmol) and propylamine (175 mg, 3.00 mmol) as starting materials.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH:21]([CH2:25][CH2:26][CH:27]([N:31]2[CH2:42][CH2:41][N:40]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35][N:34]([CH2:47][C:48]([OH:50])=[O:49])[CH2:33][CH2:32]2)[C:28]([OH:30])=[O:29])[C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[OH-:51].[K+].[CH2:53]1[O:55][CH:54]1[CH2:56][OH:57]>O>[OH:55][CH:54]([CH2:56][OH:57])[CH2:53][N:37]1[CH2:36][CH2:35][N:34]([CH2:47][C:48]([OH:50])=[O:49])[CH2:33][CH2:32][N:31]([CH:27]([CH2:26][CH2:25][CH:21]([N:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15][N:14]([CH2:53][CH:54]([OH:55])[CH2:56][OH:51])[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9]2)[C:22]([OH:24])=[O:23])[C:28]([OH:30])=[O:29])[CH2:42][CH2:41][N:40]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][CH2:38]1
Reactant: OCC1CO1
Reactant: [OH-]
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(C(CCC(C(=O)O)N2CCN(CC(=O)O)CCNCCN(CC(=O)O)CC2)C(=O)O)CC1
Agent: [K+]
Solvent: O
Product: O=C(O)CN1CCN(CC(O)CO)CCN(CC(=O)O)CCN(C(CCC(C(=O)O)N2CCN(CC(=O)O)CCN(CC(O)CO)CCN(CC(=O)O)CC2)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 75 %

Procedure:
The amine of Example 5 (1.0 g; 1.4 mmol) was dissolved in water (5 ml) and the pH adjusted to 11.5 using 1N KOH solution. Glycidol was added in five aliquots of 140 μL each over a five day period. Throughout, the system was maintained at ambient temperature under nitrogen with continuous stirring. After five days, the reaction mixture was adjusted to pH 12 and loaded on to a bed of AG1-X8 ion exchange resin (80 mL, OAc-form). After rinsing with water (1.9 L), the target compound was eluted from the column using 0.5N acetic acid solution. After repeated concentration from water to remove the acetic acid, the material was lyophilized to yield 0.9 g (75%) of material. This was then further purified by preparative HPLC to yield the title compound as a white solid. 1H NMR (D2O) δ 3.51 (br), 3.25 (br), 3.11 (br), 2.89 (br), 2.67 (br), 1.66 (br, 4H). 13C NMR (D2O, 365° K): 178.16, 177.99, 177.93, 177.83, 175.34, 175.10, 174.99, 72.44, 72.28, 72.19, 71.81, 67.94, 67.84, 67.48, 67.34, 66.91, 66.81, 60.01, 59.87, 59.57, 59.36, 54.57, 54.39, 54.29, 53.50, 50.36, 50.24, 29.31, 29.09, 28.71. MS (FAB): m/E 867.7 (MH+). Anal. Calcd for C36H60N8O16 8H2O: C, 43.02; H, 8.62; N, 11.18. Found C, 43.15; H, 8.15; N, 11.18.
Reaction SMILES: [Br:1][CH2:2][N+:3]([O-:5])=[O:4].[CH2:6]=[O:7].Cl.[CH3:9][OH:10]>>[CH2:9]([OH:10])[C:2]([Br:1])([N+:3]([O-:5])=[O:4])[CH2:6][OH:7]
Reactant: C=O
Reactant: O=[N+]([O-])CBr
Reactant: CO
Agent: Cl
Product: O=[N+]([O-])C(Br)(CO)CO
Temperature: 18 °C
Reaction time: 3 h

Procedure:
In each of the examples, a solution of 40.0 g (0.29 mole) monobromonitromethane and 70 ml of methanol was added in 18 minutes to a 55% formaldehyde solution in methanol maintained at 18° C. and containing various levels of alkaline catalyst. The reaction temperature was allowed to rise to 30° C. during the addition. Following the addition, the solution was heated to 60° C. and held there for three hours. The solution was then cooled to 20° C. and the pH adjusted to 4.3 with 1.0 molar aqueous HCl. The specific catalysts and amounts used thereof, as well as the resulting yields of bronopol, are set forth in the table below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:34]=[C:35]([NH:39][C:20]([C:19]3[CH:18]=[N:17][N:11]4[C:12]([CH:14]([F:15])[F:16])=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:9][C:10]=34)=[O:21])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:26][CH2:25]1
Reactant: CN1CCN(S(=O)(=O)c2cccc(N)c2)CC1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: CN1CCN(S(=O)(=O)c2cccc(NC(=O)c3cnn4c(C(F)F)cc(-c5ccc(Cl)cc5)nc34)c2)CC1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.3) and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine [CAS 436095-35-1] according to general procedure II. Yellow solid. MS (ISP) 561.5 [(M+H)+]; mp 147° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH2:14][C:15](O)=[O:16])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:22]=2[N:23]=1.Cl.[CH3:33][O:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:33][O:34][C@H:35]1[CH2:40][CH2:39][CH2:38][N:37]([C:15](=[O:16])[CH2:14][NH:13][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:18][C:19]4[S:20][C:21]5[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][C:22]=5[N:23]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:36]1
Reactant: Cn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: CO[C@H]1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CCCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(C(F)(F)F)cc4s2)n3C)C1
Yield: 63.3 %

Procedure:
1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-((S)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]amide (77 mg) was prepared by following General Procedure F starting from {[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (100 mg), (S)-3-methoxy-piperidine hydrochloride (37 mg), HBTU (101 mg), and DIEA (58 uL), with a modification of General Procedure F where DIEA was slowly added to the reaction mixture as the last reagent. LC/MS: m/z 546.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.51 (bs, 1H), 8.57-8.47 (m, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.89-7.66 (m, 3H), 7.54 (d, 1H), 4.33-4.15 (m, 1H), 4.15-4.00 (m, 1H), 3.81-3.56 (m, 4H), 3.55-3.44 (m, 1H), 3.43-3.18 (m, 6H), 2.01-1.21 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22].Cl>CC(C)=O.O>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([NH:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)=[O:22]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)c1c(Cl)cccc1Cl
Temperature: 10 °C
Yield: 97.5 %

Procedure:
200 mL of water and 91 mL of acetone were mixed and 72.4 g (344 mmol) of 4-nitro-L-phenylalanine was added thereto and cooled down to 10° C. or lower. 68 mL of 6M sodium hydroxide aqueous solution was added dropwise to the solution so that the temperature thereof did not exceed 15° C. Keeping around pH 14, 73.58 g (344 mmol) of 2,6-dichlorobenzoyl chloride was slowly added dropwise thereto. In order to keep around pH 14, if needed, a sodium hydroxide aqueous solution was added dropwise. 2 hours later of completion of drop, 86 mL of 6M hydrochloric acid was added with keeping the temperature of the reaction solution at 15° C. or lower to precipitate white crystals. After maturing at 10° C. or lower, the crystals were separated, dried under reduced pressure at 60° C. to obtain 128.5 g of Nα-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine. (Yield: 97%) 1H NMR (400 MHz, DMSO-d6): 9.12 (d, 1H, J=8.42 Hz), 8.16 (d, 2H, J=8.78 Hz), 7.59 (d, J=8.77 Hz), 7.42 (m, 3H), 3.29 (m), 3.07 (dd, 1H, J=3.64 and 10.42 Hz). 13C NMR (100 MHz, DMSO-d6): 172.25, 163.74, 146.68, 146.18, 131.51, 131.37, 131.05, 128.37, 123.55, 53.17, 36.74.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:13])[C:11]=1[O:12][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1c(Cl)cc(C(=O)OC)cc1Cl
Reaction time: 8 h

Procedure:
Methyl 3,5-dichloro-4-hydroxybenzoate, (173, 0.78 mol), 1-bromododecane (234 g, 0.94 mol) and potassium carbonate (130 g, 0.94 g) in DMF (1000 mL) were heated to 70° C. with good stirring for about 8 hrs. The reaction was cooled and treated with 2N-HCl to neutralize the excess potassium carbonate. The mixture was then extracted with ethyl acetate. The ethyl acetate was washed with 2N-HCl(×3), dried (MgSO4), filtered and concentrated to give an oil. This oil was taken on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.CS(C)=O.C(N(CC)CC)C>O>[CH3:1][O:2][C:3]1[C:4]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH:9]=[O:10]
Reactant: CCCCCOc1c(CO)cccc1OC
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCOc1c(C=O)cccc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
The crude product of (3-methoxy-2-pentyloxyphenyl)methanol (1.2 g), dimethyl sulfoxide (DMSO, 25 ml) and triethylamine (6.72 ml, 48.2 mmol) were mixed, and this solution was cooled to 0° C. Sulfur trioxide--pyridine complex (2.56 g, 16.1 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water to stop the reaction, and the aqueous layer was extracted 3 times with ethyl acetate (30 ml). The organic layers were combined, washed with 2N hydrochloric acid (30 ml), water (30 ml) and saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=15/1-10/1) to give 3-methoxy-2-pentyloxybenzaldehyde (1.16 g, 83% in 3 steps) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:26][C:27]1[C:32]([NH2:33])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[NH2:33][C:32]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[F:26]
Reactant: CC1(C)OB(c2cnc(F)c(N)c2)OC1(C)C
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(F)c(N)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (stage 149.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.53 min (Method A); M+H=485 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.20 (s, 1H), 8.12-8.08 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.44 (m, 1H), 7.29-7.23 (m, 2H), 5.57 (s, br, 2H), 4.54 (hp, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.44 (d, 6H))
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(-c4ccccc4)cc3)nc12
Temperature: 80 °C
Yield: 78.7 %

Procedure:
To a mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (30 mg, 0.063 mmol), phenylboronic acid (12 mg, 0.098 mmol), 2 M Na2CO3 (2 mL) and toluene (2 mL) was deoxygenated with nitrogen for 10 min, and then tetrakis(triphenylphosphine)palladium(0) (7.3 mg, 0.0063 mmol) was added. The resulting mixture was heated at 80° C. under nitrogen overnight, and then was cooled to room temperature, quenched with saturated sodium bicarbonate, extracted with methylene chloride. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-biphenyl-4-ylbenzoxazole-4-carboxamide (21 mg, 78%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.60 (d, J=7.0 Hz, 1H), 8.31 (d, J=8.0 Hz, 2H), 8.21 (d, J=7.5 Hz, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.74 (d, J=7.5 Hz, 1H), 7.69-7.67 (m, 2H), 7.52-7.42 (m, 4H), 4.36-4.30 (m, 1H), 3.53 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.17-2.84 (m, 5H), 2.19-2.10 (m, 2H), 1.80-1.63 (m, 3H); MS (ESI+) m/z 424 (M+H); HPLC 96.3% (AUC), tR=14.01 min.
Reaction SMILES: [F:1][C:2]([F:12])([C:9]([OH:11])=[O:10])[C:3]([F:8])([F:7])[C:4]([OH:6])=[O:5].C(=O)(O)O.[NH2:17][C:18]([NH2:20])=[NH:19].C(=O)=O>O>[F:1][C:2]([F:12])([C:9]([O-:11])=[O:10])[C:3]([F:7])([F:8])[C:4]([O-:6])=[O:5].[NH2:19][C:18]([NH2:20])=[NH2+:17].[NH2:19][C:18]([NH2:20])=[NH2+:17]
Reactant: O=C(O)C(F)(F)C(F)(F)C(=O)O
Reactant: N=C(N)N
Agent: O=C(O)O
Agent: O=C=O
Solvent: O
Product: NC(N)=[NH2+]
Product: O=C([O-])C(F)(F)C(F)(F)C(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tetrafluorosuccinic acid (500 mg, 2.63 mmol) was dissolved in 10 ml of distilled water. Guanidine carbonate (474 mg, 2.63 mmol) was added at room temperature (carbon dioxide gas was evolved) and the reaction was stirred at room temperature for 2 hours. The water was removed in vacuo with heating to approximately 90° C. for 4 hours. The product was isolated as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4]([CH:6]=[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[C:13]([CH:19]=1)[O:14][CH2:15][C:16]([OH:18])=[O:17])[CH3:8])=[O:5])[CH3:2].[CH:31](O)([CH3:33])[CH3:32].Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](/[CH:6]=[C:7](/[C:9]1[CH:10]=[CH:11][C:12]([O:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])=[C:13]([CH:19]=1)[O:14][CH2:15][C:16]([O:18][CH:31]([CH3:33])[CH3:32])=[O:17])\[CH3:8])=[O:5])[CH3:30]
Reactant: CC(C)O
Reactant: CCN(CC)C(=O)C=C(C)c1ccc(OC(C)c2ccccc2)c(OCC(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)/C=C(\C)c1ccc(OC(C)c2ccccc2)c(OCC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of [5-(2-diethycarbamoyl-1-methylvinyl)-2-(1-phenylethoxy)-phenoxy]-acetic acid (300 mg, 0.97 mmol), 4-dimethylaminopyridine (12 mg, 0.097 mmol) and isopropanol (117 mg, 1.95 mmol) in methylene chloride (30 mL) is cooled to 0° C., and 1-(3-dimethylaminopropyl)-3-etbylcarbodiimide.HCl (205 mg, 1.07 mmol) is added in one portion. The mixture is then allowed to stir at room temperature for 18 hours. After washing with water (50 ml), the organic layer is washed with saturated NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. Chromatography (silica, 1:1 EtOAc/hexane) yields isopropyl (E)-[5-(2-diethylcarbamoyl-1-methylvinyl)-2-(1-phenylethoxy)-phenoxy]-acetate MS: 454 (M++1), 350 (M+-PhCHCH3+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]2[CH2:39][CH2:38][C@@H:37]([CH2:40][C:41](O)=[O:42])[N:29]3[C:30](=[O:36])[C:31](=[O:35])[NH:32][C:33]([CH:34]=1)=[C:28]23>>[Br:24][C:25]1[CH:26]=[C:27]2[CH2:39][CH2:38][C@@H:37]([CH2:40][C:41](=[O:42])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=3[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[N:29]3[C:30](=[O:36])[C:31](=[O:35])[NH:32][C:33]([CH:34]=1)=[C:28]23
Reactant: COC(=O)CCCc1cc(CNC(=O)OC(C)(C)C)ccc1N
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: COC(=O)CCCc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 45.8 %

Procedure:
A procedure similar to that described in Example 9-7) was performed with 4-tert-butoxycarbonylaminomethyl-2-(3-methoxycarbonylpropyl)aniline (130 mg, 0.4 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (136 mg, 0.4 mmol) to give 118 mg of the title compound (62%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(=O)(O)[O-].[Na+].C(OCC)(=O)C.[CH3:28][N:29](C)C=O>>[C:28]([C:2]1[CH:3]=[C:4]([C:11]2([CH3:16])[O:15][CH2:14][CH2:13][O:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])#[N:29]
Reactant: CC1(c2ccc([N+](=O)[O-])c(Cl)c2)OCCO1
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC1(c2ccc([N+](=O)[O-])c(C#N)c2)OCCO1

Procedure:
A mixture of 2-(3-chloro-4-nitrophenyl)-2-methyl-1,3-dioxolane (9.8 g) and cuprous cyanide (4.0 g) in N,N-dimethylformamide (20 ml) was stirred and refluxed for 11 hours. An aqueous solution of sodium bicarbonate (200 ml) and ethyl acetate (100 ml) were added to the reaction mixture. The mixture was stirred and filtered. The filtrate was separated and the organic layer was dried and evaporated. The oily residue was purified by column chromatography on silica gel (200 g) eluting with a mixture of toluene and ethyl acetate (20:1) to give yellow plates of 2-(3-cyano-4-nitrophenyl)-2-methyl-1,3-dioxolane (4.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[N+]([C:15]1C=CC=CC=1S(Cl)(=O)=O)([O-])=O.IC.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)CS>C(N(CC)CC)C>[CH3:15][NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(N)c1
Agent: O=C(O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCN(CC)CC
Product: CNc1cccc(NC(C)=O)c1

Procedure:
N-(3-Aminophenyl)acetamide was treated with 2-nitrophenylsulfonyl chloride in the presence of triethylamine and then the resulting compound was treated with iodomethane and potassium carbonate. Thereafter, the product was treated with thioglycolic acid to obtain N-[3-(methylamino)phenyl]acetamide.