Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[C:40]([F:48])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:45])[F:47])=[C:40]([F:48])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccn1)C(CC1CCCC1)c1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of triphenylphosphine (312 mg, 1.19 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (212 mg, 1.19 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-propionic acid (300 mg, 0.99 mmol). The resulting reaction mixture was stirred at 0° C. for 15 min and then allowed to warn to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-aminopyridine (205 mg, 2.18 mmol). The resulting reaction mixture was stirred at 25° C. for 3 d. The crude reaction mixture was then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide (171 mg, 45%) as a pale yellow foam: mp 40-44° C. (foam to gel); EI-HRMS m/e calcd for C20H20F4N2O (M+) 380.1512, found 380.1519.
Reaction SMILES: C1(CBr)CC1.Br[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:29][CH2:28][NH:27][C:26]2=[O:30])[S:18][C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH:8]1([CH2:7][N:27]2[CH2:28][CH2:29][N:25]([C:17]3[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:15]([CH3:14])[N:16]=3)[C:26]2=[O:30])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCC1CCCCC1
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CCCCC3)C2=O)nc1C
Yield: 76 %

Procedure:
Following the procedure as described in Example 10, making variations as required to replace cyclopropylmethyl bromide with (bromomethyl)cyclohexane to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 76% yield: 1H NMR (300 MHZ, CDCl3) δ 4.27 (q, J=7.2 Hz, 2H), 4.09-3.99 (m, 2H), 3.57-3.40 (m, 2H), 3.11 (d, J=6.9 Hz, 2H), 2.59 (s, 3H), 1.86-1.55 (m, 5H), 1.31-1.11 (m, 7H), 0.97-0.82 (m, 2H); MS (ES+) m/z 352.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3F)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28][OH:29].O>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([F:23])=[C:17]([F:24])[C:16]=3[O:29][CH3:28])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)c(F)c(F)cc2c1O
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(F)c(F)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 140 °C

Procedure:
N-((4-Chlorophenyl)methyl)-4-hydroxy-6,7,8-trifluoro-3-quinolinecarboxamide (366 mg) from Example No. 15 and sodium hydride (60% dispersion, 40 mg) are dissolved in DMF (10 mL) and to the mixture is added methanol (200 μL). Additional sodium hydride (40 mg) is added, and the mixture is heated at 140° C. for 1 h. The reaction mixture is allowed to cool to rt, poured into water (50 mL), acidified with acetic acid (10 mL), and is filtered. The crude product is purified by column chromatography (hexane/2-propanol, 95/5) to afford 68 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19](O)([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[C:13]([CH3:27])[N:12]=1)[CH3:2].O=S(Cl)Cl>N1C=CC=CC=1>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([CH2:23][CH2:24][CH3:25])=[CH:20][CH2:21][CH3:22])=[C:13]([CH3:27])[N:12]=1)[CH3:10]
Reactant: CCCC(O)(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCC=C(CCC)c1c(C)nc(-c2c(CC)cccc2CC)nc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]heptan-4-ol (0.6 g, 1.7 mmol) in anhydrous pyridine (10 mL) is added 1.5 mL of SOCl2 dropwise under nitrogen. The reaction mixture is stirred at room temperature for 3 h, quenched with a saturated aqueous NaHCO3 solution and extracted with DCM. The organic layer is washed with water, brine, dried over Na2SO4, and concentrated. The residue is purified by flash chromatography eluting with 10% EtOAc-hexanes to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 7.24-7.29 (m, 1H), 7.13 (d, J=9 Hz, 2H), 5.39 (t, J=7.5. Hz, 1H), 3.91 (s,3H), 2.46 (s,3H),2.24-2.43 (m, 6H), 1.28-1.33 (m,4H), 1.10 (q, J=7.8, 4.8 Hz, 6H), 0.91 (t, j=7.2 Hz, 6H); LC-MS found 352 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:6]([CH3:7])[CH2:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1>C(#N)C.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][N:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: CC1CN(c2cccnc2)N=C1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC#N
Product: Cc1cn(-c2cccnc2)nc1Cl
Temperature: 22 °C
Reaction time: 20 h
Yield: 0.1 %

Procedure:
To a solution of 3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (1.0 g, 5.0 mol) in acetonitrile (10.0 mL) at 0° C. was added manganese(IV) oxide (1.3 g, 15 mmol) portionwise over 10 minutes. The mixture was slowly warmed to 22° C. over 40 minutes and then heated to 40° C. overnight. After 20 hours, additional manganese(IV) oxide (0.44 g, 5.0 mmol) was added in one portion and the mixture was stirred for 1 hour. The mixture was cooled down and filtered. The filter cake was washed with acetonitrile (3×15 mL). The organic filtrate was dried and concentrated to afford the title compound as a light yellow solid (0.92 g, 95%): 1H NMR (400 MHz, CDCl3) δ 8.90 (dd, J=2.6, 0.8 Hz, 1H), 8.52 (dd, J=4.8, 1.5 Hz, 1H), 7.99 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.74 (q, J=0.9 Hz, 1H), 7.39 (ddd, J=8.3, 4.8, 0.8 Hz, 1H), 2.13 (d, J=0.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 147.26, 142.87, 139.53, 135.90, 126.53, 125.69, 123.84, 116.86, 22.47; EIMS m/z 193 ([M]+).
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]1=[O:15])([CH2:3][CH3:4])[CH3:2].[OH-].[Li+]>O1CCCC1.CO.O>[CH:1]([N:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]1=[O:15])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)n1ccc(C(=O)OC)cc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)n1ccc(C(=O)O)cc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.2 %

Procedure:
To a solution of methyl 1-sec-butyl-2-oxo-1,2-dihydropyridine-4-carboxylate (209 mg, 1 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added lithium hydroxide (120 mg, 5 mmol) in water (7 mL), then stirred at room temperature for 12 hour, the reaction mixture was concentrated, to the residue was added water (10 mL), acidified with hydrochloric acid to PH=4, collected and dried the solid to give 1-sec-butyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (98 mg, 50%). LRMS (M+H+) m/z: calcd for 195.09. found 195.
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=1.ClN1[C:19](=[O:20])CCC1=O.CO.C[O-].[Na+].[H-].[Na+].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][N:8]1[C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:3]=[C:2]1[CH2:1][O:20][CH3:19]
Reactant: BrCCCCBr
Reactant: CC1=COc2ccccc2C(=O)N1
Reactant: O=C1CCC(=O)N1Cl
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: COCC1=COc2ccccc2C(=O)N1CCCCBr
Reaction time: 0.5 h

Procedure:
1.0 g of 4,5-dihydro-3-methyl-1,4-benzoxazepin-5-one was dissolved in 30 ml of carbon tetrachloride, 910 mg (1.2 equivalents) of N-chlorosuccinimide was added, and the resultant mixture was agitated at 90° C. for 1 hour. This was allowed to cool, then was filtered, the filtrate was concentrated, then the resultant mixture was dissolved in 20 ml of methanol. Further, 0.86 ml (1.1 equivalents) of a methanol solution of 28% sodium methylate was added, then the resultant mixture was agitated at room temperature for 40 minutes. This was concentrated, then water was added, and extraction was performed with methylene chloride. This methylene chloride extract was washed with water and saturated saline and was dried by anhydrous magnesium sulfate, then concentrated. 368 mg of the residue was dissolved in 15 ml of dimethylformamide, then 87 mg (1.2 equivalents) of 60% sodium hydride was added under ice cooling. This was agitated for 30 minutes, then 0.64 ml (1.2 equivalents) of 1,4-dibromobutane was added, then the resultant mixture was agitated at room temperature for 3 hours.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:20]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: CC(C)(C)c1ccc(-c2ccc(O)cc2)cc1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester Example 283, Step 2) and 4′-tert-butyl-biphenyl-4-ol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[ClH:5].[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: ClCCCBr
Solvent: Cc1ccccc1
Product: Cl
Product: ClCCCN1CCCC1
Temperature: 42.5 °C
Yield: 221.9 %

Procedure:
A solution of 1-bromo-3-chloropropane (99.5 kg) in toluene (237 kg) was heated to 40-45° C. To this solution was added pyrrolidine (94.5 kg) over 1.5 hours, maintaining the temperature at 40-45° C. A line wash of toluene (37 kg) was applied and the reaction maintained at 40-45° C. for a further four hours. The reaction mixture was cooled to 20-25° C. and washed with water (211 kg). Further water (138 kg) was added and the pH adjusted to 8.8-9.0 by the addition of 34% w/w hydrochloric acid (4.7 kg). The aqueous phase was separated and discarded. To the organic phase was added 34% w/w hydrochloric acid (61 kg) until the pH was 0.5-1.0. The aqueous was separated and concentrated under vacuum, maintaining the temperature <50° C. until the toluene content was <0.1%, giving an aqueous solution of 1-(3-chloropropyl)pyrrolidine hydrochloride 129.1 kg at 71.5% w/w, 79.9%
Reaction SMILES: [Br-].[C:2]1([S+:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]12[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.[C:32]([O:35][CH:36]([CH3:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[S:39]([O-:42])(=[O:41])=[O:40])(=[O:34])[CH3:33].[Na].O>ClCCl>[OH:21][C:22]12[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][C:26]([CH2:33][C:32]([O:35][CH:36]([CH3:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[S:39]([O-:42])(=[O:41])=[O:40])=[O:34])([CH2:25]3)[CH2:31]1)[CH2:29]2.[C:2]1([S+:8]2[C:9]3[CH:20]=[CH:19][CH:18]=[CH:17][C:10]=3[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)OC(C)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Agent: [Br-]
Agent: [Na]
Agent: c1ccc(-[s+]2c3ccccc3c3ccccc32)cc1
Solvent: ClCCl
Solvent: O
Product: CC(OC(=O)CC12CC3CC(CC(O)(C3)C1)C2)C(F)(F)C(F)(F)S(=O)(=O)[O-]
Yield: 97 %

Procedure:
5-phenyl-5H-dibenzo[b,d]thiophenium bromide (28.0 g, 82.04 mmol) and 3-hydroxyadamantane-acetoxy-1,1,2,2-tetrafluorobutane-1-sulfonate-sodium salt (35.68 g, 83.7 mmol) were dissolved in dichloromethane (500 mL) and water (500 mL) and stirred at r.t. for 16 h. The dichloromethane layer was separated and the aqueous phase washed with dichloromethane (3×300 mL). The combined organic layers were washed with water (4×500 mL), concentrated in vacuo and residual water removed via azeotrope with acetonitrile (2×350 mL) to afford the title compound (54.00 g, 99%) as a white solid. 1H NMR (500 MHz, (CD3)2CO) δ: 8.55 (d, J=8 Hz, 2H), 8.41 (d, J=8 Hz, 2H), 8.02 (dt, J=7.5, 0.5 Hz, 2H), 7.77-7.84 (m, 5H), 7.67 (t, J=7.5 Hz, 2H), 4.31 (t, J=6.5 Hz, 2H), 3.63 (s, 10H), 2.71 (tt, J=14, 6.5 Hz, 2H), 1.52-1.80 (m, 12H).
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17](Cl)=[O:18]>O1CCCC1.C(N(CC)CC)C>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:16]=1[C:17]([NH:9][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([C:3]([F:12])([F:13])[F:2])=[CH:5][CH:6]=1)=[O:18]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1c(Cl)cccc1Cl

Procedure:
To 21.1 g (0.1 mole) of 4-trifluoromethylbenzylamine hydrochloride was added 20.9 g (0.10 mole) of 2,6-dichlorobenzoyl chloride in 200 ml of tetrahydrofuran. Then was added in 1 portion 30 ml triethylamine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:3][CH:2]=1.I[CH2:17][CH2:18][CH:19]1[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1>>[CH2:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:19]1[CH2:18][CH2:17][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:5][CH2:6]1
Reactant: c1ccc2[nH]c(-c3ccncc3)cc2c1
Reactant: ICCC1Cc2ccccc2C1
Product: C1=C(c2cc3ccccc3[nH]2)CCN(CCC2Cc3ccccc3C2)C1

Procedure:
Prepared from 27a and 24a. Mp 175-176  C. 1H NMR (CDCl3) δ1.75-1.85 (m, 2H), 2.45-2.55 (m, 1H), 2.55-2.60 (m, 2H), 2.60-2.70 (m, 4H), 2.70-2.80 (m, 2H), 3.05-3.15 (m, 2H), 3.25 (broad s, 2H), 6.05 (broad s, 1H), 6.45 (s, 1H), 7.05 (t, 1H), 7.10-7.25 (m, 5H), 7.35 (d, 1H), 7.55 (d, 1H), 8.10 (broad s, 1H). MS m/z (%): 343 (MH+, 8%), 174 (32%), 143 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[O:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:29])[F:30])[CH:21]=2)=[S:27])=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Reactant: Nc1ccc(Sc2nc3ccccc3o2)cc1
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3nc4ccccc4o3)cc2)ccc1Cl
Yield: 0 %

Procedure:
2-(4-Aminophenylthio)benzoxazole (10.0 moles, 2.6 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (10.0 moles, 2.4 g) were reacted according to procedure A to yield of the title compound 1.6 g, 33%. Mass Spec (FD) 479. Calculated for C21H13ClF3N3OS2 : C, 52.56; H, 2.73; N, 8.75. Found: C, 52.47; H, 2.70; N, 8.48.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[I:30])[CH2:5][C@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7](=O)[NH:8][CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=O)C.[NH4+:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:6]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]2[NH:35][C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:8]=2)[CH:27]=[CH:28][C:29]=1[I:30]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)C(=O)NCC(=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)c(Cl)c1)c1ncc(-c2ccccc2)[nH]1
Temperature: 120 °C
Yield: 67 %

Procedure:
tert-Butyl (1S)-1-(3-chloro-4-iodobenzyl)-2-oxo-2-[(2-oxo-2-phenylethyl)-amino]ethylcarbamate (3.1 g, 5.7 mmol) and ammonium acetate (30.0 g, 0.389 mol) were dissolved in DMF (50 mL). The solution was separated into 6 batches, and each batch was heated in the microwave at 120° C. for 30 minutes. The solution was diluted with ethyl acetate (600 mL) and washed with water (600 mL). After the organic layer was dried over sodium sulfate, the solution was concentrated. Purification by silica gel chromatography (20–40% ethyl acetate:hexanes) afforded product as a white solid (2.0 g, 67%). 1H NMR (400 MHz, CD3OD): δ 7.86–7.78 (m, 2H), 7.73–7.68 (m, 2H), 7.59–7.50 (m, 3H), 7.40–7.37 (m, 1H), 6.89–6.87 (m, 1H), 5.13–5.11 (m, 1H), 3.40–3.25 (m, 2H), 1.38 (s, 9H). LCMS found for C22H24ClIN3O2 (M+H)+: m/z=524.
Reaction SMILES: CN(C)C=O.[C:6]([O:15][CH2:16][CH3:17])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O.C(OCC)(=O)C>[CH2:16]([O:15][C:6](=[O:14])[C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[O:9][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[CH3:17]
Reactant: CCOC(=O)c1ccccc1O
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOc1ccccc1C(=O)OCC
Reaction time: 0.5 h

Procedure:
200 ml of N,N-dimethylformamide was added to 18.3 g of ethyl salicylate, and 34.5 g of potassium carbonate and 24.9 g of lauryl bromide were added thereto dropwise over about 30 min with stirring on a steam bath. After the addition the reaction mixture was heated for 2 hours with stirring, then after cooling it was transferred into a separately funnel, and 300 ml of ethyl acetate and 1l of water were added for extraction. The ethyl acetate solution was washed with dilute hydrochloric acid and then with an aqueous sodium hydrogencarbonate solution and was concentrated, to obtain an oil of 2-dodecyloxybenzoic acid ethyl ester. The oil was dissolved in 300 ml of ethanol, and a solution of 12 g of sodium hydroxide in 50 ml of water was added dropwise thereto over about 10 min at room temperature with stirring. After the addition stirring was continued for 1 hour further and 30 ml of concentrated hydrochloric acid diluted with 300 ml of water was added dropwise. The deposited crystals were filtered, washed with water, and dried to obtain 29.1 g of 2-dodecyloxybenzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH:11]=O)=[O:8].Cl.[NH2:16][OH:17].[C:18]([O-:21])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH2:10][CH2:11][N:16]([CH:18]=[O:21])[OH:17])=[O:8]
Reactant: CC(=O)[O-]
Reactant: NO
Reactant: O=CCNC(=O)c1cc(Br)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=CN(O)CCNC(=O)c1cc(Br)ccc1Cl
Reaction time: 18 h
Yield: 85.6 %

Procedure:
To a solution of 5-bromo-2-chloro-N-(2-oxo-ethyl)-benzamide (11.8 g, 42.5 mmol) in MeOH (400 mL) was added hydroxylamine hydrochloride (5.9 g, 85 mmol) and sodium acetate (6.97 g, 85 mmol). The mixture was stirred 18 h and the MeOH was removed in vacuo. The residue was washed with water and was dried in vacuo for 18 h and used without further purification to provide the title compound (11.7 g, 94%) as a white solid. ESMS: M+H=291.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([C:13]([O:15]CC)=[O:14])[CH:4]=1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].O.[OH-].[Li+]>C(Cl)Cl.O1CCCC1.O>[CH2:18]([N:20]([CH2:2][C:3]1[N:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[N:6]=[C:5]([C:13]([OH:15])=[O:14])[CH:4]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: CCNCC
Reactant: CCOC(=O)c1cc(CBr)nc(C(F)(F)F)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN(CC)Cc1cc(C(=O)O)nc(C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 6-(bromomethyl)-2-(trifluoromethyl)pyrimidine-4-carboxylate (0.15 g, 0.32 mmol, prepared as in Example 5, Step A) in methylene chloride (3.0 mL) was added N-ethylethanamine (0.13 mL, 1.3 mmol). After 30 minutes, the solvent was removed in vacuo. The ester was hydrolyzed by stirring with lithium hydroxide monohydrate (0.12 g, 3.0 mmol) in a mixture of tetrahydrofuran (5 mL) and water (2 mL). After 1 hour, 1N HCl was added dropwise to neutralize. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as a light yellow solid. Yield: 0.050 g (60%); LC-MS: 278.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 7.97 (s, 1H), 3.74 (s, 2H), 2.52 (q, 4H), 0.99 (t, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][C@@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][C@@H:10]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][N:7]1[C:30](=[O:31])[CH2:29][NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)[C@H]1C[C@@H](CP(=O)(OCC)OCC)CCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H](CP(=O)(OCC)OCC)CCN1C(=O)CNC(=O)OC(C)(C)C

Procedure:
A solution of 1.0 g of cis 4-diethylphosphonomethyl-2-piperidinecarboxylic acid ethyl ester is reacted with 552 mg of N-t-butoxycarbonylglycine in the presence of N,N'-dicyclohexyl-carbodiimide in 10 ml of methylene chloride of room temperature for 16 hours to yield cis 1-[alpha-(t-butoxycarbonylamino)acetyl]-4-diethylphosphonomethyl-2-piperidinecarboxylic acid ethyl ester as an oil. Treatment with trimethylsilyl iodide yields cis 1-(alpha-aminoacetyl)-4-phosphonomethyl-2-piperidinecarboxylic acid ethyl ester, m.p. 150°-155° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH2:5]P(=O)([O-])[O-].[Li]CCCC.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)CCCC#C>C1COCC1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([CH:5]=[CH:23][CH2:22][CH2:21][CH2:20][C:19]#[CH:18])[CH:3]=1
Reactant: O=P([O-])([O-])Cc1cccc(Cl)c1
Reactant: CCCCCC
Agent: C#CCCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCC=Cc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
An oven-dried 250 mL three-necked round-bottomed flask under a nitrogen atmosphere was charged with 3-chlorobenzylphosphonate S6 (4.74 g, 18 mmol) and THF (60 mL). The solution was cooled to 0° C. in an ice bath for 15 min, then n-BuLi (12 mL of a 1.6 M n-hexane solution, 19 mmol) was added dropwise over 10 min via syringe. The mixture was stirred at 0° C. for 30 min, then aldehyde 4 (1.0 g, 10 mmol) in THF (40 mL) was added. The reaction was warmed to rt and was stirred for 3 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:9). The reaction was quenched by adding sat'd aq ammonium chloride solution (70 mL). The layers were separated and the aqueous phase was extracted with ether (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried over Na2SO4, gravity filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 0.5:9.5, to provide 1.9 g of the title compound as a colorless oil in a 93% yield.