Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9]CC)=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl>[OH-].[Na+]>[C:1]([CH2:6][C:7]([OH:9])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl isobutyrylacetate (20.47 g, 129 mmol) and 1.5 M aq NaOH (250 mL) is stirred at room temperature overnight. The solution is then cooled to 0° C. and acidified to pH 1-2 by the slow addition of conc. HCl (˜35 mL). The solution is then saturated with NaCl and extracted thrice with EtOAc and once with CHCl3. The combined extracts are dried over Na2SO4 and concentrated to 14.46 g (86%) of isobutyrylacetic acid as an oil. 1H NMR (CDCl3, 300 MHz) reveals a mixture of keto and enol forms (˜4:1), in favor of the keto form. Keto form: δ 3.57 (s, 2H), 2.73 (sept, J=6.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 6H) ppm. Enol form: 11.85 (s, 1H), 5.03 (s, 1H), 2.44 (sept, J=6.9 Hz, 1H) 1.10 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: O[C:2]1([C:23]([F:26])([F:25])[F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:23]([F:25])([F:26])[F:24])[N:3]=[C:4]2[C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:12][CH:11]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2cccnc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2cccnc2)cc1
Yield: 23 %

Procedure:
A mixture of the compound of step 2 (3.6 g, 9.35 mmol) and p-toluenesulfonic acid monohydrate (0.52 g, 2.7 mmol) in toluene (280 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude mixture was chromatographed on silica gel using ethyl acetate/acetone (98/2) to give pure 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine (790 mg, 23%) as a white solid: mp (DSC) 193° C. Anal Calc'd. for C16H12N3SO2F3 : C, 52.30, H, 3.29, N, 11.44, S, 8.73. Found: C, 52.38, H, 3.26, N, 11.30, S, 8.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl[S:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:13])=[O:12]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:11]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1)(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1N
Product: COc1ccccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Yield: 95.7 %

Procedure:
Using o-anisidine (0.585 ml, 5.0 mmol) and 4-(chlorosulfonyl)benzoic acid (1.15 g, 5.0 mmol), the procedure of Reference Example 2 was repeated to obtain 1.47 g (95.5%) of the title compound in the form of pink powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16]([OH:17])=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:31][C:32]([F:43])([F:42])[CH2:33]OS(C(F)(F)F)(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16]([O:17][CH2:33][C:32]([F:43])([F:42])[F:31])=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-12A-1a; 65 mg, 0.18 mmol) and Cs2CO3 (59 mg, 0.18 mmol) in DMF (1.5 ml) was added a DMF solution (0.1 ml) of trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (42 mg, 0.18 mmol). After stirring at 60° C. overnight, the mixture was extracted from pH 7 water with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4) and then concentrated, in vacuo, to afford the crude product. Purification on a Chromatotron using 1:0:0, 20:1:0, and then 20:0:1 methylene chloride/ethyl acetate/methanol as eluants afforded, in addition to two N-alkylated isomers, product 12A-1 (16.5 mg, 21%) as a solid: +ESI MS (M+1) 438.4; 1H NMR (400 MHz, CD3OD) δ 8.56 (d, J=5.0 Hz, 1H), 7.55–7.41 (m, 6H), 7.24 (d, J=8.7 Hz, 2H), 6.80 (d, J=5.0 Hz, 1H), 5.16 (q, J=7.9 Hz, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([OH:11])=[O:10])=[N+:2]=[N-:3].Br[CH2:13][CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:13]([O:10][C:9]([C:5]1[S:6][CH:7]=[CH:8][C:4]=1[N:1]=[N+:2]=[N-:3])=[O:11])[CH:14]([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=Nc1ccsc1C(=O)O
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)c1sccc1N=[N+]=[N-]
Temperature: 80 °C
Yield: 77 %

Procedure:
Compound 13a (5.8 g, 34.3 mmol) was treated with 1-bromo-2-methylpropane (4.47 mL, 1.2 equiv.) and cesium carbonate (7.82 g, 0.7 equiv.) in anhydrous DMF (0.1 M) and heated to 80° C. for 6 h under argon. The mixture was cooled, dissolved in H2O (150 mL), and extracted with 1:1 diethyl ether:ethyl acetate (3×200 mL). The organic layer was washed with distilled H2O (5×100 mL), dried over Na2SO4, and concentrated in vacuo to give 14a as an oil (6.77 g, 77% yield).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:24][CH2:25][CH2:26]O>CC(=O)OCC>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:26][CH2:25][Br:24])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCCBr
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCBr)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.150 mL (2.1 mmol) of 2-bromoethanol. MS (m/z, ES+): 446.30 (79BrM+1, 100%), 448.30 (81BrM+1, 80%); 1H NMR (400 MHz, DMSO-d6) δ: 7.30 (d, 1H), 5.67 (d, 1H), 4.49 (t, 2H), 4.16 (t, 2H), 3.73 (t, 2H), 1.72 (p, 2H), 1.3-1.45 (m, 2H), 1.25 (s, 20H), 0.85 (t, 3H); EA found for C21H35BrO4: C, 58.93: H, 8.52; calcd: C, 58.47; H, 8.18.
Reaction SMILES: [C:1](F)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11](I)([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13]>C(Cl)Cl>[C:2]1([C:1](=[O:8])[C:11]([F:10])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Reactant: O=C(F)c1ccccc1
Solvent: ClCCl
Product: O=C(c1ccccc1)C(F)(C(F)(F)F)C(F)(F)F
Temperature: -70 °C
Reaction time: 12 h
Yield: 78 %

Procedure:
Under protective gas, 22 g (0.18 mol) of benzoyl fluoride and 55.3 g (0.18 mol) of perfluoroisopropyl iodide in 150 ml of CH2Cl2 are initially introduced into a round-bottomed flask. 45 g (0.18 mol) of phosphorous acid trisdiethylamide are added dropwise at about -70° C. The mixture is stirred for 12 hours at -70° C. and, after warming, worked up analogously to Example 1. 38.5 g (78%) of 1-phenyl-2,3,3,3-tetrafluoro-2-trifluoromethyl-propan-1-one of b.p. 90°-92° C./80 mbar are obtained.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[CH2:9]([N:11]([CH2:12][CH3:13])[C:1](=[O:8])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6])[CH3:10]
Reactant: CCNCC
Reactant: C/C=C/C=C/C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C/C=C/C(=O)N(CC)CC
Yield: 99 %

Procedure:
Sorbic acid (5.01 g, 44.7 mmol) and diethylamine (3.59 g, 49 mmol) were dissolved in dimethylformamide (100 ml) and the solution was stirred under ice-cooling. To the solution was added diphenylphosphoryl azide (15.0 g, 54.5 mmol) and the mixture was stirred for 20 hours while allowing to rise the temperature to room temperature. The reaction mixture was diluted with ethyl acetate and washed with an aqueous saturated sodium chloride solution. The ethyl acetate layer was washed with an aqueous saturated sodium carbonate and aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=200:1-50:1) to obtain sorbic acid N,N-diethylamide (7.40 g, 99.9%) as pale yellow solid. This compound has the following NMR spectrum.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (100 mg, 88%), MS (ISP) m/z=453.3 [(M+H)+], mp 209.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-fluorobenzoic acid.
Reaction SMILES: [CH:1](/[S:9](Cl)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>>[CH:1](/[S:9]([NH:18][C:17]1[CH:19]=[CH:20][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:11])=[O:10])=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Product: O=S(=O)(/C=C/c1ccccc1)Nc1ccc(F)cc1
Yield: 58.7 %

Procedure:
A solution of (E)-styrylsulfonyl chloride (10 mmol) and 4-fluoroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 83-85° C., was obtained 58.7% yield.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>CS(C)=O>[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][N:41]([CH2:12][CH:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)[CH2:42][CH:43]=1
Reactant: Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Solvent: CS(C)=O
Product: Cc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6nc(C)ccc6c5O4)CC3)c2c1
Temperature: 75 °C

Procedure:
(2R)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-ylmethyl 4-methylbenzenesulfonate (0.55 g, 1.4 mmole) and 5-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 3.8 mmole) were combined in 10 mL of DMSO. The mixture was heated at 70-80° C. under nitrogen for 6 hours. After cooling to room temperature, the mixture was partitioned between 400 mL each of ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was removed, washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to dryness under vacuum. The residue was column chromatographed on silica gel using 0-2% methanol/chloroform as eluant. The product-containing fractions were concentrated in vacuum and the residue recrystallized from isopropanol with the addition of fumaric acid to give 0.32 g of the (S)-enantiomer of the title compound as a yellow solid monofumarate, three-quarter hydrate (m.p. 150-155° C.).
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Br[CH2:38][C:39]([N:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH3:48])([CH3:47])[CH2:42]1)=O>>[CH3:47][C:43]1([CH3:48])[CH2:44][CH2:45][CH2:46][N:41]([CH2:39][CH2:38][O:1][C:2]2[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[CH:18]3[CH2:27][CH2:26][C:25]4[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=4[CH2:19]3)=[CH:4][CH:3]=2)[CH2:42]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Reactant: CC1(C)CCCN(C(=O)CBr)C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCCC(C)(C)C3)cc2)c1
Yield: 59 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-bromo-1-(3,3-dimethylpiperidin-1-yl)ethanone (23 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14]([NH:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)=[O:15]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1noc2ccccc12
Solvent: Cc1ccccc1
Product: O=C(Nc1noc2ccccc12)c1c(Cl)cccc1Cl

Procedure:
3-Aminobenzisoxazole (2 gram), 2,6-dichlorobenzoylchloride (2 gram), and 50 ml. of toluene are heated at reflux for 16 hours. After evaporation of the solvent at reduced pressure, the resultant oily semi-solid is triturated with ether. The solid so formed is then washed with ether and water and constitutes the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21](Cl)=[O:22])[O:3]1.[OH-].[NH4+:25]>O1CCCC1>[O:1]=[C:2]1[NH:6][C@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[C@@H:4]([C:21]([NH2:25])=[O:22])[O:3]1
Reactant: [NH4+]
Reactant: O=C1N[C@H](c2cccc(C#Cc3ccccc3)c2)[C@@H](C(=O)Cl)O1
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)[C@H]1OC(=O)N[C@@H]1c1cccc(C#Cc2ccccc2)c1
Yield: 96.2 %

Procedure:
To (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carbonyl chloride (120 mg, 0.368 mmol) in tetrahydrofuran (1 mL) was added ammonium hydroxide (3 mL, 23.11 mmol) dropwise. One hour later, the reaction mixture was extracted with ethylacetate (10 mL×3) and the combined organic layer was dried over magnesium sulfate, filtered, and concentrated to obtain (4R,5S)-2-oxo-4-(3-(phenylethynyl)phenyl)oxazolidine-5-carboxamide (114 mg, 0.354 mmol, 96% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 4.66 (d, J=5.49 Hz, 1H) 4.88 (d, J=5.49 Hz, 1H) 7.37-7.68 (m, 11H) 7.79 (s, 1H). Mass spec.: 307.1 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[Si](C)(C)[O-:13].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(O)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
To a solution of 2-bromo-4-fluoro-benzonitrile (2000 mg, 9.9995 mmol) in DMF (20 mL), potassium trimethylsilanolate (2565.7 mg, 19.999 mmol) was added portionwise and the reaction mixture stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate (100 ml), washed with an aqueous saturated solution of ammonium chloride (100 ml) and brine (3×100 ml), dried over sodium sulphate and concentrated under vacuum to give the title compound (2000 mg) which was used in the next step without purification.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:41](OC(=O)C)(=[O:43])[CH3:42].[ClH:48]>C1COCC1>[ClH:48].[CH3:33][O:32][CH2:31][CH2:30][S:29][C:18]1[CH:19]=[C:20]([O:21][C:22]2[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=2)[C:15]([NH:14][C:12]2[S:11][N:10]=[C:9]([CH:3]3[CH2:2][CH:1]4[N:8]([C:41](=[O:43])[CH3:42])[CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:13]=2)=[N:16][CH:17]=1
Reactant: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4)ns2)c(Oc2cccnc2C)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(C)=O)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
3-(8-Azabicyclo[3.2.1]octan-3-yl)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (96 mg, 0.198 mmol) was dissolved in THF (4 mL) and triethylamine (55.2 μL, 0.396 mmol) and acetic anhydride (22.5 μL, 0.238 mmol) were added. The reaction was stirred at ambient temperature for 5 minutes. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (20% methanol in EtOAc) to afford 1-(3-(5-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (91.6 mg, 0.163 mmol, 82.1% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=527.2 (M+H—HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C@H:8]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14](O)[C:13]=1[N+:19]([O-:21])=[O:20])[CH2:9][CH3:10].CCN(C(C)C)C(C)C.Cl.P(Cl)(Cl)([Cl:34])=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[Cl:34][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[C:12]([NH:11][C@@H:8]([CH2:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[Cl:1])[CH2:9][CH3:10])[CH:17]=[CH:16][N:15]=1
Reactant: CC[C@H](Cc1sccc1Cl)Nc1ccnc(O)c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC[C@H](Cc1sccc1Cl)Nc1ccnc(Cl)c1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
A toluene solution of (R)-N-[1-[(3-chloro-2-thienyl)methyl]propyl]-2-hydroxy-3-nitro-4-pyridinamine (Compound IV) (0.1 mole in 100 mL of toluene) containing 2 equivalents of DIPEA hydrochloride is heated to 60° C. and 20.6 grams of phosphorus oxychloride is added over 10 minutes with stirring. The reaction is stirred at 60° C. until complete (3 hours). After cooling to 0° C., 245 grams of 2N sodium chloride is added at such a rate so as to maintain the reaction temperature below 10° C. The biphasic mixture is stirred 1-2 hours at 0° C. before it is allowed to warm to room temperature overnight. The bottom aqueous layer is separated from the organic layer. The organic layer is concentrated in vacuo and the residue purified by flash chromatography eluting with 25.75 ethyl acetate:heptane to give Compound V. MS (EI) m/z 345 (10%). 1HNMR (500 Mhz, CDCl3 /CD3OD)δ1.0 (2H, t); 1.5-1.8 (2H, m); 2.9-3.2 (2H, m); 3.8 (1H, m); 6.5 (1H, bd); 6.6 (1H, d); 7.15 (1H, d); 7.9 (1H, d).
Reaction SMILES: [CH3:1][C:2]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=1)([CH3:7])[C:3]([O:5]C)=[O:4].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:7][C:2]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)Oc1ccc(C#N)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1ccc(C#N)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-methyl-2-(5-cyano-2-pyridyloxy)propionate (12 mg) in tetrahydrofuran (2 mL) and water (1 mL) was added lithium hydroxide monohydrate (10 mg). After stirring at room temperature overnight, the reaction mixture was acidified with 1 N hydrochloric acid, and the resulting mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered and concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 8.23 (d, 1H), 7.96 (dd, 1H), 6.91 (d, 1H), 1.64 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:31]3[CH2:32][CH2:33][N:28]([C:23]4[N:22]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:29][CH2:30]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ncccn4)CC3)C2)cc1OC
Yield: 68.3 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (24.9 mg, 0.092 mmol), 1-(2-pyrimidyl)piperazine dihydrochloride (20.0 mg, 0.084 mmol), molecular sieve (5 beads), NaBH(OAc)3 (53.6 mg, 0.252 mmol) and diisopropylethylamine (53.9 L, 0.168 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 23.6 mg (68.2%) of the target compound was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CS(=O)(=O)c1ccc(N2CC=C(N3CCCC3)CC2)cc1
Yield: 78 %

Procedure:
A solution of 24 g (0.0947 mol) of the compound of (b), 12 ml (10.2 g/0.143 mol) of pyrrolidine, 240 mg of p-toluenesulfonic acid and 150 ml of benzene is heated at reflux with the azeotropic removel of water for 6 hours. After cooling the resulting precipitate is collected and triturated with ethyl ether to afford 22.5 g (78%) of title compound: m.p. 141°-143° C.; IR (KBr) 1650, 1580, 1300, and 1130 cm-1 ; NMR (CDCl3)δ 7.75 (d, 2H), 6.85 (d, 2H), 4.30-4.10 (m, 1H), 3.95-3.45 (m, 4H), 3.25-2.85 (m, 4H) 3.05 (s, 3H), 2.65-2.30 (m, 2H), and 1.95-1.70 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[NH:5][C:6](OCC1C=CC=CC=1)=[O:7].[N:22]1[NH:23][N:24]=[N:25][C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:51]=[CH:50][C:36]2[N:37]([CH:40]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])C(O)=O)[CH:38]=[N:39][C:35]=2[CH:34]=1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>>[O:7]=[C:6]([NH:5][C@H:4]([C:3]([OH:21])=[O:2])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:40]([N:37]1[C:36]2[CH:50]=[CH:51][C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]3[N:25]=[N:24][NH:23][N:22]=3)=[CH:34][C:35]=2[N:39]=[CH:38]1)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCC(C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Reactant: COC(=O)[C@H](CCCCN)NC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Product: CCCCCCC(C(=O)N[C@@H](CCCCN)C(=O)O)n1cnc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Yield: 13.9 %

Procedure:
N-carbobenzyloxy-L-Lysine methyl ester (1.0 mmoles, 0.295 g) and 2-[5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid (1.0 moles, 0.405 g) were reacted with 1.0 moles of hydroxybenzotriazole and dicyclohexylcarbodiimide as in Example 37. The stereoisomers were separated on silica gel eluted with 5% EtOH in chloroform with 1% acetic acid. Each was hydrolyzed with sodium hydroxide as in Example 37 and hydrogenated to remove the carbobenzyloxy group in ethanol over 5% Pd/C for 4 hours. The catalyst was removed by filtering through celite. The solvent was removed in vacuo to yield 74 mg of N-[1-Oxo-2-[5-[2-(2H-tetrazol-5-yl]phenyl]-1H-benzimidazol-1-yl]octyl]-lysine. Isomer A (MS)