Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])([CH3:7])[CH2:5][OH:6])([O-:3])=[O:2].[CH2:11]1OCO[CH2:13][O:12]1.S(=O)(=O)(O)O>C(Cl)Cl>[CH3:5][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH2:11][O:12][CH2:13][O:6][CH2:5][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH3:7]
Reactant: CC(CO)([N+](=O)[O-])[N+](=O)[O-]
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(COCOCC(C)([N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 2 h
Yield: 82 %

Procedure:
To a stirred solution of 15 g (0.1 mole) of 2,2-dinitropropanol and 1.5 g (0.05 mole) of s-trioxane in 13 mL of methylene chloride at 0° C., 15 g (98%) of a concentrated sulfuric acid solution was injected with syringe pump over 2 hours. During the reaction, temperature was controlled not to exceed 5° C. After addition was completed, the reaction was stirred for further 30 minutes. Upon completion of the reaction, the reaction solution was quenched with water. The reaction mixture was extracted with 130 mL of methylene chloride, and then, the extract was successively washed with 5% sodium hydroxide aqueous solution (130 mL×4) and saturated sodium chloride aqueous solution (130 mL×2), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. Further evaporation under 60° C., about 10 mmHg for 5 hours gave 12.8 g of BDNPF.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13]([O:17][C:18]([NH:20][C@H:21]([CH:26]=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@H:26]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:27])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)OC(C)(C)C)[C@@H](O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 21.6 %

Procedure:
To 2-bromopyridine (3.16 g) in 20 ml of dry tetrahydrofuran cooled to -78° C. under argon was added slowly 11.2 ml of n-butyl lithium in tetrahydrofuran (2M). The solution was stirred for 5 minutes and then 2.1 g of N-t-butoxycarbonyl-L-leucinal in 10 ml of tetrahydrofuran was added. The mixture was stirred for 35 minutes, then quenched with 10 ml of saturated sodium sulfate solution, warmed to room temperature and poured into 50 ml of water. The mixture was extracted with ethyl acetate. The extract was dried (Na2SO4) and the solvent removed under vacuum. The residue was chromatographed over silica gel with ethyl acetatheexane (3:7) as eluent and then ethyl acetate-hexane (1:1) as eluent to give 0.62 g of (S) 2-tert-butoxycarbonyl-amino-4-methyl(R,S)1-(2-pyridinyl)pentan-1-ol as a yellow oil; [α]D26 -21°±3° (C, 0.329, dichloromethane). A4.12 sample of the preceding compound in a mixture of 15 ml of dichloromethane and 5 ml of acetic anhydride was stirred at room temperature for 22 hours. The mixture was concentrated under vacuum. The residue was dissolved in dichloromethane and the solution washed with saturated agneous sodium carbonate, dried (Na2SO4) and the solvent removed. The residue was chromatographed over silica gel with 30% ethyl acetate in hexane to give 1.55 g of (S) 2-tert-butoxycarbonylamino-4-methyl-(S)1-(2-pyridinyl)pentan-1-ol, 0-acetate as crystals, mp 83°-84° C.; [α]D26 -62°±1° (C. 1.01, dichloromethane) and (S) 2-tert-butoxycarbonylamino-4-methyl-(R)1-(2-pyridinyl)pentan-1-ol, 0-acetate as an amber oil; [α]D26 +3°±1° (C, 1.-66, methanol).
Reaction SMILES: [C:1](=[N:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH2:18][CH2:19][CH3:20])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:7]=[C:6]1[CH2:18][CH2:19][CH3:20])([CH3:3])[CH3:2]
Reactant: CCCc1nc2cnc3ccccc3c2n1N=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1nc2cnc3ccccc3c2n1NC(C)C
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A solution of N-isopropylidene-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)amine (4.30 g, 16.1 mmol) in 100 mL of methanol was cooled in an ice water bath. The solution was treated with sodium borohydride (3.05 g, 80.7 mmol) over 5 min. The reaction mixture was allowed to warm to ambient temperature. After 2.5, the reaction was quenched by addition of 15 mL of saturated NH4Cl solution. The mixture was concentrated under reduced pressure to yield a light brown solid. The solid was partitioned between 100 mL CHCl3 and 25 mL of saturated NaHCO3 solution and then separated. The organic portion was washed with water (25 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield a light brown solid. The solid was purified by chromatography (SiO2, 97:2.5:0.5 CHCl3:MeOH:NH4OH) to give 2.48 g of N-isopropyl-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)amine as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[NH:5][C:4](=[S:16])[N:3]=1.I[CH2:18][CH3:19].C(=O)(O)[O-].[Na+].O>CS(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]([S:16][CH2:18][CH3:19])[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: CCI
Reactant: Nc1cc(-c2ccc(Cl)cc2Cl)[nH]c(=S)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
67.5 g (248 mmol) of 4-amino-6-(2,4-dichlorophenyl)pyrimidine-2(1H)-thione and 77.37 g (496.04 mmol) of iodoethane are dissolved in 560 ml of dry DMSO and, at RT, 270 ml of a saturated aqueous sodium bicarbonate solution are slowly added. The mixture is stirred at RT for 5 h and then 440 ml of water are added. The precipitate is filtered off with suction, washed with water and sucked dry. It is stirred twice with 100 ml of isopropanol each time and again filtered off with suction. It is washed once more with petroleum ether and the residue is dried under high vacuum. 50.0 g (67% of theory) of the product are obtained as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([C:23](OC)=[O:24])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([CH3:22])[C:13]([CH:23]=[O:24])=[CH:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccc(F)cc2)c(-c2ccccc2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccc(F)cc2)c1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
Under a nitrogen atmosphere, a solution (40 mL) of methyl 1-[(4-fluorophenyl)sulfonyl]-4-methyl-5-phenyl-1H-pyrrole-3-carboxylate (1.48 g) in tetrahydrofuran was cooled to −78° C., and a 1.5 mol/L solution (7.9 mL) of diisobutylaluminum hydride in toluene was added dropwise over 15 min, and the mixture was further stirred at −78° C. for 30 min. 1 mol/L Hydrochloric acid (40 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in acetonitrile solution (60 mL), added tetra-n-propylammonium perruthenate (0.14 g), N-methylmorpholine N-oxide hydrate (0.80 g) and molecular sieves 4A powder (4.0 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (200 mL) was added to the residue, the suspension was filtered through celite, and celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→3:1) to give the title compound as a colorless oil (yield 721 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](Cl)(=[O:39])=[O:38])=[N:35][CH:36]=2)[CH2:26][CH2:25]1)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[S:37]([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25][CH2:26]3)=[CH:36][N:35]=2)(=[O:38])=[O:39])=[CH:12][CH:13]=1
Reactant: CC(C)CNCc1ccc(F)cc1
Reactant: CS(=O)(=O)N1CCC(Oc2ccc(S(=O)(=O)Cl)nc2)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A solution of (4-fluorobenzyl)-isobutylamine (53 mg, 0.295 mmol) and pyridine (34 μL, 0.423 mmol) in DCM (3 mL) was treated with 5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine-2-sulfonyl chloride (75 mg, 0.211 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1 M aqueous citric acid, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and re-purification by silica gel column chromatography (0-10% EtOAc in DCM) to give the title compound (39 mg, 37%). 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=2.8 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.66 (dd, J=8.8, 2.9 Hz, 1H), 7.38-7.32 (m, 2H), 7.17-7.09 (m, 2H), 4.84-4.76 (m, 1H), 4.39 (s, 2H), 3.43-3.34 (m, 2H), 3.18-3.10 (m, 2H), 3.00 (d, J=7.5 Hz, 2H), 2.92 (s, 3H), 2.11-2.01 (m, 2H), 1.84-1.73 (m, 2H), 1.63-1.52 (m, 1H), 0.68 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 499.9 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([C:15]([CH3:23])([CH3:22])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26].CC#N.O.CC#N>O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])[C@H:10]([C:15]([CH3:22])([CH3:23])[O:16][SiH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CN
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)[C@H](C(C)(C)O[SiH2]C(C)(C)C)C1
Solvent: O
Solvent: CC#N
Product: CC(C)CNC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(C)(C)O[SiH2]C(C)(C)C

Procedure:
The title compound is prepared as described above for Example 9/step F (Scheme 5) from (3S*,4S*)-3-(tert-butyl-dimethyl-silanyloxymethyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester and isobutylamine. MS (LC-MS): 401.1 [M+H]+; tR (HPLC, Waters Symmetry C18 column, 20-95% CH3CN/H2O/3.5 min, 95% CH3CN/H2O, 2 min, CH3CN and H2O containing 0.1% TFA, flow: 0.6 mL/min): 3.70 min.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([S:7]([N:10]([CH2:12][C:13]([OH:15])=O)[CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.Cl.C[O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[NH2:23]>>[C:1]1([CH3:16])[CH:2]=[CH:3][C:4]([S:7]([N:10]([CH2:12][C:13]([NH:23][C@H:22]([C:21]([OH:31])=[O:20])[CH2:24][C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)=[O:15])[CH3:11])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccncc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N[C@@H](Cc2ccncc2)C(=O)O)cc1

Procedure:
N-(Toluene-4-sulfonyl)sarcosine was coupled to 3-(4-pyridyl)alanine methyl ester dihydrochloride using the procedure described in Method 3 to give N-(toluene-4-sulfonyl)sarcosyl-β-(4-pyridyl)alanine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:18]=[C:17]([C:19]3[C:20]([C:26]([F:29])([F:28])[F:27])=[N+:21]([O-:25])[CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C:14]2[CH:18]=[C:17]([C:19]3[C:20]([C:26]([F:27])([F:29])[F:28])=[N+:21]([O-:25])[CH:22]=[CH:23][CH:24]=3)[O:16][N:15]=2)[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(-c2cc(-c3ccc[n+]([O-])c3C(F)(F)F)on2)cc([N+](=O)[O-])c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(-c2cc(-c3ccc[n+]([O-])c3C(F)(F)F)on2)cc(O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(3-(3,4-dimethoxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine 1-oxide (0.81 g, 2 mmol) was taken up in dichloromethane (15 mL) and the yellowish suspension was cooled to −78° C. under argon whereupon boron tribromide (4.5 g, 18 mmol) was added dropwise. The reddish reaction mixture was allowed to warm to room temperature and stirred for 18 hours, then carefully poured into ice-water (100 mL) and allowed to stir for 1 hour. The yellow precipitate was filtered off, washed with water and dried over P2O5 under vacuum. Trituration with boiling ethanol gave 3-(3-(3,4-dihydroxy-5-nitrophenyl)isoxazol-5-yl)-2-(trifluoromethyl)pyridine 1-oxide as a yellow solid, 0.49 g (64%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:39])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)=O)(C)(C)C>>[N:30]1[CH:31]=[CH:32][C:27]([C:25]2[CH2:24][C:23](=[O:39])[NH:16][C:9]3[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)=[CH:28][C:29]=1[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Product: Cc1cc2c(cc1Cl)NC(=O)CC(c1ccnc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (102 mg, 0.4 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (119 mg, 0.4 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (120 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:7].[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](O)=[O:25])=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:7][C:24](=[O:25])[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH:14]([CH3:15])[CH3:16])=[CH:18][CH:19]=1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: NC(c1ccccc1)c1ncco1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CC(=O)NC(c2ccccc2)c2ncco2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
The crude 1-(1,3-oxazol-2-yl)-1-phenylmethanamine (0.10 g, 0.57 mmol) was mixed with 4-isopropylpheylacetic acid (0.10 g, 0.57 mmol), HOAt (0.086 g, 0.63 mmol) and EDC (0.12 g, 0.63 mmol) in DMF (1.0 mL) and stirred at room temperature for 0.5 h. Purification by reverse-phase HPLC gave the product (0.025 g, 13%). ES-MS [M+1]+: 335.1. 1H NMR (CDCl3, 400 MHz) δ 7.58 (s, 1H), 7.31-7.28 (m, 3H), 7.22-7.20 (m, 6H), 7.07 (s, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.32 (d, J=7.6 Hz, 1H), 3.62 (s, 2H), 2.90 (m, J=6.8 Hz, 1H), 1.24 (d, J=6.8 Hz, 6H).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]1[CH2:12][CH2:13][N:14]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:15][CH:16]=1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc(CN2CC=C(c3cc4ccccc4s3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.8 %

Procedure:
4-(Benzothiophen-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride (250 mg, 0.99 mmol) was dissolved in DMF (5 ml), potassium carbonate (412 mg, 2.9 mmol) added, and the reaction mixture stirred at room temperature for 10 minutes. 4-Chlorobenzyl bromide (306 mg, 1.5 mmol) was added and the resulting reaction mixture stirred at room temperature overnight. After dilution with water (50 ml), the product was extracted into ethyl acetate (3×40 ml). The combined organic layers were washed with brine (100 ml), dried (MgSO4) and concentrated. The crude product was triturated with methanol to yield a pale brown solid. Recrystallisation from hot dichloromethane and methanol gave the title compound as a pale yellow solid (60 mg, 18%); (Found: C, 70.33; H, 5.20; N, 4.16. C20H18 ClNS requires C, 70.68; H, 5.34; N, 4.12%); δH (CDCl3), 2.64 (2H, m, NCH2CH2), 2.72 (2H, m, NCH2CH2), 3.18 (2H, m, NCH2CH2), 3.61 (2H, s, NCH2Ar), 6.18 (1H, m, NCH2CH2), 7.12 (1H, s, ArH), 7.28 (6H, m, ArH), 7.66 (1H, d of d, J 6Hz, J 2Hz, ArH), 7.74 (1H, d of d, J 6.7Hz, J 2Hz, ArH). m/z (ES+) 340 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCCN1CCN(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
1-[3-(Ethyloxy)-4-nitrophenyl]-4-propylpiperazine (0.422 g, 1.44 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (0.28 g, 0.072 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (balloon). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step B (0.295 g, 1.12 mmol, 78%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.45-6.53 (m, 2H), 6.28 (dd, J=8.33, 2.11 Hz, 1H), 3.95 (q, J=6.96 Hz, 2H), 2.96-3.07 (m, 4H), 2.84-2.95 (m, 4H), 2.63-2.74 (m, 2H), 1.50-1.60 (m, 2H), 1.27-1.32 (m, 3H), 0.87 (t, J=7.42 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].[K+].Cl[CH2:14][C:15]([O:17][CH3:18])=[O:16]>CS(C)=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:11])=[O:10])=[CH:7][CH:8]=1)=[CH2:2]
Reactant: C=Cc1ccc(S(=O)[O-])cc1
Reactant: COC(=O)CCl
Agent: [K+]
Solvent: CS(C)=O
Product: C=Cc1ccc(S(=O)(=O)CC(=O)OC)cc1
Temperature: 50 °C

Procedure:
To 188 ml of dimethyl sulfoxide was added 54.2 g of potassium p-vinylbenzenesulfinate, and the resulting mixture was stirred while heating at 50° C. Then, 23.0 ml of methyl chloroacetate was added dropwise to the mixture over 1 hour while maintaining it at 50° C., and the resulting mixture was stirred for 1 hour while maintaining at 50° C. The reaction mixture was cooled to room temperature and extracted with ethyl acetate, and the ethyl acetate was distilled away at an outer temperature of not more than 40° C. to yield 60.1 g of oily methyl p-vinylbenzenesulfonylacetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH3:27])[O:26][CH2:25][CH2:24][O:23]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:7]=1.[F:28][C:29]([F:36])([F:35])[C:30](OCC)=[O:31]>>[F:1][C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3([CH3:27])[O:23][CH2:24][CH2:25][O:26]3)=[CH:20][CH:21]=2)[CH:5]=[C:6]([C:8]2([O:13][CH3:14])[CH2:12][CH2:11][N:10]([C:30](=[O:31])[C:29]([F:36])([F:35])[F:28])[CH2:9]2)[CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: COC1(c2cc(F)cc(Sc3ccc(C4(C)OCCO4)cc3)c2)CCNC1
Product: COC1(c2cc(F)cc(Sc3ccc(C4(C)OCCO4)cc3)c2)CCN(C(=O)C(F)(F)F)C1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in the third paragraph of the portion of Example 5 which is concerned with the preparation of starting materials, 3-{5-fluoro-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenylthio]phenyl}-3-methoxypyrrolidine was reacted with ethyl trifluoroacetate to give 3-{5-fluoro-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenylthio]phenyl}-3-methoxy-1-(trifluoroacetyl)pyrrolidine as a gum in 58% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=2)[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:13]([C:11]1[CH:12]=[C:8]([NH2:7])[N:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:18]=2)[N:10]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C)nn1-c1cccc(N2CCOCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(N)n(-c2cccc(N3CCOCC3)c2)n1
Yield: 87.2 %

Procedure:
A solution of Intermediate 23c (290 mg, 0.725 mmol) and TFA (3 mL) in DCM (4 mL) was stirred at RT for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (190 mg, 86%). LCMS (Method 1): Rt 2.29 min, m/z 301 [MH+].
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:34])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][CH2:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.[CH3:36][Mg]Br>C1COCC1>[F:35][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:34])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[C:26]([CH2:29][CH2:30][C:31]([OH:33])([CH3:36])[CH3:32])[CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1
Reactant: CC(=O)CCc1ccc2ncc(C(=O)Nc3cc(-c4noc(C5CC(F)(F)C5)n4)ccc3C)n2c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1ccc(-c2noc(C3CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccc(CCC(C)(C)O)cn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(3-oxobutyl)imidazo[1,2-a]pyridine-3-carboxamide (F53) (40 mg, 0.083 mmol) in anhydrous THF (2 mL) at −78° C. under a stream of Argon was added methylmagnesium bromide (83 uL, 0.25 mmol). The reaction was stirred to room temperature for 30 minutes. The reaction was cooled to 0° C. and was quenched with saturated NH4Cl (2 mL). The crude product was extracted with ethylacetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by reverse phase preparative HPLC to give N-(5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)-6-(3-hydroxy-3-methylbutyl)imidazo[1,2-a]pyridine-3-carboxamide (F54). 1H NMR (400 MHz, d6-DMSO) δ 10.18 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.86-7.82 (m, 2H), 7.65-7.62 (m, 1H), 7.51 (d, J=8.4 Hz, 1H), 3.91-3.84 (m, 1H), 3.25-3.04 (m, 4H), 2.78-2.73 (m, 2H), 2.37 (s, 3H), 1.71-1.67 (m, 2H), 1.16 (s, 6H). MS m/z 496.21 (M+1)+.