Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:12][C:13]1[CH:28]=[CH:27][C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.CN([P+]([O:54][N:55]1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.NO>CN(C)C=O.C(O)(=O)C>[CH2:1]([O:8][C:9](=[O:10])[CH:11]([NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:17][C:18]2[CH:19]=[CH:20][C:21]([C:22](=[O:23])[NH:55][OH:54])=[CH:25][CH:26]=2)=[CH:27][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)C(=O)OCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 44.1 %

Procedure:
Acid compound 4 (1.1 g, 2.24 mmol) was dissolved in N,N-dimethylformamide (10 mL) and stirred under an atmosphere of argon. N-Methylmorpholine (1.0 mL, 8.96 mmol) was added, the reaction mixture was cooled to 0° C. and BOP reagent (1.09 g, 2.46 mmol) was added. After 20 min, hydroxylamine hydrochloride (0.31 g, 4.48 mmol) was added and the reaction mixture was warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and residual material was partitioned between EtOAc (50 mL) and saturated NH4Cl solution (1×30 mL). The organic layer was dried and concentrated to yield the crude material. Flash chromatography on SiO2 gel using hexanes-ethyl acetate (1:1) mixture containing 1% acetic acid furnished the desired hydroxamic acid compound 5 (0.5 g, 44%). 1H NMR (DMSO-d6): 11.20 (br, 1H), 9.00 (br, 1H), 7.76 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.28-7.38 (m, 7H), 6.98 (overlapped d, J=8.4 Hz, 4H), 5.12 (s, 2H), 4.21-4.27 (m, 1H), 3.03 (dd, J=13.6 and 5.6 Hz, 1H), 2.89 (dd, J=10.0 and 14.0 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O.Cl>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:22])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])[CH:17]=1
Reactant: COC(=O)c1cccc(NCc2cccnc2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Product: O=C(O)c1cccc(NCc2cccnc2)c1C(=O)O

Procedure:
3-[(Pyridin-3-ylmethyl)-amino]-phthalic acid dimethyl ester (0.91 g, 3.03 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid except the pH of crude reaction mixture was adjusted to 2-3 by dropwise addition of concentrated HCl. The solvent was then evaporated in vacuo leaving a dry salt mixture that was used without further purification.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N+]([O-])(O)=O>>[C:1]([C:5]1[NH:6][C:7]([CH3:12])=[C:8]([CH:10]=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1[nH]c(C(C)(C)C)nc1CO
Solvent: O=[N+]([O-])O
Product: Cc1[nH]c(C(C)(C)C)nc1C=O

Procedure:
A 19.76 gm. portion of 2-tert-butyl-5-methyl-4-imidazolemethanol and 16.5 ml. of concentrated HNO3 are reacted as described in Example 25 giving the desired product, m.p. 196°-198° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][C:11]1[CH:15]=[C:14]([CH:16]2[CH2:18][CH2:17]2)[NH:13][N:12]=1.C(N(CC)CC)C>CCO>[CH:16]1([C:14]2[CH:15]=[C:11]([NH:10][C:6]3[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=3)[NH:12][N:13]=2)[CH2:18][CH2:17]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
To a solution of 2,4,6-trichloropyrimidine (600 mg, 3.27 mmol) and 3-amino-5-cyclopropylpyrazole (403 mg, 3.27 mmol) in EtOH (10 mL) was added triethylamine (456 μL, 3.27 mmol) and the reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (SiO2, Hexane/AcOEt gradient) to afford (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (705 mg, 80%).
Reaction SMILES: N1(C[CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)CCCC1.ClCC[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:27]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([C:22]#[N:23])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: ClCCN1CCCC1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCN3CCCC3)cc2)CCOCC1
Yield: 59.2 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (570 mg, 2.82 mmol), 1-(2-chloro-ethyl)-pyrrolidine (300 mg, 2.25 mmol), DMF (5.7 ml) and K2CO3 (1.56 g, 1.13 mmol) were reacted together according to general procedure E. The organic phase was washed with 2M NaOH (3.×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude material was subjected to chromatography on silica eluting with 5% MeOH in DCM and gradient to 10% MeOH in DCM to provided the title compound (400 mg, 47%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.38 (d, 2H), 6.95 (d, 2H), 4.13 (t, 2H), 4.10-4.03 (m, 2H), 3.89 (td, 2H), 2.92 (t, 2H), 2.64 (br s, 4H), 2.15-1.99 (m, 4H), 1.88-1.76 (m, 4H).
Reaction SMILES: CN(C=O)C.[C:6]([Cl:11])(=O)[C:7](Cl)=O.[N:12]1[C:17]2[S:18][CH:19]=[CH:20]C=2C(=O)[NH:14][CH:13]=1.O>ClCCl>[Cl:11][C:6]1[C:7]2[CH:20]=[CH:19][S:18][C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2sccc12
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ncnc2sccc12
Temperature: 25 °C
Yield: 95.7 %

Procedure:
DMF (1.53 ml, 19.7 mmol) in dichloromethane (50 ml) was cooled to 0° C. and oxalyl chloride (2.5 ml, 29.6 mmol) was added slowly forming a white gel. Thieno[2,3-d]pyrimidin-4(3H)-one (1.5 g, 9.86 mmol) was added and the reaction mixture was refluxed for 3 hours. The mixture was cooled down to room temperature and poured into water. The mixture was extracted with dichloromethane, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc/hexane 15:1) to yield the title compound as a white solid (1.61 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2.C([OH:20])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:20])[NH:13]2
Reactant: CCO
Reactant: Fc1cccc(F)c1-c1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To the suspension of 4-(2,6-difluoro-phenyl)-1H-indole (9.5 g, 41.4 mmol) in t-BuOH: ethanol: acetic acid (262 mL: 155 mL: 81 mL) was added pyridinium tribromide (40.28 g, 126 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added more acetic acid (200 mL). Zinc dust (14.2 g, 217 mmol) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (5×), sat. NaHCO3 (2×), brine (3×), dried over Na2SO4, concentrated, triturated with ether to give 7.1 g (70%) of 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as a white solid.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[C:32](=O)([O-])[O-].[K+].[K+].[O:38]([CH2:45][CH2:46]CBr)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C.C(Cl)Cl>[O:38]([CH:45]([CH3:46])[CH2:32][N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C([O-])[O-]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: BrCCCOc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(CN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12)Oc1ccccc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution of 50 mg (0.12 mmol) {4-[5-(2,5-diaza-bicyclo[2.2. I]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine and 30 mg (0.24 mmol) potassium carbonate in 2 mL acetonitrile was treated with 0.040 mL (0.24 mmol) 3-phenoxy-propyl bromide at 0° C. The mixture was stirred at 50° C. for 16 h at which time MS showed that all starting materials had converted to product. The reaction mixture was cooled to ambient temperature, diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by BPLC, the title compound was obtained. MS (ES+): 546 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[F:15][C:16]1[CH:17]=[C:18]([OH:31])[CH:19]=[C:20]([C@@:22]2([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]2)[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([O:31][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:19]=[C:20]([C@@:22]2([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]2)[CH:21]=1
Reactant: CO[C@]1(c2cc(O)cc(F)c2)CCO[C@@H](C)C1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CO[C@]1(c2cc(F)cc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCO[C@@H](C)C1
Yield: 66 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (2S,4R)-4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran to give (2S,4R)-4-[5-fluoro-3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran in 66% yield, m.p. 91°-93° C.
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3]1.P(Cl)(Cl)([Cl:21])=O.[OH-].[Na+]>>[Cl:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cnc(-c2ccccc2)nc1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
A mixture of ethyl 3,4-dihydro-4-oxo-2-phenylpyrimidine-5-carboxylate (12 g) and phosphorus oxychloride (22.6 g) is stirred at 90° C. for four hours. The reaction mixture is poured into ice-water, and the mixture is neutralized with 1N aqueous sodium hydroxide solution. The precipitates are collected by filtration, and washed with water to give the desired compound (11 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH:30]1([CH2:33][C:34](O)=O)[CH2:32][CH2:31]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>O.C(#N)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:34][CH2:33][CH:30]4[CH2:32][CH2:31]4)[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)CC1CC1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(CCC4CC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
To a solution of (S)-4-amino-5(piperidine-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin 2,2-dioxide hydrochloride (Example 2a, 694 mg, 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added triethylamine (228 uL, 2.0 mmol). After stirring at room temperature for 5 min a solution of 2-cyclopropylacetic acid (200 mg, 2.0 mmol), HOBt (272 mg. 2.0 mmol), and EDCI-HCl (382 mg. 2.0 mmol) in H2O/ACN (5 mL, 1:1) was added to the mixture. An additional equivalent of triethylamine (228 uL, 2.0 mmol) was added and the reaction mixture was stirred at room temperature overnight. The product crashed out of solution and is collected by vacuum filtration. The compound was purified via preparative RP HPLC (10 to 90% EtOH in water) then diluted with 10 mL water and 200 mg of NaHCO3 was added. The solution was heated at 90° C. for 20 minutes until all the compound was dissolved then cooled to 0° C. and neutralized with 1N HCl solution. The product precipitated out and was collected by filtration and dried to provide the title compound (410 mg, 52.3%). 1H NMR (DMSO-d6, 400 MHz, 80° C.): 0.12 (br s, 2H), 0.44 (m, 2H), 0.96 (br s, 1H), 1.42 (m, 2H), 1.70 (m, 1H), 1.88 (m, 1H), 1.98 (br s, 1H), 2.09 (m, 1H), 2.26 (br s, 2H), 2.91 (m, 2H), 3.67 (br s, 0.5H), 3.85 (br s, 0.5H), 4.09 (m, 3H), 6.65 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 7.46 (t, J=8.4 Hz, 1H), 7.75 (br s, 1H), 8.16 (br s, 1H), 10.79 (s, 1H). M+H=393.
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH3:15])([CH3:14])[CH:8]=[C:7]2[CH3:16])C.B(Br)(Br)Br>ClCCl>[CH3:14][C:9]1([CH3:15])[CH:8]=[C:7]([CH3:16])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([OH:3])[CH:5]=2)[NH:10]1
Reactant: CCOc1ccc2c(c1)C(C)=CC(C)(C)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC1=CC(C)(C)Nc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A solution of 31 g of 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline in 300 mL of dichloromethane was treated with 30 mL of boron tribromide dropwise at −78° C. After the addition of boron tribromide, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into crushed ice and the pH was adjusted to 9 with sodium bicarbonate. The product was the extracted into EtOAc. The organic solution was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by filtering through a short plug of silica gel eluting with 25% EtOAc in hexanes solution to give 12.4 g of 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol as a light brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].ClCCl.[CH3:10]O.C([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])C.O1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:20]1[C:10]2([CH2:16][CH2:15][NH:14][CH2:17][CH2:18]2)[CH2:23][CH2:22][CH2:21]1
Reactant: CO
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: C1CCC2(C1)CCNCC2
Yield: 95 %

Procedure:
Was prepared from (3,3-pentamethylenglutarimide by lithium aluminium hydride reduction in tetrahydrofurane under standard conditions. Flash chromatography (silica, eluent dichloromethane/methanol/triethylamine 10:2:0.1) afforded the title compound as light yellow oil (>95% yield). MS 154(M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[C:25]1([P:31]([O:34]C)[O:32][CH3:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:25]1([P:31]([C:7]2[CH:6]=[C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=3[Cl:1])[CH:10]=[CH:9][C:8]=2[N+:11]([O-:13])=[O:12])(=[O:34])[O:32][CH3:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COP(OC)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Solvent: CC#N
Product: COP(=O)(c1ccccc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 1, a mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (2.0 g, 5.52 mmol) and dimethyl phenylphosphonite (1.4 g, 8.28 mmol) in 4 ml of acetonitrile is heated under reflux overnight. The crude product is purified to yield methyl P-phenyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate, m/s 471 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:13][C:14]([NH:16][CH2:17][CH2:18][N:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:20])=[O:15]>CN(C=O)C.CCOC(C)=O>[CH:21]1([N:19]([CH3:20])[CH2:18][CH2:17][NH:16][C:14](=[O:15])[CH2:13][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: CN(CCNC(=O)CCl)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCNC(=O)Cn1ccc2ccccc21)C1CCCCC1
Temperature: 25 °C

Procedure:
Indole (20 mg, 0.17 mmol) was dissolved in DMF (400 μL) and NaH (60% dispersed in mineral oil, 9 mg, 0.22 mmol) was added and the resultant mixture was stirred at 60° C. for 30 minutes. The mixture was then cooled to room temperature to it was added crude chloride 2a (˜50 mg; excess). The reaction solution was then heated to 60° C. for 2 hours. The reaction solution was cooled to room temperature and diluted in EtOAc and the organic solution was washed with H2O (2×) and brine (1×). The organic layer was dried (MgSO4) and concentrated to provide crude 3a which was purified by preparative TLC (2:1:0.4 EtOAc/hexanes/Et3N) to give the desired product 3a (7 mg, 13% yield): LC-MS (Method B, retention time=0.448 min. MS calc'd for C19H28N3O (MH+): 314.2. Found 314.5.
Reaction SMILES: Cl.[NH:2]1[CH2:6][C@H:5]([OH:7])[C@@H:4]([OH:8])[CH2:3]1.[Cl:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12](Cl)[N:11]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([N:2]2[CH2:6][C@H:5]([OH:7])[C@@H:4]([OH:8])[CH2:3]2)[N:11]=1
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(N2C[C@H](O)[C@@H](O)C2)nc(Cl)n1
Temperature: 50 °C
Yield: 82.6 %

Procedure:
A mixture of the (3S,4S)-pyrrolidine-3,4-diol hydrochloride (0.773 g, 5.54 mmol), methyl 2,6-dichloropyrimidine-4-carboxylate (1.038 g, 5.01 mmol), and iPr2NEt (2.00 mL, 11.5 mmol) in acetonitrile (25 mL) was heated at 50° C. for 3 h. The reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 25-75% acetone in hexanes. The product fractions were evaporated in vacuo to give methyl 2-chloro-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)pyrimidine-4-carboxylate as a light tan powder (1.132 g, 4.14 mmol, 83% yield). LC/MS: m/z=274.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:19]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][CH2:17][C:18]([NH:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: COc1ccc(CNC(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CNc2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
3.93 g of 3-chloro-2-methylaniline was dissolved in 10 mL of DMF, and 2.00 g of potassium carbonate was added thereto, followed by portionwise addition of 3.55 g of 2-bromo-N-(4-methoxybenzyl)acetamide over 1 hour. The mixture was stirred at room temperature overnight, and ice water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30 to 30:70) to obtain 2.89 g of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)glycinamide.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH2:13])=[O:6])[CH3:3].N1C=CC=CC=1.[C:20](Cl)(Cl)=[O:21].[C:24]1([C:30]2[CH:31]=[CH:32][C:33]3[O:37][C:36]([CH2:38][OH:39])=[CH:35][C:34]=3[CH:40]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:2]([O:4][C:5](=[O:6])[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:13][C:20]([O:39][CH2:38][C:36]1[O:37][C:33]2[CH:32]=[CH:31][C:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:40][C:34]=2[CH:35]=1)=[O:21])[CH3:3]
Reactant: CCOC(=O)c1ccncc1N
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccncc1NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 90 °C

Procedure:
To a solution of ethyl-3-aminopyridine-4-carboxylate hydrochloride (1.0 g, 4.93 mmol) and pyridine (1.2 ml, 14.8 mmol) in toluene (10 ml) at room temperature under argon was added 20% phosgene in toluene (3.7 ml, 7.15 mmol) and the mixture was heated at 90° C. for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness. The crude material was dissolved in toluene (10 ml), (5-phenyl-benzofuran-2-yl)-methanol (0.922 g, 4.11 mmol) and DMAP (0.05 g, 0.411 mmol) were added and the mixture was heated at 90° C. for 18 h. The solvent was evaporated to dryness. Purification by chromatography gave 0.538 g of 3-(5-phenyl-benzofuran-2-ylmethoxycarbonylamino)-isonicotinic acid ethyl ester as a white solid.
Reaction SMILES: CO.O.[OH-].[Li+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:11]([O:13]C)=[O:12].Cl>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccn2)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1-c1ccccn1
Temperature: 25 °C

Procedure:
To 154 mL of a 50/50 solution of MeOH and H2O was added lithium hydroxide monohydrate (13.85 g, 330 mmol). The solution was stirred until all of the salt dissolved, at which point methyl 3-methoxy-4-pyridin-2-ylbenzoate (8.02 g, 32.9 mmol) was added. The mixture was heated at reflux and stirred overnight. The reaction mixture was cooled to rt, neutralized with 6N HCl, and acidified to pH 4 with 1N HCl. A colorless solid crashed out of solution and was filtered to give 3-methoxy-4-pyridin-2-ylbenzoic acid as a colorless solid. 1H NMR (DMSO-d6, 300 MHz) δ 8.70 (d, 1H), 7.92–7.84 (m, 3H), 7.69–7.65 (m, 2H), 7.40–7.36 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][S:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[CH2:17][C:18]1[C:19]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=2[S:21][CH:22]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:27][C:25]1[CH:24]=[CH:23][C:20]2[S:21][CH:22]=[C:18]([CH2:17][C:16]3[N:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]4=[N:9][C:8]=3[S:7][CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])[C:19]=2[CH:26]=1
Reactant: COC(=O)CCCSc1nc2ccccn2c1Cc1csc2ccc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCSc1nc2ccccn2c1Cc1csc2ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A solution of 15 mg (0.04 mmol) of 4-[3-(5-chloro-benzo[b]thiophen-3-ylmethyl)-imidazo[1,2-a]pyridin-2-ylsulfanyl]-butyric acid methyl ester in 2 mL of THF is treated with a solution of 10 mg (0.24 mmol) of lithium hydroxide monohydrate in 1 mL of water at room temperature. The resulting mixture is heated to 50° C., and stirred at this temperature for 2 h. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The residue is purified by preparative TLC on silica gel to give the title compound. LCMS (ESMS): m/z 417 (M+H+).