Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]1([N:13]2[C:26]3[CH:25]=[CH:24][C:23]([CH:27]=O)=[CH:22][C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OP([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH2:50]P(OCC)(OCC)=O)=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)(=O)OCC)C>CS(C)=O>[C:7]1([N:13]2[C:26]3[CH:25]=[CH:24][C:23]([CH:27]=[CH:50][C:47]4[CH:46]=[CH:45][C:44]([C:41]5[CH:40]=[CH:39][C:38]([CH:37]=[CH:1][C:2]6[CH:5]=[CH:25][C:26]7[N:13]([C:7]8[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=8)[C:14]8[C:19]([S:20][C:21]=7[CH:3]=6)=[CH:18][CH:17]=[CH:16][CH:15]=8)=[CH:43][CH:42]=5)=[CH:49][CH:48]=4)=[CH:22][C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccc2c(c1)Sc1ccccc1N2c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(-c2ccc(CP(=O)(OCC)OCC)cc2)cc1)OCC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C(=Cc1ccc2c(c1)Sc1ccccc1N2c1ccccc1)c1ccc(-c2ccc(C=Cc3ccc4c(c3)Sc3ccccc3N4c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.73 g (24.1 mmol) of potassium tert-butoxide and then 7.80 g (25.7 mmol) of 10-phenylphenothiazine-3-carbaldehyde were added under nitrogen at room temperature with stirring to a solution of 4.83 g (10.7 mmol) of diethyl[4′-(diethoxyphosphorylmethyl)biphenyl-4-ylmethyl]phosphonate in 80 ml of dimethyl sulfoxide dried over molecular sieve. After stirring at room temperature for four hours, the reaction solution was diluted with 200 ml of methanol and stirred for a further 15 min. The precipitate was filtered off, washed with 500 ml of methanol and dried at 35° C. under reduced pressure. The crude product (5.85 g) was recrystallized in 400 ml of toluene. 3.85 g of yellow solid having a melting point of 278-290° C. were obtained.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f18) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])[CH:16]=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:20]1C=CC=[CH:22][CH:21]=1.C([O-])(=O)C.[NH4+].C(CC(O)=O)#N>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH3:19])([CH3:18])/[CH:16]=[CH:22]/[C:21]#[N:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C=O)c1cccc(OCc2ccccc2)c1
Reactant: c1ccncc1
Agent: CC(=O)[O-]
Agent: N#CCC(=O)O
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(/C=C/C#N)c1cccc(OCc2ccccc2)c1
Yield: 91 %

Procedure:
To a solution of benzyloxy aldehyde III (320 g, 1.26 mol) in toluene (1.2 L) was added pyridine (600 mL), ammonium acetate (15 g, 0.19 mol) and cyanoacetic acid (200 g, 2.35 mol) and the mixture was refluxed for 72 hours. The reaction was diluted with ethyl acetate (3.5 L), washed with water (2 L) and washed with 1N HCl (until pH of the water layer becomes acidic), washed with brine (1 L) and the organic layer was dried and concentrated under reduced pressure to yield 317 g (91 %) cyanide XXXIV. M+1=278
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH:26]([CH3:30])[CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.Cl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:29][CH2:28][CH2:27][CH:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:21]=1)[CH3:30])(=[O:3])=[O:2]
Reactant: CC(CCO)c1cccc(OCc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)c2cccc(OCc3ccccc3)c2)cc1
Reaction time: 18 h

Procedure:
Tosyl chloride (9.8 g., 51 mM) is added to a solution of 3-(3-benzyloxyphenyl)-1-butanol (12.8 g., 50 mM) in pyridine (90 ml.) at -45° C. The reaction mixture is held at -35° C. for 18 hours and is then diluted with cold 2 N hydrochloric acid (1500 ml.) and extracted with ether (5×250 ml.). The combined extracts are washed with saturated sodium chloride solution (4×250 ml.) and then dried (Na2SO4). Concentration of the dried extract affords the product as an oil. It is crystallized by treatment with ether-hexane.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([NH:13][C:14](=[O:37])[CH2:15][CH:16]([NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCOc2cc(CO)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(7-Formyl-chroman-4-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide (Example 1, Step G) (1.83 g, 3.56 mmol) was dissolved in a 1:1 solution of THF and MeOH (100 mL). The solution was cooled to 0° C. and NaBH4 (0.135 g, 3.56 mmol) was added. The reaction was stirred for 30 min. The volatiles were removed in vacuo and the resulting residue was dissolved in EtOAc and washed sequentially with a saturated NaHCO3 solution and brine. The aqueous phases were extracted once with EtOAc. The organic phases were combined, dried over MgSO4, filtered, and concentrated in vacuo to provide the title compound. MS (ESI) m/z 517 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].O.CO>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A mixture of methyl 2-chloro-4-(1-phenoxyethyl)benzoate (750 mg, 2.7 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), water (5 mL) and methanol (5 mL) in tetrahydrofuran (15 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 2-chloro-4-(1-phenoxyethyl)benzoic acid as a white solid (500 mg, 71%). LRMS (M+H+) m/z: 276.06. found 276.
Reaction SMILES: [NH4+].[NH4+].Cl[Pd-2:4](Cl)(Cl)(Cl)(Cl)Cl.O.O.O.O.O.O.[N+:16]([O-:19])([O-:18])=[O:17].[Mg+2].[N+:21]([O-:24])([O-:23])=[O:22]>>[Pd:4].[N+3:16].[N+:21]([O-:24])([O-:23])=[O:22].[N+:16]([O-:19])([O-:18])=[O:17].[N+:16]([O-:19])([O-:18])=[O:17]
Reactant: Cl[Pd-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: O=[N+]([O-])[O-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: O
Product: [N+3]
Product: [Pd]

Procedure:
The same equipment, materials and procedure used in Example II were used in Example IX except that sufficient ammonium hexachloropalladate and magnesium nitrate hexahydrate were added to 400 g of the cut strip tobacco blend of Example VIII to give a concentration of 0.06 percent by weight metallic palladium and 0.4 percent by weight of added nitrate nitrogen in the final blend.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:15][C:16]([F:40])([F:39])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]>>[F:15][C:16]([F:39])([F:40])[CH2:17][NH:18][C:19]([C:21]1([CH2:34][CH2:35][CH2:36][CH2:37][N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][CH2:11]2)[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-(3,4-dichlorophenyl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.C(Cl)(=O)C(Cl)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:23][NH:24][O:25][CH3:26]>C1C=CC=CC=1.ClCCl.N1C=CC=CC=1.Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:23][N:24]([O:25][CH3:26])[C:8](=[O:10])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:1])([CH3:12])[O:6]1
Reactant: CONCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
A suspension of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid (4.37 g, 25.4 mmol) in benzene (30 mL) was refluxed for 1 h with oxalyl chloride (15 mL). The resulting solution was cooled and concentrated. The residue was dissolved in dichloromethane (30 mL) and cooled to 0° C. and N-(3,4-dichloro-benzyl)-O-methyl-hydroxylamine (5.3 g, 22 mmol) in dichloromethane (30 mL) and pyridine (18 mL) was added dropwise. The resulting mixture was stirred at room temp for 18 h. The mixture was diluted with 1N HCl and extracted with EtOAc. The organic phase was washed with 1N HCl, dried (sodium sulfate) and concentrated to give the title compound as a yellow solid (7.59 g, 83% yield). 1HNMR (300 MHz, CDCl3) δ: 7.44 (1H, s), 7.39 (2H, d, J=8.05 Hz), 7.19 (2H, d, J=8.05 Hz), 6.37 (1H, s), 4.75 (2H, s), 3.70 (3H, s), 1.74 (6H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10].C(OC)(OC)OC.[C:21]([O:25][C:26](=[O:37])[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31][CH:30]=1)([CH3:24])([CH3:23])[CH3:22].[BH4-].[Na+]>CO>[C:21]([O:25][C:26](=[O:37])[NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])=[CH:33][CH:34]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: CCCN(CCC)CCOCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCOCCNCc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
The compound (81.0 mg) obtained in Example 90-3 was dissolved in anhydrous methanol (2.0 ml) and added with trimethyl orthoformate (94.1 μl) and the compound (101 mg) obtained in Example 23-3 and the whole was stirred overnight at room temperature under a nitrogen atmosphere. Subsequently, sodium borohydride (32.6 mg) was added thereto in an ice bath and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with distilled water and the whole was stirred for a while. The resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (158 mg) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+].COC1C2OC3C=CC=CC=3C=2C=CC=1[N+]([O-])=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1oc1ccccc12
Reactant: O=[N+]([O-])O
Agent: COc1c([N+](=O)[O-])ccc2c1oc1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c2c1oc1ccccc12
Reaction time: 3 h
Yield: 48 %

Procedure:
To a solution of 4-methoxy-dibenzofuran (3.15 g; 15.89 mmol) in glacial acetic acid (50 mL), fuming nitric acid (2.6 mL; 63.50 mmol) was added dropwise. The reaction was kept at 20° C. during the addition and stirred for 3 h. Upon completion, the reaction mixture was poured carefully onto iced water; pH was adjusted to 7 by addition of 1 M sodium hydroxide, and the product was extracted in DCM. The organic layer was dried on magnesium sulfate, filtered and then concentrated. The residue was purified by flash chromatography using ethyl acetate/EP (1:19) as eluant. The first compound to come off the column was the 4-methoxy-3-nitro-dibenzofuran (270 mg, 1.11 mmol, 7%) then the title compound (1.85 g, 7.62 mmol, 48%) was obtained as a cream solid: Rf=0.13 (EtOAc-EP 1:19); mp: 155-156° C.; λmax (EtOH)/nm 239; IR (cm−1) 3092, 2917, 2851, 2042, 1876, 1630, 1568, 1506, 1438, 1396, 1342, 1297, 1274, 1239, 1205, 1159, 1129, 1091, 1002, 938, 888, 831, 812, 738, 676; 1H NMR, (300 MHz, CDCl3) δ 4.06 (3H, s, OCH3), 6.92 (1H, d, J=8 Hz), 7.18 (1H, t, J=8 Hz), 7.36 (2H, m), 8.17 (1H, d, J=8 Hz), 8.63 (1H, d, J=8 Hz); 13C NMR, (75 MHz, CDCl3) δ 56.81 (OCH3), 107.53, 111.81, 120.50 (Cq), 121.14 (Cq), 122.27, 123.71, 126.32, 129.55, 136.29 (Cq), 145.20 (Cq), 150.53 (Cq), 157.02 (Cq); MS (EI) m/z 243.1 M+; HRMS calcd for C13H9NO4 [M+H]+ 243.0526, found 243.0528.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][S:9][C:5]=2C(O)=[N:3][C:2]=1O.O=P(Cl)(Cl)[Cl:14].O.Cl[CH2:19][Cl:20]>>[Cl:14][C:2]1[N:3]=[C:19]([Cl:20])[C:5]2[S:9][CH2:8][CH2:7][C:6]=2[N:1]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(O)c2c(n1)CCS2
Reactant: ClCCl
Solvent: O
Product: Clc1nc(Cl)c2c(n1)CCS2
Reaction time: 0.33 h

Procedure:
500 mg 6,7-Dihydro-thieno[3,2-d]pyrimidine-2,4-diol and 10 mL phosphoroxychloride was stirred 30 min at 140° C. under microwave conditions. The reaction was added to water and then dichlormethane was added. The mixture was stirred for 20 min. The layers were separated and the dichlormethane layer was evaporated to give 586 mg of the desired product.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[O:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[CH:21]=2)=[N:13][N:12]=1)[CH:8]([CH3:10])[CH3:9].IC>CN(C)C=O>[CH3:1][O:24][C:23](=[O:25])[CH2:22][C:20]1[CH:21]=[C:16]([C:14]2[O:15][C:11]([CH2:7][CH:8]([CH3:10])[CH3:9])=[N:12][N:13]=2)[CH:17]=[CH:18][C:19]=1[CH3:26]
Reactant: Cc1ccc(-c2nnc(CC(C)C)o2)cc1CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(-c2nnc(CC(C)C)o2)ccc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.9 %

Procedure:
A suspension of potassium carbonate (0.56 g, 4.05 mmol), [5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl]-acetic acid (1.01 g, 3.68 mmol) and iodomethane (0.33 mL, 5.26 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water. The combined organic phase was washed with water and brine, dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with 0-40% ethyl acetate in hexanes to give [5-(5-isobutyl-[1,3,4]oxadiazol-2-yl)-2-methyl-phenyl]-acetic acid methyl ester (Yield: 0.54 g, 51%).
Reaction SMILES: [C:1](#N)[CH3:2].[OH:4][N:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][C:6]1([CH3:23])[CH3:22].OO.S([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C.C1CCCCC1>[CH:2]1([O:4][N:5]2[C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([O:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][C:6]2([CH3:23])[CH3:22])[CH2:1][CH2:8][CH2:7][CH2:6][CH2:22]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC#N
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 62 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
2,2′-Dipyridyl (0.056 g, 0.36 mmol) is stirred with 28 ml of acetonitrile. To the acetonitrile solution is added a solution of 0.098 g (0.36 mmol) of ferric chloride hexahydrate in 2 ml of water. This purple mixture is stirred for 10 minutes prior to adding 19 ml of cyclohexane and 5.00 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine. A solution of 3.84 g (69.5 mmol) of 50% aqueous hydrogen peroxide is added to the reaction mixture dropwise over 2.25 hours while the temperature is brought to and maintained at 62° C. After the peroxide is added, the reaction mixture is heated at reflux for 1 hour. The reaction mixture is cooled, and peroxide is decomposed by the addition of aqueous sodium sulfite solution. Ethyl acetate is added, and the organic layer is washed with water. The organic layer is concentrated, and the concentrate is purified by flash chromatography with 20:1 heptane-ethyl acetate to afford 4.82 g (74% yield) of the title compound. GC assay is 100%.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:13][CH:14]=2)[N:9]([CH3:22])[CH:8]=1>ClCCl>[ClH:3].[Cl:3][CH2:6][C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][C:12]([C:18]([F:21])([F:20])[F:19])=[CH:13][CH:14]=2)[N:9]([CH3:22])[CH:8]=1
Reactant: Cn1cc(CO)c(=O)c2ccc(C(F)(F)F)cc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: Cn1cc(CCl)c(=O)c2ccc(C(F)(F)F)cc21

Procedure:
A solution of thionyl chloride (2.32 g.) in dichloromethane (100 ml.) was added during 1.5 hours to a refluxing suspension of finely ground 3-hydroxymethyl-1-methyl-7-trifluoromethyl-4-quinolone (5.0 g.) in dichloromethane (200 ml). The solution was boiled under reflux for a further 0.5 hours then evaporated to dryness under reduced pressure to give the novel 3-chloromethyl-1-methyl-7-trifluoromethyl-4-quinolone hydrochloride, m.p. 182°-189°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH:7]=1.C(N(CC)CC)C.[C:25](Cl)(Cl)=[S:26]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH:13]3[CH2:16][CH2:15][CH2:14]3)[C:25]2=[S:26])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1NCCCNC1CCC1
Reactant: S=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1N1CCCN(C2CCC2)C1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.9 %

Procedure:
To an ice-cold solution of the diamine of Step A (3.6 g) and triethylamine (3.8 mL) in dry chloroform (40 mL) under nitrogen was added thiophosgene (1.7 mL). After 10 minutes at ambient temperature, the reaction was quenched with water and extracted with dichloromethane. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give a brown solid. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 11% ethyl acetate in hexane to 8:1:1 hexane-ethyl acetate-dichloromethane) provided pure material which was triturated with diethyl ether to give the title product (2.3 g, 54.9%) as a white solid, m.p. 152-154° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][C@@H:7]([OH:12])[CH2:8][C:9]([OH:11])=[O:10].[CH3:13]O>>[ClH:3].[NH2:5][CH2:6][C@@H:7]([OH:12])[CH2:8][C:9]([O:11][CH3:13])=[O:10]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: NC[C@@H](O)CC(=O)O
Product: COC(=O)C[C@H](O)CN
Product: Cl
Temperature: 62 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (3 mL) was added to a cold (0° C.) stirred solution of (S)-4-amino-3-hydroxybutanoic acid (300 mg, 2.9 mmol) in MeOH (3 mL) and continued stirring at 62° C. for 12 h. The reaction mixture was concentrated under reduced pressure to afford 300 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH:16]=O)=[CH:12][C:11]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][N:32]([CH2:16][CH2:15][CH2:14][C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[C:11]([CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=2)[CH2:31][CH2:30]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(OC)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(OC)cc2)n1

Procedure:
308 mg (78%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-methoxyphenyl)-3-butyl-1H-pyrazol-5-yl)propanal (251 mg, 0.876 mmol), 1-(2-fluorophenyl)piperazine (208 mL, 1.314 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:7].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:45][N:46]([CH2:48][C:49]1[CH:50]=[C:51]([NH2:55])[CH:52]=[CH:53][CH:54]=1)[CH3:47]>CN(C=O)C>[CH3:47][N:46]([CH2:48][C:49]1[CH:50]=[C:51]([NH:55][C:13]([C:12]2[CH:11]=[C:10]([CH:18]=[CH:17][CH:16]=2)[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:3]([O:2][CH3:1])[CH:4]=2)=[O:15])[CH:52]=[CH:53][CH:54]=1)[CH3:45].[CH:13]([O-:15])=[O:14]
Reactant: CN(C)Cc1cccc(N)c1
Reactant: COc1ccc(C(=O)NCc2cccc(C(=O)O)c2)cc1OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NCc2cccc(C(=O)Nc3cccc(CN(C)C)c3)c2)cc1OC
Product: O=C[O-]
Reaction time: 1 h
Yield: 1399.3 %

Procedure:
3-[(3,4-Dimethoxy-benzoylamino)-methyl]-benzoic acid (40 mg, 0.127 mmol), prepared as described in Example 8, was combined with EDC (38.3 mg, 0.2 mmol) and HOBt (24.3 mg, 0.18 mmol) in a reaction vial, and DMF (1 mL) was added followed by N-methylmorpholine (0.025 mL, 0.22 mmol). The resulting mixture was agitated for 1 h, then 3-dimethylaminomethyl-phenylamine (25.5 mg, 0.17 mmol) was added as a solution in DMF (0.5 mL), and the resulting mixture was agitated overnight. The product was purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient providing the title compound as a formate salt (40 mg, 70% yield), MS analysis electrospray, 448 (M+H).