Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1.[CH3:17][C:18]([CH3:20])=O.[BH3-]C#N.[Na+]>CO>[CH3:17][CH2:18][CH2:20][NH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[O:15])[CH:11]=2)[NH:6][CH:5]=1
Reactant: CC(C)=O
Reactant: NCCc1c[nH]c2ccc(NC(N)=O)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNCCc1c[nH]c2ccc(NC(N)=O)cc12
Reaction time: 18 h

Procedure:
A solution of 3.0 g (0.014 mole) of N-[3-(2-aminoethyl)-1H-indol-5-yl]urea, Example 1, in 100 ml MeOH was treated with 1.11 ml of acetone followed by 1.32 g (0.021 mole) of NaBH3CN and stirred for 18 hours. The solvent was removed in vacuo and the residue carefully dissolved in 20 ml of 20% HCl, heated for 15 minutes, cooled and neutralized with 4N NaOH to pH=12. The precipitated oil was extracted into EtOAc, dried over MgSO4, filtered and evaporated to give a glassy white solid. This material was purified by column chromatography (0.75% NH4OH/MeOH on silica gel) followed by recrystallization from acetone to give desired product: m.p. 145.5°-147°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13](NCCCN3CCCCC3)=[O:14])[N:12]=2)=[C:4]([NH:25][CH:26]([CH3:28])[CH3:27])[CH:3]=1.C(#N)C.[OH2:32]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:14])=[O:32])[N:12]=2)=[C:4]([NH:25][CH:26]([CH3:28])[CH3:27])[CH:3]=1
Reactant: O
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)NCCCN2CCCCC2)co1
Solvent: CC#N
Product: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)O)co1
Reaction time: 0.03 h

Procedure:
[2-(6-Chloro-4-(isopropylamino)pyridin-3-yl)-N-(3-(piperidin-1-yl)propyl)oxazole-4-carboxamide (40b)]: Ascentis Express C18, 5×2.1 mm, 2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min; retention time: 1.622 min; LCMS (ES-API), m/z 406.2 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH2:7])[CH:3]([CH3:6])[CH2:4][CH3:5].[CH2:8]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]=1[F:21])[C:9]#[CH:10]>>[CH3:1][CH:2]([NH:7][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:8][C:9]#[CH:10])=[C:13]([F:21])[CH:14]=1)[CH:3]([CH3:6])[CH2:4][CH3:5]
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Reactant: CCC(C)C(C)N
Product: C#CCOc1ccc(C(=O)NC(C)C(C)CC)cc1F

Procedure:
According to the same method as that of Production Example 1, 1,2-dimethylbutylamine was used in place of 2,2-dimethylpropylamine, and 4-(2-propynyloxy)-3-fluorobenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1,2-dimethylbutyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 26 of the present invention) represented by the formula:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[CH3:12])=[O:9]
Reactant: Cc1ccc(C(F)(F)F)cc1N
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)ccc2C)c1
Yield: 14.2 %

Procedure:
Using 5-methylsalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH2:4].[C:5](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[Br:1][CH2:2][CH2:3][NH:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: BrCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 62.7 %

Procedure:
To a solution of 2-bromoethanamine (5.00 g) and trityl chloride (6.80 g) in dichloromethane (24 mL) was slowly added triethylamine (7.48 mL) under ice-cooling, and the reaction mixture was stirred under ice-cooling for 2 hr. The resulting solid was removed by filtration, the filtrate was poured into water, and the mixture was extracted with dichloromethane. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from dichloromethane/cyclohexane to give the title compound (5.60 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:19])=O>C1C=CC=CC=1>[Cl:19][C:12]([CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])=[O:13]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)CCC(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a solution of 5 g of succinic acid monobenzyl ester in 60 ml of benzene was added 11 ml of oxalyl chloride. After 5 hrs at 20° C., gas evolution ceased and the solvent and excess oxalyl chloride was evaporated at 20° C. The residue was held at 1 torr for 1 hr to yield 5.19 g of crude benzyl 3-chloroformylpropionate; ir 1788 and 1735 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:25])[C:10]1[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=1.C(NC(C)C)(C)C.Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>ClCCl>[C:21]([C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([C:16]([CH3:18])([CH3:19])[CH3:17])[C:13]=1[OH:20])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:34](=[O:35])[O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2NC(=O)Oc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 8 h
Yield: 1095.8 %

Procedure:
N-(2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (0.85 g) and diisopropylamine (0.39 ml) were suspended in dichloromethane (20 ml) and a solution of phenyl chloroformate (16.8 g) in dichloromethane (30 ml) was added dropwise under ice-cooling. After stirring the mixture overnight, the reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4 and the solvent was distilled off. Purification of the residue by a silica gel column chromatography (chloroform:ethyl acetate=10:1) followed by crystallization from hexane/ethyl acetate afforded phenyl N-[2-(3,5-di-t-butyl-4-hydroxybenzoylamino)phenyl]carbamate (12.6 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:36]=[CH:35][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([O:33]C)=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1.[OH-].[Na+].O.Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]3)=[CH:35][CH:36]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1
Reactant: COC(=O)C1CCN(Cc2ccc(C3=C/C(=C4\C(=O)Nc5cc(F)c(F)cc54)OC3(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(CN2CCC(C(=O)O)CC2)cc1
Temperature: 50 °C

Procedure:
To a suspension of methyl 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylate (50 mg, 0.10 mmol) in MeOH (5 mL), was added 1M NaOH (1 mL). The mixture was heated in 50° C. bath for 1 hour, poured into 50 mL of water and neutralized with 0.5M HCl to pH 7. The precipitates were filtered, washed with water, and dried in vacuo to give 1-{4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzyl}piperidine-4-carboxylic acid as a yellow solid. Yield: 9 mg, 19%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[O:4][C:3]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=2[Cl:1])[CH2:11][CH2:12]1)(=[O:34])[CH3:33]
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.3 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and acetyl chloride (0.023 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give N-(1-acetylpiperidin-4-yl)-2-(2,4-dichlorophenoxy)benzamide (84 mg, 75%) as an oil. Rf: 0.15 (EtOAc) LC/MS (APCI) tr=3.78 min, m/z 409.31 (67), 407.36 (M++H, 100). HPLC tr=2.69 min (96.74%) 1H NMR (270 MHz, CDCl3) δ 1.38 (2H, m, CH2), 2.00 (2H, m, CH2), 2.08 (3H, s, CH3), 2.84 (1H, m, ½CH2), 3.74 (1H, m, ½CH2), 4.18 (1H, m, CH), 4.41 (1H, m, ½CH2), 6.79 (1H, dd, J=8.2, 1.0 Hz, ArH), 6.88 (1H, d, J=8.6 Hz, ArH), 7.22 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.26 (1H, m, ArH), 7.37 (1H, br s, NH), 7.41 (1H, m, ArH), 7.51 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.9, 1.7 Hz, ArH).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=1[OH:18]>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]([CH3:22])[C:20]#[N:21])[CH:15]=[CH:16][C:17]=2[OH:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C#N)c1ccc(O)c(N)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C#N)c1ccc(O)c(NC(=O)Cc2ccccc2)c1
Temperature: 100 °C

Procedure:
Phenyl acetyl chloride (28.0 g.) was added over 20 minutes to a cooled stirred solution of 2-(3-amino-4-hydroxyphenyl) propionitrile (29.0 g.) in anhydrous pyridine (200 ml.) at 0°-3° C. After addition was complete, the mixture was heated at 100° C. for 1 hour. After evaporation under reduced pressure, 2-(3-phenylacetamido-4-hydroxyphenyl)propionitrile was isolated as an oil.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][CH:13]=1.CN(C)[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:18]=1>[Cl-].[Zn+2].[Cl-].ClC1C=CC=CC=1>[CH2:7]([O:8][C:17]1[CH:18]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:20]=[CH:21][C:22]=1[C:10]([C:5]1[CH:4]=[CH:3][CH:13]=[CH:12][C:6]=1[C:7]([OH:9])=[O:8])=[O:11])[CH:6]([CH3:12])[CH3:5]
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CN(C)c1ccc2c(c1)C(=O)OC2=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CC(C)COc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O

Procedure:
In a manner similar to that of part A of Example 3 condensation of 4-(dimethylamino)phthalic anhydride (1.91 g.) and N,N,N',N'-tetramethyl-m-phenylenediamine (1.64 g.) in contact with zinc chloride (2.70 g.) and with chlorobenzene (50 ml.) as diluent afforded 2-(2,4-bis(dimethylamino)benzoyl)-4-(dimethylamino)benzoic acid (II: Y'2 = Y'4 = Z'5 = (CH3)2N, Z4 = Z'6 = Z7 = H) (m.p. 216°-222° C.) or the 5-(dimethylamino) isomer thereof.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][O:27][CH3:28])=[CH:21][C:20]=2[OH:29])=[O:18])=[CH:11][C:10]=1[O:30][CH2:31][O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:34].[Na+].OO>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:29][C:20]3[C:19]([C:17](=[O:18])[C:16]=2[OH:34])=[CH:24][CH:23]=[C:22]([O:25][CH2:26][O:27][CH3:28])[CH:21]=3)=[CH:11][C:10]=1[O:30][CH2:31][O:32][CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: COCOc1ccc(C(=O)/C=C/c2ccc(OCc3ccccc3)c(OCOC)c2)c(O)c1
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COCOc1ccc2c(=O)c(O)c(-c3ccc(OCc4ccccc4)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
To (E)-3-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-1-(2-hydroxy-4-(methoxymethoxy)phenyl)prop-2-en-1-one (450 mg, 1 mmol) in 1.5 mL MeOH was added 4 mL of a 15% NaOH solution, followed by hydrogen peroxide (113 mg, 30% solution). The mixture was stirred at rt for 2 h and additional 226 mg of hydrogen peroxide was added. The reaction was stirred for 15 and quenched onto NaH2PO4 (sat. 50 mL). It was extracted with EtOAc (3×50 mL) and the combined organic phase was dried over MgSO4 and concentrated. The residue was chromatographed (hexane/EtOAc) to afford 2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3-hydroxy-7-(methoxymethoxy)-4H-chromen-4-one as a off-white solid (55 mg, 12%). MS (ESI) m/z 465 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11](O)=[O:12])[CH:6]=1.C[N:18]1CCOCC1.ClC(OCC(C)C)=O.[OH-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([NH2:18])=[O:12])[CH:6]=1
Reactant: O=C(O)c1cccc(Cn2cc(Br)cn2)c1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cccc(Cn2cc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
To a solution of 3-((4-bromo-1H-pyrazol-1-yl)methyl)benzoic acid (0.20 g, 0.711 mmol) in THF (3.5 mL) at 0° C. was added N-methylmorpholine (0.086 g, 0.854 mmol), and isobutyl chloroformate (0.107 g, 0.783 mmol) slowly. The reaction was stirred at 0° C. for 1.5 h and ammonium hydroxide (0.249 g, 7.11 mmol) was slowly added. The reaction was allowed to warm to room temperature where it stirred overnight. At the conclusion of this period, the reaction mixture was partitioned between DCM and water. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography (0-100% ethyl acetate:hexanes) to afford the title compound (0.188 g, 94%). LCMS, [M+H]+=280.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:7]=[N:8][C:9]([N+:12]([O-])=O)=[CH:10][CH:11]=1.[C:16]1([C:22]2[O:23][C:24]([C:30]([F:33])([F:32])[F:31])=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:27]([C:25]2[N:26]=[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:23][C:24]=2[C:30]([F:32])([F:33])[F:31])=[O:28])=[N:8][CH:7]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCCN(C)c1ccc([N+](=O)[O-])nc1
Product: COCCN(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)nc1

Procedure:
With a procedure similar to example 66 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {5-[(2-methoxy-ethyl)-methyl-amino]-pyridin-2-yl}amide was prepared from (2-methoxyethyl)-methyl-(6-nitropyridin-3-yl)-amine and 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid. The product was isolated as a yellow solid (200 mg, 37% yield). HRMS m/z calcd for C20H19F3N4O3 [M+H]+: 421.1482; Found: 421.1481.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([CH3:8])[C:4](=[O:9])[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C>CS(C)=O>[CH3:8][N:5]1[CH:6]=[CH:7][C:2]([NH:13][C:14]2[CH:15]=[C:16]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=[CH:18][CH:19]=2)=[C:3]([N+:10]([O-:12])=[O:11])[C:4]1=[O:9]
Reactant: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Reactant: N#Cc1ccccc1-c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cn1ccc(Nc2cccc(-c3ccccc3C#N)c2)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Yield: 97.3 %

Procedure:
4-Chloro-1-methyl-3-nitro-1H-pyridin-2-one (0.71 g, 3.8 mmol) and 3′-aminobiphenyl-2-carbonitrile (0.73 g, 3.8 mmol) were dissolved in triethylamine (5.25 ml, 37.8 mmol) and DMSO (5 ml) and heated at 90° C. for 18 h. The mixture was allowed to cool to ambient temperature then poured onto water (150 ml). The aqueous phase was extracted with ethyl acetate (2×150 ml), the combined organics were washed with water (3×75 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown solid. The solid was triturated with diethyl ether (20 ml), filtered and left to air dry, to give 3′-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-ylamino)biphenyl-2-carbonitrile (1.28 g, 98%) as a brown solid: δ (400 MHz, CDCl3) 3.50 (3H, s), 6.24 (1H, d, J 8), 7.26 (1H, d, J 8), 7.34 (1H, d, J 8), 7.48 (2H, dd, J 4 and 2), 7.51-7.59 (2H, m), 7.60 (1H, t, J 8), 7.68-7.72 (1H, m), 7.81 (1H, dd, J 8 and 1), 10.47 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:14]Cl)=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12].[SH:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>CC(O)C>[NH:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[S:16][CH2:14][C:3]1[C:2]([Cl:1])=[C:7]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][N:4]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CN(CCCO)c1ccnc(CCl)c1Cl
Solvent: CC(C)O
Product: CN(CCCO)c1ccnc(CSc2nc3ccccc3[nH]2)c1Cl
Temperature: 4 °C

Procedure:
A solution of 3-[(3-chloro-2-chloromethyl-pyridin-4-yl)-methyl-amino]-propanol isolated in step a) (5.3 g) and 2-mercapto-benzimidazole (2.2 g, 14.6 mmol) in 2-propanol (150 ml) is boiled under reflux for 2 h. After cooling to 4° C. the precipitate is filtered, washed with 2-propanol and dried in vacua. The residue is dissolved in water, adjusted to pH 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is crystallized from ethyl acetate to give the title compound as an off-white solid, 3.6 g (46%). M.p. 127-30° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23]>C(OCC)(=O)C>[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23]
Reactant: COCOc1ccc(C=O)cc1C(C)C
Reactant: Cc1cc(O)ccc1Br
Solvent: CCOC(C)=O
Product: COCOc1ccc(Cc2ccc(O)cc2C)cc1C(C)C

Procedure:
Intermediate 4-(4′-methoxymethoxy-3′-iso-propylbenzyl)-3-methyl-phenol was prepared from 4-bromo-3-methyl-phenol (J. Med. Chem. 1980, 12, 1350) and 4-methoxymethoxy-3-iso-propylbenzaldehyde according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and transformed into the title compound by the procedure used for the synthesis of compound 7. 1H NMR (300 MHz, DMSO-d6): δ 9.04 (s, 1 H), 7.02-6.99 (d, J=8.7 Hz, 1 H), 6.92 (s, 1 H), 6.81-6.76 (m, 2 H), 6.67 (s, 2 H), 4.03 (d, J=10.5 Hz, 2 H), 3.76 (s, 2 H), 3.16-3.14 (m, 1 H), 2.19 (s, 3 H), 1.14-1.12 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate; Rf=0.11;
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]([NH:12][NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[C:20](OC)(OC)(OC)[CH3:21]>CCO>[I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][C:8]3[N:9]2[C:20]([CH3:21])=[N:13][N:12]=3)=[CH:4][CH:3]=1
Reactant: NNc1cc(-c2ccccc2)c2ccc(I)cc2n1
Reactant: COC(C)(OC)OC
Solvent: CCO
Product: Cc1nnc2cc(-c3ccccc3)c3ccc(I)cc3n12
Temperature: 80 °C

Procedure:
To (7-Iodo-4-phenyl-quinolin-2-yl)-hydrazine (400 mg, 1.1 mmol) in EtOH (5 mL) was added trimethyl orthoacetate (2 mL), and the reaction was heated to 80° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by silica gel chromatography (40-100% EtOAc in hexanes) to give the desired product, 5u.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C[O:17][C:18]([C:20]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:19].C1COCC1.[Li+].[OH-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:26][C:25]2[C:20]([C:18]([OH:19])=[O:17])=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: COC(=O)c1ncccc1N
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)c1ncccc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
Prepared from 0.60 g (2.17 mmol) of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride and 0.30 g (1.97 mmol) of 3-amino-pyridine-2-carboxylic acid methyl ester in 3 mL pyridine using procedure x. The solvent was switched to THF, followed by the addition of 1 M aqueous LiOH and the mixture stirred for 1 h. The pH of the mixture was adjusted to neutral and the product was extracted with ethyl acetate. LC-MSD, m/z for C13H8ClF3N2O4S [M+H]+=380.9, 383.0; HPLC retention time: 1.8 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH:9]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-3-oxopropionate (20 g, 95.1 mmol), 4-fluorobenzyl bromide (18.0 g, 85.6 mmol), potassium carbonate (26.3 g, 0.19 mol) and acetonitrile (300 ml) was stirred at 60° C. for 2 hrs. The reaction solution was concentrated under reduced pressure, water (200 ml) was added, and the mixture was extracted with ethyl acetate (200, 100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:toluene=1:1-1:5) to give ethyl 2-(4-fluorobenzyl)-3-(4-fluorophenyl)-3-oxopropionate (19.0 g, 63%) as an oil.
Reaction SMILES: [C:1]([C:3](=[C:9]([O:11][CH2:12][CH3:13])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[C:1]([C:3](=[C:9]([O:11][CH2:12][CH3:13])[CH:10]=[CH:16][N:17]([CH3:19])[CH3:18])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Product: CCOC(=O)C(C#N)=C(C=CN(C)C)OCC
Temperature: 70 °C

Procedure:
A mixture of ethyl 2-cyano-3-ethoxybut-2-enoate (194 g theory, 1.06 mol) and N,N-dimethylformamide dimethyl acetal (160 g, 1.325 mol) was heated at 70° C. for 2 h. The mixture was concentrated under high vacuum to provide crude ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate. The residue was used directly without further purification.