Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[H-].[Na+].I[CH3:13]>C1COCC1>[CH3:13][O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CCCCC(O)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(OC)C(=O)O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2-Hydroxy caproic acid (152 mg, 1.15 mmol) was dissolved in 3 mL anhydrous THF. Sodium hydride (95%, 61 mg, 2.41 mmol) was added and the mixture was stirred at room temperature for 40 min. Iodomethane (0.7 mL) was added and the mixture was stirred at room temperature overnight. It was quenched with water, stirred for 4 hours to hydrolyze the methyl ester, and then adjusted to pH 4 with 10% citric acid. The mixture was extracted with 5% methanol in dichloromethane, organic layer dried over sodium sulfate, filtered, and the filtrate was concentrated to give the crude 2-methoxy caproic acid which was used in next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][CH:9]=[N:8][C:7]=2[C:11]([O:13]C)=[O:12])=[CH:2]1.[OH-].[K+]>CO>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[O:10][CH:9]=[N:8][C:7]=2[C:11]([OH:13])=[O:12])=[CH:2]1
Reactant: COC(=O)c1ncoc1-c1ccoc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ncoc1-c1ccoc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
3 g of methyl 5-(3-furyl)oxazole-4-carboxylate and 2.6 g of 85% potassium hydroxide are dissolved in 100 ml of methanol, and the solution is stirred at room temperature overnight. Then, the reaction mixture is evaporated under reduced pressure to remove solvent, and the residue is acidified with dil. hydrochloric acid. The precipitated crystals are collected by filtration, washed with cold water and then dried. 2.6 g of 5-(3-furyl)oxazole-4-carboxylic acid are thereby obtained. Yield: 93.7%
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].[CH3:5][N:6]1[C:14]2[CH:13]=[C:12]([N:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:17][C:16]3=[O:31])[CH:11]=[CH:10][C:9]=2[C:8]2[CH2:32][NH:33][CH2:34][CH2:35][C:7]1=2.CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:33]1[CH2:34][CH2:35][C:7]2[N:6]([CH3:5])[C:14]3[CH:13]=[C:12]([N:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][N:22]=5)=[CH:17][C:16]4=[O:31])[CH:11]=[CH:10][C:9]=3[C:8]=2[CH2:32]1)(=[O:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCc2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
AcCl (0.03 mL, 0.4 mmol) was added to a solution of 1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (125 mg, 0.294 mmol), DMAP (7 mg, 0.06 mmol) and Et3N (0.08 mL, 0.6 mmol) in CH2Cl2 (10 mL) under N2, and the resulting solution was stirred at 25° C. for 17 h. H2O was added to the solution, and the phases were separated. The organic phase was washed with saturated NH4Cl solution, dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (116 mg, 84%) as a mixture of rotomers as a white powder: mp 232-236° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.59-7.54 (m, 2H), 7.28 (d, J=1.5 Hz, 1H), 7.08-7.03 (m, 2H), 4.70 (s, 0.8H), 4.68 (s, 1.2H), 3.88 (t, J=5.5 Hz, 0.8H), 3.83 (t, J=5.5 Hz, 1.2 H), 3.67 (s, 3H), 2.97-2.91 (m, 1.2H), 2.86-2.81 (m, 0.8H), 2.15 (s, 1.8H), 2.13 (s, 1.2H); ESI MS m/z 467 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2)[CH3:2].Cl.[CH3:20][N:21]([CH3:26])[CH2:22]CC[Cl:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:25].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:2][CH2:1][N:3]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6](=[O:14])[C:5]2[N:15]([CH3:18])[N:16]=[CH:17][C:4]1=2
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Reactant: CN(C)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2CCCN(C)C
Temperature: 100 °C
Reaction time: 6 h
Yield: 78.8 %

Procedure:
A mixture of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (UK-264650) (EXAMPLE 47, step 2, 100 mg, 0.375 mmol), 3-(dimethylamino)propyl chloride hydrochloride (178 mg, 1.13 mmol) and potassium carbonate (311 mg, 2.25 mmol) in N,N-dimethylformamide (2 ml) was stirred at 100° C. for 6 h. After cooling to room temperature, water (50 ml) was added and extracted with ethyl acetate (50 ml×3). The combined organic layer was dried over magnesium sulfate and evaporated. To this residue (106 mg) was added methanolic hydrochloric acid and the mixture was concentrated in vacuo. The solid was recrystallized from ethanol/diisopropyl ether to give 99 mg (79%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.[F:11][C:12]([F:19])([F:18])[C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[CH3:10][C:5]1[C:6]([S:8][CH3:9])=[N:7][C:2]([N:15]2[CH:16]=[CH:17][C:13]([C:12]([F:19])([F:18])[F:11])=[N:14]2)=[N:3][CH:4]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: CSc1nc(Cl)ncc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CSc1nc(-n2ccc(C(F)(F)F)n2)ncc1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 350 %

Procedure:
A mixture of 2-chloro-5-methyl-4-methylthiopyrimidine (2.5 g, 14 mmol), 3-(trifluoromethyl)-1H-pyrazole (2.3 g, 2.5 mmol) and potassium carbonate (4.8 g, 35 mmol) in 25 mL of N,N-dimethylformamide was heated at 70° C. with stirring for 5 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed twice with water and brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to provide a white solid which was suspended in hexane and filtered to provide 2.4 g of the title compound of Step B as a solid melting at 126-127° C. 1H NMR (CDCl3): δ 8.63 (d, 1H), 8.24 (s, 1H), 6.73 (d, 1H), 2.68 (s, 3H) 2.25 (s, 3H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:22](=[O:29])([O:26]CC)[O:23]CC)[P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:31]>C(O)C>[Na+:31].[C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([P:14](=[O:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])[P:22](=[O:23])([OH:29])[O-:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(OCC)C(NCCCCSc1ccccc1)P(=O)([O-])O

Procedure:
To a solution of tetraethyl 4-(phenylthio)butylaminomethylenebisphosphonate (2.5 g) in ethanol (20 ml) was added a solution of sodium hydroxide (450 mE) in ethanol (20 ml). The mixture was heated under reflux for 4 hours and concentrated under reduced pressure. The residue was dissolved in water and the solution was subjected to column chromatography on Amberlite CG-50 (H+ form) and eluted with water to obtain diethyl 4-(phenylthio)butylaminomethylenebisphosphonate monosodium salt (810 mg). The resultant was recrystallized from methanol-hexane, m.p. 143°-45° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1.C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH2:27]Br)[CH3:22]>CO>[CH2:21]([O:23][C:24]([CH2:25][CH2:26][CH2:27][NH:1][CH2:2][CH2:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)=[O:29])[CH3:22]
Reactant: CCOC(=O)CCCBr
Reactant: NCCC1COc2ccccc2C1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNCCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 19.5 g (0.1 mol) of 4-bromobutyric acid ethyl ester are added to the solution. The reaction mixture is stirred for 15 hours at room temperature and is then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. Oily N-(3-ethoxycarbonylpropyl)-N-[2-(chroman-3-yl)ethyl]-amine is thus obtained and can be used further in crude form.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:21].C([O-])(O)=O.[Na+].Cl[C:28]([O:30][C:31]([CH3:33])=[CH2:32])=[O:29]>CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:21][C:28](=[O:29])[O:30][C:31]([CH3:33])=[CH2:32]
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3)ccn2)cn1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A mixture of Example A1 (2.0 g, 7.04 mmol) and saturated aq NaHCO3 (100 mL) in EtOAc (100 mL) was cooled in an ice bath and treated with isopropenyl chloroformate (1.6 mL, 14.64 mmol). The reaction mixture was allowed to slowly warm to RT overnight. The organic layer was separated and washed with sat aq NaHCO3 (25 mL) and brine (25 mL), dried (MgSO4), concentrated in vacuo and re-crystallized (diethylether) to provide prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate (2.32 g, 90% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.69 (br s, 1 H), 8.38 (d, J=5.6 Hz, 1 H), 8.26 (s, 1 H), 7.96 (d, J=0.8 Hz, 1 H), 7.67 (br t, J=8.4 Hz, 1 H), 7.27 (d, J=2.4 Hz, 1 H), 7.22 (dd, J=11.2, 2.4 Hz, 1 H), 7.00 (m, 1 H), 6.69 (dd, J=5.6, 2.4 Hz, 1 H), 4.74 (m, 1 H), 4.72 (s, 1 H), 3.84 (s, 3 H), 1.92 (s, 3 H); MS (ESI) m/z: 369.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[C@@H:4]([CH3:15])[CH2:3]1.[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[C:17]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:14])([CH3:13])[C@@H:4]([CH3:15])[CH2:3][C:2]2([CH3:16])[CH3:1])=[CH:7][C:8]=1[CH3:12])(=[O:19])[CH3:18]
Reactant: Cc1ccc2c(c1)C(C)(C)[C@@H](C)CC2(C)C
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)[C@@H](C)CC2(C)C
Yield: 90.1 %

Procedure:
To a solution of (S)-1,1,3,4,4,6-hexamethyl1,2,3,4-tetrahydronaphthalene ([α]546 -49.1° (C=1 in n-hexane)) (100.0 g; 0.463 mol) in 1,2-dichloroethane (300 g), acetyl chloride (38.0 g; 0.484 mol) and anhydrous aluminum chloride (71.0 g; 0.533 mol) were added, and the resultant mixture was stirred at 20° C. for 1 hour. The reaction mixture was treated with 10% hydrochloric acid (300 ml) and then separated into a water layer and an organic layer. The organic layer was washed with dilute hydrochloric acid and saturated sodium carbonate solution, dried and concentrated to give (S)-7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (107.5 g; 0.417 mol; 90%). B.P., 109° C./0.2 mmHg. [α]546 -36.9° (C=1 in ethanol).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([C:23]1([C:33]([OH:35])=[O:34])[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]2.C([O-])(O)=O.[Na+]>>[F:7][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([C:23]1([C:33]([OH:35])=[O:34])[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[C:29]([CH3:32])([CH3:31])[CH3:30])=[N:18]2
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)N1CCNCC1(C(=O)O)c1ccc2c(CCO)cccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)N1CCNCC1(C(=O)O)c1ccc2c(CCF)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a -78° C. solution of Diethylaminosulfur trifluoride (DAST) (0.06 ml, 0.42 mmol) in dry CH2C2 was slowly added a solution of 13 (50 mg, 0.14 mmol) in dry CH2C2 (3 ml). The solution was allowed to warm to room temperature and stirred for 1 h. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The residue was purified by HPLC (Whatman Partisil M9 column, 90:10 CH2Cl2 :EtOAc) to afford the fluoroethyl derivative 14 (33 mg, 66%). 1H NMR d (ppm): 1.48 s (3 CH3), 3.36 dt (CH2), 3.56 dd (NCH2), 3.71 dd (NCH2), 4.69 dt (CH2), 6.99 d (CH arom), 7.11 d (CH arom), 7.46 dd (CH arom), 7.61 d (CH arom), 8.10 d (CH arom).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[O:17][C:18]3[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=3[C:20]=2[CH2:21][N:22]([CH3:24])[CH3:23])=[O:15])=[CH:6][CH:5]=1.[OH-].[K+:31]>CO>[K+:31].[CH3:24][N:22]([CH2:21][C:20]1[C:19]2[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=2[O:17][C:16]=1[C:14]([NH:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([O-:29])=[O:2])=[CH:9][CH:8]=1)=[O:15])[CH3:23]
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2CN(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN(C)Cc1c(C(=O)NCCOc2ccc(C(=O)[O-])cc2)oc2ccccc12
Temperature: 60 °C
Yield: 96.7 %

Procedure:
4-{2-[(3-Dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid methyl ester (70.0 g, 0.177 mol) was suspended in methanol (350 ml). 50% Potassium hydroxide (139.8 g, 1.062 mol) was added and the reaction mixture was heated to 60° C. until completion of reaction. After cooling to room temperature, the resulting crystals were filtered on a coarse frit and washed with methanol. The crystals were dried in vacuo to give 4-{2-[(3-dimethylaminomethylbenzofuran-2-carbonyl)amino]ethoxy}benzoic acid potassium salt (72.0 g) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.I.CS[C:14]1[NH:23][CH:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1>>[CH:2]1([NH:1][C:14]2[NH:23][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC1CCc2ccccc21
Reactant: CSC1=Nc2ccccc2C(c2ccccc2)N1
Agent: I
Product: c1ccc(C2NC(NC3CCc4ccccc43)=Nc3ccccc32)cc1

Procedure:
The title compound (MS: m/e=340.3 [M+H+]) was prepared in analogy to example 1 (b) from (+/−)-1-aminoindan and 2-methylsulfanyl-4-phenyl-3,4-dihydro-quinazoline hydroiodide. 2-Methylsulfanyl-4-phenyl-3,4-dihydro-quinazoline hydroiodide can be prepared by the method of Kosasayama, A.; Higashi, K.; Ishikawa, F. Chem. Pharm. Bull. 1979, 27(4), 880-892.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([CH2:28][CH2:29]O)=[CH:24][CH:23]=1>C(#N)C>[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][Br:1])=[CH:24][CH:23]=1
Reactant: BrBr
Reactant: OCCc1ccc(-c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: BrCCc1ccc(-c2ccccc2)cc1
Reaction time: 0.08 h

Procedure:
Bromine (1.5 ml) was added dropwise to an acetonitrile (60 ml) solution of triphenylphosphine (5 g). After stirring for 5 minutes, an acetonitrile solution (30 ml) of 2-(4-biphenylyl)ethanol (5 g) was added to the reaction mixture. The reaction mixture was stirred at room temperature for one hour and concentrated. Diethyl ether was added to the residue. The supernatant was collected, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: IPE) to obtain 2-(4-bipenylyl)ethylbromide(6 g). 2-(4-Bipenylyl)ethyl bromide (6 g) was dissolved in methanol (100 ml), which was stirred at 70° C. for 48 hours together with potassium thiocyanate (4.0 g). The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (4.1 g).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[NH:3][C:4]([C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3OC)=[O:26])=[CH:18][C:17]=2[F:37])[CH:7]=1)=[O:5].[CH3:39]N(C1C=CC=CC=1)C(=O)CC(O)=O>>[CH3:1][N:2]([CH3:38])[NH:3][C:4]([C:6]1[S:14][C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:36])[CH2:24][C:25]([N:27]([CH3:39])[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:26])=[CH:18][C:17]=2[F:37])[CH:7]=1)=[O:5]
Reactant: CN(C(=O)CC(=O)O)c1ccccc1
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)NN(C)C)sc23)c(F)c1
Product: CN(C)NC(=O)c1cc2nccc(Oc3ccc(NC(=O)CC(=O)N(C)c4ccccc4)cc3F)c2s1
Yield: 44 %

Procedure:
Following the procedure described above for compound 236 (example 95, scheme 63) but replacing acid 27 with 3-(methyl(phenyl)amino)-3-oxopropanoic acid (31), title compound 240 was obtained in 44% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 10.08 (br, 0.3H), 9.52 (s, 0.7H), 8.58 (dd, J=5.5 Hz, 3=8.4 Hz, 1H), 8.20 (m, 1H), 7.79 (m, 1H), 7.49-7.30 (m, 7H), 6.75 (d, J=5.5 Hz, 1H), 3.21 (s, 2H), 3.2 (s, 3H), 2.64 (s, 3H) 2.59 (s, 3H). MS (m/z): (M+1) 522.1 (100%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>O>[CH3:11][C:1]1[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 25.0 g of 4-toluenesulfonic acid and 95 ml of concentrated nitric acid was heated on a steam bath for 30 minutes during which time the solution turned deep red and gas was evolved. The reaction was allowed to cool to room temperature, poured into 250 ml of water and concentrated. An additional 30 ml of water was added and the solution again concentrated. This procedure was repeated three additional times. The resulting oil was dissolved in 30 ml of water and neutralized with the addition of 11.04 g of sodium bicarbonate. After the bubbling stopped the solution was concentrated to yield a white powder which was triturated with 300 ml of isopropanol, isolated via vacuum filtration and air dried to yield 28.9 g of the desired 4-methyl-3-nitrobenzenesulfonic acid, sodium salt.
Reaction SMILES: COC(=O)[CH:4]([O:13][CH3:14])[C:5]([C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1)=[O:6].[OH-].[Na+].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:12][C:9]1[S:10][CH:11]=[C:7]([C:5](=[O:6])[CH2:4][O:13][CH3:14])[N:8]=1
Reactant: COC(=O)C(OC)C(=O)c1csc(N)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: COCC(=O)c1csc(N)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a solution of 3-(2-amino-thiazol-4-yl)-2-methoxy-3-oxo-propionic acid methyl ester (765 mg, 3.3 mmol) in tetrahydrofuran (25 ml) was added 1M aqueous sodium hydroxide (4.0 ml, 4.0 mmol) at room temperature. The mixture was stirred for 2 hours then cooled to 0° C. 1 N aqueous sulfuric acid (33 mL, 33.2 mmol) was added and the reaction was warmed to 40° C. for 30 minutes. The reaction mixture was then cooled to 0° C. and made basic with saturated aqueous sodium bicarbonate. The suspension was extracted with ethyl acetate, the combined organic extracts washed with water, brine and dried over magnesium sulfate. The crude product was purified by chromatography over silica gel eluted with 7:3 ethyl acetate/hexanes to give 1-(2-amino-thiazol-4-yl)-2-methoxy-ethanone as a yellow oil (240 mg, 42% yield).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[N:13]=[CH:12][N:11]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:14]1[C:15]([N+:16]([O-:18])=[O:17])=[C:10]([Cl:9])[N:11]=[CH:12][N:13]=1)[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ncnc(Cl)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 78.1 %

Procedure:
The amino-acetic acid ethyl ester hydrochloride (1439.15 mg; 10.31 mmol; 1.00 eq.) and 4,6-dichloro-5-nitro-pyrimidine (2000.00 mg; 10.31 mmol; 1.00 eq.) in anhydrous DMF (26 mL) was added ethyl-diisopropyl-amine (3997.72 mg; 30.93 mmol; 3.00 eq.) and the mixture was stirred for 3 hours. LC-MS showed that the reaction was complete. DMF was removed and EtOAc was added. The mixture was washed with brine, dried over MgSO4 and purified through flash chromatography on silica (EtOAc in Hexane from 0% to 30%) to provide (6-chloro-5-nitro-pyrimidin-4-ylamino)-acetic acid ethyl ester 2.1 g with 78% yield; LC/MS: 261 (M+H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[N+:24]([C:20]1[CH:19]=[C:18]([NH:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:23]=[CH:22][CH:21]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CCCCCC
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(NCc2ccccc2)c1
Yield: 71.9 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (10 mg, 0.05 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (109 μL, 1.00 mmol), 3-iodonitrobenzene (349 mg, 1.40 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=5/1, Rf=0.4) afforded N-(3-nitrophenyl)benzylamine (164 mg, 72% isolated yield) as orange solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.; Ruggieri, F. J. Org. Chem. 1992, 57, 1842-1848.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].[NH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17](=[O:19])[CH3:18].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:17]([C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[NH:8][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:7])(=[O:19])[CH3:18]
Reactant: COc1ccc(C(C)=O)c(N)c1
Reactant: O=Cc1nccs1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(C)=O)c(NC(=O)c2nccs2)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 2-thiazolecarboxaldehyde (500 mg, 3.87 mmol) in 35 mL of pyridine, 1-(2-amino-4-methoxyphenyl)ethanone (640 mg, 3.87 mmol) was added and the solution was cooled to −30° C. before POCl3 (750 μl, 8.13 mmol) was added drop wise. The reaction mixture was stirred at −10° C. for 1 hour and then at room temperature for 2 hours. The mixture was concentrated under vacuum and the residue was triturated with NaHCO3 to pH 7. The precipitate was filtrated, washed with water and dried. The amide was pure enough for the next step without purification (972 mg, 91%).