Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15](CC#N)[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23]([OH:26])(=[O:25])[CH3:24]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:24][C:23]([OH:26])=[O:25])[C:14]=3[CH:13]=[CH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cccc2c(-c3ccc([N+](=O)[O-])cc3)nccc12
Temperature: 0 °C

Procedure:
1-(4-Nitrophenyl)isoquinoline-5-acetonitrile (2.1 g) was dissolved in 12 ml of 75% sulfuric acid and 2 ml of acetic acid, and refluxed for 3 hours. The reaction mixture was poured into ice water, and washed with ether. The aqueous layer was neutralized with an aqueous solution of sodium hydroxide. The crystals that precipitated were collected by filtration, and recrystallized from tetrahydrofuran to afford 2.1 g of 1-(4-nitrophenyl)isoquinoline-5-acetic acid having a melting point of 252.2° to 253.8° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[CH:15](OCC)(OCC)OCC>CC(O)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]2[CH:15]=[N:13][N:12]=[N:11]2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cn2cnnn2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 43.6 %

Procedure:
A mixture of 3.84 g (28.0 mmol) of (4-methoxy)benzylamine, 2.73 g (42.0 mmol) of sodium azide and 7.50 mL (45.0 mmol) triethyl orthoformate in 25 mL of HOAc was stirred at 80° C. for 20 h. The reaction was cooled and concentrated. The residue was partitioned between 100 mL of EtOAc and 100 mL of H2O and the layers were separated. The organic layer was washed with 100 mL of 2.0 N HCl, 100 mL of sat'd NaHCO3, 100 mL of sat'd NaCl, dried over MgSO4 and concentrated. Flash chromatography on 100 g of silica gel using 2:1 v/v hexanes/EtOAc, then 1:1 v/v hexanes/EtOAc as the eluant afforded 2.32 g of the title compound: 1H NMR (300 MHz) δ 3.82 (s, 3H), 5.53 (s, 2H), 6.93 (d, J=8.6, 2H), 7.27 (d, J=8.6, 2H), 8.46 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][CH2:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][N:17]=1
Reactant: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Reactant: OCc1cnccn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Cn1nnc2c(Br)c(OCc3cnccn3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (Example 1-2) (1.5 g, 5.28 mmol, 1.0 equiv.), 2-pyrazinylmethanol (13) (0.581 g, 5.28 mmol, 1.0 equiv.) and polymer-supported triphenylphosphine (2.2 mmol/g, 5.75 g, 21.91 mmol, 2.5 equiv.) in THF (37.7 ml) and DCM (37.7 ml) was slowly added di-tert-butyl azodicarboxylate (2.431 g, 10.56 mmol, 2.0 equiv.). After stirring at room temperature for 1 hr, the reaction mixture was passed through a filter. The residue was washed with DCM and THF. The filtrate was concentrated to dryness to give a solid, which was taken up in DCM (12 mL) and treated with TFA (6 mL). The mixture was stirred at room temperature until LCMS showed only the desired product. The reaction mixture was neutralized to pH=7 with saturated aqueous NaHCO3, and then extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to obtain product Example 4-1. 1H NMR δ (CDCl3): 9.06 (s, 1H), 8.59-8.57 (m, 2H), 7.42 (d, 1H, J=9.5 Hz), 7.31 (d, 1H, J=9.0 Hz), 5.38 (s, 2H), 4.38 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 376.1 and 378.1 (intensity ratio ˜1:1) found, 376.1 and 378.1 required.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:21](=O)[CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][CH2:19]1>>[CH3:26][O:25][C:23]([C:22]1[C:21]([CH:18]2[CH2:20][CH2:19]2)=[N:1][C:2]2[C:3]([C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:4][C:5]([Cl:9])=[CH:6][C:7]=2[CH3:8])=[O:24]
Reactant: Cc1cc(Cl)cc(C(=O)c2ccccc2)c1N
Reactant: COC(=O)CC(=O)C1CC1
Product: COC(=O)c1c(C2CC2)nc2c(C)cc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 6 step A from a mixture of (2-amino-5-chloro-3-methyl-phenyl)-phenyl-methanone and methyl 3-cyclopropyl-3-oxopropanoate. Off-white solid. MS (ESI): 352.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:4]1[O:3][C:2]([CH3:1])=[N:6][C:5]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc(-c2ccccc2)c(C)o1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2)c(CBr)o1
Reaction time: 0.08 h

Procedure:
A mixture of 2,5-dimethyl-4-phenyloxazole (6.0 g), N-bromosuccinimide (6.6 g), azobisisobutyronitrile (0.3 g) and carbon tetrachloride (120 ml) was refluxed with stirring for 5 minutes. The reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate and water in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the oily residue was left standing to give 5-bromomethyl-2-methyl-4-phenyloxazole as crystals, yield 9.2 g (98.9%). Recrystallization from ethanol gave colorless needles, m.p. 80°-81° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=2F)[C:5](=[S:8])[S:6][CH:7]=1.[CH3:18][NH2:19]>C(#N)C.CO>[CH3:18][N:19]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([F:15])[C:11]=2[F:16])[N:4]2[C:5](=[S:8])[S:6][CH:7]=[C:3]2[CH2:2]1
Reactant: CN
Reactant: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F
Solvent: CC#N
Solvent: CO
Product: CN1Cc2csc(=S)n2-c2ccc(F)c(F)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
4-Chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione (2.5 g) is dissolved in acetonitrile (25 ml) and thereto is added 40% solution of methylamine in methanol (3.3 g), and the mixture is stirred at 50° C. for 16 hours. The reaction mixture is evaporated to dryness under reduced pressure, and water is added to the residue and the mixture is extracted with chloroform. The extract is washed with saline solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from cyclohexane-ethyl acetate to give the title compound (2.0 g) as yellow crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:19][NH:20][CH3:21].C(=O)([O-])O.[Na+]>>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([N:20]([CH3:21])[CH3:19])=[CH:13][CH:12]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N1CCCC(C(=O)c2ccc(F)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1CCCC(C(=O)c2ccc(N(C)C)cc2)C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture consisting of 2.49 g of 1-acetyl-3-(4-fluorobenzoyl)piperidine and 8 ml of 50% aqueous dimethylamine solution was stirred for 5 days at room temperature, followed by addition of a saturated aqueous solution of sodium hydrogen carbonate. The solution was extracted with ethyl acetate and the extract was dried. The solvent was then distilled off and the remaining oil was purified by silica gel column chromatography (eluent: ethyl acetate) to give 2.6 g of 1-acetyl-3-(4-dimethylaminobenzoyl)piperidine as a pale yellow oil.
Reaction SMILES: [ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[C:27]([CH2:31][CH2:32][C:33](=[O:35])[NH2:34])=[C:26](O)[CH:25]=[CH:24]2)(=[NH:20])[NH2:19].Cl.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[ClH:1].[ClH:1].[OH:2][CH2:3][CH2:4][NH:5][N:6]=[CH:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:18](=[NH:19])[NH2:20])[CH:22]=3)[C:27]=2[CH2:31][CH2:32][C:33](=[O:35])[NH2:34])=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(NC=NNCCO)cc1
Reactant: N=C(N)c1ccc2c(CCC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CCC(N)=O)c(OC(=O)c3ccc(NC=NNCCO)cc3)ccc2c1
Reaction time: 2 h
Yield: 78.3 %

Procedure:
20 Milliliters of 20% hydrous pyridine was added to 1.45 g of 4-[(2-hydroxyethyl)aminoiminomethylamino]benzoic acid.hydrochloride, 1.5 g of 6-amidino-1-(2-carbamoylethyl)-2-naphthol.hydrochloric acid, 1.26 g of DCC and 62.3 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Thereafter, the same procedure as in Example 1 was effected to obtain 1.17 g of the desired product.
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:9]1[CH2:13][C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:21])([CH3:8])[CH3:7].O[O:26][S:27]([O-:29])=O.[K+].[CH:31](OC(C)C)(C)C>CO.O>[CH3:31][S:27]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[C:6]([N:9]1[CH2:13][C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]1=[O:21])([CH3:7])[CH3:8])(=[O:29])=[O:26]
Reactant: CSc1cccc(C(C)(C)N2CC(C)=C(c3ccccc3)C2=O)c1
Reactant: CC(C)OC(C)C
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cccc(S(C)(=O)=O)c2)C1
Temperature: 5 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
A methanol/water (1/1) solution of 2.2 g (0.0065 mol) of 1-(3-methylthio-α,α-dimethylbenzyl)-4-methyl-3-phenyl-3-pyrrolin-2-one (Compound No. 364) prepared in accordance with the method of Example 2, was cooled to 5° C., and 30 ml of an aqueous solution of 12 g (0.020 mol) of Oxone was dropwise added thereto at a temperature not higher than 5° C. The mixture was stirred at 5° C. for 2 hours and then at room temperature for further 2 hours. 200 ml of ice water and 100 ml of isopropyl ether were added thereto, and the mixture was stirred for 10 minutes. Then, the product was isolated by filtration and washed with diethyl ether to obtain 1.5 g (yield: 62.3%) of the desired compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:13].[H-].[Na+].[CH:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:6]2=[O:13]
Reactant: Cc1cc(C)c2c(c1O)C(=O)CC2
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 2,3-dihydro-4,6dimethyl-7-hydroxy-1H-inden-1-one was dissolved in 200 ml of dimethylformamide, then 5.45 g of 60%-sodium hydride was added gradually thereto and the reaction mixture was stirred at room temperature for 30 minutes. Next, 6.91 ml of p-anisaldehyde was added to the reaction mixture and further stirred at room temperature for 1 hour. The reaction mixture was poured into 500 ml of ice-water, then acidified by adding hydrochloric acid, and the crystals formed were collected by filtration. The crystals were washed with water and with n-hexane and dried. Recrystallized from ethanol to obtain 16.09 g of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one. Yellow needle-like crystals. Melting point: 192°-193° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24](I)[CH:23]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2].B(O)(O)[C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:23]=[C:24]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)[CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:30]([O:32][CH3:33])=[O:31])#[N:2]
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(I)c4)cc3)c(C#N)cc21
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)cc5)c4)cc3)c(C#N)cc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
In a vial were placed methyl 6-cyano-7-(4-(3-iodophenylcarbamoyl)phenoxy)chroman-4-carboxylate (Preparation 3) (56 mg, 0.1010 mmol), p-tolylboronic acid (17.855 mg, 0.1313 mmol), Na2CO3 (32.121 mg, 0.3030 mmol), toluene (1 ml), and water (0.1 ml). The mixture was degassed with Argon for few minutes. Tetrakis(triphenylphosphine)palladium(0) (5.836 mg, 0.005 mmol) was added and the vial was sealed. The mixture was stirred at 100° C. for 24 hours. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 33.1 mg of the title compound as foamy solid (63%).
Reaction SMILES: O.[OH:2][C:3]1[CH:13]=[CH:12][C:6](C(O)C([O-])=O)=[CH:5][CH:4]=1.[Na+].[C:15]([O-:18])(=[O:17])[CH3:16].[NH4+:19]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([NH:19][CH2:16][C:15]([OH:18])=[O:17])=[CH:12][CH:13]=1
Reactant: CC(=O)[O-]
Reactant: O=C([O-])C(O)c1ccc(O)cc1
Reactant: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=C(O)CNc1ccc(O)cc1
Temperature: 125 °C
Yield: 67 %

Procedure:
A mixture of sodium p-hydroxymandelate monohydrate (1.04 g.), ammonium acetate (2.0 g.) and water (0.5 ml.) is stirred and heated under reflux (internal temperature 125° C.) for 2.5 hours. Water (3 ml.) is added to the thick slurry thus obtained, the mixture is cooled and filtered and the solid residue is washed twice with water and then with acetone. There is thus obtained p-hydroxyphenylglycine (0.56 g., 66% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=2)[CH2:14][NH:15][C:16]2[C:25]3[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=3)[N:19]=[CH:18][N:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.CC(O)(C)C.CS(C)=O.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>O>[N:41]1([C:2]2[CH:7]=[C:6]([C:8]([NH:10][C:11]3[CH:12]=[C:13]([CH:29]=[CH:30][CH:31]=3)[CH2:14][NH:15][C:16]3[C:25]4[C:20](=[C:21]([C:26]([NH2:28])=[O:27])[CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][N:17]=3)=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(Cl)c4)c3)ncnc12
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4ccnc(N5CCCC5)c4)c3)ncnc12
Temperature: 110 °C
Yield: 49 %

Procedure:
To a 10-mL microwave-rated vial with magnetic stir bar at r.t. was added 4-{3-[(2-Chloro-pyridine-4-carbonyl)-amino]-benzylamino}-quinazoline-8-carboxylic acid amide (0.05 g, 0.115 mmol, 1 eq.), t-BuOH (2 mL), DMSO (1 mL), and pyrrolidine (0.1 mL, 1.15 mmol, 10 eq.). The vial was capped and heated under microwave conditions (50 W, 3 min. ramp, 110° C., STND, 1 hr. hold time) followed by addition of another aliquot of pyrrolidine (0.1 mL) then microwaved (70 W, 3 min. ramp, 140° C., STND, 1 hr. hold time). Reaction was diluted with water (20 mL) and extracted with DCM (3×30 mL). The combined organics were washed with brine, dried (e.g., Na2SO4), filtered and concentrated. The resulting residue was purified by column chromatography (ISCO CombiFlash) using a 0-30% gradient (10% MeOH in EtOAc/EtOAc) afforded 25 mg (49% yield). LCMS (ESI) 468 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH2:10][C:11]2[NH:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[N:12]=2)=[CH:5][CH:4]=1.C[O-].[Na+].[C:24](OC)(=[O:27])[C:25]#[CH:26]>>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:10]2[CH:26]=[CH:25][C:24](=[O:27])[N:15]3[C:14]4[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=4[NH:12][C:11]=23)=[O:20])=[CH:5][CH:4]=1
Reactant: C#CC(=O)OC
Reactant: Cc1ccc(C(=O)Cc2nc3c([nH]2)CCCC3)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(C(=O)c2ccc(=O)n3c4c([nH]c23)CCCC4)cc1

Procedure:
The compound is prepared as described in example 25 with 500 mg (1.49 mmol) of 1-(4-methylphenyl)-2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone hydrochloride (example IL), 160.7 mg (2.98 mmol) of sodium methylate and 125 mg (1.49 mmol) methyl propiolate.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:29][O:28][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[S:19][C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COc1cc2c(Sc3ccc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Sc3ccc([N+](=O)[O-])s3)ccnc2cc1O
Yield: 85.7 %

Procedure:
7-(Benzyloxy)-6-methoxy-4-[(5-nitro-2-thienyl)sulfanyl]quinoline (4.0 g), trifluoroacetic acid (40 ml) and thioanisole (4 ml) were stirred together at 65° C. for 2 hours. The mixture was returned to room temperature, the solvent was distilled off under reduced pressure, 80 ml of methanol was added to the residue, and then bicarbonate water was added until the foaming subsided. The precipitated solid was filtered out to obtain 2.7 g of a yellow powder.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([CH:7]2[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[CH2:10][CH2:9][N:8]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[N:3]1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:21]([O:20][C:18]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([OH:15])=[O:14])[CH2:12][CH:7]1[C:4]1[N:5]=[N:6][N:2]([CH3:1])[N:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn(C)n2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc(C2CC(C(=O)O)CCN2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.6 %

Procedure:
1-Benzyl 4-ethyl 2-(2-methyl-2H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (0.92 g, 2.36 mmol) was dissolved in THF (10 mL) and water (10 mL) and LiOH (0.239 g, 9.98 mmol) was added. The mixture was stirred at room temperature for 1 h 10 min and then diluted with water and acidified with 2 M HCl. The aqueous phase was extracted 3 times with EtOAc, the combined organic phase dried over Na2SO4 and evaporated to yield 1-(benzyloxycarbonyl)-2-(2-methyl-2H-tetrazol-5-yl)piperidine-4-carboxylic acid (828 mg, quant.). 1H NMR (400 MHz, cdcl3) δ 1.80-1.91 (m, 1H), 2.01-2.11 (m, 1H), 2.34 (dt, 1H), 2.63-2.79 (m, 2H), 3.55-3.65 (m, 1H), 4.01-4.09 (m, 1H), 4.24 (s, 3H), 5.13 (d, 2H), 5.60 (dd, 1H), 7.27-7.39 (m, 5H). MS m/z 346 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:19]=[C:18](C)[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C.[C:41]([Cl:45])(Cl)(Cl)Cl>>[Cl:45][C:41]1[C:17]([CH3:16])=[C:18]([Br:21])[CH:19]=[CH:2][C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Oc1ccc(C)cc1Cl)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC(=O)C(Oc1ccc(Br)c(C)c1Cl)c1ccccc1
Yield: 34 %

Procedure:
To a solution of 1.70 g (5.86 mmol) of the product from Step A dissolved in 20 mL of CCl4 was added 1.04 g (5.86 mmol) of N-bromosuccinimide and 50 mg (catalytic amount) of AIBN. The reaction mixture was stirred and heated at reflux for 7 hours, then an additional 0.20 g of NBS was added. The reaction was refluxed for 48 hours, then cooled and concentrated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 10% ethyl acetate/hexane to afford 0.730 g (34%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH3:17])[C:14](O)=[O:15])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C>CCOC(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]([CH3:17])[C:14]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:15])[CH:12]=2)=[CH:4][C:3]=1[C:18]1[S:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: CC(C(=O)O)n1cc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cn1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C(=O)N1CCOCC1)n1cc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-[4-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-pyrazol-1-yl]-propionic acid (5.00 mg, 0.0142 mmol), morpholine (10.0 mg, 0.11 mmol), TBTU (9.14 mg, 0.0284 mmol), DIPEA (0.02 mL, 0.1 mmol) and DMF (2 mL, 0.03 mol) was stirred at rt for 10 min. The solution was transferred to a separatory funnel, diluted with EtOAc and washed 3× with water. The organic layer was concentrated in vacuo and loaded onto a prep TLC plate, eluting with 5% MeOH/DCM. The band containing the pure product was filtered off using 1:1 MeOH/DCM, and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=1.74 (d, J=7.1 Hz, 3H), 3.50-3.72 (m, 8H), 5.62 (q, J=7.1 Hz, 1H), 7.42-7.47 (m, 1H), 7.50-7.56 (m, 1H), 7.88 (s, 1H), 8.01 (dd, J=10.7, 8.2 Hz, 2H), 8.17 (s, 1H), 8.21 (d, J=2.0 Hz, 1H), 8.34 (d, J=2.3 Hz, 1H). MS (ES+): m/z=435.16 (100) [MH+]. HPLC: tR=2.89 min (ZQ3, polar—5 min).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.O.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Sc1ccccc1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2 g of 2-fluoro-4-chloro-nitrobenzene in 50 ml DMF and 1.25 ml of thiophenol was added 1.9 ml triethylamine at room temperature. The mixture was stirred for one hour. One hundred mL of water was added and a yellow solid crashed out of solution. The solid was collected by filtration and dried. Yield: 50-70%. LC-MS showed a single peak with the expected (M+H+) of 267.