Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:4]([NH2:8])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[Br-:9].[Cl:10][CH2:11][CH2:12][CH2:13][N+:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([CH3:16])[CH3:15]>CO>[Br-:9].[Cl-:10].[CH3:15][N+:14]([CH2:13][CH2:12][CH2:11][NH2+:8][CH:4]([CH2:5][CH:6]=[CH2:7])[CH2:1][CH:2]=[CH2:3])([CH3:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCC[N+](C)(C)CCCCl
Reactant: C=CCC(N)CC=C
Agent: [Br-]
Solvent: CO
Product: C=CCC(CC=C)[NH2+]CCC[N+](C)(C)CCCCCCCCCCCC
Product: [Cl-]
Temperature: 65 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
A mixture of 22 g of diallylmethylamine and 74 g 3-chloropropyldodecyldimethylammonium bromide was dissolved in 100 mL of methanol and the reaction mixture was stirred at 65° C. for 48 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residual viscous oil was precipitated into 800 mL of ether with rapid stirring. The ether layer was decanted and the residue was again treated with 500 mL of ether. After stirring for 15 minutes the solvent was removed and the oily residue was dried under vacuum at 35° C. for 48 hours, yielding 70 g of the product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]1[C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=[N:30]1>C(Cl)Cl.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][C:34]([C:33]4[O:29][N:30]=[CH:31][CH:32]=4)=[O:35])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C(O)c1ccno1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNC(=O)c1ccno1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
To a solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.08 g, 0.21 mmol) in DCM-THF mixture (1:1, 4 ml) at 0° C. was added 1.0 eq. of isoxazole-5-carboxylic acid loaded TFP resin. The resulting mixture was stirred vigorously for 1 hour at 0° C., and then filtered. The remaining resin was then washed with DCM-THF (1:1, 2×10 ml portions) for 30 min, and then filtered. The combined filtrates were concentrated, and the resulting oil was purified by column chromatography to give the title compound (3.4 mg, 4%). MS: Calcd.: 479. Found: [M+H]+ 480.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C([O-])(=O)C.[Na+].[CH3:10][O:11][N:12]=[C:13]([C:29](=O)[CH:30](Br)Br)[C:14]([NH:16][CH:17]1[C:27](=[O:28])[N:19]2[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]12)=[O:15].Cl>O1CCCC1.O>[NH2:1][C:2]1[S:3][CH:30]=[C:29]([C:13](=[N:12][O:11][CH3:10])[C:14]([NH:16][CH:17]2[C:27](=[O:28])[N:19]3[C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH2:22][S:23][C@H:18]23)=[O:15])[N:4]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)C(=O)C(Br)Br
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Temperature: 30 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
Thiourea (235 mg) and sodium acetate (253 mg) were added to a solution of 7-(2-methoxyimino-3-oxo-4,4-dibromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 500 mg) in tetrahydrofuran (10 ml) and water (100 ml), and the mixture was stirred at 30° C. for 4 hours. The resultant solution was adjusted to pH 3.5 with 6 N hydrochloric acid, and concentrated under reduced pressure. The precipitates were collected by filtration, washed with water and dried to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 163 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:4]=2[O:3]1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:23]=[C:11]([C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[O:1])[O:3][C:4]=4[CH:10]=3)[O:13][N:15]=2)[CH:18]=1
Reactant: O=C(O)c1ccc2[nH]c(=O)oc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: O=c1[nH]c2ccc(-c3nc(-c4cccnc4)no3)cc2o1

Procedure:
The title compound was prepared according to Method C using 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (Eur. J. Med. Chem. 1974, 9, 491-6.) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.35 (d, J=8.7 Hz, 1 H), 7.65 (dd, J=7.5, 4.4 Hz, 1 H), 8.04 (d, J=1.6 Hz, 1 H), 8.07 (s, 1 H), 8.44 (dt, J=7.9, 2.0 Hz, 1 H), 8.82 (dd, J=4.8, 1.6 Hz, 1 H), 9.25 (d, J=1.6 Hz, 1 H) ppm; MS (DCI/NH3) m/z 281 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]([C:11]([F:35])([F:34])[C@@:12](C(=O)C1C=CC=CC=1)([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C:9]([C:11]([F:34])([F:35])[C@@H:12]([C@@H:14]([CH:16]([C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:17])[OH:15])[OH:13])=[O:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@@](O)(C(=O)c1ccccc1)[C@H](O)C(O)C(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC(=O)C(F)(F)[C@H](O)[C@H](O)C(O)C(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89.5 %

Procedure:
To a solution of 0.97 g (2.0 mmol) of 1-(t-butyldimethylsilyloxy)-3,5-bis(benzoyl)-2-deoxy-2,2-difluororibose in tetrahydrofuran (40 ml) cooled to -78° C. were added 4.0 ml of a 1M solution of potassium t-butoxide in tetrahydrofuran (4.0 mmol) dropwise. The reaction mixture was stirred 15 minutes at -78° C. and was then quenched with 0.45 ml glacial acetic acid (8.0 mmol). The reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine (50 ml). The separated organic layer was dried with sodium sulfate and evaporated under reduced pressure. The resulting residue was chromatographed on silica gel and eluted with hexane containing 10-15% ethyl acetate. The product fractions were combined and concentrated under reduced pressure to yield 0.724 g (93%) of 1-(t-butyldimethylsilyloxy)-5-benzoyl-2-deoxy-2,2-difluororibose. Mass spec.: m/e=389=P+1, m/e=331=P-t-butyl.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13]Cl)[N:6]=[CH:5]2.[I-].[K+].C([O-])([O-])=O.[K+].[K+].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][CH2:13][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[N:6]=[CH:5]2
Reactant: ClCCCn1ncc2cc(Br)ccc21
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2c(cnn2CCCN2CCCC2)c1
Temperature: 50 °C
Yield: 102.6 %

Procedure:
To a solution of 5-bromo-1-(3-chloropropyl)-1H-indazole (2.14 g, 7.84 mmol) in DMF (40 mL) was added potassium iodide (1.3 mg, 7.8 mmol) and K2CO3 (5.40 g, 39.2 mmol) under N2 (g). Then pyrrolidine (17.2 ml, 26.6 mmol) was added. The reaction was heated to 50° C. for 20 h. The reaction was diluted with EtOAc (100 mL) and washed with a 5% LiCl solution (4×). The organics were dried (Na2SO4), filtered, and concentrated to give the title compound (2.48 g, quant.) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.45-7.41 (dd, J=8.9, 1.7 Hz, 1H), 7.36 (d, J=8.9 Hz, 1H), 4.45 (t, J=6.7 Hz, 1H), 2.44-2.36 (m, 6H), 2.15-2.07 (m, 2H), 1.78-1.74 (m, 4H); ESI MS m/z 308 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#N>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:16]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-cyanophenylboronic acid in step 1.F.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:12]OC(C)(C)C)(C)(C)C.[C]=O.[CH2:20]([OH:24])[CH2:21][CH2:22][CH3:23]>>[C:1]1([CH2:7][C:8]([O:24][CH2:20][CH2:21][CH2:22][CH3:23])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1ccccc1
Reactant: CCCCO
Agent: [C]=O
Product: CCCCOC(=O)Cc1ccccc1
Temperature: 120 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
Toluene (1.38 g), n-butanol (74 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 65 mg n-butyl phenylacetate was obtained by column chromatography, in a yield of 68%. 1HNMR (400 MHz, CDCl3) δ 0.88 (t, J=7.6 Hz, 3H), 1.29-1.38 (m, 2H), 1.55-1.62 (m, 2H), 3.60 (s, 2H), 4.06 (t, J=6.8 Hz, 2H), 7.23-7.33 (m, 5H); 13CNMR (100 MHz, CDCl3) δ 13.7, 19.1, 30.6, 41.5, 64.7, 127.0, 128.5, 129.3, 134.3, 171.7; HRMS (ESI) calcd. for C12H16NaO2 [M+Na]: 215.1043. found: 215.1042. The n-butyl phenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 43 mg product phenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 94%.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[CH2:6]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](F)=[CH:12][C:11]=1[F:20])[CH3:7].O>C1COCC1>[CH2:6]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[CH:12][C:11]=1[F:20])[CH3:7]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: NCC(F)F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(NCC(F)F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Difluoro-ethylamine (2.4 g, 29.8 mmol) in THF is added at 0° C. to ethyl-2,4-difluoro-5-nitro-benzoate (4.6 g, 20 mmol) and it is stirred overnight at rt. Water is added to the mixture and the mixture is concentrated. The precipitate is filtered, washed with water and dried with P2O5 in vacuo. Yield: 3.8 g (66%).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O-:19])([O-])=O.[K+].[K+].[ClH:22]>CC(C)=O>[Cl:22][C:2]1[CH:7]=[CH:6][C:5]([C:16]([CH2:11][CH2:10][CH2:15][N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccc(Cl)cc1

Procedure:
A mixture of 3-(4-chlorobenzol)propyl bromide (640 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2CO3 (1.01 g, 7.34 mmol) in 50 ml of acetone was heated at reflux temperature for 48 h. The cooled reaction mixture was filtered to remove the solids, concentrated in vacuo, giving a yellow solid, which was purified by chromatography (MeOH/CHCl3, 5/95). The product (320 mg 33.9%) was isolated as a white powder: 1H NMR δ 1.46 (dq, J1=1.0 Hz, J2=8.4 Hz, 2H), 1.90-2.10 (m, 4H), 2.16 (m, 2H), 2.43 (t, J=6.9 Hz, 2H), 2.80-2.90 (m, 2H), 2.97 (t, J=6.9 Hz, 2H), 3.97 (m, 1H), 5.92 (d, J=7.8 Hz, 1H, N—H), 7.40-8.00 (m, 9H). The product was converted to the HCl salt and recrystallized from MeOH/Et2O, m.p. 243-244° C.; Anal. Calcd for C22H25ClN2O2+HCl+H2O: C, 60.15; H, 6.37; N, 6.37; Found: C, 60.18; H, 6.34; N, 6.29.
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[C:20](N(C(C)(C)C(NC(C)(C)C)=O)O)(C)(C)[CH3:21].BrCC=CC=C>>[CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH:3][CH:20]=[CH2:21]
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Agent: C=CC=CCBr
Product: C=CC=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Yield: 80 %

Procedure:
The compound is prepared in analogy to compound 204 from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and 1-brom-2,4-pentadien in 80% yield as colorless oil.
Reaction SMILES: O.[NH2:2][NH2:3].F[C:5]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][N:6]=1>C(O)C>[NH:2]([C:5]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][N:6]=1)[NH2:3]
Reactant: NN
Reactant: Fc1ncccc1I
Solvent: CCO
Solvent: O
Product: NNc1ncccc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
Hydrazine hydrate (12.50 mL, 256 mmol) was added dropwise to a solution of 2-fluoro-3-iodopyridine (preparation 26a, 5.72 g, 25.7 mmol) in ethanol (43 mL) and the resulting mixture was stirred at room temperature for 24 hours and then at 35° C. for a further 24 hours. The solvent was then evaporated in vacuo and water was added. The white solid that formed was filtered, washed with water and dried to yield the title compound (2.78 g, 46%) as a white solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22]>C1C=CC=CC=1>[N+:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25])=[CH:19][C:6]=2[C:7]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: CCCN=C=O
Solvent: c1ccccc1
Product: CCCNC(=O)Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1

Procedure:
To a solution of 2 g. of 5-amino-2-nitro-3-phenylbenzofuran in 100 ml. of hot benzene is added 4 ml. of n-propyl isocyanate. The mixture is heated on a steam bath for 30 minutes, then evaporated to dryness. The residue is recrystallized from aqueous methanol to provide orange crystals of 2-nitro-3-phenyl-5-(n-propyl)ureidobenzofuran, m.p. 199°-201° C., having the structure ##STR21##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([Cl:11])[CH:4]=1
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c(Cl)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-amino-3-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-amino-3-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][C:13](=O)[CH2:14][CH3:15].O>C(C(C)=O)C>[CH2:14]([C:13]1[N:1]=[C:2]2[N:6]([CH:12]=1)[C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[S:3]2)[CH3:15]
Reactant: Nc1nc2ccccc2s1
Reactant: CCC(=O)CBr
Solvent: O
Solvent: CCC(C)=O
Product: CCc1cn2c(n1)sc1ccccc12
Yield: 110 %

Procedure:
After 5.40 g of 2-aminobenzothiazole and 7.52 g of 1-bromo-2-butanone were allowed to stand in 40 ml of methyl ethyl ketone at room temperature overnight, 40 ml of water was added to the reaction mixture. Methyl ethyl ketone was distilled off on a water bath of 50° C. under reduced pressure. The residue was crystallized with ether and the crystals were then taken out by filtration to give 8.0 g of 2-ethylimidazo[2,1-b]benzothiazole.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27](O)=[O:28])=[CH:22][CH:21]=[CH:20]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.O[C:62]1[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:62]1[CH:68]=[CH:67][C:65]([NH:66][C:27]([C:23]2[C:24]3[C:19](=[CH:18][C:17]([O:16][C:7]4[C:6]5[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([O:3][CH3:2])[CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:26][CH:25]=3)[CH:20]=[CH:21][CH:22]=2)=[O:28])=[CH:64][CH:63]=1
Reactant: COc1cc2nccc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Cl
Reactant: Nc1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccc(Cl)cc5)cccc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A slurry of 6-(6,7-dimethoxy-quinolin-4-yloxy)-naphthalene-1-carboxylic acid hydrochloride (0.200 g, 0.532 mmol, step a), HATU (0.264 g, 0.692 mmol), and Et3N (0.296 ml, 2.12 mmol) in 1.33 mL of DMF under argon was stirred at RT. After 1 h, 4-hydroxyaniline (0.116 g, 1.064 mmol) was added. The solution was stirred at RT for 0.5 h then at 50° C. After 2 h, the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3, water, and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue remaining after concentration was dissolved in acetone and purified by reverse-phase HPLC (pH 1 CH3CN/water solvent system). The fractions containing the desired product were concentrated, dissolved in CH2Cl2, and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the titled compound as a pale yellow solid. M+H −467.1. Calc'd for C28H22N2O5−466.49.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[C:14]1([C:20]2[C:24]3[CH2:25][NH:26][CH2:27][CH2:28][C:23]=3[O:22][N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:27][CH2:28][C:23]4[O:22][N:21]=[C:20]([C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:24]=4[CH2:25]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1ccc(-c2noc3c2CNCC3)cc1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2onc(-c3ccccc3)c2C1
Yield: 69 %

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Phenyl-4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(#N)C.O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH:9]1[CH2:10][N:11]([CH2:26][CH2:27][CH:28]=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[N:39][C:34]=3[CH2:33][O:32][C:31]3[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]2=3)[CH2:12][CH2:13][N:8]1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: COC(=O)CC1CNCCN1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)CC1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3-methoxycarbonylmethyl-piperazine (0.13 g, 0.5 mmol) in acetonitrile/water (8:2) (10 mL) was added K2CO3 (0.2 g, 0.42 mmol) and 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.16 g, 0.42 mmol). The solution was allowed to stir at room temperature for 48 h. The reaction was concentrated, partitioned between EtOAc/H2O, and extracted with EtOAc (3×). The organics were combined, dried over Mg2SO4, filtered and evaporated in vacuo, then purified by Biotage flash chromatography (50% ethyl acetate/50% hexane to 75% ethyl acetate/25% hexane to 100% ethyl acetate) to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:19]2[C:6](=[C:7]3[C:16](=[CH:17][CH:18]=2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[S:9](=[O:21])(=[O:20])[NH:8]3)[N:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26].CCN(C(C)C)C(C)C>CCCCO>[O:20]=[S:9]1(=[O:21])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[C:7](=[C:6]3[C:19](=[CH:18][CH:17]=2)[C:2]([NH:26][CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])=[CH:3][CH:4]=[N:5]3)[NH:8]1
Reactant: CN(C)CCN
Reactant: O=S1(=O)Nc2c(ccc3c(Cl)ccnc23)-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CN(C)CCNc1ccnc2c3c(ccc12)-c1ccccc1S(=O)(=O)N3
Yield: 27.1 %

Procedure:
In a similar fashion using route 48 general procedure 114, 1-chloro-5H-6-thia-4,5-diaza-chrysene 6,6-dioxide 305 (75 mg, 0.23 mmol), N,N-dimethylethylenediamine (0.08 ml, 0.71 mmol), DIPEA (0.09 ml, 0.53 mmol) and n-BuOH (1 ml) gave the title compound (23 mg, 26%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32]C)([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N1CCCC(C(O)=O)CC1.C(=O)([O-])[O-].CO.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH2:32][CH:26]([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: O=C(O)C1CCCNCC1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCCC(C(=O)O)CC4)ccc3c2)CC1
Yield: 24 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using Perhydro-azepine-4-carboxylic acid (0.138 g, 0.967 mmol) HCl, 250 mg solid supported carbonate resin (1.34 mmol/g), Methanol (1.6 mL, 4.0E1 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.250 g, 0.805 mmol) and Acetic acid (0.16 mL, 2.8 mmol) to give 86 mg the title compound as a white solid (24%). ESI-LCMS 438 (M+H). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 7.96 (s, 1H), 7.81-7.91 (m, 2H), 7.51-7.65 (m, 1H), 7.43 (d, J=1.8 Hz, 1H), 7.14-7.26 (m, 1H), 4.45 (br. s., 3H), 3.00-3.57 (m, 4H), 2.63-2.75 (m, 1H), 1.58-2.33 (m, 10H), 1.00-1.51 (m, 6H), 0.89 (s, 9H)
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([CH:8]([C:18]([NH:20][C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[N:26][CH:25]=[CH:24]3)=[O:19])[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:5][CH:4]=1.C(Cl)[Cl:32]>>[ClH:32].[ClH:32].[NH2:10][CH2:9][CH:8]([C:6]1[S:7][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[C:18]([NH:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][CH:25]=[CH:24]2)=[O:19]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Reactant: ClCCl
Product: Cl
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)s1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 2-(5-(hydroxymethyl)thiophen-2-yl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E238) in CH2Cl2 was added 4 NHCl-dioxane and the solution was stirred for 4 h. The solvents were evaporated to give 3-amino-2-(5-(hydroxymethyl)thiophen-2-yl)-N-(isoquinolin-6-yl)propanamide dihydrochloride (E239).