Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(/C=C/CO)C=CC=CC=1.CC1C(O)=CC=CC=1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[C:43]([CH3:48])[C:42]=1[OH:49])[CH:33]=[CH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(C1C=C(CC=CC2C=CC=CC=2)C(O)=C(C)C=1O)C=CC1C=CC=CC=1>ClCCCl.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:48][C:43]1[C:44]([OH:47])=[CH:45][CH:46]=[C:41]2[C:42]=1[O:49][CH:34]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:33][CH2:32]2
Reactant: Cc1c(O)ccc(CC=Cc2ccccc2)c1O
Agent: Cc1c(O)c(CC=Cc2ccccc2)cc(CC=Cc2ccccc2)c1O
Agent: Cc1c(O)cccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: O
Product: Cc1c(O)ccc2c1OC(c1ccccc1)CC2
Temperature: 25 °C

Procedure:
Step 1 A suspension of (E)-3-phenylprop-2-en-1-ol (2.22 g, 16.51 mmol) and 2-methylbenzene-1,3-diol (2.05 g, 16.51 mmol) in 1,2-dichloroethane (100 mL) was treated with p-toluenesulfonic acid monohydrate (0.157 g, 0.826 mmol) and the mixture was heated at reflux for 1 h. The mixture was cooled to rt and concentrated, and the residue was subjected to column chromatography (eluting with a gradient from 90:10 to 75:25 hexane-EtOAc) provided a mixture of 4-cinnamyl-2-methylbenzene-1,3-diol and 4,6-dicinnamyl-2-methylbenzene-1,3-diol (2:1, 1.97 g). This material (1.89 g) was dissolved in toluene (60 mL) and treated with p-toluenesulfonic acid monohydrate (299 mg, 1.57 mmol) and heated at reflux for 6 h. The mixture was cooled to rt, diluted with EtOAc (100 mL), washed with NaHCO3 (aq) (2×30 mL), water (30 mL) and brine (30 mL), dried and concentrated. Column chromatography (eluting with a gradient from 95:5 to 70:30 hexane-EtOAc) provided 8-methyl-2-phenylchroman-7-ol as a brown liquid (ca. 85% purity, 672 mg, 17%) used without further purification. 1H NMR (400 MHz, chloroform-d) δ 7.35-7.50 (4 H, m), 7.27-7.35 (1H, m), 6.79 (1H, d, J=8.36 Hz), 6.38 (1H, d, J=8.14 Hz), 5.07 (1H, dd, J=10.12, 2.42 Hz), 4.64 (1H, s), 2.83-3.02 (1H, m), 2.71 (1H, ddd, J=16.01, 4.90, 3.74 Hz), 2.16-2.27 (1H, m), 2.14 (3H, s), 1.86-2.04 (1H, m). Mass spectrum m/z 241.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[C:24]([CH3:31])=[N:23]2.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[C:25]([CH3:30])[C:24]([CH3:31])=[N:23]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1nc2ccc(N)cc2nc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1nc2ccc(NS(=O)(=O)c3cccc(Cl)c3C)cc2nc1C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (109 mg, 0.485 mmol) in dichloromethane (3 mL) was added pyridine (90 μL, 1.2 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2,3-dimethylquinoxaline [22] (80 mg, 0.46 mmol) was added. The resulting mixture was stirred for 6 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford an off-white solid (152 mg, 91%), single spot at Rf 0.70 (ethyl acetate). mp 225.3-225.7° C. HPLC purity 99+% (tR 2.29 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.99 (1H, d, 4=7.9. Hz), 7.85 (1H, d, J=9.2 Hz), 7.54-7.52 (2H, m), 7.40 (1H, dd, J=9.1, 2.6 Hz), 7.21 (1H, t, J=7.9 Hz), 6.95 (1H, s, N—H, 2.75 (3H, s), 2.67 (6H, s). LCMS: 360.24 (M−). FAB-MS (MH+, C17H16ClN3O2S): calcd 362.0730, found 362.0732.
Reaction SMILES: Cl[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(#N)C>[CH2:34]([NH:41][CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCl
Solvent: CC#N
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CNCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A solution of Compound 3 (100 mg) and benzylamine (70 μL) in acetonitrile (2 mL) was heated at 110° C. over 8 hours. Solvent was removed under reduced pressure and the crude product was stirred in trifluoroacetic acid (1 mL) for 2 hours at room temperature. Finally, trifluoroacetic acid was removed under reduced pressure and the crude product was partitioned between chloroform (20 mL) and 7% aqueous NaHCO3 solution (10 mL). The chloroform layer was dried and concentrated and purified on a silica gel column using 4% ethanol in dichloromethane to obtain the product in 50% yield (57 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1>CN(C)C=O>[C:16]([C:15]1[CH:19]=[CH:20][C:12]([O:11][CH2:10][CH2:9][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)=[CH:13][CH:14]=1)(=[O:17])[NH2:18]
Reactant: c1c[nH]cn1
Reactant: NC(=O)c1ccc(OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(OCCn2ccnc2)cc1
Temperature: 100 °C
Yield: 50.8 %

Procedure:
Sodium hydride (14.4 g, 50% suspension in mineral oil) was added cautiously to a stirred and cooled solution of imidazole (20.4 g) in dry N,N-dimethylformamide (100 ml). After the initial vigorous reaction had subsided the mixture was heated to 100° C. for 10 minutes and then stirred at room temperature for a further 1 hour. A solution of 4-(2-chloroethoxy)benzamide (60.0 g) in the minimum volume of N,N-dimethylformamide was added and the mixture was heated at 100° C. for 5.5 hours. The solvent was evaporated and the residue was poured into water. The mixture was extracted several times with chloroform and the combined chloroform extracts were dried (MgSO4) and evaporated to give a mixture of oil and solid. The mixture was triturated with ether and the solid was collected and crystallised from a mixture of methanol and ethyl acetate to give 1-[2-(4-carbamoyl phenoxy)ethyl]imidazole (35.2 g), m.p. 148°-149° C. Found: C, 62.25; H, 5.61; N, 18.54. C12H13N3O2 requires: C, 62.32; H, 5.67; N, 18.17%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.Cl.Cl.[CH3:15][NH:16][NH:17][CH3:18].CCN(CC)CC.Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[N:17]([CH3:18])[N:16]([CH3:15])[C:9]2=[O:8]
Reactant: CNNC
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2ccc(Br)cc2c(=O)n1C
Yield: 43.5 %

Procedure:
A suspension of 4-bromophthalic anhydride (1.0 g) in EtOH (10 mL) was treated with 1,2,-dimethylhydrazine dihydrochloride (650 mg) and NEt3 (1.35 mL) and heated at reflux during 16 h. The reaction mixture was cooled and diluted into 0.1M HCl (100 mL). The resμLting white solid was collected by filtration, washed with water, and dried in vacuo to give 6-bromo-2,3-dimethyl-2,3-dihydrophthalazine-1,4-dione (516 mg), m.p. 207-209.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[Cl-].[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1.O>O1CCCC1>[CH2:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][NH:15][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([C:27]([O:26][CH3:25])=[O:37])=[CH:36][CH:35]=2)=[O:13])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCCCCCOc1ccc(C(=O)NN)cc1
Agent: [Cl-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
To a solution of 4-n-Hexyloxybenzoylhydrazine (1.96 g) and pyridine (0.74 ml) in tetrahydrofuran (20 ml) was added a solution of terephthalic acid monomethyl ester chloride (1.56 g) in tetrahydrofuran (15 ml) dropwise at 0° C. The reaction mixture was stirred at room temperature for 2 hours, and poured into water. The precipitate was collected by filtration and washed with acetonitrile. The residue was dried under reduced pressure to give 1-(4-n-Hexyloxybenzoyl)-2-(4-methoxycarbonylbenzoyl)hydrazine (2.99 g).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(O)=O.C([O:29][C:30]([C@@H:32]1[CH2:37][C@@H:36]2[C@@H:34]([CH2:35]2)[N:33]1[C:38](=[O:52])[CH2:39][N:40]1[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42]([C:49](=[O:51])[CH3:50])=[N:41]1)=[O:31])C=C>CN(C=O)C.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[C:49]([C:42]1[C:43]2[C:44](=[N:45][CH:46]=[CH:47][CH:48]=2)[N:40]([CH2:39][C:38]([N:33]2[C@H:32]([C:30]([OH:31])=[O:29])[CH2:37][C@@H:36]3[C@H:34]2[CH2:35]3)=[O:52])[N:41]=1)(=[O:51])[CH3:50]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(C)=O)c2cccnc21
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: O=CO
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were dissolved in DMF (7.69 mL) under argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10° C., formic acid (0.513 mL, 13.38 mmol) was added followed by TEA (1.865 mL, 13.38 mmol) and a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.38 mL). The reaction mixture was stirred at 10° C. during 1 h. DMF was evaporated. The residue was poured into NH4Cl (saturated aqueous solution) and extracted with EtOAc (3×50 mL). The organic phases were combined, dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; tR (HPLC conditions I): 1.84 min. 1H NMR (400 MHz, DMSO-d6): (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1H), 8.58 (m, J=6.36 Hz, 1H), 7.35-7.50 (m, 1H), 8.54-8.61 (m, 1H), 5.88 (d, J=16.87 Hz, 1H), 5.55 (d, J=17.12 Hz, 1H), 4.14-4.24 (m, 1H), 3.75-3.83 (m, 1H), 2.64 (s, 3H), 2.26-2.36 (m, 1H), 2.10-2.23 (m, 1H), 1.80-1.95 (m, 1H), 0.95-1.07 (m, 1H), 0.67-0.81 (m, 1H).
Reaction SMILES: B([O-])=O.[Na+].[CH2:5]([O:8][C:9]1[CH:27]=[CH:26][C:12]([O:13][CH:14]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH:6]=[CH2:7]>CO>[CH2:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[CH:15]([OH:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:26][CH:27]=1)[CH:6]=[CH2:7]
Reactant: C=CCOc1ccc(OC(C(=O)C(C)(C)C)n2cncn2)cc1
Agent: O=B[O-]
Agent: [Na+]
Solvent: CO
Product: C=CCOc1ccc(OC(C(O)C(C)(C)C)n2cncn2)cc1
Yield: 95.9 %

Procedure:
1 g (0.027 mole) of sodium boranate is added in portions to 7.2 g (0.023 mole) of 1-(4-allyloxyphenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanone (Example 1) in 80 ml of methanol at 20° C., while stirring. The mixture is subsequently stirred for 1 hour and is then concentrated in vacuo by distilling off the solvent. The residue is partitioned between methylene chloride and water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 7 g (97.2% of theory) of 1-(4-allyloxyphenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 85° C. are obtained.
Reaction SMILES: [CH2:1]([NH:3][CH3:4])[CH3:2].[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]>>[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([N:3]([CH2:1][CH3:2])[CH3:4])[N:27]=4)=[CH:22][CH:21]=3)[CH:14]=2)[NH:9][CH:8]=1)#[N:6]
Reactant: CCNC
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CCN(C)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using ethylmethylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.15 (t, 3H, J=7 Hz); 2.99 (bt, 2H); 3.17 (s, 3H); 3.56 (m, 2H); 3.73 (m, 2H); 7.20 (m, 2H); 7.50 (m, 2H); 7.94 (d, 2H, J=7 Hz); 8.20 (m, 3H); 8.44 (d, 1H, J=5 Hz); 8.69 (bs, 1H); 12.14 (bs, 1H). MS (ion spray) m/z 425 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])=O)(C)(C)C.C(N(CC)CC)C.ClC(OCC)=O.[CH3:28][S:29][C:30]([CH3:37])([CH:32]([NH2:36])[CH:33]([CH3:35])[CH3:34])[CH3:31]>C(OCC)(=O)C.O1CCCC1>[CH3:28][S:29][C:30]([CH3:37])([CH:32]([NH:36][C:12](=[O:14])[C@@H:9]([CH2:10][OH:11])[NH2:8])[CH:33]([CH3:35])[CH3:34])[CH3:31]
Reactant: CSC(C)(C)C(N)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC(C)(C)C(NC(=O)[C@H](N)CO)C(C)C
Reaction time: 0.25 h

Procedure:
To a solution of 3.47 g. (0.017 mole) N-t-butoxycarbonyl-D-serine and 2.5 g. (0.017 mole) triethylamine in 100 ml. of tetrahydrofuran at -15° C. is added 1.63 ml. of ethyl chloroformate. After stirring for 15 minutes, 2.49 g. (0.017 mole) 2-methylthio-2,4-dimethyl-3-aminopentane is added and the mixture stirred for one hour. The reaction mixture is diluted with ethyl acetate, washed with water, 5% aqueous citric acid (w/v), sodium bicarbonate solution and brine. The organic phase is evaporated to dryness. The residue is taken up in 100 ml. methanol, 60 ml. of concentrated hydrochloric acid added and the mixture refluxed for one hour. After evaporation of methanol, the residue is taken up in water, washed with ether, the aqueous phase adjusted to pH 12 with sodium hydroxide and extracted with ethyl ether. Evaporation of the extracts affords the desired D-serine amide.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1cnc2ccc(Br)cc2n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccc2ncc(N3CCOCC3)nc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 7-bromo-2-chloroquinoxaline (50 g, 0.2 mol, 1.0 eq.) in CH3CN (200 mL) were added morpholine (89 g, 1.02 mol, 5.0 eq.) and K2CO3 (85 g, 0.61 mol, 3.0 eq). The resulting mixture was stirred at 90° C. for 2 h, then cooled and filtered. The filtrate was concentrated and the residue was re-crystallized from EA to afford 4-(7-bromoquinoxalin-2-yl)morpholine (59 g, 98.3%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20](=[O:28])[NH:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])=[CH:19][C:14]=2[N:13]=[C:12]1[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=2[N:34]=1)C)(C)(C)C>Cl.O1CCOCC1>[ClH:39].[ClH:39].[OH:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]2[N:11]([CH2:10][CH2:9][NH:7][CH3:6])[C:12]([NH:29][C:30]3[S:31][C:32]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=4[N:34]=3)=[N:13][C:14]=2[CH:19]=1)=[O:28]
Reactant: CN(CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Yield: 258.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methylamino-ethyl)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide dihydrochloride (60 mg) was prepared by following General Procedure L starting from (2-{2-(6-chloro-benzothiazol-2-ylamino)-5-[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-benzoimidazol-1-yl}-ethyl)-methyl-carbamic acid tert-butyl ester (73 mg) in 4M HCl in dioxane (1 mL). LC/MS: m/z 488.5.
Reaction SMILES: [CH3:1][C:2]1[C:7]([SH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][N:20]=1.P([O-])(O)(O)=O.[Na+]>O1CCCC1>[CH3:1][C:2]1[C:7]([S:8][C:15]2[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][N:20]=2)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccnc1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1S
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc([N+](=O)[O-])c1Sc1nccnc1Cl
Reaction time: 0.17 h
Yield: 35.3 %

Procedure:
To a solution of 1.254 g of 6-methyl-2-nitrobenzenethiol in tetrahydrofuran (10 ml) was added 0.326 g of sodium hydride under ice-cooling in a nitrogen atmosphere. After stirring for 10 minutes, 1.67 g of dichloropyrazine was added thereto and the resulting mixture was stirred at room temperature for 1 hour and heated under reflux for 1.5 hour. Then the reaction mixture was poured into a saturated aqueous solution of sodium dihydrogenphosphate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. Then the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 0.737 g of the title compound as a red oily substance.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:16]=[C:15]([C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[OH-].[Li+].Cl>CO>[C:17]([C:15]1[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=[C:4]([CH:16]=1)[C:3]([OH:25])=[O:2])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCN(C)C(=O)c1cc(C(=O)OC)cc(C(=O)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Dissolve 5-benzoyl-N-methyl-N-propyl-isophthalamic acid methyl ester (60 mg, 0.17 mmol) in methanol (4 mL). Add dropwise 1 N lithium hydroxide (0.23 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute the residue with ethyl acetate and wash with saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate to give the title compound (83%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]([CH:14]=O)[CH2:8][CH2:7]1.[CH2:26]([NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1)[C:27]#[CH:28].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:24][C:2]([F:25])([F:1])[C:3]1[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:14]=[C:34]2/[C:30]([NH:29][CH2:26][C:27]#[CH:28])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:10][CH2:11][C:12]1=[O:13]
Reactant: C#CCNC1=NC(=O)SC1
Reactant: O=CC1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCC(=O)N(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]-7-oxoazepane-4-carbaldehyde (1.00 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (0.63 g) in 2-propanol (10 mL) was added piperidinium acetate (0.40 g). The reaction mixture was stirred at 80° C. for 2 hr and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.48 g).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[C:6]([F:13])[CH:5]=1.C(OCC)(=O)C.CCCCCC>C(O)(=O)C.C(Cl)Cl>[Br:1][CH2:11][C:10]([C:7]1[CH:8]=[CH:9][C:4]([Br:3])=[CH:5][C:6]=1[F:13])=[O:12]
Reactant: CC(=O)c1ccc(Br)cc1F
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Br)cc1F
Temperature: 25 °C
Yield: 97 %

Procedure:
Bromine (1.2 mL, 23.0 mmol) in 10 mL of glacial acetic acid was added drop-wise to a solution of 1-(4-bromo-2-fluoro-phenyl)-ethanone (5.0 g, 23.0 mmol), prepared in the previous step, in 150 mL of dry methylene chloride at 0° C. After the addition, the reaction was allowed to warm to room temperature. TLC (5% ethyl acetate:hexane) indicated the starting material was consumed. The reaction was diluted with methylene chloride and washed with 5% sodium thiosulfate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2-bromo-1-(4-bromo-2-fluoro-phenyl)-ethanone (6.6 g, 97%) as a light green oil. This compound was used without further purification. MS (ES) m/z 297 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:11]1[C:16](Br)=[CH:15][C:14]([F:18])=[C:13]([N:19]=[N:20][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:12]=1[F:26])[CH2:7][N+:8]([O-])=O)[CH3:2]>CCN(CC)CC.C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:11]1[CH:16]=[CH:15][C:14]([F:18])=[C:13]([N:19]=[N:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)[C:12]=1[F:26])[CH2:7][NH2:8])[CH3:2]
Reactant: CCOC(=O)CC(C[N+](=O)[O-])c1c(Br)cc(F)c(N=NN2CCCC2)c1F
Agent: [Ni]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(CN)c1ccc(F)c(N=NN2CCCC2)c1F
Temperature: 0 °C
Yield: 75.5 %

Procedure:
In a 500 ml pressure jar, under inert atmosphere, 6.29 g (14 mmol) of 3-[6-bromo-2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-4-nitro-butyric acid ethyl ester all and Et3N (5.9 ml) are dissolved in 120 ml of ethanol. A suspension of 6 g of predried (3 times, ethanol) Raney nickel is added and the mixture hydrogenated on a Parr hydrogenator at a maximum of 20 psi H2 pressure (strongly exothermically reaction, ice/water cooling required). The mixture is degassed, filtered on a Celite/Norite pad, and the filtrate concentrated in vacuo, to give 6.2 g of crude. It is again hydrogenated as described above to remove the bromide using 0.59 g of Pd/C instead of Raney nickel during 0.75 h on a Parr hydrogenator at a maximum of 40 psi H2 pressure. The crude amino-ester is purified by chromatography on silicagel (CH2Cl2/EtOH/NH4OH: 94.5/5/0.5 (v/v/v)) to give 3.6 g of 4-amino-3-[2,4-difluoro-3-(pyrrolidin-1-ylazo)-phenyl]-butyric acid ethyl ester a12 (76% yield) used as such in the next step.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCC[CH2:23]1.Cl>O.CO>[CH3:23][C:17]1[CH:18]=[C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(COc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of methyl 4-(phenoxymethyl)benzoate (1.1 g, 4.55 mmol), lithium hydroxide monohydrate (955 mg, 22.8 mmol), tetrahydrofuran (20 mL), methanol (7 mL) and water (7 mL) were stirred at room temperature for 5 hours. The mixture was neutralized to pH to 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was separated, dried over sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give methyl 4-(phenoxymethyl)benzoic acid as a white solid (840 mg, 81%). LRMS (M+H)− m/z: calcd 228.08. found 228.