Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][CH:24]([C@H:26]5[CH2:29][C@H:28]([O:30]C(=O)C6C=CC([N+]([O-])=O)=CC=6)[CH2:27]5)[CH3:25])=[O:22])=[CH:19][N:18]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:49])([CH3:48])[CH3:47])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[OH-].[Na+].CO>C1COCC1.O>[OH:30][C@H:28]1[CH2:27][C@H:26]([CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:42][O:43][CH2:44][CH2:45][Si:46]([CH3:47])([CH3:49])[CH3:48])[CH:19]=2)=[O:22])[CH3:25])[CH2:29]1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a suspension of 4-nitrobenzoic acid trans-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester (250 mg, 0.36 mmol) in THF (12 mL) was added 10% aqueous sodium hydroxide (0.44 mL, 1.09 mmol), water (1 mL), and MeOH (2 mL). The reaction mixture was stirred at room temperature for 30 min then diluted with water and extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 30% to 80% EtOAc/hexanes to afford 140 mg (72%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(trans-3-hydroxy-cyclobutyl)-ethyl]-amide as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:22](=[O:23])[CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)N1CCN(Cc2ccccc2)CC1

Procedure:
1-Benzylpiperazine (8g, 45.4 mmol), 3-fluorophenyl acetic acid (7.7 g, 50 mmol), triethylamine (7 ml, 50.6 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.6 g, 50 mmol) were stirred together in dry dichloromethane (150 ml) for 24 hours. The volatiles were evaporated then the residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried then evaporated. The residue was purified by column chromatography on silica using 2% methanol in dichloromethane→10% methanol in dichloromethane. The title compound was obtained as a yellow oil (11.1 g, 77%). δ (250 MHz, CDCl3) 2.28 (2H, t, J=5 Hz), 2.42 (2H, t, J=5 Hz), 3.43 (2H, t, J=5 Hz), 3.44 (2H, s), 3.65 (2H, t, J=5 Hz), 3.71 (2H, s), 6.90-7.37 (9H, m).
Reaction SMILES: CO[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH3:13])[C:9]2=[O:12])=[CH:5][CH:4]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17].II.[CH2:22]([OH:24])C>C1C=CC=CC=1.CCOCC.C(O)(=O)C>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH:7]1[C:6]2[C:10](=[CH:11][CH:3]=[CH:4][CH:5]=2)[C:9]([O:12][CH2:22][OH:24])=[C:8]1[CH3:13]
Reactant: CCO
Reactant: COc1ccc2c(c1)C(=O)C(C)C2
Reactant: COC(=O)CBr
Agent: II
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COC(=O)CC1C(C)=C(OCO)c2ccccc21
Temperature: 65 °C

Procedure:
A solution of 13.4 g of 6-methoxy-2-methylindanone and 19.3 g of methyl bromoacetate in 45 ml benzene is added over a period of 5 minutes to 21 g of zinc amalgam (prepared according to Org. Syn. Coll., vol. 3) in 110 ml benzene and 40 ml dry ether. A few crystals of iodine are added to start the reaction, and the reaction mixture is maintained at reflux temperature (ca. 65° C.) with external heating. At 3 hour intervals, two batches of 10 g zinc amalgam and 10 g bromoester are added, and the mixture is then refluxed for 8 hours. After addition of 30 ml ethanol and 150 ml of acetic acid, the mixture is poured into 700 ml of 1:1 aqueous acetic acid. The organic layer is separated, and the aqueous layer is extracted twice with ether. The combined organic layers are washed thoroughly with water, ammonium hydroxide and water. Drying over sodium sulfate, evaporation of solvent in vacuo followed by pumping at 80° C. (bath temp.) (1-2 mm) gives crude methyl(1-hydroxy-2-methyl-methoxy-indenyl)acetate.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([Pb+3:17])[CH:24]=1
Reactant: Cc1ccc(Br)cc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Br)cc1[Pb+3]
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 78.9 %

Procedure:
To a mixture of lead tetraacetate (11.25 g, 25.40 mmol) and mercuric diacetate (0.40 g, 1.27 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (35 ml). This mixture is warmed to 40° C., and 5-bromo-2-methylphenylboronic acid (4.96 g, 23.10 mmol) is added in one portion and the suspension is heated at this temperature for 5 hours. The mixture is then allowed to cool to room temperature, followed by further cooling to 0° C. then powdered anhydrous potassium carbonate (1.61 g) is added with rapid stirring for 5 minutes. The mixture is filtered, the filtrate is concentrated to half its volume, and hexanes added to induce precipitation. This mixture is further concentrated, the solvent decanted, and the solid washed with hexanes to afford 5-bromo-2-methylphenyllead triacetate (10.10 g) as a sandy coloured solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][CH2:6][CH3:7])[CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1.CO>C1COCC1>[OH:4][CH2:3][C@@H:2]([NH:1][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)=[O:18])[CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCC[C@H](N)CO
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@@H](CO)NC(=O)Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 105.3 %

Procedure:
A solution of (2S)-2-aminopentan-1-ol (500 mg) in THF (6 mL) was cooled in a dry ice-acetone bath under nitrogen atmosphere, and a solution of 4-methoxyphenyl isocyanate (657 mg) in THF (4 mL) was added dropwise thereto. After the mixture was stirred for 17 hr while gradually warming to room temperature, methanol was added thereto, and the solvent was distilled off under reduced pressure to afford 1-[(2S)-1-hydroxypentan-2-yl]-3-(4-methoxyphenyl)urea (1.17 g).
Reaction SMILES: S(=O)(=O)(O)O.[NH:6]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])[NH2:7].[CH3:17][C:18]([CH3:25])([CH3:24])[C:19](=O)[CH2:20][C:21]#[N:22].[CH3:26][CH2:27]O>>[NH2:22][C:21]1[N:6]([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([O:13][CH2:26][CH3:27])=[O:12])[N:7]=[C:19]([C:18]([CH3:25])([CH3:24])[CH3:17])[CH:20]=1
Reactant: NNc1cccc(C(=O)O)c1
Reactant: CCO
Reactant: CC(C)(C)C(=O)CC#N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(-n2nc(C(C)(C)C)cc2N)c1
Temperature: 90 °C
Yield: 71 %

Procedure:
Sulfuric acid (concentrated, 15.7 mL, 295.7 mmol) was carefully added drop-wise to cold EtOH (600 mL) with stirring. To this, 3-hydrazinobenzoic acid (45 g, 295.7 mmol) and 4,4-dimethyl-3-oxopentanenitrile (40.7 g, 325.3 mmol) were added and then the mixture was heated at 90° C. for 48 h. Most of the solvent was evaporated at reduced pressure, and the residual mixture was diluted with ethyl acetate. The resulting mixture was washed with ice cold 2M NaOH followed by brine, and dried (Na2SO4). The solution was filtered through a bed of silica gel, washing with more ethyl acetate. Evaporation of ethyl acetate and treatment of the residue with dichloromethane/hexanes gave the product as an off-white crystalline solid (61 g, 71%). MS m/z 288.2 (M+H)+; calcd. mass 287. Retention time (LC-MS): 2.99 min. 1H-NMR (DMSO-d6): δ 8.16 (m 1H); 7.88 (m, 2H); 7.60 (t, 1H); 5.40 (s, 1H); 5.32 (s, 2H); 4.36 (q, 2H); 1.34 (t, 3H); 1.21 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH2:20])=[N:16][NH:17]2)=[CH:13][CH:12]=1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([NH:20][C:7](=[O:8])[CH2:6][C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:16][NH:17]2)=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 3 °C
Reaction time: 21 h

Procedure:
0.73 cm3 of 2-thiopheneacetyl chloride is added to 1 g of 6-chloro-1H-indazole-3-amine in 15 cm3 of pyridine, cooled to about 3° C. The reaction medium is allowed to return to about 19° C. over 21 hours and is then evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 25 cm3 of ethyl acetate, 10 cm3 of tetrahydrofuran and 25 cm3 of distilled water. The organic phase is washed with 25 cm3 of distilled water and 25 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered on a sinter funnel, rinsed with 5 cm3 of dimethylformamide and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a dichloromethane/methanol mixture (99/1 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 210 mg of N-[6-chloro-1H-indazol-3-yl]-2-thiophenacetamide are obtained in the form of a white solid melting at 210° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH3:20])[C:13]3=[O:21])[CH:8]=1.[Br:23][C:24]1[CH:25]=[C:26]([C:36](O)=[O:37])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:23][C:24]1[CH:25]=[C:26]([C:36]([NH:2][C:3]2[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]([CH3:20])[C:13]4=[O:21])[CH:8]=2)=[O:37])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:28]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: O=C(O)c1cc(Br)nn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cc(Br)nn2-c2ccc(F)cc2)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reaction time: 20 h
Yield: 68.5 %

Procedure:
6-(5-Amino-2-methyl-phenylamino)-3-methyl-3H-quinazolin-4-one HCl salt (30 mg, 0.08 mmol) was dissolved in DMF (5 mL) with 5-bromo-2-(4-fluoro-phenyl)-2H-pyrazole-3-carboxylic acid (45 mg, 0.16 mmol) at RT. HATU (60 mg, 0.16 mmol) was added, followed by DIEA (0.14 mL, 0.8 mmol). The mixture was stirred for 20 h. Water (10 mL) was added and the mixture was extracted with EtOAc (20 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 30 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 549.0.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[CH3:29][N:30]1[C:35](=[O:36])[N:34](COCC[Si](C)(C)C)[C:33]2[CH:45]=[CH:46][C:47](B3OC(C)(C)C(C)(C)O3)=[CH:48][C:32]=2[S:31]1(=[O:59])=[O:58].C(O)(C(F)(F)F)=O>>[CH3:29][N:30]1[C:35](=[O:36])[NH:34][C:33]2[CH:45]=[CH:46][C:47]([C:2]3[N:7]4[CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:4][CH:3]=3)=[CH:48][C:32]=2[S:31]1(=[O:59])=[O:58]
Reactant: CN1C(=O)N(COCC[Si](C)(C)C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2S1(=O)=O
Reactant: Brc1cnc(N2CCOCC2)c2nc(/C=C/c3ccc4ccccc4n3)cn12
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)Nc2ccc(-c3cnc(N4CCOCC4)c4nc(/C=C/c5ccc6ccccc6n5)cn34)cc2S1(=O)=O

Procedure:
Compound 2b was subjected to Suzuki coupling conditions using the methods described in Example 1, Step G, with compound 42c and the resulting product was deprotected with TFA using the methods described Example 37, Steps B and C to obtain the title compound 19. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.71 (s, 1H), 8.35 (d, J=8.6 Hz, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.96 (t, J=8.6 Hz, 2H), 7.83-7.90 (m, 2H), 7.75 (t, J=7.6 Hz, 1H), 7.64 (d, J=16.2 Hz, 1H), 7.53-7.60 (m, 1H), 7.43-7.51 (m, 2H), 4.31 (br. s., 4H), 3.82 (br. s., 4H), 3.25 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H25N7O4S: 568.2 (M+H). Found 568.5.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37](Cl)=[O:38])[C:25]=2[CH3:40])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:27]=[C:26]([C:37]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:38])[C:25]=2[CH3:40])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1c(C(=O)Cl)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)NNC(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A mixture of 1.82 g of tert-butyl hydrazinecarboxylate and 2.4 ml of triethylamine in 50 ml of DCM is cooled to 0° C., a solution of 5.24 g of the compound obtained in stage A in 50 ml of DCM is added and the mixture is left stirring while allowing the temperature to rise to AT. The reaction mixture is washed with water, with a buffer solution at pH=2 and with a saturated NaHCO3 solution, the organic phase is dried over MgSO4 and the solvent is evaporated under vacuum. The residue is taken up in isopropyl ether, pentane is added and the precipitate formed is filtered off. 6.2 g of the expected compound are obtained.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[C:10](=S)=[S:11].N#CCl>C(Cl)Cl.O>[CH:1]1([N:7]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: S=C=S
Agent: N#CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: S=C=NC1CCCCC1
Yield: 98.4 %

Procedure:
In one hour 0.5 mole of cyclohexyl amine, 0.5 mole of sodium hydroxide and 60 grams of water were treated with 0.5 mole of carbon disulfide. The N-cyclohexyl sodium dithiocarbamate solution was stirred for a further hour at 50° C. There were added 1,000 cc of water, 20 grams of sodium hydroxide and 250 cc of methylene chloride. Under stirring there were led in at 6° C, 0.515 mol of cyanogen chloride. After the separation the methylene chloride layer was distilled. There were isolated 69.5 grams of cyclohexyl isothiocyanate (B.P. 98.5° C/13 mm Hg), corresponding to a yield of 98.4% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](Br)[CH:41]=[CH2:42]>CN(C)C=O.O>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:42][CH:41]=[CH2:40])[C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: CC(C)c1oc2c(Br)c(NC(=O)OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OCc1ccccc1)c1ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc2c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [8-bromo-3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromen-7-yl]carbamic acid benzyl ester (0.231 g, 0.44 mmol) and cesium carbonate (0.228 g, 0.701 mmol, 1.6 eq.) in N,N-dimethylformamide (10 ml) is treated with allyl bromide (0.058 g, 0.042 ml, 0.48 mmol, 1.1 eq.), and the mixture is stirred at room temperature for 4 h. The mixture is diluted with water and washed twice with ethyl acetate. The aqueous phase is additionally washed with methylene chloride. The combined organic phases are dried (magnesium sulfate) and filtered and the solvent is removed by evaporation in vacuo to afford the title compound as a yellow solid. The product is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]([F:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(CBr)ccc1F
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of 2-fluoro-5-methylbenzonitrile (3.00 g, 22 mmol), N-bromosuccinimide (4.12 g, 23 mmol) and benzoyl peroxide (1.07 g, 4.4 mmol) in CCl4 (100 mL) was heated at reflux 6 h. The reaction mixture was cooled to room temperature and then combined with water. The separated organic phase was dried over MgSO4, filtered through a Celite™ pad, and evaporated under reduced pressure. Purification by flash chromatography (Hex/EtOAc, 20:1) gave 5-(bromomethyl)-2-fluorobenzonitrile (1.58 g, 33% yield) as an oil. 1H NMR (CDCl3, 400 MHz): δ 4.45 (s, 2H), 7.21 (m, 1H), 7.65 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[C:26]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:24]=[N:23]3)[CH:17]=1)[C:10]([CH3:35])([CH3:34])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH2:27]([C:26]1[N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:35])([CH3:34])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[N:23]=[N:24][N:25]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(-n3nnnc3Cc3ccccc3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(-n2nnnc2Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a stirred mixture solution of 2-[3-(5-benzyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (1.4 g, 3.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(5-benzyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.2 g, 90%) as a white solid: LC/MS m/e calcd for C26H25N5O2 (M+H)+: 440.52, observed: 440.2.
Reaction SMILES: [NH:1]([CH:19]=O)[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.CO.Br.C(O)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[NH:1]([CH3:19])[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)OC
Reaction time: 0.33 h
Yield: 89.7 %

Procedure:
To a solution of N-formyl-Tyr(3-tBu)-OMe (23.8 g, 85.3 mmol) in THF (400 ml), 1.0M borane-THF complex (170 ml) was added dropwise under cooling with ice over 30 min. The mixture was stirred for 20 min., mixed with methanol (50 ml) and further stirred for 30 min. The reaction mixture was mixed with 33% hydrobromic acid/acetic acid (31 ml) and stirred for 2 hours. The mixture was neutralized by saturated aqueous NaHCO3 under cooling with ice and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol=20:1), giving N-Me-Tyr(3-tBu)-OMe (20.3 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[S:31](N)([NH2:34])(=[O:33])=[O:32]>O1CCOCC1>[C:17]1([CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:31](=[O:33])(=[O:32])[NH2:34])=[CH:30][CH:29]=3)[CH2:13][CH2:12]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)Nc1ccc(CCN2CCC(COC(c3ccccc3)c3ccccc3)CC2)cc1
Yield: 41.7 %

Procedure:
A solution of 1-(4-aminophenethyl)-4-(diphenylmethoxymethyl)piperidine (200 mg, 0.50 mmol) (see Example 21) and sulphamide (480 mg, 5.0 mmol) in dioxane (5 ml) was heated under reflux for 3 hours and evaporated. The residue was partitioned between ethyl acetate and 10% aqueous potassium carbonate solution and the layers separated. The aqueous layer was extracted into ethyl acetate and the combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-4% methanol as eluant. Appropriate fractions were combined and evaporated and the residue triturated with diisopropyl ether. The resulting solid was collected, washed with diisopropyl ether and dried to give the title compound (100 mg) as a pale yellow solid, m.p. 172°-174° C., which was characterised by its 1H-NMR spectrum.
Reaction SMILES: C[C:2]1[N:3]=[C:4]([N:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=CC=CC=3)[C:13]2=[O:23])[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[CH2:24](N1CCN(C2SC(C([O-])=O)=C(C)N=2)C1=O)C>>[CH2:17]([N:14]1[CH2:15][CH2:16][N:12]([C:4]2[SH:5]([CH3:24])[C:6]([C:7]([OH:9])=[O:8])=[CH:2][N:3]=2)[C:13]1=[O:23])[CH3:22]
Reactant: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Reactant: CCN1CCN(c2nc(C)c(C(=O)[O-])s2)C1=O
Product: CCN1CCN(C2=NC=C(C(=O)O)[SH]2C)C1=O
Yield: 80 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with 2-(3-ethyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 80% yield: 1H NMR (300 MHZ, DMSO-d6) δ 3.97-3.91 (m, 2H), 3.54-3.48 (m, 2H), 3.23 (q, J=7.2 Hz, 2H), 2.49 (s, 3H), 0.98 (t, J=7.2 Hz, 3H); MS (ES+) m/z 256.3 (M+1).