Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:19][CH3:20])=[CH:9][CH:10]=2)\[CH3:18])=[CH:35][CH:36]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: COc1ccc(Cl)cc1-c1ccc(/C(C)=C/CO)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)ccc3OC)cc2)cc1)OCC
Yield: 61.3 %

Procedure:
The title compound (0.54 g, 61% yield) was prepared from (E)-3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.73 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.433 g, 1.82 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:11][OH:12])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][N:11]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(C=NO)c1=O
Reactant: C=Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Cn1nc(Cl)cc(C2=NOC(c3ccccc3)C2)c1=O
Temperature: 25 °C
Yield: 54 %

Procedure:
To an ice cold mixture of 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde oxime (300 mg, 1.599 mmol, Preparation #31) and styrene (250 mg, 2.399 mmol, Aldrich) in DCM (15 mL) was added 5% aqueous sodium hypochlorite solution (5 mL, 1.599 mmol). The reaction mixture was warmed to RT over 1 h. The reaction mixture was diluted with dichloromethane (15 mL) and washed with water (10 mL). The organic layer was dried over sodium sulphate and evaporated under reduced pressure. The residue obtained was purified by solvent washings with hexane to afford 6-chloro-2-methyl-4-(5-phenyl-4,5-dihydroisoxazol-3-yl)pyridazin-3(2H)-one 0.250 g (54%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.816 (s, 1H), 7.400-7.327 (m, 5H), 5.807-5.758 (m, 1H) 4.001-3.927 (m, 1H) 3.773 (s, 3H) 3.627-3.558 (m, 1H); MS m/z: 312.2 (M+H)+;
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.N1C(C)=CC=CC=1C.Cl[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>ClCCl>[O:1]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)[Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: OCCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
Commercially available 4-(2-hydroxyethyl)pyridine (10.0 g, 81.2 mmol) was dissolved in dichloromethane (400 mL), then 2,6-lutidine (26.1 g, 244 mmol) and chloro-tert-butyldimethylsilane (32.0 g, 121 mmol) were added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction was confirmed by thin-layer chromatography, water was added to the reaction mixture, and the resulting mixture was separated into organic layer and aqueous layer. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure to give 4-[2-(tert-butyldimethylsiloxy)ethyl]pyridine (19.2 g, quantitative yield).
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:40][C:14]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)[C:16](=[O:24])[CH:17]3[CH2:23][CH2:22][CH2:21][N:18]3[C:19](=[O:20])[C:13]=2[CH:12]=1)[CH3:10].[N:41]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:40][C:14]2[N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:41][C:4](=[O:7])[O:5][N:39]=4)=[CH:28][CH:27]=3)[C:16](=[O:24])[CH:17]3[CH2:23][CH2:22][CH2:21][N:18]3[C:19](=[O:20])[C:13]=2[CH:12]=1)[CH3:10]
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)C1CCCN1C2=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3-c3noc(=O)[nH]3)cc1)C(=O)C1CCCN1C2=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of hydroxylammonium chloride (0.45 g), sodium hydrogencarbonate (0.66 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-[(2-ethyl-4,9-dioxo-7,8,8a,9-tetrahydro-4H-pyrrolo[1,2-a]thieno[2,3-e][1,4]diazepin-10(6H)-yl)methyl]biphenyl-2-carbonitrile (0.35 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.14 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.21 g, 52%).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH2:11].C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH2:45][CH:44]3[N:46]([CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH:41]([CH2:42][CH2:43]3)[CH2:40]2)=[CH:35][CH:34]=1>C(Cl)Cl>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[NH:11][C:21](=[O:23])[N:51]([CH2:50][CH2:49][CH2:48][CH2:47][N:46]1[CH:44]3[CH2:43][CH2:42][CH:41]1[CH2:40][N:39]([C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)[CH2:45]3)[C:3]2=[O:12]
Reactant: NCCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cccc(Cl)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(Cl)cccc2c(=O)n1CCCCN1C2CCC1CN(c1ccc(Cl)cc1)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 184.3 %

Procedure:
2-Amino-3-chloro-benzoic acid methyl ester (0.126 g, .681 mmol) and triethylamine (0.22 mL, 1.57 mmol) were dissolved in methylene chloride (3 mL) and cooled to 0° C. Triphosgene (0.067 g, 0.227 mmol) in methylene chloride (1 mL) was added dropwise to the reaction and then stirred in the cold for 1 hour. Next 4-[3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butylamine (0.20 g, 0.681 mmol) was added in one portion and the reaction was stirred at room temperature for 15 hours. Mix was evaporated to dryness, diluted with toluene (40 mL) and refluxed for 6 hours, cooled, diluted with saturated sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried with magnesium sulfate and concentrated to a light brown solid. Silica gel flash chromatography using 3.5% methanol/chloroform as eluent yielded 8-Chloro-3-{4-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-butyl}-1H-quinazoline-2,4-dione (0.198 g, 61%) as a white solid. Maleate salt was formed by dissolving the solid in warm chloroform (30 ml) and maleic acid (0.058 g, 1.2 eq) in warm ethyl acetate (20 ml) was added. Cooling yielded the maleate salt (0.196 g) as a white solid which had the following properties: Mp. 235-238° C., 1H NMR DMSO-d6 δ: 11.02 (brd s, 1H), 9.85 (brd s, 1H), 7.91 (d, J=7.1 Hz, 1H), 7.79 (d, J=6.6 Hz, 1H), 7.26-7.18 (m, 3H), 6.90 (d, J=9.1 Hz, 2H), 6.00 (s, 2H), 4.17 (brd s, 2H), 3.98-3.87 (m, 2H), 3.66 (d, J=14.1 Hz, 2H), 3.11-2.93 ( m,4H), 2.19-2.06 (m, 2H), 1.97-1.85 (m, 2H), 1.77-1.6 (m, 4H). IR (KBr): 3355, 3216, 3190, 3161, 3071, 2960, 2849, 2706, 2397, 1717, 1655, 1610, 1500, 1473, 1456, 1435, 1420, 1404, 1365, 1332, 1311, 1269, 1254, 1221, 1185, 1163, 1134, 1101, 1068, 1041, 989, 973, 954, 925, 915, 882, 851, 821, 814, 790, 761, 747, 729, 701, 671, 650, 580, 545, 515, 496, 484, 437, 411, 404, (cm−1). Analysis calculated for C24H26Cl2N4O2.C4H4O4.1½ H2O: C, 54.55; H, 5.39; N, 9.08. Found: C, 54.81; H, 5.06; N, 8.91.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH2:14][C@H:15]([C:24]([OH:26])=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1>C(O)(C)C>[ClH:1].[CH:15]([O:12][C:11](=[O:13])[C@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:2])([CH3:24])[CH3:16].[ClH:1].[CH:3]([O:25][C:24](=[O:26])[C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[NH2:14])([CH3:11])[CH3:4]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Product: CC(C)OC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Excess HCl gas was added with stirring to a suspension of L-phenylalanine or L-tyrosine in excess isopropanol. The mixture was heated to reflux for 16 h, and then the volatiles were evaporated under vacuum to give L-phenylalanine isopropyl ester hydrochloride or L-tyrosine isopropyl ester hydrochloride of sufficient purity for immediate use.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34]O)[CH2:9]1)=O)(C)(C)C.[CH2:36]([N:43]=[C:44]=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CC#N.[OH2:49].CC#N>O>[CH:31]([N:14]([CH2:13][C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[CH2:34][O:45][C:44](=[O:49])[NH:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)([CH3:32])[CH3:33]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Reactant: O=C=NCc1ccccc1
Reactant: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2COC(=O)NCc2ccccc2)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 3 from (3S*,4R*)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and benzylisocyanate. MS (LC-MS): 528.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 4.52 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[OH-].[Na+].[CH2:12]([O:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.O>[CH2:12]([O:19][C:20]([NH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)OCc1ccccc1
Temperature: 2.5 °C

Procedure:
Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0 to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0 to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12](=O)[CH2:13][CH3:14])=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[S:5][C:6]=1[CH3:7].[OH-].[Na+].CC(O)=O>CCO>[CH2:13]([C:12]1[C:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]=2[NH:8][C:9](=[O:10])[N:11]=1)[CH3:14]
Reactant: CCC(=O)c1c(NC(N)=O)sc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1nc(=O)[nH]c2sc(C)c(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of 1-(4,5-dimethyl-3-propionylthiophen-2-yl)urea (Example 51a) (15.4 mg, 0.068 mmol) in dry EtOH (10 mL) was added sodium hydroxide (8.4 mg, 0.20 mmol). The reaction mixture was then stirred at RT for 30 minutes under nitrogen. The reaction mixture was neutralized with 10% AcOH and then concentrated to dryness. The residue was purified by chromatography on silica gel (Gradient 0-10% MeOH in dichloromethane) to give the title compound (2.7 mg, 19%). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, J=7.6 Hz, 3H), 2.31 (s, 3H), 2.33 (s, 3H), 3.06 (q, J=7.6 Hz, 2H). MS 209 (MH+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([O:17][CH3:18])=[CH:9][CH:8]=1.[F:19][C:20]([F:30])([F:29])[C:21]([NH:23][C@@H:24]([C:26](O)=[O:27])[CH3:25])=[O:22]>ClCCl>[CH3:18][O:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([O:6][CH3:5])=[CH:8][C:9]=1[C:26](=[O:27])[C@H:24]([NH:23][C:21](=[O:22])[C:20]([F:19])([F:29])[F:30])[CH3:25]
Reactant: COc1ccc(OC)c2ccccc12
Reactant: C[C@@H](NC(=O)C(F)(F)F)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C(=O)[C@@H](C)NC(=O)C(F)(F)F)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
To a suspension of AlCl3 (3.8 g, 28.6 mmol) in dichloromethane (100 mL) was added a solution of 1,4-dimethoxynaphthalene (4.88 g, 25.9 mmol) in dichloromethane (50 mL). To this mixture was added a solution of (R)-N-trifluoroacetylalanine (16 g, 86.5 mmol) in CH2Cl2 (50 mL); this mixture was stirred at room temperature for 3 h. The reaction mixture was poured slowly into ice (200 g) to quench the reaction and the organic layer was separated and dried (MgSO4). The solvent was evaporated and the residue was purified by flash chromatography (silica gel, ethyl acetate/hexane: 1/9) to give a yellow oil (3 g): 1H NMR (DMSO-d6) δ 1.24 (d, 3H, CH3), 3.93 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 5.51 (m, 1H), 6.99 (s, 1H, Ar—H), 7.96 (m, 2H, Ar—H), 8.17 (m, 2H, Ar—H), 9.83 (d, NH); MS 356 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:7]([CH3:8])=[C:6]([Cl:9])[S:5][C:4]=1[Cl:10].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[Cl-:1].[Cl:10][C:4]1[S:5][C:6]([Cl:9])=[C:7]([CH3:8])[C:3]=1[CH2:2][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(Cl)sc(Cl)c1CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1c(Cl)sc(Cl)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
A mixture of 25.4 g. (0.12 mol) of 3-chloromethyl-2,5-dichloro-4-methylthiophene, 34.6 g. (0.132 mol) of triphenylphosphine and 200 ml. of benzene was heated to the reflux overnight. The resulting beige solid was filtered to yield (2,5-dichloro-4-methyl-3-thenyl)-triphenylphosphonium chloride, m.p. 238°-240° C.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O>>[Cl:12][C:11]1[C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:13][CH3:14])=[CH:6][CH:5]=2
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2nc(Cl)c(Cl)cc2c1
Product: COc1ccc2nc(-c3ccc(C(=O)O)cc3)c(Cl)cc2c1

Procedure:
Followed Scheme 3 where the starting materials were 2,3-dichloro-6-methoxyquinoline (Intermediate 4) and 4-boronobenzoic acid.
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])N[C:12]3=[O:18])=[CH:7][CH:6]=1>CO>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:1]([CH3:3])[C:12]3=[O:18])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C23CC2C(=O)NC3=O)cc1
Reactant: C=[N+]=[N-]
Solvent: CO
Product: CN1C(=O)C2CC2(c2ccc(N)cc2)C1=O
Reaction time: 16 h

Procedure:
An approx. 0.3 molar solution of diazomethane is added dropwise at 0° C. to a solution of 202 mg of 1-(4-aminophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 10 ml of methanol. The reaction mixture is allowed to stand for 16 hours, concentrated, and partitioned twice between ethyl acetate and water. The organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is crystallised from ethyl acetate/petroleum ether, affording the title compound which is identical with the title compound of Example 3(a).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:22](I)[I:23]>C1COCC1>[I:23][CH2:22][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: ICI
Reactant: COC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CI)CCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a stirred solution of HN(iPr)2 (1.31 mL, 9.36 mmol) in THF (5 mL) was added n-BuLi (1.58 M in hexane, 5.43 mL, 8.58 mmol) with keeping −10° C. under N2, and the mixture was stirred at −10° C. for 1 h. Then, to this mixture was added a solution of methyl cyclopentanecarboxylate (1.00 g, 7.80 mmol) in THF (3 mL) dropwise at 0° C., and the mixture was stirred at 0° C. for 2 h. Finally, to this mixture was added CH2I2 (0.628 mL, 7.80 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with sat. NH4Cl aq. (50 mL), extracted with Et2O (75 mL) for two times, and the combined organic layer was washed with brine (75 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with EtOAc/hexane (1:20→1:10) to give 1.085 g (52%) of title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(OC(=O)CCC1C=NC(Br)=CC=1)C.FC1C=CC(B(O)O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(-c2ccc(F)cc2)nc1
Agent: CCOC(=O)CCc1ccc(Br)nc1
Agent: OB(O)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(F)cc2)nc1
Reaction time: 5 h

Procedure:
544.8 mg (4.75 mmol) of methanesulfonyl chloride were added dropwise with cooling to 1000 mg (4.32 mmol) of 3-(6-(4-fluorophenyl)pyridin-3-yl)propan-1-ol (prepared analogously to example 1a), starting from 3-(6-bromopyridin-3-yl)propionic acid ethyl ester and 4-fluorophenylboronic acid) and 656.3 mg (6.48 mmol) of triethylamine in 50 ml of methylene chloride. After 5 h at room temperature, the mixture was extracted with water, and the organic phase was separated and concentrated. Yield: 1.3 g (97%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:40]1[S:44][N:43]=[CH:42][N:41]=1)[S:7]([C:10]1[C:38]([F:39])=[CH:37][C:13]2[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]4[F:36])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].C(O)(C(F)(F)F)=O.C(Cl)[Cl:59]>>[ClH:59].[F:39][C:38]1[C:10]([S:7]([NH:6][C:40]2[S:44][N:43]=[CH:42][N:41]=2)(=[O:9])=[O:8])=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[CH2:27][NH:26][CH2:25][CH:24]4[F:36])[C:13]=2[CH:37]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n(Cc4cccc5c4CN(C(=O)OC(C)(C)C)CC5F)c3cc2F)c(OC)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)c(F)cc2n1Cc1cccc2c1CNCC2F
Temperature: 25 °C

Procedure:
To a flask containing tert-butyl 8-((6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)methyl)-4-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (24-8) (48 mg, 0.066 mmol) in DCM (3 ml) was added TFA (0.5 ml, 6.49 mmol). The reaction mixture was then stirred at room temperature. Followed by LC/MS . . . after ˜20 minutes the reaction mixture was diluted/quenched with DMSO, then MeOH, then filtered (syringe filter) then concentrated (to remove DCM), then diluted with MeOH/DMSO & purified (without workup) by reverse phase chromatography (5-75% MeCN/H2O; 0.1% TFA in AQ; 20 min gradient; Waters 30×150 mm Sunfire 5 micron C18 column); desired fractions concentrated (GENEVAC), then dissolved in MeOH/DCM & added saturated HCl in EtOAc (˜4N) & concentrated to yield 5-fluoro-3-((4-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)methyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide hydrochloride (24-9). HRMS [M+H]: calculated; 480.0606, observed; 480.0587. 1H NMR (400 MHz, CD3 OD): δ 8.22 (s, 1H); 7.80 (d, J=5.5 Hz, 1H); 7.63-7.57 (m, 1H); 7.57-7.48 (m, 2H); 7.11 (d, J=9.3 Hz, 1H); 5.81 (d, J=48.5 Hz, 1H); 5.16-5.10 (m, 2H); 4.74-4.66 (m, 1H); 4.47-4.39 (m, 1H); 4.02-3.92 (m, 1H); 3.71-3.55 (m, 1H);
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].[C:12](=O)([O-])[O-].[Na+].[Na+].O.CO[CH2:21][CH2:22][O:23][CH3:24]>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:23]1[CH:24]=[CH:12][CH:21]=[C:22]1[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11]
Reactant: COCCOC
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Nc1nc(C)c(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2ccco2)s1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
A mixture of N-(5-bromo-4-methylthiazol-2-yl)acetamide (4 g), furan-2-yl-2-boronic acid (4.22 g), tetrakis(triphenylphosphine)palladium (1.8 g) and 2 N sodium carbonate (36 ml) in DME (60 ml) was stirred at 95° C. for 18 h. After cooling, water (100 ml) was added. Extraction with ethyl acetate (3×80 ml), drying, concentration and purification (SiO2, 0 to 100% ethyl acetate in hexane) gave pure N-(5-(furan-2-yl)-4-methylthiazol-2-yl)acetamide (2.95 g).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:4][CH2:3]1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)C1=CCC(F)(F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1=CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the above ester (0.58 g, 2.29 mmol) in 6 mL of methanol and 0.5 mL of THF was added 2.5 mL of 1 molar sodium hydroxide solution. The solution was stirred for 4 hours at ambient temperature, and then the pH was adjusted to 6 by the addition of 2 M HCl. The reaction mixture was men concentrated under vacuum, and the residue was azeotroped with toluene to provide 4,4-difluorocyclohex-1-ene-1-carboxylic acid an oily solid.