Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][S:42][C:43]1[S:44][CH:45]=[CH:46][CH:47]=1>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14](=[O:32])[N:15]2[CH2:18][CH2:19][CH2:20][C:21]2([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:26][CH2:25][N:24]([CH2:40][CH2:41][S:42][C:43]3[S:44][CH:45]=[CH:46][CH:47]=3)[CH2:23][CH2:22]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCNCC1
Reactant: BrCCSc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccc(OC)cc32)CCN(CCSc2cccs2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 1.25 mL of an N,N-dimethylformamide solution containing 70 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)piperidine-4-carboxylate, 57 mg of potassium carbonate and 0.25 mL of N,N-dimethylformamide containing 47 mg of 2-(2-bromoethylthio)thiophene were added at room temperature, and stirred at 60° C. for 3 hours. To the reaction mixture, ethyl acetate and water were added. The organic layer was separated, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform: methanol=10:1], to give 91 mg of ethyl 4-(3-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH2:16]O)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>C(#N)C>[Cl:20][CH2:16][C:14]1[CH:15]=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:9])[CH:11]=[N:12][CH:13]=1
Reactant: O=C(c1ccc(F)cc1)c1cncc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)c1cncc(CCl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of (4-fluoro-phenyl)-(5-hydroxymethyl-pyridin-3-yl)-methanone (1I) (410 mg, 1.8 mmol) in 25 mL of acetonitrile at 0° C., is added thionyl chloride (0.65 mL, 8.9 mmol) drop wise. After being stirred at room temperature for 2 hours, the reaction mixture is concentrated to remove most of thionyl chloride and acetonitrile. The residue is dissolved in 30 mL of CH2Cl2 and basified by saturated sodium bicarbonate to PH˜8.0. The organic layer is dried over sodium sulfate and concentrated to give (5-chloromethyl-pyridin-3-yl)-(4-fluoro-phenyl)-methanone (1J) (390 mg, yield 87%) as light yellow waxy solid. MS (ESI) m/e 250 (M+H+).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:25]C1N=C(CN)C=CC=1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[N:20]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: Cc1cccc(CN)n1
Agent: Cl
Product: Cc1cccc(CNc2nc(C)c(C)c(NC3CCCCC3)n2)n1

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(6-methylpyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-grey solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.13-1.18 (m, 5H), 1.56-1.59 (m, 5H), 1.87 (s, 3H), 2.21 (s, 3H), 2.49 (s, 3H), 3.63 (d, J=6.72 Hz, 1H), 4.62 (d, J=4.30 Hz, 2H), 7.21-7.23 (m, 2H), 7.56 (d, J=5.64 Hz, 1H), 7.76-7.80 (m, 1H), 8.24 (s, 1H), 12.39 (s, 1H); MS (ESI) m/z 326.5 (M+1)+.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([S:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(SC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-((trifluoromethyl)thio)phenyl)nicotinamide (Stage 186.1, 92 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na2CO3 (0.300 mL, 0.6 mmol) was added, the mixture was flushed with argon, heated to 100° C. in a pressure safe vial, then Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) was added. The RM was stirred under argon at 80-90° C. for 2 h. After cooling at RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue that was purified by flash chromatography (RediSep® Silica gel column, (DCM/MeOH 98:2)/MeOH, from 0 to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a beige crystalline powder. HPLC (Condition 4) tR=5.02 min, HPLC Chiral (CHIRALPAK® AD-H, 250×4.6 mm, 5 μm, eluent: EtOH/MeOH (50:50), 1 mL/min, UV 220 nm, tR=10.32 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=462.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.78-1.91 (m, 1H) 2.87 (d, J=1.00 Hz, 1H) 3.21 (m, J=6.60 Hz, 2H) 3.32-3.42 (m, 1H) 4.14-4.24 (m, 1H) 4.87 (d, J=3.13 Hz, 1H) 7.68 (d, J=8.60 Hz, 2H) 7.90 (d, J=8.60 Hz, 2H) 8.09 (d, J=1.95 Hz, 1H) 8.76-8.80 (m, 1H) 8.88 (s, 2H) 9.18 (s, 1H) 10.26 (s, 1H).
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][CH:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:25]=[O:26].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[Si:5]([O:6][CH:7]1[C:12]2[CH:13]=[C:14]([CH:25]=[O:26])[O:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2occc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CCCc2oc(C=O)cc21
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of t-butyl(dimethyl)(4,5,6,7-tetrahydro-1-benzofuran-4-yloxy)silane (4.1 g, 16 mmol) that was obtained in Example 7 (7a) in tetrahydrofuran (30 ml) was slowly added dropwise n-butyllithium (a 1.6 M solution in hexane, 31 ml, 49 mmol) at −78° C. with stirring, and after raising the reaction temperature to 0° C., the resulting mixture was stirred for 30 minutes. After cooling again the reaction mixture to −78° C. while stirring, N,N-dimethylformamide (13 ml, 162 mmol) was added to the reaction mixture with stirring, and the resulting mixture was stirred for 30 minutes. After stirring, a saturated aqueous solution of ammonium chloride (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (50 ml) and extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9) as the eluent to afford the title compound (4.3 g) in a yield of 94% as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:16])([C:12]([F:13])([F:14])[F:15])[C:8]([OH:10])=[O:9])=[CH:17][CH:18]=1
Reactant: COC(=O)C(C)(Oc1ccc(Cl)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(Oc1ccc(Cl)cc1)(C(=O)O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of (±)-methyl 2-(4-chlorophenoxy)-3,3,3-trifluoro-2-methylpropionate (1.41 g.), methanol (4.0 ml.), and 4.5 N-aqueous potassium hydroxide (2.3 ml.) is stirred at ambient temperature for 10 minutes. The resulting solution is diluted with water, washed with ether, acidified with concentrated hydrochloric acid, and extracted with ether. The extract is washed with water, dried with sodium sulphate and evaporated to a residue which is crystallised from light petroleum (b.p. 60°-80° C.) to give (±)-2-(4-chlorophenoxy)-3,3,3-trifluoro-2-methylpropionic acid, m.p. 141°-142° C. (0.7 g.).
Reaction SMILES: [CH2:1]([N:4]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:5][CH2:6][CH2:7][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:9]/[CH:10]=[CH:11]/[CH2:12][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:2]=[CH2:3].[H-].[Na+].[CH2:48](I)[CH2:49][CH3:50]>CN(C=O)C>[CH2:50]([N:17]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:12]/[CH:11]=[CH:10]/[CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:49]=[CH2:48]
Reactant: C=CCN(CCCN(C/C=C/CN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(CCCN(C/C=C/CN(CCCN(CCC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
To a solution of 0.7 g (1.092 mmol) of (E)-1-allyl-1,5,10,14-tetra-BOC-1,5,10,14-tetraazatetradec-7-ene (see Example 2a) in 9.4 ml of DMF there are added, with stirring, 0.087 g (2.175 mmol) of sodium hydride dispersion (approx. 60%) and, after 5 min., 0.212 ml (2.176 mmol) of propyl iodide. The reaction mixture is stirred for 15 h at room temperature; a further 0.043 g (1.075 mmol) of sodium hydride dispersion (approx. 60%) and 0.106 ml (1.088 mmol) of propyl iodide are added, and the mixture is stirred for a further 96 h at 20° C. and is then concentrated by evaporation in vacuo. Working up analogously to Example 1a) yields the oily title compound, Rf value=0.46 (silica gel/ethyl acetate:hexane (2:3)).
Reaction SMILES: FC(F)(F)CS([Cl:7])(=O)=O.[N:10]1([CH:16](O)[CH3:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[OH:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl.C(OCCCCC)(=O)C>[ClH:7].[N:10]1([CH2:16][CH2:17][O:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC(O)N1CCCCC1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCCOC(C)=O
Product: Cl
Product: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 140 °C
Reaction time: 12 h
Yield: 93.2 %

Procedure:
Into a 50 ml round bottom flask is placed 4.93 g (27.0 mmol) of 2,2,2-trifluoroethanesulfonyl chloride and 25 ml of methylene chloride. The resulting solution is cooled with an ice bath as 3.22 g (24.9 mmol) of 1-piperidinoethanol in 7 ml of methylene chloride is added dropwise. After the addition is complete, the ice bath is removed and the resulting slurry is stirred for about 12 hours. The reaction mixture is concentrated on a rotary evaporator to yield a waxy residue. The solid residue is slurried in 45 ml of amyl acetate and then potassium carbonate (5.50 g, 39.9 mmol) and methyl 4-hydroxybenzoate (2.26 g, 14.8 mmol) are added. The resulting mixture is heated to 140° C. for 2 hours. The reaction mixture is cooled to room temperature and washed twice with water and the organic layer is extracted with 10.5 ml of 8N hydrochloric acid. The aqueous layer is heated at gentle reflux for 4 hours. The resulting slurry is cooled to 50° C. and 11 ml of acetone is added. The slurry is cooled to 0°-5° C. and stirred for 1 hour. The product is filtered, washed with cold acetone, and dried at 50° C. in vacuo to yield 3.94 g of product, (90%). 1H NMR. HPLC 96.9%. TRS 2.78%.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[N:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:18]=[N:19][CH:20]=[C:15]([F:14])[CH:16]=2)[C:11]=1[CH3:12]
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1c(Cl)nc2cnccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2cncc(F)c2)nc2cnccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,7-naphthyridine (100 mg, 0.469 mmol), 5-fluoropyridine-3-boronic acid (66.1 mg, 0.469 mmol), sodium carbonate (87 mg, 0.821 mmol) and Pd(PPh3)4 (54.2 mg, 0.047 mmol). Product used without further purification in the next step. Mass Spectrum (ESI) m/e=274.0 (M+1).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[O:6][CH2:7][C@H:8]([OH:21])/[CH:9]=[CH:10]/[C@@H:11]1[C@@H:18]2[C@@H:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH2:13][C@H:12]1[OH:20].[O:27]1[CH:32]=[CH:31][CH2:30][CH2:29][CH2:28]1.[C:33](=[O:36])(O)[O-].[Na+]>C1COCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]1[O:20][C@@H:12]1[CH2:13][C@@H:14]2[O:15][C:16](=[O:19])[CH2:17][C@@H:18]2[C@H:11]1/[CH:10]=[CH:9]/[C@@H:8]([O:21][CH:23]1[CH2:24][CH2:3][CH2:2][CH2:33][O:36]1)[CH2:7][O:6][C:5]1[CH:22]=[CH:23][CH:24]=[C:3]([C:2]([F:25])([F:1])[F:26])[CH:4]=1
Reactant: O=C([O-])O
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)COc3cccc(C(F)(F)F)c3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@H](COc3cccc(C(F)(F)F)c3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reaction time: 2.5 h
Yield: 87.5 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.35 g, 1.8 mmol) was added to a solution of (3aR,4R,5R,6aS)-4-((R,E)-4-(3-(trifluoromethyl)phenoxy)-3-hydroxybut-1-enyl)-hexahydro-5-hydroxycyclopenta[b]furan-2-one (15.0 g, 40.3 mmol) and 3,4-dihydro-2H-pyran (8.47 g, 100.7 mmol) in THF (200 mL) at room temperature and the mixture was stirred for 2.5 hr (TLC monitoring). Saturated aqueous solution of sodium bicarbonate (200 mL) was poured into the reaction mixture and the mixture was stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over magnesium sulfate, filtered off solid and concentrated under reduced pressure to give 24.0 g of crude product. The crude product was purified by column chromatography and then concentrated under reduced pressure to provide 19.0 g of the titled compound (87.5% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[CH3:30][S:31]([NH:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C@@H:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])=[O:20])[CH2:13][C@H:12]2[CH3:29])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32]
Reactant: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(N)c2)[C@@H](C)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(NS(C)(=O)=O)c2)[C@@H](C)C1
Reaction time: 18 h

Procedure:
The title compound was prepared from the product of Example 57 and methane sulphonyl chloride by the method of Example 62. The solid obtained at the end of the reaction was suspended in ethanol (50 ml) to which a solution of K2CO3 (0.2 g) in water (10 ml) was added, and stirred for 18 hours, in order to hydrolyse any bis-sulphonamide. The ethanol was removed, water (50 ml) was added and the pH was adjusted to 5.0. The solid was filtered off, washed with water and ether and dried in vacuo to give the title compound as a white solid. Yield 0.13 g.
Reaction SMILES: CN1C=CN=C1.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:14]([O:16]CC)=[O:15])[N:12]=1.CO.O1CCCC1>[OH-].[Na+]>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[C:14]([OH:16])=[O:15])[N:12]=1
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)c1csc(N)n1
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(C(=NOCc2ccc(Cl)cc2Cl)C(=O)O)cs1
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A solution of 1-methylimidazole (0.5 g.) in 1N sodium hydroxide aqueous solution (48 ml.) was added to a solution of ethyl 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetate (syn isomer, 12.0 g.), methanol (120 ml.) and tetrahydrofuran (100 ml.) at 15° to 20° C., and stirred at 35° to 40° C. for 6 hours. After removing methanol and tetrahydrofuran in vacuo from the resultant mixture, the aqueous residue was washed with ethyl acetate. Ethyl acetate was completely removed from the aqueous solution and adjusted to pH 2.0 with hydrochloric acid. The precipitates were collected by filtration to give 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetic acid (syn isomer, 10.0 g.).
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([C:10]2[C:11]([CH3:27])=[C:12]([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1>C(O)C.[Pt]=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[C:11]([CH3:27])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: Cc1c(C=CCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(CCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 87.4 %

Procedure:
Hydrogen was passed through a solution of 6.3 g of the acid of Step A in 100 ml of ethanol in the presence of 120 mg of platinum oxide and after the absorption of 3.86 ml of hydrogen, the mixture was filtered. The filtrate was evaporated to dryness and the 6.3 g of raw product were dissolved in 10 ml of hot isopropyl ether to which 10 ml of petroleum ether were then added. The mixture stood at room temperature, was iced and vacuum filtered. The precipitate was washed with a 1:1 isopropyl ether-petroleum ether mixture and was dried under reduced pressure to obtain 5.535 g of 9-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-nonanoic acid melting at 64° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH2:29][CH3:30]
Reactant: CCCOc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.70 g), 4-propoxyphenyl borate (0.38 g) and potassium carbonate (0.58 g) in toluene/ethanol/water (20/2/2 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.12 g), and the mixture was refluxed for 18 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2→1:1) to give pale yellow crystals of methyl 7-(4-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (616.4 mg).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CC1C=CC=C2C=1COC2=O>C(Cl)(Cl)(Cl)Cl>[C:12]([C:11]1[CH:16]=[CH:17][C:18]([CH2:20][Br:1])=[CH:19][C:10]=1[CH3:9])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(C)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cccc2c1COC2=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1C

Procedure:
N-Bromosuccinimide (44.9 g) was added to a solution of methyl 2,4-dimethylbenzoate (41.36 g) in carbon tetrachloride containing a trace of dibenzoyl peroxide. The mixture was heated under reflux until no orange colour persisted then cooled, filtered and the filtrate evaporated to leave an oil. This was distilled until ~16 g distilate bp 98°-140°/0.8-5 mm (starting material) had been collected. The residue was then heated at atmospheric pressure until no more methyl bromide was evolved, to give a mixture of the title compound and 4-methylphthalide. Addition of hot petrol and filtration from the phthalide gave after evaporation the title compound. τ (CDCl3) 7.48 (3H, s), 6.21 (3H, s), 5.65 (2H, s), 2.6-2.93 (2H, m), 2.18 (1H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=2)[CH:19]=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH3:23].[NH:24]1[CH2:28][CH2:27][C@@H:26]([C:29]([OH:31])=[O:30])[CH2:25]1.CC(O)=O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH3:22])=[C:18]([CH:21]=2)[CH2:19][N:24]2[CH2:28][CH2:27][C@@H:26]([C:29]([OH:31])=[O:30])[CH2:25]2)[C:9]([F:11])([F:12])[F:10])=[CH:4][C:3]=1[CH3:23]
Reactant: O=C(O)[C@@H]1CCNC1
Reactant: Cc1cc([C@H](Nc2ccc(C)c(C=O)c2)C(F)(F)F)ccc1Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc([C@H](Nc2ccc(C)c(CN3CC[C@@H](C(=O)O)C3)c2)C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of aldehyde INT 33 (2.50 g, 7.32 mmol) and (R)-pyrrolidine-3-carboxylic acid (0.93 g, 8.05 mmol) in MeOH (74 mL) was added HOAc (0.42 mL, 7.32 mmol) followed by PS—CNBH3 (2.5 mmol/g, 2.93 g, 7.32 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through Celite. The filtrate was concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 and water. The aqueous layers were extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH) to afford the title compound Example 21.