Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([OH:30])(=[O:29])[CH:26]([CH3:28])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH:26]([C:25]([OH:30])=[O:29])[CH3:28])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCC2CCCCC2)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-(8-cyclohexyloctylamino)benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [N:1]1([C:6]2([C:9](OCC)=[O:10])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[N:1]1([C:6]2([CH2:9][OH:10])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(N2CCCC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(N2CCCC2)CC1

Procedure:
20.5 g of the product obtained in Step 3 and 100 ml of tetrahydrofuran are poured, over 5 minutes, into a suspension containing 8.57 g of lithium aluminium hydride and 400 ml of tetrahydrofuran. The mixture is heated at reflux for 2 hours, cooled to 5° C. and hydrolysed by successive additions of 9 ml of water, 9 ml of 4N sodium hydroxide solution and then 27 ml of water. The aluminium compound is filtered off and rinsed with tetrahydroflran. The combined filtrates are concentrated to dryness, allowing the desired product to be obtained (liquid).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=NO)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a solution of 4-bromobenzonitrile (5.0 g, 27.5 mmol) in ethanol (42 ml) at room temperature, hydroxylamine hydrochloride (1.91 g, 27.5 mmol) and DIPEA (4.8 ml, 27.5 mmol) were added. The reaction mixture was stirred at 90° C. for 5 hours. After cooled to room temperature, the resulting mixture was concentrated to yield a colorless viscous liquid. The liquid was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and then concentrated to give a crude compound, which was washed with n-hexane to yield product 15 as a white solid (5.0 g).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=2[OH:28])[CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:6]=[CH:7][CH:8]=1.[C:31]([O:35][C:36](=[O:40])[C@H:37](O)[CH3:38])([CH3:34])([CH3:33])[CH3:32].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:31]([O:35][C:36](=[O:40])[C@@H:37]([O:28][C:27]1[CH:26]=[CH:25][C:11]([CH2:12][N:13]([CH3:24])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:29])[F:30])[CH:4]=1)[CH3:38])([CH3:34])([CH3:33])[CH3:32]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(CN(C)S(=O)(=O)c2ccc(F)cc2)cc1-c1cccc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 13.9 %

Procedure:
A solution of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36) (50.0 mg, 0.114 mmol) and (R)-t-butyl-2-hydroxypropanoate (18.3 mg, 0.125 mmol, 1.1 eq, Chem-Impex International, Inc., Wood Dale, Ill., USA) in THF (2 mL) at 0° C. was added diethyl azodicarboxylate (20 μL, 0.125 mmol, 1.1 eq) and triphenylphosphine (33 mg 0.125 mmol, 1.1 eq). After stirring at 0° C. for 4 h the mixture was extracted between saturated sodium bicarbonate and ethyl acetate, dried (Na2SO4) and concentrated in vacuo. This crude product was purified on reversed phase semi-preparative HPLC to give 9 mg of t-butyl-(S)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanate. This intermediate was then dissolved in TFA/DCM (1 mL/1 mL) and stirred at room temperature for 30 min. Solvent was removed in vacuo and the residue was purified via reversed phase semi-preparative HPLC to afford 4.9 mg of (S)-2-(2-(3-trifluoromethylphenyl)-4-((4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)propanoic acid (Example 36). 1HNMR (CDCl3, 400 MHz): δ 7.84 (m, 3H), 7.70 (d, 1H), 7.56 (m, 2H), 7.26 (m, 3H), 7.20 (d, 1H), 6.88 (d, 1H), 4.80 (m, 1H), 4.15 (s, 2H), 2.64 (s, 3H), 1.57 (d, 3H). MS (ESI): MH+=512.1. HPLC (Method B) tR=2.78 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10](C3C=CC(Cl)=CC=3)=[C:9]([O:18][CH3:19])[C:8]([CH3:20])=[CH:7][C:5]=2[N:6]=1.[C:21]([CH:23]1[CH2:25][CH2:24]1)#[CH:22].CCN(CC)CC>C1COCC1.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:23]1([C:21]#[C:22][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:18][CH3:19])[C:8]([CH3:20])=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24]1
Reactant: C#CC1CC1
Reactant: COc1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2sc(C#CC3CC3)nc2cc1C
Temperature: 60 °C

Procedure:
To a solution of 2-bromo-7-(4-chlorophenyl)-6-methoxy-5-methylbenzo[d]thiazole (8C) (188 mg, 0.512 mmol) in THF (3 ml), was added ethynylcyclopropane (0.09 ml, 1.2 mmol), CuI (10 mg, 0.052 mmol), Et3N (0.36 ml, 2.58 mmol) and PdCl2(dppf) (19 mg, 0.026 mmol). The reaction mixture was stirred at 60° C. for 2 hs. The reaction mixture was washed by water, extracted by EtOAc. The organic phase was combined, dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:25][CH:24]=[N:23][CH:22]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:25]([CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:13])([CH3:1])[CH:3]3[OH:12])[CH:24]=[N:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(-c2cnc[nH]2)cc1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2C(n2cncc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene (literature known compound) and 5-(4-chloro-phenyl)-1H-imidazole as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[S:21][C:20]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:27])[CH:18]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[S:21][C:20]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:27])[CH:18]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(=O)c1sc(Br)cc1C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Product: CCNC(=O)c1sc(-n2ccc(OCc3ccccc3)cc2=O)cc1C
Yield: 45 %

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-(benzyloxy)pyridin-2(1H)-one in place of 4-aminopyridin-2(1H)-one to react with 5-bromo-N-ethyl-3-methylthiophene-2-carboxamide in place of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide, the title compound was obtained as a light yellow solid in 45% yield: mp 158-160° C.; 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=7.8 Hz, 1H), 7.43-7.36 (m, 5H), 6.82 (s, 1H), 6.13 (dd, J=7.8, 2.7 Hz, 1H), 6.06 (d, J=2.7 Hz, 1H), 5.84 (br s, 1H), 5.04 (s, 2H), 3.49-3.38 (m, 2H), 2.51 (s, 3H), 1.22 (t, J=7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 166.8, 162.9, 162.3, 139.4, 139.0, 134.8, 134.7, 128.8, 128.6, 127.7, 127.5, 122.2, 103.2, 98.2, 70.6, 34.8, 15.8, 14.9; MS (ES+) m/z 369.3 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Br:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:16][CH2:17][CH2:18][N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrCCBr
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)OCC)n(CCBr)c1
Yield: 76 %

Procedure:
To a stirred solution of diethyl 1H-pyrrole-2,4-dicarboxylate (0.7 g, 3.31 mmol), and 1,2-dibromoethane (2.8 mL, 32.5 mmol) in MeCN (30 mL) was added K2CO3 (0.55 g, 39.7 mmol). This reaction mixture was refluxed overnight then filtered. The filtrate was collected and concentrated to give diethyl 1-(2-bromoethyl)-1H-pyrrole-2,4-dicarboxylate (0.8 g, 76%). 1H NMR (CDCl3, 300 MHz) δ7.42 (d, J=1.8 Hz, 1 H), 7.33 (d, J=1.8 Hz, 1 H), 4.60 (t, J=6.0 Hz, 2 H), 4.22 (q, J=7.2 Hz, 4 H), 3.62 (t, J=6.4 Hz, 2 H), 1.28 (m, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])[CH:19]=[CH:18][C:3]=1[NH:4][C:5](=[O:17])[CH:6]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])Br.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:23])[CH:19]=[CH:18][C:3]=1[NH:4][C:5](=[O:17])[CH:6]([C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[N:41]1[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]2[C:37]1=[O:47]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(NC(=O)C(Br)C(=O)c2ccccc2C)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)c1ccc(NC(=O)C(C(=O)c2ccccc2C)N2C(=O)c3ccccc3C2=O)c(Cl)c1

Procedure:
29 g of 2'-chloro-4'-dodecyloxycarbonyl-2-methyl-α-bromo-benzoylacetanilide, 29 g of phthalimide and 20 g of triethylamine were stirred for 3 hours at room temperature in 200 ml of dimethylformamide. The reaction mixture was processed in a manner similar to Synthesis example 1 except for using ligroin for recrystallization to obtain 20 g of coupler 9 having a melting point of from 100° to 101° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:4][N:3]=1.Cl.CN.C1C=CC2N(O)N=[N:31][C:29]=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:17]=[CH:18]/[C:19]([NH:31][CH3:29])=[O:21])=[CH:4][N:3]=1
Reactant: Nc1ncc(/C=C/C(=O)O)c2scc(-c3ccccc3)c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)/C=C/c1cnc(N)c2c(-c3ccccc3)csc12
Yield: 84.6 %

Procedure:
A mixture of Example 13 (0.1 g, 0.34 mmol), methylamine hydrochloride (0.115 g, 1.69 mmol), HOBT (0.137 g, 1.01 mmol), N-methylmorpholine (0.25 mL, 2.36 mmol), and EDCI (0.199 g, 1.01 mmol) in DMF (5 mL) was stirred at room temperature for 2 hours, diluted with water (20 mL), and extracted with ethyl acetate (2×20 mL). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide 89 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.73 (d, J=4.8 Hz, 3H), 5.75-5.85 (br s, 2H), 6.58 (d, J=15.9 Hz, 1H), 7.53 (m, 5H), 7.58 (d, J=15.9 Hz, 1H), 7.67 (s, 1H), 8.14 (m, 2H); MS (ESI(+)) m/e 310 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[CH:4]=[O:5].[CH3:14][C:15]([CH3:19])=[CH:16][CH:17]=O.N1C=CC=CC=1>>[OH:1][C:2]1[C:3]([CH:4]=[O:5])=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[C:8]2[C:9]=1[CH:17]=[CH:16][C:15]([CH3:19])([CH3:14])[O:10]2
Reactant: O=Cc1c(O)cc(O)cc1[N+](=O)[O-]
Reactant: CC(C)=CC=O
Solvent: c1ccncc1
Product: CC1(C)C=Cc2c(cc([N+](=O)[O-])c(C=O)c2O)O1
Reaction time: 18 h

Procedure:
A solution of 2,4-dihydroxy-6-nitro-benzaldehyde (10.61 g, 58 mmol) in Me2CO (6 mL) is added during a 5.5 h period to a stirring solution of 3-methyl-but-2-enal (4.00 g, 29 mmol) in pyridine (2.29 g, 2.34 mL, 29 mmol) at 120° C. After completion of addition heating is continued for an additional 18 h. The Me2CO is evaporated and the pyridine is removed by azeotrope distillation with toluene to afford a crude product. The crude product is purified using silica gel chromatography with 1% ethyl acetate in hexanes to afford 5-hydroxy-2,2-dimethyl-7-nitro-2H-chromene-6-carbaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[N:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:5]2=[N:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cnc2nc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
To a solution of 6-bromo-1H-imidazo[4,5-b]pyridine (2.7 g, 11.0 mmol) in dimethylformamide (30 mL) at 0° C. was added 60% sodium hydride in mineral oil (0.53 g, 13.2 mmol) and the reaction mixture was stirred for 30 minutes, followed by the addition of a solution of triphenylmethyl chloride (3.2 g, 11.55 mmol) in dimethylformamide (5 mL). The reaction mixture was stirred at room temperature for 24 hours then quenched by the careful addition of water then partitioned with ethyl acetate (250 mL). The organic phase was washed with 10% aqueous citric acid (2×, 100 mL), brine (100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. Silica gel chromatography (hexane ethyl acetate 9:1 to 4:1) provided 6-bromo-3-trityl-3H-imidazo[4,5-b]pyridine (1.8 g, 37%). 1H NMR (400 MHz, CDCl3): 8.18 (d, 1H), 8.14 (d, 1H), 8.02 (s, 1H), 7.36-7.28 (m, 10H), 7.18-7.14 (m, 5H) and 6-bromo-1-trityl-1H-imidazo[4,5-b]pyridine (2.9 g, 60%) 1H NMR (400 MHz, CDCl3): 8.50 (d, 1H), 8.14 (s, 1H), 7.38-7.34 (m, 10H), 7.16-7.12 (m, 5H), 6.84 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: O=C(O)CCc1cccc(O)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1cccc(O)c1
Temperature: 25 °C

Procedure:
To an ice-cooled solution of 3-(3-hydroxyphenyl)propionic acid (20.0 g, 120 mmol) in ethanol was dropwise added thionyl chloride (8.8 ml, 120 mmol). The mixture was stirred at room temperature over night, concentrated in vacuo and submitted to flash chromatography (10% ethyl acetate in toluene eluent) to give 23.3 g of 3-(3-hydroxy-phenyl)propionic acid ethyl ester.
Reaction SMILES: [C:1](=[S:4])([S-:3])[NH2:2].[NH4+].[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH:18](Br)[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C.C(OCC)(=O)C>[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[N:2]=[C:1]([SH:3])[S:4][C:18]=2[CH2:17]1)=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NC(=S)[S-]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1Br
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCc2nc(S)sc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a solution of ammonium dithiocarbamate (0.19 g, 1.7 mmol) in 2 mL of ethanol was added 1-benzyloxycarbonyl-3-bromo-4-piperidone (0.53 g, 1.7 mol). The reaction was stirred at rt overnight. The next morning the reaction was heated at 75° C. for 2 h. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water (2X) and then brine. The solvent was removed under reduced pressure and the product subjected to flash chromatography (2:1 hexane/ethyl acetate). Crystallization from ethyl acetate/hexane afforded 0.14 g of 5-benzyloxycarbonyl-2-mercapto-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:17])=[C:4]([CH3:18])[C:3]=1[NH2:19].C([O:23][CH2:24][CH3:25])(=O)C>>[CH3:1][C:2]([CH3:7])([CH3:3])[CH2:25][C:24]([NH:19][C:3]1[C:4]([CH3:18])=[C:5]([CH3:17])[C:6]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[C:2]=1[CH3:1])=[O:23]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)CO2
Reactant: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccccc1)CO2
Yield: 50 %

Procedure:
Using 4,6,7-trimethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 306, the title compound was synthesized in the same manner as in Example 1. Yield: 50%. Melting point: 146-147° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)(=[O:14])=[O:13].O>CS(C)=O>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 93.1 %

Procedure:
To a solution of 7.41 g (0.0576 mole) of 4-chlorophenol dissolved in 150 ml of DMSO was added 2.30 g (0.0576 mole) of NaOH. The mixture was heated to 60° C. and 10.0 g (0.0524 mole) of 4-chlorophenyl methyl sulfone was added. The reaction mixture was heated at 160° C. for 3 hrs and cooled. The mixture was poured into a solution of 400 ml of 2 Normal (N) aqueous NaOH and 300 ml of water. The crystalline product was collected by filtration, washed well with water, and dried, which gave 13.8 g (93.2% yield) of product, m.p. 109°-111° C. Recrystallization from ethanol afforded purified 4-(4-(methylsulfonyl)phenoxy)-1-chlorobenzene, mp 111°-112° C.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[C@H:3]1[N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:5](=[O:11])[O:4]1.[Li+].CC([N-]C(C)C)C.CCCCCC.C1C[O:31][CH2:30]C1>>[O:11]=[C:5]1[O:4][C@@H:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[N:7]2[CH2:8][CH2:9][CH2:10][C@:6]12[CH:30]=[O:31]
Reactant: C1CCOC1
Reactant: O=C1O[C@@H](C(Cl)(Cl)Cl)N2CCC[C@H]12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: O=C[C@]12CCCN1[C@H](C(Cl)(Cl)Cl)OC2=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37 %

Procedure:
To reactant 155a (4.8 g, 19.8 mmol) suspended in anhydrous THF (100 mL) at −78° C., was added 2.0 M LDA in Hexane (14.9 mL, 29.7 mmol) over 20 min period. The mixture was stirred at −78° C. for 45 min, then let it warm up to 0° C. over 3 hour. Reaction was monitored by TLC. After completion, the reaction was quenched by adding aq. 10% citric acid slowly. It was extracted with EtOAc twice, washed with brine. The organic layer was dried through (Na2SO4), and concentrated; the residue was purified by CombiFlash using EtOAC/Hexane as eluents to give (3S,7aS)-1-oxo-3-(trichloromethyl)hexahydropyrrolo-[1,2-c]oxazole-7a-carbaldehyde 155b 1.99 g, 37%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(NS(=O)(=O)c2ccc(C)cc2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(NS(=O)(=O)c2ccc(C)cc2)nc1-c1ccc(C)cc1
Yield: 94 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(4-methylphenylsulfonamido)-6-p-tolylpyrimidin-5-yl)pentanoate (0.032 g; 0.068 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.029 g (93%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:13])[CH:10]([CH3:12])[CH3:11].[Br:14]Br.[Cl-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:14][C:10]([CH3:11])([CH3:12])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:13]
Reactant: BrBr
Reactant: CC(C)C(=O)c1ccc(F)cc1F
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
In 260 ml of methylene chloride was dissolved 145.5 g (0.79 mol) of 1-(2,4-difluorophenyl)-2-methylpropan-1-one, and 134.2 g (0.84 mol) of bromine was slowly added dropwise thereto at 20° C. or lower. The mixture was warmed to room temperature and stirred for 1 hour. A saturated sodium chloride aqueous solution and a saturated sodium thiosulfate aqueous solution were added to the reaction mixture. The organic layer was separated, washed successively with a saturated sodium chloride aqueous solution, a saturated sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure to obtain 205.7 g (99%) of 2-bromo-1-(2,4-difluorophenyl)-2-methylpropan-1-one as a pale yellow oily substance.
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]([I:10])=[C:7]([CH3:9])[N:8]=2)[CH2:3]C1.[CH2:11]([O:18]CCC=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][CH2:3][CH2:1][C:4]1[NH:5][C:6]([I:10])=[C:7]([CH3:9])[N:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCOCc1ccccc1
Reactant: Cc1nc(C2CC2)[nH]c1I
Product: Cc1nc(CCOCc2ccccc2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 160.2, except 3-(benzyloxy)propanal (compound 227.1) was used in place of cyclopropanecarbaldehyde.