Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]>>[ClH:23].[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:9][CH:7]2[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]3[S:12][CH:11]=[CH:10][C:6]2=3)=[C:18]([Cl:23])[CH:17]=1)(=[O:15])[NH2:14]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: CN1CCc2sccc2C(O)C1
Product: CN1CCc2sccc2C(Oc2ccc(C(N)=O)cc2Cl)C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][CH2:2]N(CC)CC.Br[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[NH:23][C:22]([CH3:24])=[N:21][C:20]=2[Cl:25])=[O:18])=[C:11]([F:26])[C:10]=1[O:27][C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[C:30]([Cl:36])[CH:29]=1.C([B-](F)(F)F)=C.[K+]>C(O)CC>[Cl:25][C:20]1[N:21]=[C:22]([CH3:24])[NH:23][C:19]=1[C:17]([NH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH:1]=[CH2:2])=[C:10]([O:27][C:28]2[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[C:30]([Cl:36])[CH:29]=2)[C:11]=1[F:26])=[O:18]
Reactant: CCN(CC)CC
Reactant: Cc1nc(Cl)c(C(=O)NCc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCCO
Product: C=Cc1ccc(CNC(=O)c2[nH]c(C)nc2Cl)c(F)c1Oc1cc(Cl)cc(C#N)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
Et3N (0.351 ml, 2.52 mmol) was added to a mixture of N-({4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (251 mg, 0.504 mmol), potassium vinyltrifluoroborate (101 mg, 0.756 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (41.1 mg, 0.050 mmol) in n-propanol (5 ml) under N2. The mixture was heated to 100° C. and stirred for 4 h. Cooled down to RT and the reaction mixture was filtered through a pad of celite and concentrated to dryness. The residue was dissolved in EtOAC, washed with Sat. NaHCO3, dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on silica gel eluted with 0-5% 2M NH3 solution of MeOH in CH2Cl2 to give the title compound as a light-yellow solid (154 mg, 69%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.33 (1H, br. s.) 7.40 (1H, d, J=8.2 Hz) 7.31 (1H, s) 7.26-7.29 (1H, m) 7.12 (2H, br. s.) 6.98 (1H, s) 6.69 (1H, dd, J=17.6, 11.2 Hz) 5.81 (1H, d, J=17.6 Hz) 5.37 (1H, d, J=11.1 Hz) 4.70 (2H, d, J=5.9 Hz) 2.39 (3H, s). LCMS: m/z 445 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([OH:12])[CH:6]=1)[CH3:2].[H-].[Na+].Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1.[Na+].[Cl-]>CN(C)C=O.C(O)(=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:6][C:7]=1[O:12][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1
Reactant: Clc1cnccn1
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(F)c(Oc2cnccn2)c1
Temperature: 80 °C
Yield: 49.5 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (2.2 g, 11.95 mmol) in N,N-dimethylformamide (50 ml) was added 60% NaH in mineral oil (0.72 g, 17.93 mmol) and chloropyrazine (1.64 g, 14.34 mmol) and heated at 80° C. for overnight. One more equivalent of chloropyrazine was added and heated at the same temperature for 10 h. The reaction mixture was poured into a flask containing 150 ml of aqueous saturated NaCl solution and 0.6 ml of acetic acid. The mixture was extracted with ethyl acetate (3×100 ml), the combined organic extracts were washed with sat NaCl (150 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography using dichloromethane to yield 1.55 g (50%) of product. MS (ESI+) m/z 263 (M+H)+;
Reaction SMILES: OC1C=CC=CC=1[C:8]1[C:16]2[N:15]=[N:14][NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.OC1C=CC(C)=CC=1C1C2N=NNC=2C=CC=1.OC1C(C(C)(C)C)=CC(C)=CC=1C1C2N=NNC=2C=CC=1Cl>>[NH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:16]=2[N:15]=[N:14]1
Reactant: Oc1ccccc1-c1cccc2[nH]nnc12
Agent: Cc1cc(-c2c(Cl)ccc3[nH]nnc23)c(O)c(C(C)(C)C)c1
Agent: Cc1ccc(O)c(-c2cccc3[nH]nnc23)c1
Product: c1ccc2[nH]nnc2c1

Procedure:
(2′-hydroxyphenyl)benzotriazole, (2′-hydroxy-5′-methylphenyl)benzotriazole, (2′-hydroxy-5′-methyl phenyl)benzotriazole, and (2′-hydroxy-3′-tertiary butyl-5′-methylphenyl)-5-chlorobenzotriazole. (2′-hydroxyphenyl)benzotriazole, (2′-hydroxy-5′-methylphenyl)benzotriazole, (2′-hydroxy-5′-methyl phenyl)benzotriazole, and (2′-hydroxy-3′-tertiary butyl-5′-methylphenyl)-5-chlorobenzotriazole.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:12]2[S:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[N:9][S:10][CH:11]=1)(=O)=O.O[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:21]([CH3:32])[C:20]=1[CH3:33]>>[Cl:17][C:14]1[S:13][C:12]([C:8]2[C:7]([CH2:6][O:5][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[C:21]([CH3:32])[C:20]=3[CH3:33])=[CH:11][S:10][N:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: CS(=O)(=O)OCc1csnc1-c1ccc(Cl)s1
Product: Cc1c(CCC(=O)O)ccc(OCc2csnc2-c2ccc(Cl)s2)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 91 following Step 5 and 6 by coupling (3-(5-chlorothiophen-2-yl)isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 7.19 (s, 1H), 7.03 (d, J=5.5 Hz, 1H), 6.89 (s, 1H), 6.76 (d, J=5.5 Hz, 1H), 5.15 (s, 2H), 2.96 (t, J=5.0 Hz, 2H), 2.62 (t, J=5.1 Hz, 2H), 2.24 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.[OH-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[OH2:6].[ClH:2].[ClH:1].[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH:27]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=2)[CH:28]2[CH2:33][CH2:32][N:31]([CH2:3][CH2:4][CH:5]3[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]4[CH:14]=[CH:15][CH:16]=[N:17][C:7]=4[O:6]3)[CH2:30][CH2:29]2)=[CH:35][CH:36]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:3][CH2:4][CH:5]3[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]4[CH:14]=[CH:15][CH:16]=[N:17][C:7]=4[O:6]3)[CH2:32][CH2:33]2)[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[CH:23][CH:22]=1.[ClH:2].[ClH:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CN1CC(CCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)Oc2ncccc2C1=O
Product: O

Procedure:
Ten grams (0.036 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)-one hydrochloride were partitioned between dilute sodium hydroxide and chloroform. The chloroform was dried over sodium sulfate and concentrated on the rotary evaporator. The residue was dissolved in 50 ml of ethanol and 10.3 g (0.036 mole) of 4-[bis(4-fluorophenyl)-methyl]piperidine was added. The solution was heated to reflux for 18 hr and concentrated on the rotary evaporator. The residue was partitioned between dilute sodium hydroxide and chloroform. The chloroform was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a Waters 500 HPlC (silica/92% ethyl acetate-8% triethylamine). After concentration of the desired product, the residue was dissolved in isopropyl alcohol and treated with ethereal hydrogen chloride. The resulting crystals weighed 3 g (14%) and melted at 160°-180° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][C:14]=3[C:6]=2[S:5](=[O:19])(=[O:18])[NH:4][C:3]=1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[CH3:26]I>CO>[CH3:26][N:4]1[C:3]([C:20]([O:22][CH3:23])=[O:21])=[C:2]([OH:1])[C:7]2[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][C:14]=3[C:6]=2[S:5]1(=[O:19])=[O:18]
Reactant: CI
Reactant: COC(=O)C1=C(O)c2c(c3cc(OC)ccc3n2C)S(=O)(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1=C(O)c2c(c3cc(OC)ccc3n2C)S(=O)(=O)N1C
Yield: 85 %

Procedure:
20.4 gm (60 millimols) of methyl 2,5-dihydro-4-hydroxy-8-methoxy-5-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide were reacted analogous to Example 18 (f) wtih a sodium hydroxide solution and methyl iodide in methanol to yield 17.9 gm (85% of theory) of methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-8-methoxy-1,2-thiazino[5,6-b]indole-3-carboxylate 1,1-dioxide; M.p.: 200°-201° C.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])#N.[OH-:13].[Na+].S(=O)(=O)(O)[OH:16]>C(O)CO.COC.O>[C:10]([OH:12])(=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]([OH:16])=[O:13]
Reactant: [OH-]
Reactant: O=S(=O)(O)O
Reactant: N#CCCCCCCCC(=O)O
Agent: COC
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: O=C(O)CCCCCCCC(=O)O

Procedure:
83.5 g of 8-cyanooctanoic acid dissolved in 300 ml of dimethyl ether ethylene glycol are heated to 130° C. for 4 hours in the presence of 50g of 40% caustic soda. After cooling, the reaction mixture is diluted with water, then acidified to pH 5 with diluted sulfuric acid, and then the precipitated solid is filtered. After drying, 92 g of azelaic acid with a m.p. of 107° C. are obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][N:17]4[C:25](=[O:26])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]4=[O:27])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:28]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:46].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:46][C:7]1[C:6]2[N:28]=[C:3]([CH2:1][CH3:2])[N:4]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:5]=2[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][CH2:16][N:17]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:27])=[CH:10][C:9]=2[N:8]=1
Reactant: [NH4+]
Reactant: CCc1nc2cnc3cc(CCN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cc(CCN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Reaction time: 18 h

Procedure:
2-{2-[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethyl}-1H-isoindole-1,3(2H)-dione (1.90 g, 4.29 mmol) in dichloromethane (75 mL) was combined with 3-chloroperoxybenzoic acid (60% pure, 1.24 g, 4.72 mmol) and the reaction was stirred for 18 hours. Concentrated ammonium hydroxide (40 mL) was added and the mixture was vigorously stirred for an additional 10 minutes. p-Toluenesulfonyl chloride (900 mg, 4.72 mmol) was added and the mixture was stirred for an additional 1 hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×50 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-8% gradient of methanol in dichloromethane) provided 1.05 g of 2-{2-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethyl}-1H-isoindole-1,3(2H)-dione as an off-white foam. MS (APCI) m/z 458 (M+H)+.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:2]=1.[N:20]([CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])=[O:25])=[N+]=[N-].C(Cl)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:23][N:20]=1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1[N+](=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)Cl
Product: Cc1ncc(-c2ccccc2[N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triphenylphosphine, polymer bound, (5.3 g, 3 mmol/g, Fluka Chimica, Buchs, Switzerland) was scurried in toluene (75 mL). A solution of 2-azido-2′-nitroacetophenone (2.18 g, 10.6 mmol) and acetyl chloride (0.848 g, 10.8 mmol) in toluene (25 mL) was added at room temperature, under a nitrogen atmosphere. The solution was stirred at room temperature for six hours, then filtered over celite. All volatiles were removed from the filtrate by evaporation under reduced pressure to yield 0.91 g of crude 2-methyl-5-(2-nitrophenyl)oxazole. Crude 2-methyl-5-(2-nitrophenyl)oxazole (0.905 g, 4.44 mmol) was reduced as in Example 64, and the product purified by silica chromatography to give 0.51 g of 5-(2-aminophenyl)-2-methyloxazole.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])[N:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:8]=2[O:9][CH2:10][CH2:11][CH2:12][CH:13]([NH2:15])[CH3:14])[N:3]=1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCC(C)N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To an ice-cold solution of tert-butyl (5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-yl)carbamate (1.5 g, 3.70 mmol) in DCM (50 mL) was added TFA (5 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure and treated with saturated sodium bicarbonate solution (150 mL), and extracted with ethyl acetate (2×150 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get 5-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)pentan-2-amine (920 mg, 81%). LC-MS (M+H)+=306.2. 1H NMR: (400 MHz, CDCl3) δ ppm 8.97 (1H, s), 8.08 (1H, d, J=8.8 Hz), 8.00-7.91 (2H, m), 4.29-4.23 (2H, m), 3.27-3.25 (1H, m), 2.46 (3H, s), 2.16-2.03 (4H, m), 1.32-1.27 (3H, m).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(Cl)(=O)C(Cl)=O.[C:22]1([CH2:28][C@H:29]2[CH2:33][O:32][C:31](=[O:34])[NH:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC>ClCCl.C1COCC1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]([N:30]2[C@@H:29]([CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:33][O:32][C:31]2=[O:34])=[O:15])=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCc1ccc(CCCC(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCc1ccc(CCCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reaction time: 0.08 h
Yield: 60.8 %

Procedure:
4-(4-(1-n-Propyl)phenyl)butanoic acid (19.3 g) was disolved in dichloromethane and 25 mL of oxalyl chloride was added. After gas evolution ceased (~3 h) the mixture was concentrated in vacuo. To a solution of 4(S)-phenylmethyl-2-oxazolidinone (16.6 g, 93.6 mmol) in 250 mL of dry THF at -78° C. was added butyl lithium (64.4 mL, 1.6M, 102.99 mmol). After 5 min, a solution of the acid chloride in THF was added via cannula. After 15 min, the reaction was partitioned between ethyl acetate and 2N hydrchloric acid and the layers separated. The organics were washed twice with 2N hydrochloric acid and three times with dilute sodium bicarbonate then dried over sodium sulfate, filtered, and concentrated in vacuo. The product was purified by flash filtration through silica-gel eluting with 10% ethyl acetate in hexane to give a pale-yellow oil which crystallized upon dissolution in 5% ethyl acetate in hexane. The mixture was concentrated and recrystallized from hexane to afford the title compound as colorless needles (20.8 g): 400 MHz 1H NMR (CDCl3) δ 7.4-7.0 (m, 9H), 4.63 (m, 1H), 4.14 (m, 2H), 3.20 (dd, 1H, J=3.30, 13.27 Hz), 2.97 (m, 2H), 2.73 (dd, 1H, J=9.72, 13.42 Hz), 2.67 (t, 2H, J=7.68 Hz), 2.53 (t, 2H, J=7.61 Hz), 2.00 (m, 2H), 1.61 (m, 2H), 0.92 (t, 3H, J=7.33 Hz).
Reaction SMILES: CSC.C([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)C1C=CC=CC=1.O>C(Cl)Cl>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[OH:11])=[CH:24][CH:23]=1
Reactant: Clc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: Oc1ccccc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95.5 %

Procedure:
In a nitrogen stream, dimethylsulfide (105.1 μL, 2.43 mmol) and a boron trifluoride-diethyl ether complex (51.3 μL, 0.4 mmol) were added to a solution of 1-benzyloxy-2-(4-chlorobenzyl)benzene (50.0 mg, 0.16 mmol) in methylene chloride (2.0 mL) under cooling with ice, and the reaction mixture was stirred for 19 hours while gradually raising its temperature to room temperature. Thereafter water was added thereto under cooling with ice and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate: n-hexane (1:5)] to obtain the title compound (33.4 mg, 94%).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16].[CH3:18][C:19]1[O:20][C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([CH2:31]C(OCC)=O)=[N:27][S:28](=[O:30])(=[O:29])[C:23]=3[C:22]=2[N:39]=1.[H-].[Na+].Cl>O1CCCC1.O.C(O)(=O)C>[OH:15][C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:17])[C:6](=[O:16])[C:31]=1[C:26]1[NH:25][C:24]2[CH:37]=[CH:38][C:21]3[O:20][C:19]([CH3:18])=[N:39][C:22]=3[C:23]=2[S:28](=[O:30])(=[O:29])[N:27]=1
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc3oc(C)nc23)N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c3c(ccc2o1)NC(c1c(O)c2cccnc2n(CCC(C)C)c1=O)=NS3(=O)=O
Temperature: 0 °C
Yield: 59.9 %

Procedure:
To a solution of the product of Example 12A (16.7 mg, 0.0714 mmol) and the product of Example 352F (23.1 mg, 0.0714 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (60%, 11.4 mg, 0.286 mmol) under a nitrogen atmosphere. The reaction was heated at reflux for 3 hours, cooled to 0° C., and treated with glacial acetic acid (0.165 mL). The resulting yellow solution was heated at reflux for 2 hours, cooled to 0° C., diluted with water (5 mL), and acidified with 1N aqueous hydrochloric acid to pH 3. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a yellow solid (20 mg, 60%). MS (ESI−) m/z 466 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.58 (m, 2 H) 1.71 (m, 1 H) 2.73 (s, 3H) 4.50 (m, 2 H) 7.50 (dd, J=7.72, 4.41 Hz, 1 H) 7.64 (d, J=8.82 Hz, 1 H) 8.10 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=7.91, 2.02 Hz, 1 H) 8.89 (dd, J=4.60, 2.02 Hz, 1 H) 14.18 (s, 1 H). A suspension of the product of Example 352G (14.6 mg, 0.0312 mmol) in anhydrous tetrahydrofuran (3 mL) and distilled water (1 mL) was treated with 0.998 N aqueous sodium hydroxide (0.0313 mL, 0.0312 mmol) and the yellow solution mixed for 15 minutes. The solvent was removed under reduced pressure and the residue dried to afford the sodium salt of Example 352G (15 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.48 (m, 2 H) 1.65 (m, 1 H) 2.67 (s, 3 H) 4.30 (m, J=8.82, 6.25 Hz, 2 H) 7.13 (dd, J=7.91, 4.60 Hz, 1 H) 7.21 (d, J=8.82 Hz, 1 H) 7.86 (d, J=8.82 Hz, 1 H) 8.38 (dd, J=8.09, 1.47 Hz, 1 H) 8.53 (m, J=2.94 Hz, 1 H) 16.09 (s, 1 H).
Reaction SMILES: [CH3:1][C@@:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6]C(=O)N[C:3]1=[O:8].[OH2:15].N>C(OCC)(=O)C>[NH2:6][C@:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[C:3]([OH:15])=[O:8]
Reactant: O
Reactant: C[C@@]1(c2ccccc2)NC(=O)NC1=O
Agent: N
Solvent: CCOC(C)=O
Product: C[C@@](N)(C(=O)O)c1ccccc1
Temperature: 160 °C

Procedure:
22 g (0.115 mol) of (+)-(5S)-5-methyl-5-phenylhydantoin, 100 ml of water and 100 ml of 28% aqueous ammonia are introduced successively into a 1 liter autoclave. The medium is heated at 160° C. for 15 hours. After cooling to room temperature, the solution is concentrated under reduced pressure. The white solid obtained is treated with 100 ml of ethyl acetate for 2 hours and then filtered and dried under vacuum at 80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:12])[CH:7]=1
Reactant: O=C(CBr)c1c[nH]c2ccccc12
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Cl)cnc1=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Yield: 57.4 %

Procedure:
A mixture of 5-chloropyrimidin-2-one (522 mg) and 3-bromoacetylindole (1.19 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1.5 h the mixture was heated to 55° C. After a further 1.5 h the mixture was cooled and the resulting precipitate collected and washed with cold ethanol. Recrystallisation twice from ethyl acetate and once from ethanol gave the title pyrimidinone (660 mg), m.p. 228°-229° C., λmax (EtOH) 240 nm (ε 16,370) 300.5 nm (ε 13,090).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][CH2:11][O:12][C:13]([C@H:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:14].[Cl-].[NH4+]>O1CCCC1>[CH2:11]([O:12][C:13](=[O:14])[C@H:15]([NH:16][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:18][C:17]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:20])[CH3:10]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1ccc(F)cc1)NC(=O)OC(C)(C)C

Procedure:
Under a nitrogen atmosphere, 4-fluorophenyl magnesium bromide (25.6 mL, 1 M tetrahydrofuran solution) was added dropwise at −40° C. into a tetrahydrofuran (100 mL) solution containing (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester (6 g). After stirring for 1 hour at the same temperature, saturated ammonium chloride aqueous solution was added, and the resultant was extracted with ethyl acetate. After washing the organic layer with brine, the resultant was dried over anhydrous magnesium sulfate. After removing the solvent under a vacuum, the residue was purified with silica gel column chromatography, and the title compound (6.33 g) was obtained. The physical property values are as follows.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([O:30][CH3:31])[CH:5]=1)=[S:3].Cl[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C:34]1=O>CCO>[CH3:31][O:30][C:6]1[CH:5]=[C:4]([C:2]2[S:3][C:33]3[CH2:38][CH2:37][CH2:36][CH2:35][C:34]=3[N:1]=2)[CH:29]=[CH:28][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Reactant: O=C1CCCCC1Cl
Solvent: CCO
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3OC)ccc21
Yield: 59.4 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 146, 90 mg, 0.2 mmol) and 2-chlorocyclohexanone (215 mg 1.6 mmol) in anhydrous EtOH (8 mL) was stirred at 70° C. for 48 h. The reaction was cooled, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash chromatography (2:1 hexanes/ethyl acetate) to provide the title compound (62 mg, 58%) as clear oil. LC-MS: RT=4.08 min, (M+H)+ 522.5.