Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44](Cl)(=[O:48])[CH2:45][CH2:46][CH3:47]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:48])[CH2:45][CH2:46][CH3:47]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: CCCC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise butyryl chloride (0.1 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.389 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.149 g colorless crystals. Mp 122° C. Mass spectrum, m+ =399. Anal (C24H35N5O6) theory C, 58.88; H, 7.21; N, 14.32; found C, 58.60; H, 7.15; N, 14.30.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[O:13]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]([C:23]2[CH:24]=[CH:25][C:20]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:21][CH:22]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Product: O=Cc1c(Cl)n(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Yield: 34 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-phenoxyphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-phenoxyphenyl)-1H-indole-3-carboxaldehyde (34% yield) as a cream solid. ESI/MS 348 (M+H), 389 [(M+1+CH3CN) adduct], RT 3.74 min.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.NO.C([N:17](CC)CC)C.CCCP(=O)=O>CN(C)C=O.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]#[N:17])[CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: O=Cc1ccnc(C2CC2)n1
Agent: CCCP(=O)=O
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccnc(C2CC2)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 2-cyclopropylpyrimidine-4-carbaldehyde (1.0 g, 6.68 mmol) in N,N-dimethylformamide (10 mL) were added hydroxylamine hydrochloride (500 mg, 7.02 mmol) and triethylamine (1.2 mL). The reaction mixture was heated to 50° C. and propylphosphonic anhydride (T3P) was added dropwise. After 16 h at 110° C., the mixture was cooled to room temperature, diluted with water and quenched with solid sodium bicarbonate. The mixture was extracted with ethyl acetate, then the organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified via silica gel chromatography to afford 2-cyclopropylpyrimidine-4-carbonitrile (600 mg, 62%) as a pale yellow liquid. MS (ES+APCI) (M+H) 145.9; LMCS retention time 2.224 min (Method G).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]([C:27]([N:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH:30]2[CH2:38][CH3:39])=[O:28])[CH:22]=1.Cl>CC(O)C>[CH2:38]([CH:30]1[CH2:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]1[C:27]([C:23]1[N:24]=[CH:25][N:26]=[C:21]([NH:1][C:2]2[CH:3]=[C:4]3[C:17](=[CH:18][CH:19]=2)[CH2:16][C:6]2([C:14]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[NH:8][C:7]2=[O:15])[CH2:5]3)[CH:22]=1)=[O:28])[CH3:39]
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: CCC1Cc2ccccc2N1C(=O)c1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Product: CCC1Cc2ccccc2N1C(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1

Procedure:
103 mg (0.40 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 113 mg (0.40 mmol) (6-chloro-pyrimidin-4-yl)-(2-ethyl-2,3-dihydro-indol-1-yl)-methanone and 13 μL of a 4 molar aqueous hydrochloric acid solution were added to 2.0 mL of 2-propanol and the mixture was refluxed for 2 h. Then the reaction mixture was evaporated down and purified by preparative HPLC-MS. The product-containing fractions were combined and the organic solvent was evaporated down. The residue was made alkaline with a 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried under HV.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][CH:10]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: C(=CC1CCCCCCCCCCC1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CCCC2CCCCCCCCCCC2)cc1
Reaction time: 8 h

Procedure:
To 6.4 g (22.5 mmoles) of 1-(3-phenyl-1-propenyl)cyclododecane in 50 mL of ethanol is added 0.48 g of 10% palladium on carbon. The reaction mixture is subjected to hydrogen (50 psi) atmosphere using a Paar hydrogenerator and shaken overnight after which time no starting material is evident by TLC. The reaction mixture is filtered through Celite which is washed with additional ethanol. The filtrate is evaporated and the crude residue (5.8 g) is used directly for the next step: NMR (CDCl3) δ1.2-1.4 (m, 10H), 1.6 (m, 2H), 2.55 (t, 2H, J=8 Hz), 7.2 (m, 5H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:29][C:28]([F:31])([F:30])[CH2:27]2)=[CH:24][CH:25]=1>>[F:31][C:28]1([F:30])[CH2:29][N:26]([C:23]2[N:22]=[CH:21][C:20]([NH:19][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:25][CH:24]=2)[CH2:27]1
Reactant: Nc1ccc(N2CC(F)(F)C2)nc1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: O=C(Nc1ccc(N2CC(F)(F)C2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
With a method similar to example 16 above, 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid-[6-(3,3-difluoroazetidin-1-yl)pyridin-3-yl]amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and 3-amino-6-(3,3-difluoroazetidin-1-yl)pyridine. LCMS calcd for C19H13F5N4O2 m/e 424.33, obsd 425.0 (ES, M+H).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:7][CH:6]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([C@@H:18]2[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15][C@H:14]2[C:12]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:42])=[O:2])=[CH:10][CH:9]=2)=[O:13])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)Cc1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(CC(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
A mixture of (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid methyl ester (72 mg, 0.117 mmol) was dissolved in THF (3 mL) and methanol (1 mL), then 2N LiOH (1 mL) was added and stirred at room temperature for 2 hours. The mixture was concentrated and diluted with water and ethyl acetate. The organic phase was separated then concentrated to yield chiral (4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-phenyl)-acetic acid (37 mg, 52.6%) as an white powder. HRMS (ES+) m/z Calcd for C31H29Cl2F2N3O3+H [(M+H)+]: 600.1627. found: 600.1626.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:12]([C:10]1[C:9]([N:15]2[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([F:1])[CH:11]=1)[CH3:13]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(F)c2cccnc2c1N1CC[C@@H](O)C1
Temperature: 65 °C

Procedure:
A mixture of 1-{5-fluoro-8-[(3R)-3-hydroxypyrrolidin-1-yl]quinolin-7-yl}ethanone (10 mg, 0.04 mmol) and ammonium acetate (28.1 mg, 0.364 mmol) in methanol (0.20 mL) and acetonitrile (0.21 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (4.6 mg, 0.073 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate, extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in the next step. LCMS calculated for C15H19FN3O (M+H)+: m/z=276.1; Found: 276.1.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)=[N-].[BrH:14].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:14][CH2:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=CC(=O)Cc1ccc(I)cc1
Reactant: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CBr)Cc1ccc(I)cc1
Temperature: 0 °C
Yield: 94.4 %

Procedure:
1-Diazo-3-(4-iodophenyl)propan-2-one (13) (1.27 g, 4.43 mmol) was dissolved in acetic acid (20 mL) and cooled to 0° C. To this was added 47% hydrobromic acid (1.55 mL, 13.3 mmol) and stirred for an hour after warming to room temperature. After neutralization by adding saturated aqueous solution of sodium bicarbonate, the product was extracted with ethyl acetate (×3) and the organic layer was washed sequentially with saturated aqueous solution of sodium bicarbonate (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=7/1) to give 1-bromo-3-(4-iodophenyl)propan-2-one (16) as a colorless solid (1.42 g, 4.18 mmol, 94.4%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:9])[C:2]#[CH:3].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O.C(Cl)Cl>[C:13]([O:9][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][C:2]#[CH:3])[CH:6]=1)(=[O:15])[CH3:14]
Reactant: C#CCOc1cccc(CO)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C#CCOc1cccc(COC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 5.0 L flange flask was charged with 3 (706 g, approx. 4.36 mol, 1 eq) and acetic anhydride (99.5%, ex. Fisher, 1300 ml, 1 mol) to give a clear solution. Sulfuric acid (conc. 98%, 150 drops, ˜3 ml, catalytic) was then added very slowly (dropwise) over 30 minutes, with cooling to 0° C. by aid of an ice/water bath to control the exotherm to give a very dark reaction mixture. Maximum internal temperature observed was 45° C. After the addition the reaction mixture was stirred for 30 min, then the reaction mixture was stirred at 99° C. for 3 h. TLC-examination (silica-gel plate, DCM eluent, PMA stain) showed that all the starting material had been consumed. The mixture was cooled to room temperature (r.t.) overnight to give a dark green solution, which was poured onto an ice-water mixture (2.5 L water and 2.5 Kg of ice) with vigorous stirring. The product was extracted with DCM (5.0 L×3), and the combined extracts washed with water (3.0 L×3), dried over Na2SO4, and evaporated to give a black/brown oily residue.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][O:15][C:16]1[C:17]([S:28](F)(=[O:30])=[O:29])=[CH:18][C:19]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21][C:20]=2[CH:27]=1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:28]([C:17]2[C:16]([O:15][CH3:14])=[CH:27][C:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:19]=3[CH:18]=2)(=[O:29])=[O:30])=[CH:3][CH:4]=1
Reactant: COc1cc2c(cc1S(=O)(=O)F)CCN(C)CC2
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(Br)cc1)CCN(C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1,4-dibromobenzene (0.665 g, 2.82 mmol, 2.0 eq) in dry tetrahydrofuran (7 mL) under argon at −78° C. was added butyllithium (1.25 mL 2.5M in hexanes, 3.10 mmol, 2.2 eq) dropwise over 10 min. After a further 30 min. a suspension of sulfonyl fluoride D4 (0.385 g, 1.41 mmol, 1.0 eq) was added portionwise. The resultant mixture was allowed to warm to room temperature then stirred for 2 h. The mixture was quenched with water (40 mL) then extracted twice with ethyl acetate (2×40 mL). The organic layer was washed sequentially with water (50 mL) and brine (50 mL) then dried over MgSO4 and evaporated to dryness. Purification by Biotage chromatography, eluting with 1-6% MeOH—CH2Cl2 containing 0.5% NH3 afforded the desired product D13 as a solid, 0.289 g (50%). MH+411. 1H NMR δ (CDCl3) 2.37 (3H, s), 2.55 (4H, m), 2.93 (4H, m), 3.75 (3H, s), 6.65 (1H, s), 7.60 (2H, d), 7.80 (3H, m).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].Cl>CN1C(=O)CCC1>[C:11]([NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CN1CCCC1=O
Product: CC(C)(C)Nc1ncccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
To a solution of 2-chloro-3-nitropyridine (5.0 g, 31.53 mmol) in anhydrous NMP (100 mL) was added tert-butylamine (10 mL, 94.52 mmol). The solution was heated at 60° C. for 14 hours and cooled. The mixture was poured into 1N HCl solution (400 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with saturated NaHCO3 solution and dried over MgSO4. After filtration, the solvent was evaporated under vacuum to afford N-tert-butyl-3-nitropyridin-2-amine as dark brown syrup.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:13](=[O:14])[CH:12]3[C:10]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=4)([CH2:11]3)[C:9]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]23[CH2:11][CH:12]2[C:13](=[O:14])[N:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:9]3=[O:24])=[CH:20][CH:19]=1
Reactant: O=C1C2CC2(c2ccc([N+](=O)[O-])cc2)C(=O)N1CC1CCCCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C23CC2C(=O)N(CC2CCCCC2)C3=O)cc1

Procedure:
Following the procedure of Example 3, a solution of 0.5 g of 3-cyclohexylmethyl-1-(4-nitrophenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione in 30 ml of ethanol is hydrogenated in the presence of 0.1 g of 5% palladium on carbon and the reaction mixture is worked up, affording the title compound which melts at 125°-126° C. after recrystallisation from ethyl acetate/petroleum ether.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:31][CH2:32][S:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.7 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.11 mL, 0.11 mmol) was added to a solution of [4′-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 138-(4); 20 mg, 0.037 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane:methanol=10:1) to give the target compound as a colorless oil (15 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[S:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=[O:24])=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[S:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=[O:24])=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)sc2c2c1OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)sc23)O1
Yield: 64.8 %

Procedure:
The title compound was prepared following the procedure described for step-2 of intermediate-3 using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydrofuro[2,3-g][1,3]benzothiazole-5-carboxylate (0.080 g, 0.188 mmol), methanol (2.0 mL) and (50%) aqueous solution of sodium hydroxide (0.200 g, 5.00 mmol) to afford 0.050 g of the desired product. 1HNMR (DMSO-d6): δ 1.43 (s, 6H), 2.98 (s, 2H), 7.37 (s, 1H), 7.30 (s, 1H), 8.61 (m, 2H), 12-13 (s, 1H); MS [M+H]+: 424.18.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccnc2ccccc12

Procedure:
A solution of methanesulfonyl chloride (4.84 ml) in 20 ml of methylene chloride is slowly added over 20 minutes to a solution of 8.29 g of 4-hydroxymethylquinoline and 11 ml of triethylamine in 200 ml of methylene chloride at 0°. After completion of the reaction at room temperature, the reaction mixture is partitioned between methylene chloride and saturated potassium carbonate solution. The organic layer is dried over sodium sulfate and evaporated to dryness to yield 4-(methanesulfonyloxymethyl)quinoline as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:24]2[CH2:28][CH2:27][CH2:26][S:25]2(=[O:30])=[O:29])[CH:3]=1.[CH3:31][C:32]1([CH3:38])[CH2:36][O:35][C:34](=[O:37])[NH:33]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[C:32]([CH3:38])([CH3:31])[CH2:36][O:35][C:34]4=[O:37])=[CH:3][C:4]=3[N:24]3[CH2:28][CH2:27][CH2:26][S:25]3(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC1(C)COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OCC4(C)C)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Yield: 24.1 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (247 mg) described in Preparation Example 118 and 4,4-dimethyloxazolidin-2-one (57.6 mg), the title compound (63.6 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Product: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
4-Fluoro-3-nitro-aniline (45.0 g, 288.2 mmol) was added portionwise to acetic anhydride (150 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The white solid was collected and dried in vacuo to give the desired title compound (42.0 g, 70%).
Reaction SMILES: [CH2:1]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]([NH:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl>C1C=CC=CC=1>[CH2:1]([C:8]1[CH:26]=[CH:25][CH:24]=[CH:23][C:9]=1[C:10]1[O:22][C:14]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)NNC(=O)c2ccccc2Cc2ccccc2)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cccc(-c2nnc(-c3ccccc3Cc3ccccc3)o2)c1
Yield: 95.9 %

Procedure:
To a solution of 19 (1.1 g, 3.194 mmol) in 4 mL benzene was added SOCl2 (2.2 mL, 30.13 mmol). The mixture was heated to reflux overnight and then solvent and excess SOCl2 were evaporated. The yellow residue was dissolved in EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution, H2O and brine, dried over MgSO4 and concentrated. The crude product was purified by flash column chromatography (8-10% EtOAc in n-hexane) to give 2-(2-benzyl-phenyl)-5-m-tolyl-[1,3,4]-oxadiazole 21 (1.0 g, 3.064 mmol, 96% yield).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:26]1([CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:24][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([I:23])[CH:18]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:38])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(I)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCN(Cc2cccc(I)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3-iodo-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4f). (0.5 g, 0.0008 mol) in methanol (7.5 mL) was treated with 2N NaOH (5 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (25 mL) and water was added (10 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 0.32 g in 67% yield. 1H NMR (CD3OD) δ 7.92 (s, 1H), 7.53 (d, 2H), 7.27 (m, 8H), 7.19 (t, 2H), 6.93 (t, 1H), 6.88 (d, 1H), 6.67 (s, 1H), 6.64 (d, 1H), 4.25 (t, 1H), 3.70 (s, 2H), 3.65 (t, 2H), 3.58 (s, 2H), 3.16 (d, 2H), 2.69 (t, 2H), 1.86 (t, 2H); 13C NMR (CD3OD) δ 175.7, 160.4, 144.8, 144.7, 143.2, 139.3, 137.3, 137.2, 137.1, 131.0, 130.9, 130.4, 129.5, 129.3, 127.4. 122.5, 122.4, 116.6, 114.3, 94.9, 66.5, 60.7, 59.5, 51.7, 50.9, 42.2, 27.7. Anal. Calcd for C32H32INO3.H2O: C, 61.62; H, 5.17; I, 20.34; N, 2.25. Found: C, 61.70; H, 5.06; I, 20.68; N, 2.74.