Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C@H:12]([N:14]1[CH2:18][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[O:16][C:15]1=[O:26])[CH3:13].C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O>O1CCCC1>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:17]2[O:16][C:15](=[O:26])[N:14]([C@H:12]([CH3:13])[CH2:11][C:7]3[C:6]4[C:10](=[C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])[CH:3]=[CH:4][CH:5]=4)[NH:9][CH:8]=3)[CH2:18]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CCC(=O)Cl
Reactant: C[C@H](Cc1c[nH]c2c(N)cccc12)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)Nc1cccc2c(C[C@@H](C)N3C[C@@H](c4cccc(Cl)c4)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To a solution of (5R)-3-((1R)-2-(7-amino-1H-indol-3-yl)-1-methylethyl)-5-(3-chlorophenyl)-1,3-oxazolidin-2-one (28.4 mg, 0.0768 mmol) in tetrahydrofuran (1 mL) are added triethylamine (13.5 μL, 0.0969 mmol) and propionyl chloride (8 μL, 0.0921 mmol) under nitrogen atmosphere, and the mixture is stirred at room temperature for 1 hour. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained crude product is purified by preparative thin layer chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (34.3 mg, yield: 100%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.C(Cl)Cl.C([OH:29])C>O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[O:29]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc(CC(=O)O)cc1
Yield: 87 %

Procedure:
To a solution of 2-[4-(bromomethyl)phenyl]acetic acid (770 mg, 3.36 mmol) in ethanol (6 mL) and water (6 mL) was added hexamethylenetetramine (1.26 g, 9.0 mmol) and the mixture was heated to reflux for 4 hours. Concentrated HCl (1.5 mL) was added cautiously to the mixture at reflux. The mixture was heated to reflux for 30 minutes and then allowed to cool. Water (20 mL) and DCM (20 mL) were added and the organic phase was passed through a hydrophobic fit and the solvent was removed in vacuo to afford the title compound as an off-white solid (479 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 7.86 (d, J=7.9 Hz, 2H), 7.47 (d, J=7.9 Hz, 2H), 3.75 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([OH:7])[CH:3]=1.N12CCCN=C1CCCCC2.[CH3:19][O:20][CH2:21]Cl.O>O1CCCC1>[Cl:1][C:2]1[S:6][N:5]=[C:4]([O:7][CH2:19][O:20][CH3:21])[CH:3]=1
Reactant: COCCl
Reactant: Oc1cc(Cl)sn1
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COCOc1cc(Cl)sn1
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
To a solution of 5-chloro-isothiazol-3-ol (5.00 g) in tetrahydrofuran (50 mL), 1,8-diazabicyclo[5.4.0]undeca-7-ene (8.42 g) was added, and to the resultant reaction mixture, a solution of chloromethyl methyl ether (4.45 g) in tetrahydrofuran (25 mL) was dropped under ice-cooling at an inside temperature of 10° C. or less. After the completion of dropping, the inside temperature was elevated to room temperature and the reaction mixture was stirred for 10 minutes. To the reaction mixture, water was added and the resultant reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated saline and was dried over anhydrous sodium sulfate. From the organic phase, the solvent was distilled off under reduced pressure to obtain the subject compound (6.15 g) as a brown oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9]2=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1C(Cc2ccccc2)CCCN1Cc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
1-Phenylmethyl-2-piperidinone (See: Yamaguchi M, Hirao I (1985) "A direct synthesis of [(tert-butoxycarbonyl)methylidene]-azacycloalkanes from N-alkyllactams" J. Org. Chem., 50, 1975-1977) (3.40 g, 18 mmol) was reacted with benzyl bromide (4.84 g, 28.3 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.73 g, 27 mmol) with butyllithium in hexanes (2.5M, 10.3 mL, 25.7 mmol)) in THF (45 mL) and HMPA (2.7 mL, 15.5 mmol) as described above in the preparation of Example 7. After the addition of benzyl bromide, the reaction mixture was stirred for 2 h at -78° C., and then quenched with saturated NH4Cl (50 mL). The reaction mixture was extracted with ether (3×40 mL) and the combined ether extract washed with brine (40 mL) and dried over MgSO4. The solvent was removed in vacuo, and the residue (8.40 g) thus obtained, was chromatographed over silica gel (hexanes-CHCl3 -EtOAC, 15:4:1 and then 7:2:1) to give the product lactam (3.14 g, 63%) as a colorless solid: mp 94°-95° C. (CH2Cl2 -hexanes).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4]1=[O:10].[H][H]>CO.[Rh]>[NH2:2][N:3]1[CH2:7][CH:6]([CH3:8])[N:5]([CH3:9])[C:4]1=[O:10]
Reactant: [H][H]
Reactant: Cc1cn(N)c(=O)n1C
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: CC1CN(N)C(=O)N1C
Reaction time: 4 h

Procedure:
1.6 g of Rh/C are added to a solution of 1-amino-3,4-dimethyl-2-oxo-1,3-dihydroimidazole hydrochloride in 150 ml of methanol and the reaction mixture is hydrogenated with hydrogen under normal pressure. After 4 hours, 1.13 litres of hydrogen have been taken up and the reaction ceases. The reaction mixture is then filtered over Celite and concentrated by evaporation. The residue is stirred with tetrahydrofuran. The crystals are filtered off with suction and dried in vacuo at 60°. 7 g of the title compound in the form of the hydrochloride having a melting point of 162°-164° are obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[O:9][C:8]2[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=2[CH2:6]1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2([OH:34])[CH2:29][CH2:30][N:31]([CH2:2][CH2:3][CH:4]=[C:5]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[O:9][C:8]4[CH:16]=[CH:17][CH:18]=[C:19]([OH:20])[C:7]=4[CH2:6]3)[CH2:32][CH2:33]2)=[CH:24][CH:23]=1
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Reactant: Oc1cccc2c1CC(=CCCBr)c1cccnc1O2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(F)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 23 h
Yield: 38.6 %

Procedure:
To a solution of 5-(3-bromopropylidene)-5,11-dihydro-7-hydroxy-[1]benzoxepino[2,3-b]pyridine (2.59 g) in DMF (10 ml) was added 4-(4-Fluorophenyl)-4-hydroxypiperidine (1.02 g) and triethylamine (835 μM). The solution was stirred at room temperature for 23 hours. The reaction was quenched with water, extracted with ethyl acetate, and evaporated in vacuo. The residue was purified by silica gel chromatography (87:10:3 ethyl acetate: methanol:triethylamine) to yield 0.9 g (39%) of the title compound. 1H-NMR (DMSO) d: 1.64–1.69 (2H, m), 1.74–1.85 (2H, m), 2.27–2.52 (8H, m), 4.81 (1H, s), 5.16 (2H, brs), 6.08 (1H, t), 6.62–6.71 (3H, m), 7.12 (2H, t), 7.40–7.51 (3H, m), 7.72 (1H, dd), 8.48 (1H, dd), 9.09 (1H, s). ESI-MS m/z: 447 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([N:15]3[CH2:20][CH2:19][C:18]([CH2:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(O)[CH2:17][CH2:16]3)[CH3:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)=O.CC(C)=O.CCN(S(F)(F)[F:44])CC.[Cl:47]CCl>>[ClH:47].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([N:15]3[CH2:20][CH2:19][C:18]([CH2:22][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([F:44])[CH2:17][CH2:16]3)[CH3:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(c1ccc(N2CCOCC2)cc1)N1CCC(O)(CC(=O)c2ccccc2)CC1
Reactant: ClCCl
Agent: O=C=O
Solvent: CC(C)=O
Product: CC(c1ccc(N2CCOCC2)cc1)N1CCC(F)(CC(=O)c2ccccc2)CC1
Product: Cl
Temperature: -75 °C
Reaction time: 1 h
Yield: 40.5 %

Procedure:
N-(1-(4-morpholinophenyl)ethyl)-4-benzoylmethyl-4-piperidinol (III-27) is firstly prepared according to the method of synthesis and post-treatment in Example 27. 1.63 g (4.0 mmol) of N-(1-(4-morpholino phenyl)ethyl)-4-benzoylmethyl-4-piperidinol is dissolved into 20 ml of anhydrous dichloromethane and cooled with dry ice-acetone with temperature controlled at below <−70° C. The reaction solution is added dropwise a dichloromethane solution (8 mol, 25 ml) of DAST protecting of nitrogen gas. After completion of addition, the temperature is maintained at −75° C. and reacting for 1 hour, and the temperature is raised slowly and maintained at −10° C. and reacting for 2 hours. Then operating according to the post-treatment method in General Method six obtains 0.81 g of a white crystal, with yield of 40.5%.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:29]=2[CH2:28][CH2:27]1>>[Cl:21][C:17]1[C:16]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:15][C:14]([NH:37][C:34]2[CH:35]=[CH:36][C:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:32][CH2:31][C:30]=3[CH:33]=2)=[N:19][CH:18]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Nc1ccccc1-n1cccn1
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4-n4cccn4)n3)cc2CC1

Procedure:
5-Chloro-N*2*-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-N*4*-(2-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine was prepared from 2-(1H-pyrazol-1-yl)aniline, 2,4,5-trichloropyrimidine, and 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 308. Product isolated as a white foam (108 mg, 65%). LCMS (m/e) 490 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.20 (s, 1H), 8.52 (d, 1H, J=8.3 Hz), 8.04 (d, 1H, J=1.6 Hz), 7.86 (s 1H), 7.81 (d, 1H, J=1.9 Hz), 7.41-7.14 (m, 5H), 7.10-6.90 (m, 2H), 6.54-6.50 (m, 1H), 3.69-3.54 (m, 2H), 3.39 (s, 3H), 2.96-2.86 (m, 4H), 2.80-2.69 (m, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[Br:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH:21]=[C:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[Br:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][CH:35]([NH:1][CH2:2][CH:3]([C:5]2[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=2)[OH:4])[CH2:36][CH2:37]1
Reactant: O=C1CCN(c2ccc(C=C3SC(=O)NC3=O)cc2Br)CC1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3Br)CC2)ccc1O

Procedure:
The title compound was prepared from N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) and 5-[3-bromo-4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 58) according to the procedure of Example 63 as a dull yellow solid; mp >200° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.70-1.82 (m, 2H), 2.07-2.17 (m, 2H), 2.65-2.73 (m, 3H), 2.95 (s, 3H), 3.07-3.17 (m, 4H), 4.74-4.77 (m, 3H), 6.00 (brs, 1H), 6.89 (d, J=8.3 Hz, 1H), 7.09 (dd, J=8.4, 2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.26-7.27 (m, 2H), 7.50 (dd, J=8.4, 2.0 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 8.7 (brs, 1H), 9.9 (brs, 1H); MS (ES) m/z: 612.8 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:34]1([N:40]2[C:44]3([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[C:43](=[O:50])[NH:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:47]3[CH2:46][CH2:45][C:44]4([N:40]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:41][NH:42][C:43]4=[O:50])[CH2:49][CH2:48]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a mixture of indole-5-carboxylic acid (300 mg, 1.86 mmol) and HOBT (278 mg, 2.05 mmol) in dry DMF (10 mL) was added EDAC (464 mg, 2.42 mmol). The resulting mixture was stirred for 10 min followed by addition of a mixture of TEA (0.78 ml, 5.58 mmol) and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (473 mg, 2.04 mmol). The reaction mixture was stirred for an additional 16 hrs. To the reaction mixture was added water (25 ml) and the resulting precipitate was filtered and washed with water. The resulting solid was recrystalised from a mixture of EtOH-water (4:1, 10 mL) the precipitate was filtered off, washed with water and dried in vacuo at 40° C. affording 472 mg (67%) of the title compound as a solid.
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].[C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[CH3:7].CI>CN(C)C=O.O>[C:6]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:1])=[O:13])(=[O:8])[CH3:7]
Reactant: CC(=O)CCCC(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)CCCC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a rapidly stirred slurry of sodium bicarbonate (25 g) in a solution of 4-acetylbutyric acid (13 g, 0.1 mol) in dimethylformamide (150 ml) was added methyl iodide (47 g). After stirring overnight at room temperature under nitrogen, the reaction mixture was diluted with water (300 ml) and extracted with ethyl ether (250 ml). The organic phase was washed with water and dried over sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator to give 12 g of the title compound as a light yellow oil. The product can be purified by distillation: b.p. 59°-60° (0.1 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]#[C:14][C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:19][CH:20]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]#[C:14][C:15]1[CH:20]=[N:19][C:18]([NH:21][C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:31])=[N:17][CH:16]=1
Reactant: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3[N+](=O)[O-])nc2)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c(Cl)c(C#Cc2cnc(Nc3c(C)cccc3N)nc2)c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
A mixture of 5-((2,6-dichloro-3,5-dimethoxyphenyl)ethynyl)-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (150 mg, 0.33 mmol), Iron (147 mg, 2.64 mmol) and ammonium chloride (214 mg, 3.96 mmol) in ethanol (20 mL) and water (2 mL) was stirred at 85° C. for 1 h. LCMS showed the reaction was completed. The reaction was cooled to RT, and the solid was filtered off. The filtrate was concentrated, and the residue was purified by Prep-HPLC to afford the title compound as a white solid (58 mg, 35%). MS (ES+) C21H18Cl2N4O2 requires: 429, 431. found: 430, 432 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.55-8.44 (br, 2H), 6.97 (s, 1H), 6.89-6.86 (m, 1H), 6.57 (d, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.6 Hz), 4.75 (s, 2H), 3.94 (s, 6H), 2.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])CC2.[C:12]([O:19]CC)(=[O:18])[C:13](OCC)=O.C[O-:23].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]([OH:11])=[O:23])=[C:4]([CH2:13][C:12]([OH:19])=[O:18])[CH:3]=1
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: CCOC(=O)C(=O)OCC
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)Cc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.3 %

Procedure:
A solution of 5-bromo-1-indanone (25 g) and diethyl oxalate (27.7 g) in toluene (500 mL) was added to a suspension of sodium methoxide (13.1 g) in toluene (50 mL) at 0° C. The mixture was warmed to room temperature and stirred for 90 minutes. The solvent was removed and the residue suspended in methanol (800 mL). Potassium hydroxide (53.1 g) was added portionwise keeping the temp below 50° C. Hydrogen peroxide solution (30% w/w, 135 mL) was then added keeping the temperature below 64° C., the reaction mixture was then stirred at room temperature for 17 hours. Sodium sulfite (5% aqueous solution) was added and the reaction stirred for 30 minutes. The reaction mixture was filtered and the filtrate was reduced to half volume then washed with 2-methoxy-2-methyl-propane. The aqueous layer was then acidified with hydrochloric acid and extracted into ethyl acetate. The organic phase was dried, filtered and evaporated then triturated with diethyl ether to yield sub-title compound (9.0 g).
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[Br:19])=CC=2)C=CC=1)=O)C.[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][Br:19])[CH:32]=2)=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:24])[CH3:21]
Reactant: CCOC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Reactant: CCOC(=O)c1ccccc1-c1cccc(C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccccc1-c1cccc(CBr)c1

Procedure:
3′-Bromomethyl-biphenyl-2-carboxylic acid ethyl ester was synthesized as described for 4′-bromomethyl-biphenyl-3-carboxylic acid ethyl ester. 3′-Methyl-biphenyl-2-carboxylic acid ethyl ester (4.3 g, 17.89 mmol, 1 eq.) in carbon tetrachloride was treated with N-bromosuccinimide (3.82 g, 21.47 mmol, 1.2 eq.) and 2,2′-azobisisobutyronitrile (0.15 g, 0.89 mmol, 5 mol %). When complete, the reaction was worked up as described leaving a tan oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.Cl[C:50]([O:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:51]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:50]([O:52][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[O:51])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)Oc1ccccc1
Reaction time: 8 h

Procedure:
1.5 g of the compound obtained in Step A of Example 12 are dissolved in 20 ml of ethyl acetate; 1.06 ml of triethylamine are then added and the temperature is lowered to 0° C. 0.637 ml of phenyl chloroformate is then added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][C:17]=3[Cl:27])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1.C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Cl:27])=[CH:28][CH:29]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Cl)c1
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetate (33 mg, 0.0720 mmol) was diluted with THF (500 μL) followed by the addition NaOH (0.144 ml, 0.720 mmol) and 100 μL of water. After stirring for 2 hours, the reaction was diluted with DCM and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetic acid (19 mg, 59.4% yield) as a white solid. 1H NMR (400 MHz, CDCl3/CD3OD) δ 7.65 (d, 2H), 7.42 (m, 1H), 7.25 (d, 2H), 7.20 (d, 1H), 7.15 (d, 2H), 7.05 (d, 1H), 6.85 (d, 2H), 3.65 (1, 2H), 3.60 (s, 2H), 2.90 (t, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH2:14])[C:8]([OH:21])=[C:7]([CH3:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Ca+2].[I:29](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1.CO>[C:1]([O:4][C:5]1[C:6]([CH3:23])=[C:7]([CH3:22])[C:8]2[O:21][CH:13]([CH2:14][I:29])[CH:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9]=2[C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: C=CC(c1ccccc1)c1c(C)c(OC(C)=O)c(C)c(C)c1O
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(c1ccccc1)C(CI)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a suspension of 4-hydroxy-2,3,6-trimethyl-5-(1-phenyl-2-propenyl)phenyl acetate (5.10 g, 16.4 mmol) and calcium carbonate (2.13 g, 21.3 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was added benzyltrimethylammonium dichloroiodate (6.28 g, 18.0 mmol) slowly. The mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with 10% aqueous sodium hydrogen sulfite, water, an aqueous saturated solution of sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, treated with activated carbon, filtrated and the filtrate was concentrated in vacuo to provide 5.30 g of 2-iodomethyl-4,6,7-trimethyl-3-phenyl-2,3-dihydrobenzofuran-5-yl acetate. A mixture of this compound (5.30 g, 12.1 mmol) and 1,8-diazabicyclo[5,4,0]-7-undecene (9.0 m, 60.0 mmol) in toluene (20 mL) was stirred under an argon atmosphere at 100° C. for 3 hours. To that mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with 2N hydrochloric acid, and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1) to obtain the title compound (4.0 g, yield 79%). This was oily.