Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.O1CCCC1.[CH3:25][NH2:26]>[Ti](Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:26][CH3:25])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1

Procedure:
A solution of 63.2 g. (0.2 mol) of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one in 1.7 l. of tetrahydrofuran and 400 ml. of benzene was saturated with methylamine. A solution of 45.5 g. of titanium tetrachloride in 400 ml. of benzene was added slowly with ice cooling. After addition was complete, the reaction mixture was stirred and refluxed for 2 hours. It was then partitioned between water and methylene chloride. The organic layer was dried over sodium sulfate and evaporated. Crystallization from methylene chloride/hexane yielded 7-bromo-2-methylamino-5-(2-pyridyl)-3H-1,4-benzodiazepine, having a melting point of 208°-214°.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[C:7]([C:9]2[S:19][C:12]3=[N:13][CH:14]=[C:15]([CH:17]=O)[CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.[NH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:8]=[C:7]([C:9]2[S:19][C:12]3=[N:13][CH:14]=[C:15]([CH2:17][NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCC(=O)O
Reactant: O=Cc1cnc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCNCc1cnc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
To a solution of 2-(2-trifluoromethyl-biphenyl-4-yl)-thieno[2,3-b]pyridine-5-carbaldehyde (32 mg, 0.083 mmol) in MeOH (2 mL) is added β-alanine HCl salt (37 mg, 0.42 mmol) and triethylamine (23 uL, 0.16 mmol). The mixture is stirred at 50° C. for 20 minutes. Sodium borohydride (30 mg, 0.8 mmol) is added at room temperature and it is stirred for 10 minutes. The mixture is purified with preparative LCMS to give 22 mg of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-thieno[2,3-b]pyridin-5-ylmethyl]-amino}-propionic acid, which is converted to HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.56 (d, 1 H), 8.30 (d, 1 H), 8.08 (d, 1 H), 7.98 (dd, 1 H), 7.84 (s, 1 H), 7.42 (d, 1 H), 7.40-7.34 (m, 3 H), 7.30-7.24 (m, 2 H); MS (ES) 457.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24]([CH2:26]Br)=[O:25])[CH:18]=1>CC(C)=O>[Cl:23][C:21]1[CH:20]=[C:19]([C:24](=[O:25])[CH2:26][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2)[CH:18]=[CH:17][CH:22]=1
Reactant: CN(C)c1cccc(O)c1
Reactant: O=C(CBr)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)c1cccc(OCC(=O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 47.3 %

Procedure:
A slurry of 3.0 g of 3-dimethylaminophenol, 6.05 g of milled potassium carbonate and 75 ml of acetone was stirred at room temperature under nitrogen for 30 minutes and then a solution of 7.66 g of α-bromo-3-chloroacetophenone in 75 ml of acetone was added dropwise. The slurry was stirred at room temperature for 72 hours. Filtration and evaporation gave a residue which was purified by high performance liquid chromatography (7:1 hexane-ethyl acetate). The resulting solid was recrystallized from ethyl acetate-hexane to give 3.0 g of 1-(3-chlorophenyl)-2-[3-(dimethylamino)phenoxy]ethanone, m.p. 101°-103° C.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19].CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>ClCCl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:20]1[CH:24]=[C:23]([C:25]([NH:27][CH:39]3[CH2:40][CH2:41][CH2:42][CH2:37]3)=[O:26])[CH:22]=[N:21]1)=[N:14][C:15]=2[NH2:19]
Reactant: NC(=O)c1cnn(-c2nc(N)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Nc1nc(-n2cc(C(=O)NC3CCCC3)cn2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The trisilyl derivative acid 20 (0.14 g, 0.2 mmol) was then dissolved in 5 mL dichloromethane. To the solution was added HBTU (0.19 g, 0.4 mmol), HOBt (.076 g, 4 mmol), N-methylmorpholine (0.04 g, 0.4 mmol) and cat. DMAP. The mixture was allowed to stir at RT for 24 h. The mixture was then washed with 10% citric acid, saturated NaHCO3, brine and dried over MgSO4. The solvent was removed and the residue was treated with 5 mL 0.5N NH4F/MeOH. The solution was heated at reflux for 24 h. The solvent was evaporated and the residue was purified by preparative TLC to afford compound 21, MS 445.26 (M+1).
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].[CH2:6]([O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=O)[CH2:26]Br)=[CH:21][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O-]CC.[Na+]>C(O)C>[CH2:6]([O:13][C:14](=[O:29])[NH:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:4]=[C:2]([CH3:3])[NH:5][CH:26]=2)=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NCCOc1ccc(C(=O)CBr)cc1)OCc1ccccc1
Reactant: CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)c[nH]1
Temperature: 80 °C
Yield: 67.1 %

Procedure:
Acetamidine hydrochloride (112 mg, 1.18 mmol), benzyl-[2-(4-bromoacetyl-phenoxy)-ethyl]-carbamate (160 mg, 0.39 mmol), and sodium ethoxide (80.3 mg, 1.18 mmol) were combined in a round-bottomed flask, dissolved in ethanol, and heated to about 80° C. for about two hours. The reaction mixture was then allowed to cool to room temperature, and the resulting heterogenous mixture was filtered. The filtrate was then concentrated in vacuo to an oil which was purified by column chromatography (silica gel; 5% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 92 mg (64% yield) of the desired product. LRMS ([M+H]+)=352.2.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1cccc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2cccc(F)c2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a suspension of 5.86 g of magnesium in 25 ml of THF is slowly added a solution of 42.16 g of 1-bromo-3-fluorobenzene in 100 ml of THF so as to reach and then maintain reflux of the THF, and the mixture is left at reflux for 1 hour with stirring. After cooling to rt, a solution of 38 g of 1-benzyl-4-piperidinone in 175 ml of THF is then added dropwise and the mixture is refluxed for 1 hour. After cooling to rt, the reaction mixture is poured into ice and extracted with EtOAc, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 38 g of the expected product are obtained after crystallization from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[OH-].[NH4+:11]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH2:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: [NH4+]
Reactant: Cc1cc(Cl)nc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(N)nc(Cl)c1
Yield: 51 %

Procedure:
A solution of 2,6-Dichloro-4-methylpyridine (Chem. Mater., 2004, 16, 1564-1572, 30 g, 0.185 mol) in ammonium hydroxide (200 mL, 25% solution in water) was heated at 200° C. in a pressure vessel for 10 h. The reaction mixture was then concentrated under reduced pressure. The brown solid obtained was suspended in DCM for 30 min at 25-26° C. and filtered. Filtrate was concentrated under reduced pressure. Purification of the crude thus obtained by flash chromatography (20% ethyl acetate in pet ether) afforded the title compound as off-white solid (13.5 g, Yield 51%). LC/MS: M+(ESI): 142.7; 1H NMR (DMSO d6: 400 MHz) δ 6.34 (1H, s), 6.23 (2H, s), 6.15 (1H, s), 2.1 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](I)=[C:9]([CH2:11][O:12][CH3:13])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2=[C:20]([CH:36]=1)[O:21][CH2:22][C:23]1[CH:33]=[C:32]([CH:34]=[O:35])[CH:31]=[CH:30][C:24]=1/[C:25]/2=[C:26](/[CH3:29])\[C:27]#[N:28]>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:34]([OH:35])[C:32]3[CH:31]=[CH:30][C:24]4/[C:25](=[C:26](/[CH3:29])\[C:27]#[N:28])/[C:19]5[CH:18]=[CH:17][C:16]([F:15])=[CH:36][C:20]=5[O:21][CH2:22][C:23]=4[CH:33]=3)=[C:9]([CH2:11][O:12][CH3:13])[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCc1nc2c(Cl)cccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: COCc1nc2c(Cl)cccn2c1C(O)c1ccc2c(c1)COc1cc(F)ccc1/C2=C(\C)C#N
Yield: 54 %

Procedure:
[step 4] Using 8-chloro-3-iodo-2-(methoxymethyl)imidazo[1,2-a]pyridine (500 mg, 1.55 mmol) obtained in step 3 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (227 mg, 0.775 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8F, step 4, (E)-2-(8-{[8-chloro-2-(methoxymethyl)imidazo[1,2-a]pyridin-3-yl](hydroxy)methyl}-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (205 mg, 54%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[N:12][NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C(=O)([O-])O.[Na+].ClCCl>C(#N)C>[Cl:21][C:10]1[N:11]=[N:12][C:13]([C:14]([F:17])([F:16])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(F)cc2)c(C(F)(F)F)n[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Fc1ccc(-c2cc(Cl)nnc2C(F)(F)F)cc1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a stirred solution of 5-(4-fluorophenyl)-6-trifluoromethyl-2H-pyridazine-3-one (D6) (0.96 g, 3.7 mmol) in acetonitrile (10 ml) was added phosphorous oxychloride (0.866 ml, 9.3 mmol) and the reaction was stirred at 180° C. for 30 min., under microwave irradiation. After this period, the reaction mixture was poured into a saturated solution of sodium hydrogen carbonate, ice and dichloromethane. Further solid sodium hydrogen carbonate was then added until gas evolution had ceased. The organic layer was then separated, dried (Na2SO4) and the solvents evaporated in vacuo to yield D7 (0.81 g, 79%). Only traces of the undesired isomer were detected after work-up. C11H5ClF4N2 requires 276; Found 277 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:35](CC)[CH2:36]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10](=[O:11])[N:35]([CH3:36])[CH3:33])=[CH:15][CH:16]=1
Reactant: COC(=O)CCc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Temperature: 25 °C

Procedure:
The hydrogenated compound 60 (2.2 g, 4.96 mmol) was dissolved in CH2Cl2 and stirred at room temperature under an atmosphere of argon. Triethylamine (0.829 mL, 5.95 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 2.413 g, 5.456 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 12.4 mL, 24.8 mmol) was added and the resulting solution was stirred at room temperature for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (100 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×50.0 mL) and brine (1×50.0 mL). Drying and concentration of the organic layer gave the desired amide crude (1.2 g, ˜98%). Flash chromatography on silica gel (methanol-chloroform 1%-2%) yielded the desired amide 75(0.8 g 98%) 1H NMR (400 MHz, DMSO-d6): 7.32 (dd, J=7.6 and 2 HZ, 1H), 7.21 (m, 3H), 7.08 (dd, J=14 and 7.2 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 6.75 (d, J=8.0 Hz, 1H), 4.53 (m, 1H) 3.55 (s, 3H), 2.89 (s, 3H), 2.85-2.58 (m, 7H), 2.59 (t, J=7.6 Hz, 2H), 1.31 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH:31]=[O:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1>C1COCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:3][C:2]=1[CH:31]([OH:32])[C:27]1[CH:26]=[C:25]2[C:30](=[CH:29][CH:28]=1)[N:21]=[CH:22][CH:23]=[N:24]2
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(Br)c1
Reactant: O=Cc1ccc2nccnc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc(F)c(C(O)c2ccc3nccnc3c2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of N-(3-bromo-4-fluorophenyl)pivalamide (9.48 g, 34.6 mmol, 1.2 eq.) in THF (100 mL) cooled at −78° C. was added n-BuLi (27.6 mL, 69 mmol, 2.4 eq.) dropwise. The resulting mixture was stirred at −78° C. for 1 h, then was added a solution of quinoxaline-6-carbaldehyde (4.5 g, 28.8 mmol, 1.0 eq.) in THF (200 mL) dropwise. The mixture was stirred at −78° C. for 1 h, then quenched by the addition of NH4Cl solution. The mixture was extracted with EA (100 mL ×3) and the combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=1/1, v/v) to afford N-(4-fluoro-3-(hydroxy(quinoxalin-6-yl)methyl)phenyl)pivalamide as a yellow foam (5.16 g, 50.7%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10]>>[C:8]([NH:1][C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1)([CH:9]=[CH2:10])=[O:11]
Reactant: Cc1nc(N)cs1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1csc(C)n1

Procedure:
4-Amino-2-methylthiazole (prepared by hydrolysing 4-acetamido-2-methylthiazole) is treated with acryloylchloride to give the title compound.
Reaction SMILES: O[Li].O.[C:4]([O:8][C:9]([C@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)[C:12]([O:14]C)=[O:13])=[O:10])([CH3:7])([CH3:6])[CH3:5].C1COCC1>O>[C:4]([O:8][C:9]([C@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([F:24])[CH:18]=1)[C:12]([OH:14])=[O:13])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H](Cc1ccc(Cl)c(F)c1)C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(Cl)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
LiOH—H2O (0.6246 g, 14.88 mmol) was added to a solution of (R)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)propanoate (1.646 g, 4.961 mmol) in 1:1 THF:H2O (26 mL). The reaction mixture was stirred at room temperature for 2 hours, after which it was diluted with H2O and washed with EtOAc. The aqueous layer was then acidified with solid KHSO4 and extracted with DCM. The combined extracts were dried (Na2SO4), filtered, concentrated, and then re-concentrated from DCM/hexanes to give (R)-2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)-propanoic acid (1.31 g, 83.10% yield) as a white powder. LCMS (APCI) m/z 316 [M−H]−.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][C@@H:34]([CH3:38])[CH2:33]2)=[CH:28][CH:27]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=3)[CH2:33][C@@H:34]2[CH3:38])=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: C[C@H]1CN(c2ccc(Cl)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)C[C@@H]1C

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chlorophenyl)-3-(S)-methylpiperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 300 MHz) 7.25 (d 2H), 6.83 (d, 2H), 4.91 (m, 3H), 4.28 (m, 1H), 3.80–3.10 (m, 4H), 2.86 (m, 1H), 2.71 (m, 1H), 2.29 (s, 3H), 1.40 (m, 3H) ppm; MS (ES) M+H expected=435.1, found=435.0.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.CC1(C)C(C)(C)[O:36][B:35]([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[O:34]1.[CH3:48][N:49]([CH3:53])[CH2:50][CH2:51]O>C(Cl)Cl>[CH3:48][N:49]([CH2:50][CH2:51][O:46][C:43]1[CH:42]=[CH:41][C:40]([B:35]([OH:34])[OH:36])=[CH:45][CH:44]=1)[CH3:53]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CN(C)CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(B(O)O)cc1
Reaction time: 1 h

Procedure:
To a suspension of solid-supported triphenylphosphine (30.0 g, 30.0 mmol) in DCM (150 mL) was added DEAD (3.93 mL, 25.0 mmol) dropwise via a syringe at room temperature. The reaction mixture was stirred for 1 hr, and then a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenol (4.40 g, 20.0 mmol) and 2-(dimethylamino) ethanol (2.01 mL, 20.0 mmol) in DCM (30 mL) was introduced. The reaction mixture was stirred at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting with 95:5, DCM/MeOH) to afford 4-dimethylaminoethoxyphenyl boronic acid, pinacol ester (2.25 g) as an yellow oil. MS (MH+) 292.4; Calculated 29 for C16H26BNO3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]([NH2:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:19][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=O)C(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCC(c1ccccc1)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
To a stirred solution of the crude 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropanamide in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into brine (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 50 mg (65% yield, 3 steps) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,3-diphenylpropan-1-amine
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3]>CO.[OH-].[K+].O>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[O:18][CH:19]=[C:20]([CH3:22])[N:21]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:24][CH3:25]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nc(C)co2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nc(C)co2)c1
Yield: 97.9 %

Procedure:
A solution of methyl 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoate (118 mg, 0.34 mmol) in methanol (1 mL) and potassium hydroxide (1 mL of a 1.0 M solution in water, 1 mmol) was stirred at room temperature for 45 min. The solvent was removed under reduced pressure, the residue was dissolved in water, extracted with ethyl acetate, the aqueous layer was acidified to pH 4 with 1 N hydrochloric acid, extracted with chloroform (3×100 mL), and the combined organics were concentrated under reduced pressure to afford 3-[(dipropylamino)carbonyl]-5-(4-methyl-1,3-oxazol-2-yl)benzoic acid (110 mg): 1H NMR (300 MHz, CD3OD) δ 8.66 (d, J=1 Hz, 1H), 8.17 (d, J=1 Hz, 1H), 8.07 (d, J=1 Hz, 1H), 7.75 (d, J=1 Hz, 1H), 3.51 (t, J=7 Hz, 2H), 3.25 (t, J=7 Hz, 2H), 2.23 (s, 3H), 1.74 (d, J=7 Hz, 2H), 1.60 (d, J=7 Hz, 2H), 1.01 (t, J=7 Hz, 3H), 0.76 (t, J=7 Hz, 3H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].I[CH2:21][CH2:22][CH:23]1[O:30][CH2:29][CH2:28][O:27][CH:24]1[CH2:25]I>C1COCC1>[CH2:29]1[CH2:28][O:27][C:23]2([CH2:24][CH2:25][C:1]3([C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[CH2:21][CH2:22]2)[O:30]1
Reactant: C1=Cc2ccccc2C1
Reactant: ICCC1OCCOC1CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCC21CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of indene (0.84 g, 7.3 mmol) in THF at 0° C. was added lithium bis(trimethylsilyl)amide (14.6 ml, 14.6 mmol). After 30 minutes of stirring the anion was cannulated into a solution of 1,5-diiodo-3-ethylenedioxypentane (2.79 g, 7.3 mmol) prepared as described in J. Am. Chem. Soc. 1990, 9001-9003). The reaction mixture was stirred for 1 h and then warmed to room temperature over night. The reaction mixture was concentrated and purified by flash chromatography (silica gel, hexane/ethyl acetate 10:1) to give the title compound (1.2 g, 4.9 mmol).
Reaction SMILES: [C:1]12([C:11]34[CH2:20][CH:15]5[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]5)[CH2:12]3)[CH2:18]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:22]12CC3CC(CC(C45CC6CC(CC(C6)C4)C5)(C3)[CH2:23]1)C2>>[CH:22]([C:5]12[CH2:6][CH:7]3[CH2:9][CH:3]([CH2:2][C:1]([C:11]45[CH2:18][CH:17]6[CH2:19][CH:13]([CH2:14][CH:15]([CH2:16]6)[CH2:20]4)[CH2:12]5)([CH2:8]3)[CH2:10]1)[CH2:4]2)=[CH2:23]
Reactant: BrC12CC3CC(C1)CC(C14CC5CC(CC(C5)C1)C4)(C3)C2
Reactant: C1C2CC3CC1CC(C14CC5CC(CC(C5)C1)C4)(C2)C3
Product: C=CC12CC3CC(C1)CC(C14CC5CC(CC(C5)C1)C4)(C3)C2

Procedure:
Biadamantane is brominated into 3-bromo-1,1′-biadamantane. In accordance with the synthesis process shown in Example 12, Exemplified compound (D-101) (3-vinyl-1,1′-biadamantane) is obtained as a target product.