Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17](=[O:27])(=[O:26])[NH:18][CH:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC>>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([NH:18][S:17]([C:4]2[S:3][CH:2]=[C:6]([C:7]3[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=3[CH3:16])[CH:5]=2)(=[O:26])=[O:27])[CH2:20][CH2:21]1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NC3CCC(O)CC3)sc2Br)s1
Agent: [Li]CCCC
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N[C@H]3CC[C@@H](O)CC3)c2)s1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
N-{5-[2-Bromo-5-(4-hydroxy-cyclohexylsulfamoyl)-thiophen-3-yl]-4-methyl-thiazo-2-yl}-acetamide obtained in Step I as described above (120 mg; 0.24 mmol; 1 eq), is dissolved anhydrous TBF (10 ml). The reaction mixture is cooled down to −70° C. and put under nitrogen. n-Butyllithium (1.5 ml; 1.6 M; 2.43 mmol; 8 eq) is added dropwise. The reaction is stirred overnight and quenched with water. Solvents are evaporated and the resulting crude product is purified by preparative HPLC, affording Compound (33) as white-off powder (28 mg; 21%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].Cl[CH2:15][CH2:16][N:17]([CH2:25][CH2:26]Cl)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>CS(C)=O>[C:21]([O:20][C:18]([N:17]1[CH2:25][CH2:26][C:11]([C:12]#[N:13])([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:15][CH2:16]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc3ccccc3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine naphth-2-ylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol) in DMSO (30 mL). Add portionwise, NaNH2 (22 mmol). After the addition, stir for an additional 0.5 h. Pour the contents of the flask over ice (150 g). Extract the mixture with dichloromethane. Dry the organic phase over MgSO4, filter, and concentrate in vacuo to give a residue. Purify to give the title compound.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][C:7]=1[OH:13].C([O-])(=O)C.[Na+]>B(F)(F)F.CCOCC>[Cl:5][C:6]1[C:7]([OH:13])=[CH:8][C:9]([OH:10])=[C:11]([C:1](=[O:4])[CH3:2])[CH:12]=1
Reactant: CC(=O)O
Reactant: Oc1ccc(Cl)c(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)c(O)cc1O
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 58 %

Procedure:
Acetic acid (17.5 mL) was added dropwise to a suspension of 4-chlororesorcinol (42.5 g, 0.293 mmol) in boron trifluoride etherate (200 mL) under a nitrogen atmosphere. The reaction mixture was heated at 90° C. for 3.5 hours and then allowed to cool to room temperature. A solid had formed after around 1 hour of cooling. The mixture was poured into 700 mL of a 10% w/v aqueous sodium acetate solution. This mixture was stirred vigorously for 2.5 hours. A light brown solid had formed which was filtered, washed with water and air-dried overnight to afford 1-(5-chloro-2,4-dihydroxy-phenyl)-ethanone (31.6 g, 58%). LCMS: [M-H]+185.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.[C:30]1(=[CH:34][C:35]#[N:36])[CH2:33][CH2:32][CH2:31]1.N12CCCN=C1CCCCC2>C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([C:30]5([CH2:34][C:35]#[N:36])[CH2:33][CH2:32][CH2:31]5)[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: N#CC=C1CCC1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CN(C2(CC#N)CCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
To a solution of 1-[(1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (10 mg, 0.022 mmol, chiral intermediate from Example 1, Step 7) in acetonitrile (0.1 mL) was added cyclobutylideneacetonitrile (4.1 mg, 0.044 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (13 μL, 0.087 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with acetonitrile and purified by preparative RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (4.3 mg, 41%). The product was isolated as a single enantiomer. LCMS calculated for C25H31ClN7O (M+H)+: m/z=480.2; Found: 480.0.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.S(Cl)(Cl)=O>O>[CH3:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cnc2ccccc2c1
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1cnc2c(S(=O)(=O)Cl)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
The title compound was prepared according to the procedure of U.S. Pat. No. 5,332,822. To 9 mL (135 mmol) of chlorosulfonic acid at 0° C. was added slowly 3-methylquinoline (5.2 g, 36 mmol). The bath was removed and stirring was continued at 100° C. overnight. The reaction mixture was cooled to ambient temperature and then treated with 3.3 mL (45 mmol) of thionyl chloride. The reaction mixture was heated at 70° C. for 1 h, cooled to 0° C. and carefully quenched with ice (very vigorous reaction). The reaction mixture was diluted with 100 mL of water and extracted into dichloromethane (100 mL). The organic phase was washed with water, dried (MgSO4) and concentrated. The residue was triturated with dichloromethane/diethyl ether to provide 1.58 g (18%) of the title compound as a tan solid. 1H-NMR (300 MHz, DMSO-d6) δ9.17-9.29 (m, 2H), 8.32-8.38 (m, 2H), 7.96 (dd, 1H, J=7 Hz), and 2.51 (t, 3H, J=2 Hz).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=O)[CH2:2][CH3:3].C[O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=1>>[CH2:8]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:13]([OH:23])=[O:12])=[CH:17][CH:18]=1)=[O:7])[CH2:9][CH3:10]
Reactant: COC(=O)C=Cc1ccc(N)cc1
Reactant: CCCC(CCC)C(=O)O
Product: CCCC(CCC)C(=O)c1ccc(C=CC(=O)O)cc1

Procedure:
This compound, a precursor to compounds 9 and 10, was synthesized from 2-propyl-pentanoic acid (0.78 mL, 4.9 mmol) and 3-(4-amino-phenyl)-acrylic acid methyl ester (0.86 g, 4.9 mmol) according to Methods a and b aforementioned. Total yield, 1.05 g (70% for 2 steps); 1H NMR (CDCl3, 10% DMSO-d6) δ 9.49 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.55 (d, J=15.9 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 6.31 (d, J=15.9 Hz, 1H), 2.40 (m, 1H), 1.7-1.1 (m, 8H), 0.87 (t, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:12]=2[CH3:19])=[C:8]([CH3:10])[CH:9]=1)=[O:4].B(Br)(Br)Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:19])=[C:8]([CH3:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)cc2C)s1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(-c2ccc(O)cc2C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 5-(4-methoxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acid methyl ester (540 mg, 2 mmol) in dichloromethane (30 mL) at 0° C. is added BBr3 in dichloromethane (1N, 5.0 mL). The mixture is stirred at ambient temperature overnight. The reaction is quenched by addition of methanol and is evaporated. The residue is purified by column chromatography (0-20% EtOAc in hexanes) to give 5-(4-hydroxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acid methyl ester (420 mg, 82%). 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.10 (d, 1H, J=7.9 Hz), 6.76 (s, 1H), 6.70 (d, 1H, J=7.9 Hz), 4.79 (bs, 1H), 3.88 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[C:16](=O)[C:15]3[C:14]([C:18]([O:20]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][N:4]=[CH:3]1.O.[NH2:30][NH2:31]>CO>[CH3:1][N:2]1[C:6]([CH:7]2[C:16]3=[N:30][NH:31][C:18](=[O:20])[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([C:15]=43)[NH:9][CH:8]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:5][N:4]=[CH:3]1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1cncn1C)C(c1ccccc1)N2
Solvent: O
Solvent: CO
Product: Cn1cncc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
A mixture of ethyl 3-(1-methyl-1H-imidazol-5-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (170 mg) in 85% hydrazine monohydrate (3 mL) and methanol (3 mL) was stirred at room temperature for 5 h. Filtered and washed the cake by methanol (2 mL) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain 9-(1-methyl-1H-imidazol-5-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (70 mg, yield 46%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.50 (s, 3H), 4.52-4.54 (d, J=9.2 Hz, 1H), 4.83-4.85 (d, J=9.2 Hz, 1H), 6.66 (s, 1H), 7.17-7.19 (d, J=7.6 Hz, 1H), 7.25-7.32 (m, 3H), 7.36-7.44 (m, 5H), 7.56-7.60 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 348 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30]C(=O)C1C=C(C)C=CC=1O)[CH2:18][CH2:17]2>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH2:20][N:19]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:11])[CH:9]=[CH:10][C:2]=1[OH:1])[CH2:18][CH2:17]2
Reactant: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(C)ccc1O)CC2
Reactant: O=C(O)c1cc(I)ccc1O
Product: COc1cc2c(cc1OC)CN(CCCCNC(=O)c1cc(I)ccc1O)CC2

Procedure:
Compound 2e was prepared form 2-hydroxy-5-iodo-benzoic acid and 1b as described above for 2a. The yield of 2c was 27.0%. The 1H-NMR spectrum (300 MHz, CDCl3) of the purified product was: 1.69-1.81 (m, 4H), 2.54-2.65 (m, 2H), 2.75-2.83 (m, 2H), 3.44-3.48 (m, 2H), 3.58 (s, 2H), 3.82 (s, 3H), 3.85 (s, 3H), 6.50 (s, 1H), 6.58 (s, 1H), 6.70-6.74 (d, 1H), 7.54-7.55 (d, 1H), 7.65-7.67 (d, 1H), 8.20 (s, 1H). Anal. (C22H27IN2O4.0.75H2O) C, H, N.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1)([CH3:5])[CH3:4].[H-].[Na+].F[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(O)(=O)C>[CH3:4][C:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=1)([CH3:5])[CH2:2][O:1][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([N+:33]([O-:35])=[O:34])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)CO)ccn1
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cc(C(C)(C)COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Yield: 67.4 %

Procedure:
To a stirred solution of the alcohol (59) (1.11 g, 4.17 mmol) in DMF (10.0 mL) at 0° C. under nitrogen was added sodium hydride (350 mg, 8.75 mmol) in a single portion. The mixture was warmed to RT for 30 min and was then sonicated, flushed with nitrogen and re-cooled to 0° C. A solution of 1-fluoro-4-nitronaphthalene (14) (797 mg, 4.17 mmol) in DMF (4.0 mL) was added over 5 min and the reaction mixture allowed to warm to RT and after 30 min glacial acetic acid (1.0 mL) was added. The reaction mixture was poured onto saturated aqueous NaHCO3 solution and extracted twice with EtOAc. The combined organic extracts were washed three times with water and with brine and then dried (MgSO4), and evaporated in vacuo. The residue was triturated from EtOAc and washed with ether (20 mL) to afford the title compound (60) as a yellow solid (1.23 g, 64%): m/z 438 (M+H)+ (ES+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C>[OH:10][CH2:9][C:7]1[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cn1nc([N+](=O)[O-])cc1CO
Temperature: 40 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with acetonitrile (30 mL), (3-nitro-1H-pyrazol-5-yl)methanol (1.43 g, 10.0 mmol), Cs2CO3 (490 mg, 1.5 mmol), and ethyl 2-bromoacetate (2.00 g, 12 mmol). The mixture was stirred at 40° C. for 5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 313a (1.65 g, 72%) as a yellow solid. MS-ESI: [M+H]+ 229.9
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:20][O:21]C(Cl)Cl>ClCCCl>[CH:20]([C:5]1[CH:4]=[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:2]([CH3:1])[CH:6]=1)=[O:21]
Reactant: CCOC(=O)c1cccn1C
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1cc(C=O)cn1C
Temperature: -30 °C
Reaction time: 16 h
Yield: 94 %

Procedure:
Ethyl 1-methyl-1H-pyrrole-2-carboxylate (3.69 g, 28.24 mmol; see step (ii) above) and AlCl3 (8.02 g, 60.11 mmol) were added to a solution of nitromethane (40 mL), and 1,2-dichloroethane (40 mL) at −30° C. Dichloromethyl methyl ether (2.5 mL, 28 mmol) in 1,2-dichloroethane (10 mL) was added rapidly to the solution and the mixture was allowed to stir at −30° C. for 16 h. The solution was then poured onto ice (50 g) and the layers were separated. The aqueous layer was then extracted with ether (50 mL). The combined organic fractions were dried (MgSO4), filtered and the solvent removed under reduced pressure, to yield the title compound as a crystalline brown/black solid (4.77 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)=[O:31])=[CH:26][CH:25]=1)=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(C(=O)N2CCCC2)cc1)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.39 g), 3-oxo-2-[4-(pyrrolidine-1-carbonyl)benzyl]pentanoic acid methyl ester (1.0 g), polyphosphoric acid (2 g) and dioxane (20 mL) was heated at 120° C. for 18 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (9:1 by volume) to afford title compound, 0.25 g.
Reaction SMILES: O.[ClH:2].[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[F:10].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.C(=O)(O)[O-].[Na+].Cl>C(O)C>[ClH:2].[ClH:2].[F:3][C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH:13]2[CH2:18][CH2:17][N:16]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=3)[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCNCC2)cc1
Reactant: BrCc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Fc1ccc(C(Nc2ccc(F)c(F)c2)C2CCN(Cc3ccc4ccccc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
A mixture of 3.10 g (7.5 mmol) of 4-[[(3,4-difluorophenyl)amino](4-fluorophenyl)methyl]piperidine hydrochloride hydrate, 1.70 g (7.7 mmol) of 2-bromomethylnaphthalene and 5.1 g (60.7 mmol) of sodium bicarbonate in 200 mL of absolute ethanol was stirred at room temperature for 20 h. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute NaOH. The organic phase was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected to flash chromatography (silica gel, elution with 1-4% MeOH in CH2Cl2) to give an oil. This was converted to the HCl salt, and the salt was recrystallized from a mixture of methanol and diethylether to give 1.53 g (38.3%) of the title compound as a crystalline solid, mp 187°-190° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22](O)[CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[N+:26]([C:25]1[CH:20]=[CH:21][C:22]([O:18][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:23][CH:24]=1)([O-:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
To a solution of N-tert-butoxycarbonylphenylalanine (53 g, 0.2 mol) and p-nitrophenol (27.8 g, 0.2 mol) in ethyl acetate (200 ml) in an ice-water bath was dropwise added a solution of N,N'-dicyclohexylcarbodiimide (41.2 g, 0.2 mol) in ethyl acetate (100 ml), and the mixture was stirred in an ice-water bath for 3 hours and then at room temperature for 20 hours. The precipitated N,N'-dicyclohexylcarbodiurea was filtered off and the filtrate was concentrated under reduced pressure. The residue thus obtained was recrystallized from ethyl acetate-hexane to give N-tert-butoxycarbonylphenylalanine p-nitrophenyl ester [61.7 g, 80% (% by weight, hereinafter the same)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28]Br)[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH3:32][NH:33][CH3:34]>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[C:13](=[O:31])[NH:14][C:15](=[O:30])[C:16]=2[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:26][CH2:27][CH2:28][N:33]([CH3:34])[CH3:32])[CH:18]=2)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: COc1cc(C2=C(c3cn(CCCBr)c4ccccc34)C(=O)NC2=O)c2occc2c1
Reactant: CNC
Solvent: CN1CCCC1=O
Product: COc1cc(C2=C(c3cn(CCCN(C)C)c4ccccc34)C(=O)NC2=O)c2occc2c1
Temperature: 60 °C

Procedure:
Dissolve 3-(5-methoxybenzofur-7-yl)-4-[1-(3-hydroxypropyl)-1H-indol-3-yl]pyrrole-2,5-dione (0.058 g, 0.118 mmol) in 10 mL dichloromethane. Add carbon tetrabromide (0.077 g, 1 equivalent) and triphenyl phosphine (0.061 g, 1 equivalent). Stir for 10 min, add another equivalent of both reagents. Stir 10 min then dilute with dichloromethane and wash with water followed by brine. Dry over magnesium sulfate then filter and concentrate. Purification by column chromatography (2% methanol:dichloromethane) affords the 3-(5-methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl)pyrrole-2,5-dione. 3-(5-Methoxybenzofur-7-yl)-4-[1-(3-bromopropyl)-1H-indol-3-yl]pyrrole-2,5-dione is dissolved in 1.5 mL 1-methyl-2-pyrrolidinone and add dimethylamine (2M solution in tetrahydrofuran, 0.3 mL, 5 equivalents). Heat to 60° C. for 16 hrs. Extract with ethyl acetate versus water, concentrate organic layer. Redissolve in a minimal amount of methanol and load onto an SCX™ Varian column (pretreated with a 5% acetic acid: methanol solution). Wash with methanol and ethyl acetate to remove impurities, flush with 2M ammonia methanol to recover product. ES(M++H)444.0.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]>ClCCl>[CH2:5]([C@H:10]1[CH2:11][CH2:12][C@H:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[CH2:14][CH2:15]1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OC)cc2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(O)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
A solution of 2.6 g of boron tribromide in 50 ml of absolute dichloromethane was treated dropwise at 0° C. with a solution of 2.0 g of 2-(trans-4-pentylcyclohexyl)-1-(4-methoxyphenyl)ethane in 50 ml of absolute dichloromethane. The mixture was stirred for 1 hour and then poured into ice-water. The organic phase was separated and the aqueous phase was back-extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the resulting crude product from hexane at 0° C. gave 1.8 g of 4-[2-(trans-4-pentylcyclohexyl)ethyl]phenol of m.p. 102°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:41])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:19][C:13]=3[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)[C:11]2=[O:40])=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:41])[CH2:9][N:10]2[C:15](=[O:16])[C:14]3[CH:17]=[C:18]([CH2:20][C:21]([F:24])([F:23])[F:22])[S:19][C:13]=3[N:12]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)[C:11]2=[O:40])=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(Cn2c(=O)n(CC(O)c3ccc(F)cc3)c(=O)c3cc(CC(F)(F)F)sc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
To a mixture of 4′-{[3-[2-(4-fluorophenyl)-2-oxoethyl]-2,4-dioxo-6-(2,2,2-trifluoroethyl)-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.9 g), tetrahydrofuran (20 mL) and methanol (20 mL) was added sodium borohydride (0.19 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate and saturated aqueous ammonium chloride solution. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless oil (0.41 g, 45%).