Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C:62]1[C:63]([CH3:77])=[CH:64][C:65]([NH:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[N:66][C:67]=1[CH3:68]>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:60][CH2:61][C:62]2[C:67]([CH3:68])=[N:66][C:65]([NH:69][C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71])=[CH:64][C:63]=2[CH3:77])=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (25 mg, 73 μmol), as prepared in step 15 of Example 1, in DMF (0.25 mL) was added BOP (52 mg, 116 μmol), a solution of DIEA (38 mg, 295 mol) in DMF (0.1 mL), and N-[5-(aminomethyl)-4,6-dimethyl(2-pyridyl)](tert-butoxy)carboxamide (23 mg, 91 μmol) (Sanderson, P. E., et al. WO 97/01338 (1997)). After stirring at ambient temperature for 2 days, additional amine (7 mg, 28 μmol) BOP (16 mg, 36 μmol), and DIEA (9 mg, 70 μmol) were added, and the mixture was stirred for another 16 hours. The solvents were evaporated, and the resulting residue was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with 10% citric acid, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1, 2%) to produce the title compound (18.5 mg, 44% yield) as a pale brown solid. 1H-NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.50-7.41 (m, 5H), 7.24 (s, 1H), 6.98 (dd, J=8.8, 1.1 Hz, 1H), 6.55 (t, J=9.0 Hz, 1H), 5.33 (bs, 1H), 4.40 (d, J=4.7 Hz, 2H), 4.24-4.20 (m, 1H), 3.78-3.70 (m, 4H), 2.39 (s, 3H), 2.28 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calcd for C29H33ClF3N4O3 (M+H): 577.0. Found: 577.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([O:31]CC)=O)[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:35][NH2:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29]([NH:36][CH3:35])=[O:31])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine using methods similar to Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.10 (1H, b), 8.53 (1H, s), 8.15 (1H, s), 7.37 (2H, dd, J=6, 8 Hz), 7.11 (2H, t, J=9 Hz), 4.34 (2H, t, J=7 Hz), 4.12 (2H, s), 3.46 (2H, t, J=7 Hz), 3.22 (2H, t, J=6 Hz), 2.88 (3H, d, J=5 Hz), 2.01 (2H, t, J=7 Hz), 1.48-1.62 (4H, m); ES+ MS: 553 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:5]2[S:10][C:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)O1>>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[C:5]4[S:10][C:9]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CCC(=O)Nc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CCC(=O)Nc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
The crude N-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propionamide (42 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 19.8 mg of 162. MS (Q1) 409 (M)+
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH2:9][O:10][CH:11]([CH3:13])[CH3:12])[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1CCN2C(=NCCC2)CC1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(#N)C>[CH:11]([O:10][CH2:9][C:4]1[CH:5]=[C:6]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)[N:7]=[C:2]([NH2:1])[N:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)OCc1cc(=O)[nH]c(N)n1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)OCc1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 14 %

Procedure:
To a solution of 2-amino-6-isopropoxymethyl-3H-pyrimidin-4-one (0.050 g, 0.27 mmol) in acetonitrile (2.37 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.157 g, 0.355 mmol), DBU (0.82 mL, 0.55 mmol), and 1-methyl-piperazine (0.091 ml, 0.82 mmol). The reaction mixture was stirred at rt for 12 h, then at 60° C. for 3 h. The mixture was concentrated and the resultant residue was purified (2 M NH3 in MeOH/CH2Cl2) to yield a white solid (10 mg, 14%). MS (ESI): mass calcd. for C13H23N5O, 265.4; m/z found, 266.3 [M+H]+. 1H NMR (MeOD): 6.55 (s, 1H), 4.49 (s, 2H), 3.78 (quintet, J=6.1, 1H), 3.70-3.00 (m, 8H), 2.95 (s, 3H), 1.25 (d, J=6.1, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[C:12]([C:14](O)=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].CO>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[C:12]([CH2:14][OH:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)O)c(C2(C)CC2)s1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(CO)c(C2(C)CC2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
Dissolve 2-tert-butoxycarbonylamino-5-(1-methyl-cyclopropyl)-thiazole-4-carboxylic acid (2 g, 6.7 mmol) in THF (100 mL) and cool to 0° C. under nitrogen. Add triethylamine (0.93 mL, 1 equiv.) followed by the dropwise addition of isobutyl chloroformate (0.87 mL, 1 equiv.). Stir 30 minutes at 0° C. then filter, washing with THF. Cool filtrate back to 0° C. then add sodium borohydride (0.76 g, 3 equiv.) in one sum followed by the dropwise addition of methanol (4.1 mL, 15 equiv.). After 45 minutes at 0° C. remove cooling bath and let warm to room temperature for 15 minutes. Quench reaction (cautiously) with 1 N HCl (aq), approximately 50 mL. Extract with DCM. Wash organics with aqueous saturated sodium chloride. Dry organics over MgSO4 then filter and concentrate. Purify on silica gel (2:1 Hexanes:Ethyl Acetate→1:1 Hexanes:Ethyl Acetate) to give a white solid (1.11 g, 58%). LCMS (ES), m/z 229 (M+1, product→t Butyl).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].Cl.[NH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1C=CC=CC=1.O>ClCCl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([NH:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
180 mg of 4-nitrophenyl chloroformate was dissolved in 3.0 ml of dichloromethane, and 140 mg of ethyl 3-aminopropanoate hydrochloride and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and then concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was obtained. 180 mg of ethyl 3-{[(4-nitrophenoxy)carbonyl]amino}propanoate was dissolved in 2.0 ml of dichloromethane, and 220 mg of 3-amino-7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoroquinolin-4(1H)-one and 0.15 ml of pyridine were added, followed by overnight stirring at room temperature. Water was added, followed by extraction with chloroform. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then filtered and concentrated under a reduced pressure. By purifying the resulting residue by silica gel column chromatography, 120 mg of ethyl 3-[({[7-(cyclohexylamino)-1-(1-ethylpropyl)-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]amino}carbonyl)amino]propanoate was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[CH2:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH2:30][CH2:29][NH:28][CH2:27]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:30]1[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH2:26][CH2:27][N:28]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:24])[CH2:29]1
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2ccccc2CC1

Procedure:
100.0 mg (0.29 mmol) 6-[4-(2-oxo-2,3-dihydro-imidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 50.0 mg (0.34 mmol) 2,3,4,5-tetrahydro-1H-3-benzazepine, 100 μL (0.71 mmol) triethylamine and 100.0 mg (0.31 mmol) TBTU in 1.5 mL DMF were stirred overnight at RT. The reaction mixture was filtered through a syringe filter and the solution was purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9]C.[CH3:11][O:12][CH:13](Cl)Cl>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([CH3:1])[C:13]([O:12][CH3:11])=[C:4]([CH:5]=1)[CH:3]=[O:9]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(Cl)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)cc(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Titanium tetrachloride (21.6 g, 0.114 mole) was added to a solution of 2-methyl-4-chloroanisole (9 g, 0.057 mole) in methylene chloride at 0° C. Then, 1,1-dichloromethyl methyl ether (7.24 g, 0.063 mole) was added dropwise over a three minute period and the reaction mixture stirred at 0° C. for 30 minutes. The reaction was quenched by carefully pouring it into water (600 ml). The organic layer was separated and the aqueous phase extracted with methylene chloride (2×100 ml). The combined organic layer and extracts was washed with brine, dried (MgSO4) and concentrated under reduced pressure to a pale yellow solid (10.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:6][CH2:7][NH2:8].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C=O.[CH2:24](O)C>[Pd].C(O)C.C(Cl)Cl>[CH2:14]([N:8]([CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCO
Reactant: COc1ccc(CCN)cc1OC
Agent: [Pd]
Agent: C=O
Solvent: ClCCl
Product: COc1ccc(CCN(C)Cc2ccccc2)cc1OC

Procedure:
In the first step 3,4-dimethoxyphenethylamine, benzaldehyde and formaldehyde are hydrogenated in the presence of a catalyst, e.g. palladium on carbon, either at normal or slightly elevated pressure, preferably a pressure of 2-3 atm (0.2-0.3 MPa), and the temperature is room temperature or slightly elevated temperature, preferably 20°-30° C. As solvent is used an organic solvent, e.g. ethanol or an ethanol-methylenechloride (1:1)-mixture. The desired product, N-benzyl-N-methyl-3,4-dimethoxyphenethylamine (II) is obtained in a very pure state, when it is precipitated as an acid addition salt, e.g. hydrobromide. As free base the product is oily and difficult to handle.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[H][H]>C(O)C.[Pd]>[NH2:12][C:4]1[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]c(=O)oc12
Temperature: 45 °C
Yield: 94 %

Procedure:
107.5 g (1 mole) of 5-chloro-7-nitro-2(3H)-benzoxazolone prepared according to Example 1d was suspended in 1000 ml of ethanol. 9.25 g of Pd/C 5% and 50 ml of ethanol were added and the mixture was hydrogenated at 4 bar hydrogen pressure for four to six hours at 60-65° C. while vigorously stirring. When the hydrogenation was complete, the mixture was cooled to 45° C. and filtered over Hyflo®. The Hyflo®) was washed twice with 175 ml of methanol. 500 ml of solvent was distilled off under reduced pressure at 50° C., followed by addition of 250 ml of water and removal of 300 ml of solvent was by distillation under reduced pressure at 50° C. The last procedure was repeated twice and finally 250 ml of water was added and 400 ml of solvent was distilled of. The resulting mixture was cooled to 0-5° C. in about one hour. The solid was filtered off and, washed three times with 125 ml of cold water, and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 94%.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:16][C:17](=O)[CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=O)OC.O.[NH2:25][NH2:26]>>[CH3:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]1[CH:16]=[C:3]2[C:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)=[N:26][N:25]=1
Reactant: COP(=O)(CC(=O)CC(C)(C)C)OC
Reactant: NN
Reactant: O=C1C(=O)C2CCC1C2
Solvent: O
Product: CC(C)(C)Cc1cc2c(nn1)C1CCC2C1

Procedure:
light-yellow solid. MS (ESI): 217.2 (MH+). Prepared from bicyclo[2.2.1]heptan-2,3-dione, (4,4-dimethyl-2-oxo-pentyl)-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:11])[NH2:10].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[CH:15][N:14]=1.N>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:10][C:13]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:11]
Reactant: CC(N)c1c(Cl)cccc1Cl
Reactant: N#Cc1cccnc1Cl
Agent: N
Solvent: CC(=O)N(C)C
Product: CC(Nc1ncccc1C#N)c1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 20 h
Yield: 41.1 %

Procedure:
A mixture of 2,6-dichloro-α-methylbenzenemethanamine (0.03 mol) and 2-chloro-3-pyridinecarbonitrile (0.03 mol) in N,N-dimethylacetamide (few drops) was stirred for 20 hours at 90° C. The reaction mixture was cooled and poured out into aqueous ammonia. The mixture was extracted twice with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2C2 /hexane 50/50). The pure fractions were collected and the solvent was evaporated, yielding 3.6 g (±)-2-[[1-(2,6-dichlorophenyl)ethyl]amino]-3-pyridinecarbonitrile (41.4%); mp. 84.4° C. (comp. 9).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C@:14]([CH3:24])([CH2:21][CH2:22][OH:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].N1C=CC=CC=1.C.C(OC1C(C)=C2C(=C(C)C=1C)O[C@](C)(CCO)CC2)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:26][S:27]([O:23][CH2:22][CH2:21][C@:14]1([CH3:24])[CH2:13][CH2:12][C:11]2[C:16](=[C:17]([CH3:20])[C:18]([CH3:19])=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:10]=2[CH3:25])[O:15]1)(=[O:29])=[O:28]
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CCO)O2
Reactant: CS(=O)(=O)Cl
Agent: C
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC[C@@](C)(CCOS(C)(=O)=O)O2
Temperature: 0 °C

Procedure:
A solution of 0.5 g. (1.47 mmoles) of (S)-(-)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol and 0.25 ml. (0.37 g.; 3.2 mmoles) of methanesulfonyl chloride in 5 ml. of anhydrous pyridine was kept at 0° C. for 45 hours then poured into 100 ml. of ice-water and the resulting mixture was stirred for 15 minutes. The mixture was then extracted three times with ether and the combined ether extracts were washed with cold 1 N aqueous HCl followed by water and saturated brine. After drying and filtration, the ether extracts were concentrated in vacuo giving 0.587 g. (95.6%) of (S)-6-benzyloxy-2,5,7,8-tetramethylchroman-2-ethanol methane as a colorless solid, m.p. 81°-83° C.; [α]25D-0.36° (c 0.82, C6H6).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[CH2:14]1.Cl[Si:33]([CH3:36])([CH3:35])[CH3:34]>CCCCCC.O1CCCC1>[O:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][C:28]([O:31][Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH2:30]2)[CH2:14]1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCN(CCC2COc3ccccc3C2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)OC1=CCN(CCC2COc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
17.4 ml of n-butyllithium in hexane are added at 0°-5° to a solution of 2.81 g of diisopropylamine in 30 ml of dry tetrahydrofuran. The whole is stirred for 30 minutes at room temperature, then cooled to -15° and a solution of 6.24 g (25 mmol) of 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine in 30 ml of tetrahydrofuran is added. After 15 minutes, a solution of 3.05 g (28 mmol) of chlorotrimethylsilane in 15 ml of tetrahydrofuran is added dropwise. The whole is stirred overnight at room temperature, the solution is filtered and the filtrate is concentrated to dryness by evaporation under reduced pressure. 1-[2-(chroman-3-yl)ethyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydropyridine is thus obtained in the form of a pale yellow oil. 6.63 g (20 mmol) of the 1-[2-(chroman-3-yl)ethyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydropyridine obtained are dissolved in 50 ml of dichloromethane and the solution is added dropwise to a solution, cooled to 0°, of 2.3 g (24 mmol) of chloroformic acid methyl ester and 60 mg (2.4 mmol) of anhydrous zinc bromide in 50 ml of absolute dichloromethane. After warming up to room temperature, the reaction solution is stirred for one hour and then poured onto 150 ml of saturated sodium hydrogen carbonate solution. Extraction is carried out with dichloromethane, and the combined organic phases are dried over sodium sulphate and then concentrated by evaporation. The residue is dissolved in 70 ml of ethanol and the solution is acidified with ethanolic hydrochloric acid. After adding diethyl ether and after cooling, 1-[2-(chroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride, respectively, having a melting point of 175°-177° crystallises out.
Reaction SMILES: [C:1]([C:9]1[O:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:32][C:33](=[O:43])[CH:34]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)O>>[C:1]([C:9]1[O:10][C:11]2[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:34]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:33]([OH:43])=[O:32])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: O=C(c1ccccc1)c1oc2ccccc2c1-c1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-benzoyl-benzofuran-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a yellow solid, mp 159-161° C.; MS m/e 538 (M+);
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([C:21](O)=[O:22])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>C(Cl)Cl>[CH2:28]([N:30]([CH2:31][CH3:32])[C:21]([C:9]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH3:20])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=[CH:7][CH:8]=1)=[O:22])[CH3:29]
Reactant: CCNCC
Reactant: COc1ccc(-c2c(OC(C)C)cccc2C(=O)O)c(OC)c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1cccc(OC(C)C)c1-c1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Prepare a stirred solution of 6-isopropoxy-2',4'-dimethoxy-biphenyl-2-carboxylic acid (8.60 g, 0.0276 mole) in CH2Cl2 (200 mL) at ambient temperature under argon. Dropwise add thionyl chloride (4.6 g, 54 mmol, 2.8 mL). Continue stirring for about 60 minutes. Cool the reaction to 0° C. and dropwise add diethylamine (19.7 g, 28 mL, 0.27 mole), ensuring the temperature does not rise above 25° C. Continue stirring the reaction for about 30 minutes after addition is complete. Wash the organic layer with water, separate, and wash twice with 100 mL 5% sodium bicarbonate. Separate again, wash with brine (sat'd NaCl) and dry over magnesium sulfate. Filter through celite and condense on a rotovap to give a viscous light brown liquid. Dissolve (partially) in methylene chloride (20 mL) and filter. Flash chromatograph, in 30% ethyl acetate/70% hexane, to remove a solid impurity which is discarded. Continue eluting to obtain a mixture of the discardable and desired product. Further chromatography isolates the title compound as a pale yellow liquid (6.80 g, 68%). (EtOAc/hexane 30:70; Rf =0.15).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:18][C:16]1[CH:15]=[CH:14][C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CN
Reactant: Fc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Yield: 84.5 %

Procedure:
A suspension of the product of Step 228c (181 mg, 0.550 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (108 mg, 0.655 mmol), and K2CO3 (152 mg, 1.10 mmol) in anhydrous DMF (4 mL) was heated at 100° C. under nitrogen for 3 h. The reaction mixture was cooled to rt, diluted with EtOAc (100 mL), washed with 10% aq. LiCl (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% EtOAc/hexanes) then lyophilized from acetonitrile/water (2:1) to afford the title compound as a white solid (220 mg, 84%). 1H NMR (500 MHz, CDCl3) δ 8.95-6.05 (m, 10H), 5.25-2.85 (m, 5H), 2.15-0.75 (m, 8H); ESI MS (M+H) 474.