Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[N:19][CH:20]=2)=[CH:11][CH:10]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][C:25]=1[Cl:38]>CN(C=O)C.CCOC(C)=O.[Cu]I>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]#[C:22][C:24]3[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][C:25]=3[Cl:38])=[N:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Clc1cc(OCCN2CCCC2)ccc1Br
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3Cl)nc2)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere 0.13 mL (1.00 mmol) triethylamine, 22 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium and 3.7 mg (0.02 mmol) CuI are added successively to a solution of 80 mg (0.37 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine and 114 mg (0.37 mmol) 1-[2-(4-bromo-3-chloro-phenoxy)-ethyl]-pyrrolidine in 3.0 mL DMF. The mixture is stirred for 15 min at 100° C. and at 200 W in the microwave. The reaction solution is diluted with 40 mL EtOAc, washed twice with semisaturated NaHCO3 solution and the organic phase is dried over MgSO4. The solvent is eliminated i.vac. and the residue is triturated with tert-butylmethylether. The solvent is eliminated i.vac. and further purification is carried out by column chromatography with HPLC-MS.
Reaction SMILES: [Cl:1][C:2](Cl)([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].S([O-])([O-])=O.[Na+].[Na+]>C(O)C.O>[Cl:1][CH:2]([P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CCOP(=O)(OCC)C(Cl)(Cl)C(=O)OC(C)(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOP(=O)(OCC)C(Cl)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 100 %

Procedure:
The title compound of Step B (18.4 g, 0.0572 mol) was dissolved in ethanol (140 mL) and cooled to 0° C. A solution of sodium sulfite (14.4 g, 0.1144 mol) in H2O (63 mL) was added with stirring such that the internal temperature remained below 14° C. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with chloroform (5×), and the combined organic phase was dried (MgSO4), filtered and concentrated to afford 16.4 g of the title compound of Step C as a clear oil. 1H NMR (300 MHz, CDCl3): δ 4.43 (d,1H, J=15.9 Hz), 4.30-4.24 (m,4H), 1.52 (s,9H), 1.38 (t,6H, J=6.9 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1([CH3:34])[C@H:28]2[CH2:29][C@@H:24]1[CH2:25][CH2:26][C@H:27]2[CH2:30][C:31](O)=[O:32]>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:31](=[O:32])[CH2:30][C@@H:27]2[CH2:26][CH2:25][C@H:24]3[CH2:29][C@@H:28]2[C:23]3([CH3:22])[CH3:34])[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)C[C@@H]2CC[C@H]3C[C@@H]2C3(C)C)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid (Eigenmann, G. W.; Arnold, R. T. JACS 1959, 81, 3440-2) were treated using a method similar to that described in Example 56 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.24 (s, 1H), 8.36-8.28 (m, 1H), 8.10 (d, J=7.8, 1H), 7.98 (dd, J=11.1, 4.1, 1H), 7.90 (t, J=7.1, 1H), 7.40 (s, 1H), 4.45 (d, J=5.7, 2H), 2.41-2.29 (m, 3H), 2.07-1.80 (m, 5H), 1.64-1.47 (m, 1H), 1.43-1.29 (m, 10H), 1.21 (s, 3H), 1.07 (s, 3H), 0.91 (d, J=9.5, 1H). MS (ESI+) M/Z 472 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[S:11][C:10]2[C:9](=O)[C:8](=[CH:13][N:14](C)[CH3:15])[CH2:7][CH2:6][N:5]([C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C:4]=2[CH:3]=1.C[NH:29]N>CO>[Cl:1][C:2]1[S:11][C:10]2[C:9]3=[N:29][N:14]([CH3:15])[CH:13]=[C:8]3[CH2:7][CH2:6][N:5]([C:17](=[O:27])[C:18]3[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=3)[C:4]=2[CH:3]=1
Reactant: CNN
Reactant: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cc(Cl)sc2C1=O
Solvent: CO
Product: Cn1cc2c(n1)-c1sc(Cl)cc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Temperature: 80 °C

Procedure:
A mixture of 500 mg of 2-chloro-7-[(dimethylamino)methylene]-4,5,6,7-tetrahydro-4-(4-nitrobenzoyl)-8H-thieno[3,2-b]azepin-8-one in 15 ml of absolute methanol is stirred under argon while 131 μl of N-methylhydrazine is added. The reaction mixture is heated at 80° C. for 18 hours. The reaction mixture is cooled to room temperature and concentrated in vacuo to give 420 mg of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([O:17][C:16]([F:15])([F:25])[F:26])=[CH:19][CH:20]=2)=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)CCC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)c1cccc(F)c1)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
Stir 4-(3-fluoro-phenyl)-4-oxo-butyric acid [C.A. 69797-46-2] (J. Med. Chem. (1983) 26 381) (1.96 g, 10 mmol), 4-trifluoromethoxyaniline (1.77 g, 10 mmol) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) (3.5 g, 11 mmol) in dimethylformamide (30 mL). Add triethylamine (2.02 g, 20 mmol). Stir at room temperature for 48 hours. Pour into dilute aqueous HCl (250 mL) and extract into ethyl acetate. Wash the organic phase three times with water, dry over anhydrous magnesium sulfate, evaporate and purify on a silica gel column (dichloromethane-ethyl acetate) to give the titled compound (3.13 g, 88% yield) MS (m/z): 356 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1cccc2cc[nH]c12
Product: Cc1ccccc1-c1cccc2cc[nH]c12

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 2-methylphenylboronic acid: ESMS m/e: 208 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH3:26][O-:27].[Na+]>>[CH3:26][O:27][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: C[O-]
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 61 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.50 g) and sodium methoxide solution (from sodium, 0.16 g, and methanol, 20 ml) yielded the title compound, 0.29 g, m.p. 231-2° C. (recrystallized from methanol).
Reaction SMILES: [Cl:1][C:2]1([Cl:11])[C:6]([Cl:7])=[C:5]([Cl:8])[C:4]([Cl:9])=[C:3]1[Cl:10].[C:12]([C:16]1[C:17](=[O:23])[CH:18]=[CH:19][C:20](=[O:22])[CH:21]=1)([CH3:15])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[C:12]([C:16]1[C:17](=[O:23])[CH:18]2[CH:19]([C:20](=[O:22])[CH:21]=1)[C:3]1([Cl:10])[C:2]([Cl:11])([Cl:1])[C:6]2([Cl:7])[C:5]([Cl:8])=[C:4]1[Cl:9])([CH3:15])([CH3:13])[CH3:14]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: CC(C)(C)C1=CC(=O)C=CC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
Hexachlorocyclopentadiene, 40 g., and 15.4 g. of tert-butyl-p-benzoquinone were dissolved in 300 ml. of toluene and refluxed for four hours. The solution solidified upon cooling to room temperature. The solid was washed with methanol and recrystallized from benzene. Yellow crystals were obtained, melting at 124° -125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH2:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][NH:28][CH3:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCN)c(C)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Reaction time: 1.67 h
Yield: 87.2 %

Procedure:
To a solution of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)ethanamine (1.0 g, 2.65 mmol) in dioxane (6.6 mL) was added di-tert-butyldicarbonate (730 μL, 3.19 mmol), followed by aqueous sodium hydroxide (2.5 M solution, 1.28 mL, 3.19 mmol). The reaction mixture was stirred for 100 min, At this time, HPLC analysis indicated complete conversion to product. The mixture was then diluted in ethyl acetate (25 mL), transferred to a separatory funnel, and washed with 1 M aqueous sodium bicarbonate (2×10 mL), saturated ammonium chloride (10 mL), and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The carbamate product was then dissolved in THF (13 mL), and the solution was treated with lithium aluminum hydride (800 mg). The resulting slurry was warmed to reflux and stirred for 90 min, after which HPLC analysis indicated consumption of starting material. The mixture was subsequently added slowly to 75 mL 2.5 M aqueous sodium hydroxide stirred over ice. The resulting grey suspension was stirred for 10 min, during which time the solids became white. To the suspension was added 100 mL isopropyl acetate, and the resulting mixture was filtered, and transferred to a separatory funnel. The organics were removed and the aqueous layer washed with 50 mL isopropyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 900 mg of 2-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-methylethanamine. 1H-NMR (400 MHz, CD3OD) 7.51-7.30 (m, 10H), 4.72 (s, 3H), 2.84 (s, 2H), 2.42 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H), 2.21 (s, 3H) ppm.
Reaction SMILES: C(OC[N:10]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]([CH3:38])[C:22](=[O:37])[C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)=[C:13]([CH3:39])[CH:12]=[N:11]1)C1C=CC=CC=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[CH3:38][N:21]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[C:14]1[NH:10][N:11]=[CH:12][C:13]=1[CH3:39])[C:22](=[O:37])[C:23]1[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=1
Reactant: Cc1cnn(COCc2ccccc2)c1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn[nH]c1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of N-[4-(2-benzyloxymethyl-4-methyl-2H-pyrazol-3-yl)-pyridin-3-yl]-N-methyl-3,5-bis-trifluoromethyl-benzamide (70 mg, 128 μmol) in TFA (3 mL) was added CH2Cl2 (300 μL). The reaction mixture was stirred at 80° C. for 2 hours and then concentrated in vacuum. The reaction mixture was poured on 30 mL 10% aqueous NaHCO3 solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless foam (20 mg, 37%). MS (ESI): m/z=429.114 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.[CH2:15]([N:17]1[C:21]([OH:22])=[CH:20][CH:19]=[N:18]1)[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.CC(C)(O)C#N.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([C:20]2[CH:19]=[N:18][N:17]([CH2:15][CH3:16])[C:21]=2[OH:22])=[O:14])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: O=C(O)c1ccc(Br)c2ncccc12
Reactant: CCn1nccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1ncc(C(=O)c2ccc(Br)c3ncccc23)c1O
Reaction time: 1.5 h

Procedure:
1.00 g of 8-bromoquinoline-5-carboxylic acid, 0.44 g of 1-ethyl-5-hydroxypyrazole and 0.80 g of dicyclohexylcarbodiimide were stirred in 15 ml of acetonitrile at room temperature. After the addition of 0.2 ml of acetone cyanohydrin and 0.60 g of triethylamine, stirring was continued for 1.5 hours and the mixture was then poured into aqueous sodium carbonate solution. The alkaline phase was washed with ethyl acetate and diethyl ether and then acidified. The precipitate was filtered off under suction and the aqueous phase was extracted with ethyl acetate. This organic phase was dried and concentrated. The residue and the precipitate were combined.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[I:14](O)(=O)(=O)=O.II>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[I:14]
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CO
Product: COC(=O)c1nc(Cl)c(F)c(N)c1I
Reaction time: 0.17 h
Yield: 194 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (2.2 g, 10.8 mmol) was dissolved in methyl alcohol (20 mL). The solution was treated with periodic acid (880 mg, 3.9 mmol) and iodine (2.2 g, 8.6 mmol) and then heated at reflux for 20 h. The mixture was cooled, and the volatiles were removed under vacuum. The residue was dissolved in EtOAc (50 mL) and then stirred with 10% NaHSO3 solution (20 mL) for 10 min. The organic phase was separated and washed with satd aq NaCl (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexane gradient) to give the title compound as a light orange solid (2.5 g, 70%): mp 149-151° C.; ESIMS m/z 330 ([M]+); 1H NMR (400 MHz, CDCl3) δ 5.17 (s, 2H, NH2), 3.97 (s, 3H, OMe); 19F NMR (376 MHz, CDCl3) δ −135.79 (s).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].C1C([N+]([O-])=O)=CC=C([O:16][P:17](O)([OH:19])=[O:18])C=1.C(O)C>C(OC)(C)(C)C>[P:17]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])([OH:19])([OH:18])=[O:16]
Reactant: O=[N+]([O-])c1ccc(OP(=O)(O)O)cc1
Reactant: OCC(O)CO
Solvent: COC(C)(C)C
Solvent: CCO
Product: O=P(O)(O)OCC(O)CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Glycerol (10 mmol; 0.92 g) is adsorbed to an approximately equal amount of silica gel (1.0 g) and then suspended in 20 ml of t-BuOMe. To this mixture is added p-nitrophenylphosphate (10 mmol) followed by acid phosphatase from potato (1000 U; 200 mg). The mixture is stirred at room temperature for 24 hours. The solvent is removed by vacuum, the residue is thoroughly extracted with water (3×150 ml), and all solids are removed by filtration. The resulting aqueous solution is concentrated under vacuum to 75 ml and treated with a solution 21 mmol of BaCl2.2H2O to form a precipitate. To the suspension is added 500 ml of 95% ethanol and the precipitate is allowed to settle overnight. The. suspension is filtered and the solid material is dried over CaSO4. Glycerol-1-phosphate (8.5 mmol) is obtained containing 94% of the title compound as the barium salt.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([C:19]#[N:20])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:4][CH2:3]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=O.C(O)(=O)C>CC(O)C>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[N:1][N:2]1[CH2:3][CH2:4][N:5]([CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH:12]=[C:11]([C:19]#[N:20])[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]2=3)[CH2:6][CH2:7]1
Reactant: O=Cc1ccccn1
Reactant: N#CC1=Cc2ccccc2C(N2CCN(N)CC2)c2ccccc21
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#CC1=Cc2ccccc2C(N2CCN(N=Cc3ccccn3)CC2)c2ccccc21

Procedure:
A mixture of 40 parts of 5-(4-amino-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile, 50 parts of 2-pyridinecarboxaldehyde, 3 parts of glacial acetic acid, and 400 parts of 2-propanol is heated at the boiling point under reflux for 5 hours, then refrigerated until precipitation is complete. Insoluble solids are removed by filtration, consecutively washed with absolute ethanol and hexane, and air-dried. Recrystallization of this material from a mixture of chloroform and hexane affords 5-[4-(2-pyridylmethylene)amino-1-piperazinyl]-5H-dibenzo[a,d]cycloheptene- 10-carbonitrile as a light tan solid which, dried in air, melts at 182.5°-184°.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:29]C)=[CH:10][C:11]([O:27]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24]C)=[CH:14][C:13]3=[O:26])[CH2:6][CH2:5][N:4]1[CH3:31].Cl.N1C=CC=CC=1>>[OH:27][C:11]1[CH:10]=[C:9]([OH:29])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:31])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:26])[CH:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])[O:16]2
Reactant: COc1ccccc1-c1cc(=O)c2c(OC)cc(OC)c([C@@H]3CCN(C)[C@H]3CO)c2o1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4O)oc23)[C@@H]1CO

Procedure:
Compound of example 95 (0.4 g, 0.9 mmol) was demethylated using pyridine hydrochloride (6 g, 52.0 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]([F:19])([F:18])C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:18][CH:14]([F:19])[O:12][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(O)C(F)(F)Cl
Reactant: COC(=O)c1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(F)c1OC(F)F
Yield: 41.3 %

Procedure:
A mixture of methyl 3-fluoro-2-hydroxy-benzoate (1.5 g, 8.8 mmol), 2-chloro-2,2-difluoro-acetic acid (1.62 g, 1.05 mL, 10.6 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were heated in DMF (5 mL) at 120° C. for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ether (2×10 mL). The organics were separated and washed sequentially with water (5 mL) and brine solution (5 mL). The organics were dried (MgSO4) and concentrated in vacuo to give residue which was purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 39%). To methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 3.64 mmol) was added 12% aq. NaOH (3 mL) and the reaction mixture was heated at 50° C. for 1 hour. The aqueous layer was extracted with 1:1 ether/hexane (2×5 mL). The aqueous layer was acidified to pH 1 with 6 N HCl solution to give a suspension. The solid was filtered and washed with water, then dried in vacuo to give 2-(difluoromethoxy)-3-fluoro-benzoic acid (555 mg, 31%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.8 Hz, 1H), 7.43 (dd, J=13.1, 4.8 Hz, 1H), 7.35 (td, J=8.1, 4.9 Hz, 1H), 6.68 (t, J=74.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:23][C:24]1[CH:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33](I)=[C:32]([F:39])[CH:31]=2)[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:33]2[C:34]([O:36][CH3:37])=[CH:35][C:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)=[CH:31][C:32]=2[F:39])=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1cc(-c2cccc(Cl)c2)cc(F)c1I
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1c(F)cc(-c2cccc(Cl)c2)cc1OC
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A pressure vessel was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (497.91 mg, 1.589 mmol, made via Method 42, Steps 1-2), 3′-chloro-3-fluoro-4-iodo-5-methoxy-1,1′-biphenyl (605 mg, 1.668 mmol), Xantphos (46.0 mg, 0.079 mmol), Pd2(dba)3 (36.4 mg, 0.040 mmol), and cesium carbonate (1035 mg, 3.18 mmol) were added. The vessel was flushed with Ar (g), then toluene (3177 μl) was added. The vessel was sealed and lowered into a 110° C. heating bath for 4 h. The heating bath was turned off, and the vessel was allowed to cool to RT with the bath. In the morning, the mixture was filtered through celite. The filter pad was washed with EtOAc (3×). The filtrate was concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-30% EtOAc/Heptane with 5% DCM) to give (E)-ethyl 3-(5-(benzylthio)-2-((3′-chloro-3-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)amino)phenyl)acrylate (468.1 mg, 0.854 mmol, 53.8% yield) as a yellow solid. m/z (ESI) 548.2 (M+H)+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[S:1]1[CH2:2][CH2:3][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:5][CH2:6]1
Reactant: CN(CCC(=O)N1CCSCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCC(=O)N1CCSCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of benzyl 2(S)-[N-(2-thiomorpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (418 mg) in methanol (5 ml), which was cooled to 0° C., was added 1N sodium hydroxide aqueous solution (1.33 ml). The mixture was stirred at ambient temperature for one hour. After evaporation of methanol, the residual basic aqueous solution was washed with chloroform (5 ml×2). Then the aqueous solution was acidified to pH 2 with 5% hydrochloric acid, and extracted with ethyl acetate (10 ml×2). The extract was washed with water (10 ml) and saturated sodium chloride solution (10 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give 2(S)-[N-(2-thiomorpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionic acid (315 mg).