Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]([CH:19]=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:36])([CH3:35])[C:25]=3[CH:24]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5])[CH3:2].[O-:37]S(C(F)(F)F)(=O)=O>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:18]([C:19]([OH:37])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:29]([CH3:34])([CH3:33])[CH2:28][CH2:27][C:26]([CH3:35])([CH3:36])[C:25]=3[CH:24]=2)[CH:10]=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1cccc(-c2c(C=O)cccc2OCc2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Reactant: O=S(=O)([O-])C(F)(F)F
Product: CCOC(=O)Cc1cccc(-c2c(OCc3ccc4c(c3)C(C)(C)CCC4(C)C)cccc2C(=O)O)c1

Procedure:
3'-Ethoxycarbonylmethyl-2-(5,6,7,8-tetrahydro-5,5,8,8 -tetramethyl-2-naphthalenyl)methoxy-1,1'-biphenyl-6-carboxaldehyde (16q) (0.394 g., 0.84 mmol) obtained above (as a mixture with triflate 20a) is oxidized via the method of Example 4 to yield 3'ethoxycarbonylmethyl-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)methoxy-1,1'-biphenyl-6-carboxylic acid (0.210 g., 0.43 mmol, 25% overall from triflate 20a): chromatographed on silica gel using methanol/CH2Cl2 to afford a yellow oil; 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8 Hz, 1H, ArH), 7.33 (m, 2H, ArH), 7.26-7.15 (m, 5H, ArH), 7.05 (d, J=2 Hz, 1H, ArH), 6.89 (dd, J=2, 8 Hz, 1H, ArH), 4.94 (s, 2H, ArCH2O), 4.05 (q, J=7Hz, 2H, CO2CH2), 3.59 (s, 2H, ArCH2CO2), 1.63 (s, 4H, CH2CH2), 1.22 (s, 6H, 2×CH3), 1.15 (s, 6H, 2×CH3), 1.15 (t, J=7 Hz, 3H, CO2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 171.68 (C=O) , 171.64 (C=O), 156.21, 144.87, 144.23, 136.72, 133.58, 133.44, 132.16, 130.56, 128.42, 128.37, 128.01, 127.89, 126.55, 124.67, 123.89, 122.57, 116.76, 70.69, 60.80, 41.43, 35.03, 34.19, 34.07, 31.82, 31.74, 14.12; IR (film) 2960, 2926, 1734, 1700, 1456, 1364, 1300, 1260, 1152, 758 cm-1 ; MS (DCI) m/e 501 (MH+), 483 (M-OH), 201 (C15H21+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:14])=[C:4]([C:10]([Cl:13])=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)Cl.ClCCl>[Br:15][CH2:14][C:3]1[C:2]([Cl:1])=[CH:12][CH:11]=[C:10]([Cl:13])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1c(Cl)ccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)ccc(Cl)c1CBr
Temperature: 25 °C
Yield: 98.6 %

Procedure:
A solution of 3,6-dichloro-2-methylbenzoate (253b, 120 g, 0.52 mol) and N-bromosuccinimide (147 g, 0.82 mol) in chloroform (1 L) was treated with azobisisobutyronitrile (25.3 g, 0.15 mol) and the mixture refluxed overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (800 mL) and washed with water (1.2 L). The aqueous layer was extracted with dichloromethane (800 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (1.5 L), dried over sodium sulfate, and concentrated in vacuo to give ethyl 2-(bromomethyl)-3,6-dichlorobenzoate (253c, 160 g, 100% yield) which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])=[CH2:2]>O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: C=Cc1ccccc1O
Solvent: O
Product: CCc1ccccc1O

Procedure:
The process according to claim 1, wherein said vinylphenol-containing polymerization raw material comprises vinylphenol, non-polymerizable phenols and water, and is a crude reaction product or a partially purified reaction product obtained by dehydrogenation of ethylphenol.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13])=[O:5].[Cl-].[Cl-].[Cl-].[Al+3]>>[F:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: O=C(CCCl)Nc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCc2cccc(F)c2N1
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
3-Chloro-N-(2-fluorophenyl)propanamide (3.3 g, 16.4 mmol) and aluminum trichloride (10.9 g, 81.8 mmol) were combined in a RB flask with a stirbar and purged with argon. The mixture of the two solids was heated to 160° C. to form a melt, which was stirred for 1.5 h. The mixture was then removed from the heating bath and when it had cooled to below 100° C., was quenched by careful addition of water. The resulting mixture was cooled to room temperature, neutralized with NaOH, and extracted with dichloromethane (3×). The combined organics were dried, filtered and evaporated, then chromatographed on silica gel using 20% EtOAc in hexanes, giving the desired product. 1H NMR showed some impurities. Yield: 2.35 g, 88%. 1H NMR (CDCl3) δ 2.66 (t, 2H, J=7.6 Hz), 3.01 (t, 2H, J=7.6 Hz), 6.96 (m, 3H), 8.11 (brs, 1H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=[O:13].[OH-].[Na+].C>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)c1cnc2ccncc2c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cnc2ccncc2c1O
Yield: 62.2 %

Procedure:
Ethyl 4-hydroxy-1,6-naphthyridine-3-carboxylate (2.6 g, 11 mmol) was refluxed for six hours with sodium hydroxide (25 mL, 4%). The hot solution was decolorized with charcoal, filtered and acidified to pH 3. After cooling, the precipitate was removed by filtration, washed with water and dried to give the title compound (1.3 g) as a tan powder. 1H NMR (DMSO_d6): δ: 14.66 (s, 1H), 12.8-14 (br, 1H), 9.42 (s, 1H), 8.98 (s, 1H), 8.80 (d, J=5.6, 1H), 7.69 (d, J=5.6, 1H), MS (ESI) m/e (M+H+) 191.12.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][S:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([OH:34])=O)[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[O:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:1][C:2]1[C:6]([CH2:7][S:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:34])[CH2:30][CH2:31]4)=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCCc1ccccc1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1CSCCc1ccccc1

Procedure:
1-[4′-(3-Methyl-4-phenethylsulfanylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (0.2 g, 0.43 mmol) was dissolved in dioxane along with carbonyldiimidazole (0.2 g, 1.23 mmol), methanesulfonamide (0.14 g, 1.47 mmol) and Hünig's base. The reaction was heated to reflux overnight then cooled and submitted to standard aqueous workup. The residue was purified via silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH:39]1[CH2:42][NH:41][CH2:40]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:17]([O:24][C:25]1[CH:30]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:28]=[CH:27][C:26]=1[CH:39]1[CH2:42][N:41]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])[CH2:40]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(COc2ccc(C3CNC3)c(OCc3ccccc3)c2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccccc1)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
In a 10 ml round-bottomed flask, 0.25 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate in 5 ml of tetrahydrofuran is dissolved in the presence of 0.1 ml of N,N-diisopropylethylamine. 0.07 ml of benzoyl chloride is added and the mixture is then stirred for 24 hours at ambient temperature. The reaction mixture is extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 0.2 g of [3-(2,4-bis(benzyloxy)phenyl)azetidin-1-yl]phenylmethanone is obtained. Yield=82%.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[N:5]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]2[S:12][C:11]([C:13]3([OH:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:10][C:8]=2[N:9]=1.[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[CH:31]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:3][C:4]1[N:5]=[C:6]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]2[S:12][C:11]([C:13]3([OH:19])[CH2:14][CH2:15][N:16]([CH2:31][C:27]4[S:26][CH:30]=[CH:29][N:28]=4)[CH2:17][CH2:18]3)=[CH:10][C:8]=2[N:9]=1
Reactant: OC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCNCC1
Reactant: O=Cc1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: OC1(c2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN(Cc2nccs2)CC1

Procedure:
4-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)piperidin-4-ol dihydrochloride salt (250 mg) and 2-thiazole-carboxaldehyde (0.08 ml) were stirred together in 1,2-dichloroethane (3 ml) and triethylamine (0.18 ml) with sodium triacetoxyborohydride (187 mg) at room temperature overnight. Dichloromethane/brine extraction and purification on silica yielded 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-1-thiazol-2-ylmethyl-piperidin-4-ol (119 mg).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([F:11])[C:7](F)=[N:8][CH:9]=1>O>[Cl:3][C:4]1[CH:5]=[C:6]([F:11])[C:7]([OH:1])=[N:8][CH:9]=1
Reactant: [OH-]
Reactant: Fc1cc(Cl)cnc1F
Agent: [Na+]
Solvent: O
Product: Oc1ncc(Cl)cc1F
Temperature: 25 °C

Procedure:
To a solution of NaOH (101 g, 2.5 mol) in water (500 mL) was added 5-chloro-2,3-difluoropyridine (101 g, 0.68 mol) as a liquid, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the mixture was filtered through a pad of celite and the pH was adjusted to 1 by the addition of concentrated HCl. The resulting solid was dissolved in ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a white solid (78 g, 78%) and was used without additional purification. The product was characterized by 1H NMR.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13]>B(F)(F)F.CCOCC>[Cl:5][C:6]1[C:7]([OH:13])=[CH:8][C:9]([OH:12])=[C:10]([C:1](=[O:4])[CH3:2])[CH:11]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CC(=O)O
Agent: FB(F)F
Solvent: CCOCC
Product: CC(=O)c1cc(Cl)c(O)cc1O
Temperature: 90 °C
Reaction time: 3.5 h
Yield: 44 %

Procedure:
Acetic acid (17.5 ml) was added dropwise to a suspension of 4-chlorobenzene-1,3-diol (20 g, 0.138 mol) in BF3.OEt2 (100 ml) under a nitrogen atmosphere. The reaction mixture was stirred at 90° C. for 3.5 h and then allowed to cool to RT, causing a solid to precipitate. The mixture was poured into a 10% w/v aqueous sodium acetate solution (350 ml). This mixture was then stirred vigorously for 2.5 h to afford a light brown solid, which was filtered, washed with water, and air-dried overnight to afford the title compound 1-(5-chloro-2,4-dihydroxyphenyl)-ethanone (11.3 g, 44%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([C:19]1[C:27]2[C:22](=[C:23]([CH2:29][S:30][CH3:31])[C:24]([F:28])=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)(=O)=O.ClC1C=CC(C(C2C3C(=C(CSC)C(F)=CC=3)NC=2)CC[C:42]#[N:43])=CC=1>>[F:28][C:24]1[C:23]([CH2:29][S:30][CH3:31])=[C:22]2[C:27]([C:19]([CH:8]([C:9]3[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=3)[CH2:7][CH2:6][C:42]#[N:43])=[CH:20][NH:21]2)=[CH:26][CH:25]=1
Reactant: CSCc1c(F)ccc2c(C(CCOS(C)(=O)=O)c3ccc(C(F)(F)F)cc3)c[nH]c12
Reactant: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Product: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(C(F)(F)F)cc3)c[nH]c12

Procedure:
The title compound was prepared starting from 2.20 g (4.62 mmol) of the compound from Example 67A in analogy to the synthesis of the compound from Example 50. 1.66 g (88% of theory) of the target compound were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Reactant: Nc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)c1ccc(-c2cccc(N)c2)cc1
Temperature: 80 °C
Yield: 49.6 %

Procedure:
To a solution of 4-bromo-N-methyl-benzene sulfonamide (2.49 g, 10 mmol) in DMF (20 mL) was added 3-amino-phenyl boronic acid (1.51 g, 11 mmol), Pd(PPh3)4 (90 mg, 0.30 mmol), potassium carbonate (1.52 g, 11 mmol) and water (5 mL). The resulting mixture was degassed by gently bubbling argon through the solution for 5 minutes at 20° C. The reaction mixture was then heated at 80° C. overnight. The reaction was filtered through a pad of silica gel, which was washed with CH2Cl2 (50 mL×3). The combined organics were concentrated under reduced pressure to give crude product, which was washed with EtOAc to give pure 3′-amino-N-methylbiphenyl-4-sulfonamide (C-3) (1.3 g, 50%). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.7 Hz, 2 H), 7.75 (d, J=8.7 Hz, 2 H), 7.19 (t, J=7.8 Hz, 1 H), 6.95-7.01 (m, 2 H), 6.73-6.77 (m, 1 H), 2.54 (s, 3 H). MS (ESI) m/e (M+H+) 263.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[O:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[CH:45]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3](=[O:39])[C@@H:4]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)=[O:22])[CH2:5][N:6]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:45][C:41]1[O:40][CH:44]=[CH:43][CH:42]=1
Reactant: O=Cc1ccco1
Reactant: COC(=O)[C@H](CNCc1ccc(-c2ccccc2)cc1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COC(=O)[C@H](CN(Cc1ccc(-c2ccccc2)cc1)Cc1ccco1)NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
3-[(Biphenyl-4-ylmethyl)-amino]-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester (0.050 g, 0.093 mmol) prepared as per the above listed example 657 and was subjected to reductive amination as per procedure E with furan-2-carbaldehyde (0.009 g, 0.093 mmol) and sodium triacetoxyborohydride (0.039 gms, 0.186 mmol) to yield the corresponding 3-(biphenyl-4-ylmethyl-furan-2-ylmethyl-amino)-(2S)-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.030 g, 60%). 1H-NMR(400 MHz, DMSOd6): 3.21 (m, 2H), 4.0 (m, 3H), 6.7 (d, 1H), 7.6 (m, 2H), 7.8 (m, 8H), 8.24 (m, 8H); LC/MS (m/z): 599.3 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[C:33](O)(=[O:37])[C@H:34]([CH3:36])[OH:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:33](=[O:37])[C@@H:34]([OH:35])[CH3:36])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: C[C@H](O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)[C@H](C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.4 %

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.23 mmol), L-lactic acid (23 mg, 0.25 mmol) and DIPEA (45 μL, 0.25 mmol) in DCM (2 mL) was added HATU (96 mg, 0.25 mmol). The resulting yellow mixture was stirred for 2.5 h at r.t. then partitioned between DCM and H2O. The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% HCO2H in water on a gradient acetonitrile 20-35%) affording 718 as a white solid (19 mg, 16%). LCMS (method I): RT 2.92 min, [M+H]+ 505.2. 1H NMR (CDCl3, 400 MHz): δ 7.98-7.97 (1 H, m), 7.90-7.80 (1 H, m), 7.40-7.30 (2 H, m), 4.33-4.32 (7 H, m), 4.01-4.00 (1 H, m), 3.86-3.85 (5 H, m), 3.77 (3 H, d, J=1.96 Hz), 3.50-3.35 (4 H, m), 3.19-3.17 (2 H, m), 1.48 (3 H, t, J=7.42 Hz), 1.34 (3 H, dd, J=6.69, 4.73 Hz),
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:28][NH2:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:29][CH3:28])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Yield: 101.3 %

Procedure:
In a mixture of 2.3 g of 40% methylamine aqueous solution and 10 mL of tetrahydrofuran, a solution of 1.0 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 in 10 mL of tetrahydrofuran was added dropwise under cooling with ice and with stirring. After the completion of the addition dropwise, it was continued to stir further for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate, washed with 50 mL of water, then dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.0 g of the aimed product as pale yellow crystal.
Reaction SMILES: [CH:1](=[N:5]/[C@H:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])\[CH2:2][CH2:3][CH3:4].C[Si](C)(C)[O:16][C:17]([O:25][CH2:26][CH3:27])=[C:18]([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21].O.[OH-].[Na+]>CC1CCCO1>[CH2:23]([O:22][C:18]([O:19][CH2:20][CH3:21])([C@@H:1]([NH:5][C@H:6]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[CH2:2][CH2:3][CH3:4])[C:17]([O:25][CH2:26][CH3:27])=[O:16])[CH3:24]
Reactant: CCOC(OCC)=C(OCC)O[Si](C)(C)C
Reactant: CCC/C=N/[C@@H](C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
With HBF4OEt2: (S,E)-N-butylidene-1-phenylethanamine (Example 1, 10.0 g, 57.0 mmol) was dissolved in 250 mL 2-methyltetrahydrofuran and cooled to 0° C. HBF4OEt2 (9.24 g, 57.0 mmol) was added to the mixture followed by a solution of trimethyl((1,2,2-triethoxyvinyl)oxy)silane (Example 10, 11.34 g, 45.6 mmol) in 80 mL 2-methyltetrahydrofuran, and the mixture was stirred at 0° C. for three hours and fifteen minutes. Water (400 mL) was added to quench the reaction, the mixture was neutralized (pH=7.6) with 10N NaOH, the phases were separated and the organic phase was extracted once more with further 400 mL water. Water (300 mL) and 2-methyltetrahydrofuran (50 mL) were added to the mixture, the pH was acidified (pH=5.6) with 2N HCl and the phases were separated. The organic phase was extracted with further 300 mL water and 50 mL 2-methyltetrahydrofuran and the solvent of the organic phase was removed in vacuo to yield 17.1 g crude (S)-ethyl 2,2-diethoxy-3-(((S)-1-phenylethyl)amino)hexanoate as a 86.14 (syn:anti) diastereomeric mixture.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=[C:8]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1)=[O:5])C.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].O>[O:18]([CH2:17][C:8]1[N:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1ccc(COc2ccccc2)nc1C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Product: O=C(O)c1ccc(COc2ccccc2)nc1C(=O)O

Procedure:
42 g of 6-phenoxymethylpyridine-2,3-dicarboxylic acid diethyl ester are added to a solution of 0.5 g of tetrabutylammonium bromide in 140 ml of 15% aqueous sodium hydroxide solution while stirring. The resulting suspension is heated to 80° and stirred for one hour. The reaction mixture is then diluted with 300 ml of water and the solution is acidified to pH 2 using concentrated hydrochloric acid, during the course of which a precipitate forms which is filtered off with suction. The filtration residue is stirred with methylene chloride/tetrahydrofuran and filtered. The filtrate is dried over magnesium sulphate, concentrated and combined with the contents of the suction filter. After the whole has been dried again over phosphorus pentoxide, 34 g of the above acid, having a melting point of 270° with decomposition, are obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:27]4=[O:28])[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=2)[CH2:4][CH2:3]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C.CNN1C=CC(NC)=CC1>ClCCl.O>[C:39]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:38]=[CH:37][C:17]([C:18]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[CH2:30][CH2:29][C:27]4=[O:28])[CH2:24][CH2:25]3)=[O:19])=[CH:16][CH:15]=2)[CH2:6][CH2:7]1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CCN(CCCCCOc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)cc2)CC1
Agent: CNC1=CCN(NC)C=C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NC1CCN(CCCCCOc2ccc(C(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1-{4-[5-(4-Amino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (0.6 g) and acetic anhydride (0.2 ml) are dissolved in dichloromethane (20 ml), and thereto are added triethylamine (0.56 ml) and 1,4-dimethylaminopyridine (20 mg), and the mixture is stirred at room temperature overnight. Water is added to the reaction mixture and the mixture is extracted with chloroform, dried over sodium carbonate, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to give 1-[1-{4-[5-(4-acetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (310 mg) as colorless oil.