Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1.C1(=O)O[CH2:20][CH2:19][O:18]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:18][CH2:19][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccc(O)cc1)C1CCOCC1
Reactant: O=C1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Product: O=C(Nc1ccc(OCCO)cc1)C1CCOCC1
Temperature: 166 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
4′-Hydroxy-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (13.5 g), ethylene carbonate (5.96 g) and tetrabutylammonium iodide (2.26 g) were combined and stirred for 2 hours at 166° C. After being cooled, the mixture was added with water (100 ml) and further mixed. Crystals formed were collected by filtration, washed with water and then dried under vacuum at 60° C. to obtain 4′-(2-hydroxyethoxy)-3,4,5,6-tetrahydro-2H-pyran-4-carboxanilide (14.5 g) as white crystal.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Br:10][C:11]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14].[I-].CN1C=C[N+](C)=C1.[H-].[Na+]>C1COCC1>[Br:10][C:11]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1)=[O:14]
Reactant: CSc1nccc(Cl)n1
Reactant: Cc1cccc(C=O)c1Br
Agent: Cn1cc[n+](C)c1
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CSc1nccc(C(=O)c2cccc(C)c2Br)n1
Temperature: 0 °C

Procedure:
To a mixture of 4-chloro-2-(methylthio)pyrimidine (0.36 mL, 3.11 mmol), 2-bromo-3-methylbenzaldehyde (0.744 g, 3.74 mmol), and 1,3-dimethyl-1H-imidazol-3-ium iodide (0.697 g, 3.11 mmol) in THF (3 mL) was added NaH (0.149 g, 3.74 mmol) and the resulting mixture was refluxed for 30 min. Product was observed and the reaction went to completion. The mixture was brought to RT and poured into ice-water, extracted with DCM and purified using hexanes to afford a light yellow solid as (2-bromo-3-methylphenyl)(2-(methylthio)pyrimidin-4-yl)methanone.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:5][O:4]1.C(=O)(O)[O-].[Na+].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([N:18]1[CH2:5][CH:3]([OH:4])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCC1CO1
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: OC1CN(Cc2ccccc2)C1

Procedure:
reacting (±)-2-(chloromethyl)oxirane, sodium bicarbonate and benzylamine to provide 1-benzyl-3-azetidinol, reacting the 1-benzyl-3-azetidinol and (2E/Z)-2-butenedioic acid at about 35° C. to about 45° C., and isolating 1-benzyl-3-azetidinol (2E/Z)-2-butenedioate;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[C:4]([CH3:9])[N:3]=1.C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:3][C:4]=1[CH3:9]
Reactant: Cc1nc(N)ccc1I
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1ccc(I)c(C)n1)C(=O)OCC
Temperature: 25 °C
Yield: 83 %

Procedure:
A solution of 2-amino-5-iodo-6-picoline (Prep 2 4.48 g) and diethyl ethoxymethylenemalonate (4.25 mL) is heated at 95° C. for 1.5 h. The reaction is cooled to room temperature. Hexanes (20 mL) are added and the resulting solid is filtered, washed with a minimal amount of hexanes, and dried to give the desired enamine (6.45 g, 83%). Physical Characteristics are as follows: m.p. 138-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.70, 8.96, 8.11, 7.03, 4.21, 4.14, 1.26, 1.24; IR (drift) 2989, 1686, 1641, 1603, 1568, 1548, 1421, 1373, 1363, 1333, 1272, 1251, 1232, 1211, 800 cm−1; MS (ESI) m/z 404.9 (M+H)+, 402.9 (M−H)−; Anal. Calcd for C14H17IN2O4: C, 41.60; H, 4.24; N, 6.93; Found: C, 41.68; H, 4.35; N, 6.83.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([O:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[O:30]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O1CCOCC1.O.[NH4+].[Cl-]>[OH:30][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([O:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)c1cc(-c2cccc(OS(=O)(=O)c3ccccc3)c2)c2ncccc2c1
Agent: [Ce+4]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)c1cc(-c2cccc(OS(=O)(=O)c3ccccc3)c2)c2ncccc2c1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To solution of KBrO3 (1.1 eq) in 5 mL of dioxane/water (3/2; 0.14M) was added the quinoline of EXAMPLE 25 (1.0 eq) and CAN (0.1 eq). The mixture was stirred at 75° C. for 16 h, poured in saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:1) afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:27][CH:26]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].O.[OH-].[Li+]>C1OCCOC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:25][CH:26]([C:28](=[O:36])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH2:27]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=2)[CH2:11][CH2:12]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(C(=O)c4cccc(F)c4)C3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(C(=O)c4cccc(F)c4)C3)CC2)cc1
Temperature: 70 °C
Yield: 74.3 %

Procedure:
To a solution of methyl 6-((5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinamido)methyl)nicotinate (D160) (40.5 mg, 0.079 mmol) in a mixture 1-4 dioxane/water (1.5 ml/0.5 ml), lithium hydroxide hydrate (10 mg, 0.24 mmol) was added. The reaction mixture was heated to 70° C. under microwave irradiation for 20 min (4 cycles of 5 min each). After solvent evaporation the residue was taken in water (5 ml) and 1M HCl (5 ml) and extracted with ethylacetate (3×10 ml). Collected organics after solvent evaporation afforded the title compound (E25) (29 mg)
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.Cl[C:51]1[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]2[CH:76]=[CH:75][C:65]([CH2:66][P:67](=[O:74])([O:71][CH2:72][CH3:73])[O:68][CH2:69][CH3:70])=[CH:64][C:63]=2[O:77][CH3:78])[N:52]=1.[NH2:79][C:80]1[CH:92]=[CH:91][C:90]([C:93]2[CH:94]=[N:95][N:96]([CH2:98][CH2:99][CH2:100][OH:101])[CH:97]=2)=[CH:89][C:81]=1[C:82]([N:84]([CH2:87][CH3:88])[CH2:85][CH3:86])=[O:83]>>[CH2:87]([N:84]([CH2:85][CH3:86])[C:82]([C:81]1[CH:89]=[C:90]([C:93]2[CH:94]=[N:95][N:96]([CH2:98][CH2:99][CH2:100][OH:101])[CH:97]=2)[CH:91]=[CH:92][C:80]=1[NH:79][C:51]1[C:56]([C:57]([F:59])([F:58])[F:60])=[CH:55][N:54]=[C:53]([NH:61][C:62]2[CH:76]=[CH:75][C:65]([CH2:66][P:67](=[O:74])([O:68][CH2:69][CH3:70])[O:71][CH2:72][CH3:73])=[CH:64][C:63]=2[O:77][CH3:78])[N:52]=1)=[O:83])[CH3:88]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1)OCC
Yield: 50.1 %

Procedure:
Prepared analogously to Compound 1B using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 1 E, 282.1 mg, 0.62 mmol) and 2-amino-N,N-diethyl-5-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]benzamide (Compound 3C, 196.7 mg, 0.62 mmol) to afford 228 mg of the title compound (50%). 1H NMR (400 MHz, CD3OD) δ 8.33 (br. s., 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.77 (dd, J=2.02, 8.34 Hz, 1H), 7.59-7.67 (m, 2H), 7.57 (d, J=8.08 Hz, 1H), 6.97 (br. s., 1H), 6.57 (br. s., 1H), 4.32 (t, J=6.95 Hz, 2H), 3.99 (quin, J=7.14 Hz, 4H), 3.89 (s, 3H), 3.59 (t, J=6.06 Hz, 2H), 3.43-3.52 (m, 2H), 3.08-3.22 (m, 4H), 2.11 (quin, J=6.57 Hz, 2H), 1.22 (t, J=7.07 Hz, 6H), 1.11 (t, J=6.95 Hz, 3H), 0.97 (br. s., 3H). MS (ESI): m/z 734.85 [M+H]+. UPLC: tR=1.22 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH-](CC)CC)C.[Li+].C(OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH3:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COS(C)(=O)=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
2-(S)-Methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester was (4.83 g, 18.2 mmol) was taken up in THF (11 mL), cooled to 0° C. under N2, treated drop-wise with a lithium triethylborohydride (1.0 M in THF, 73 mL), stirred at ambient temperature for 6 hours, treated with ethyl acetate (500 mL), washed with water, washed with 0.25 M HCl, washed with NaHCO3 solution, washed with brine (2×), dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel eluting with a gradient of 10:1 and then 5:1 hexane:ethyl acetate to provide 0.95 g (30%) of the title compound. 1H NMR (300 MHz, CDCl3) δ 1.37 (d, J=6.10 Hz, 3 H) 1.44 (s, 9 H) 1.76 (m, 1 H) 2.27 (m, 1 H) 3.81 (t, J=7.46 Hz, 2 H) 4.28 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH:11]([S:13]([CH:16]=[CH2:17])(=[O:15])=[O:14])=[CH2:12]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:17][CH2:16][S:13](=[O:15])(=[O:14])[CH2:11][CH2:12]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: C=CS(=O)(=O)C=C
Solvent: CCO
Product: C[C@@H](c1ccc(Br)cc1)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A solution of (S)-1-(4-bromophenyl)ethanamine (0.144 ml, 1.0 mmol) and vinylsulfonylethene (0.100 ml, 1.0 mmol) in EtOH (4.0 ml) was heated at 100° C. and stirred for 3 h. The reaction mixture was cooled to RT and evaporated to dryness. The resulting crude material was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (gradient elution, heptane/AcOEt 95:5 to 4:6) to yield the title compound (256 mg, 0.804 mmol, 80% yield) as a colorless oil which crystallized on standing into a colorless solid. TLC: RF=0.40 (heptane/AcOEt 1:1); HPLC: BtRet=1.29 min; LC-MS: m/z 320.2 [M+H]+; 1H NMR (400 MHz, CDCl3): 1.39 (d, J=6.8, 3H), 2.92-3.09 (m, 8H), 3.76 (q, J=6.8, 1H), 7.19-7.26 (m, 2H), 7.45-7.53 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH:7]([CH3:11])[C:8]([OH:10])=O)[O:6][CH2:5][CH2:4][O:3]1.C(Cl)(=O)C(Cl)=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1([CH:7]([CH3:11])[C:8]([NH:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:10])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC(C(=O)O)C1(C)OCCO1
Reactant: NCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C(=O)NCCc1ccccc1)C1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.7 %

Procedure:
2-(2-Methyl-[1,3]dioxolan-2-yl)-propionic acid of Example 1b (1.60 g, 10 mmol) in dry dichloromethane (15 mL) was cooled to 0° C. under an argon atmosphere. A solution of oxalyl dichloride (2.92 g, 2.0 mL, 23.0 mmol) in dichloromethane (5 mL) was added dropwise. After 5 min at 0° C., the mixture was allowed to warm to room temperature. After stirring for 2 h at room temperature, the excess oxalyl dichloride was removed under reduced pressure to produce a yellow oil which was dissolved in dichloromethane (7 mL). The solution was cooled in an ice bath and phenethylamine (1.12 g, 10.0 mmol) in pyridine (5 mL) was added drop-wise. After the addition was complete, the reaction was warmed to room temperature and allowed to stir overnight. The solution was diluted with dicholoromethane (100 mL) and poured into ice-cold hydrochloric acid (1N, 150 mL). The organic layer was separated and washed with water (100 mL), sodium bicarbonate solution (5%, 50 mL), water (100 mL), and brine (100 mL). After drying with sodium sulfate and concentration on a rotary evaporator, the product was purified by flash chromatography on silica gel, eluting with hexanes-ethyl acetate (3:2) to give 2-(2-methyl-[1,3]dioxolan-2-yl)-N-phenethyl-propionamide (1.81 g, 69%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([O-])(=O)=O.[NH2:6][C:7]1[N:15]=[CH:14][N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:16]1[CH:20]2[O:21][CH2:22][CH:23](O)[CH:19]2[O:18][CH2:17]1>>[CH3:1][S:2][C@@H:23]1[CH:19]2[O:18][CH2:17][C@@H:16]([N:11]3[CH:10]=[N:9][C:8]4[C:12]3=[N:13][CH:14]=[N:15][C:7]=4[NH2:6])[CH:20]2[O:21][CH2:22]1
Reactant: Nc1ncnc2c1ncn2C1COC2C(O)COC21
Reactant: CS(=O)(=O)[O-]
Product: CS[C@H]1COC2C1OC[C@H]2n1cnc2c(N)ncnc21

Procedure:
In an analogous manner to Example 4 the title compound is prepared from the methanesulfonate derivative of 6-(6-amino-purin-9-yl)-hexahydro-furo[3,2-b]furan-3-ol.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14].[NH:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:5]([CH:6]=[C:22]2[NH:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])=[CH:4][C:3]=1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: O=C1CNC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(C=C2NC(=S)NC2=O)cc(C(C)C)c1O
Yield: 32.9 %

Procedure:
Prepared according to the procedure described in Example 1 using 4-hydroxy-3,5-bis(1-methylethyl)benzaldehyde (3.0 g, 15 mmoles), 2-thiohydantoin (1.6 g, 14 mmoles), sodium acetate (4.2 g, 51 mmoles), and acetic acid (35 ml), filtered off, dried, and recrystallized from acetonitrile to afford the pure product (1.4 g), mp 225°-230° C.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:32].[H-].[Na+]>CN(C=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.50 g), 2-bromo-1-(4-fluorophenyl)ethanone (1.01 g) in DMF (50 ml) was added under ice-cooling 60% sodium hydride (0.093 g) and the mixture was stirred at 70° C. for 1 hr. The solvent was concentrated, water was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Silica gel column chromatography gave the title compound as a colorless solid (1.40 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:25])[NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[OH:24])=[O:25]
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1c2ccccc2CC1O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(N)C(=O)NC1c2ccccc2CC1O

Procedure:
Compound 17 was kept in DCM-TFA 2:1 (2 mL) for 60 min at RT. The solution was cb-evaporated with toluene to dryness.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.BrC1C=CC=CC=1C1C=CC=CC=1.[C:27](=[NH:40])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CC(C)([O-])C.[Na+].C1(C(C2C=CC=CC=2)=C(P(C2CCCCC2)C2CCCCC2)C)C=CC=CC=1.[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:34]1([C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[N:40][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: Brc1ccccc1-c1ccccc1
Agent: CC(=C(c1ccccc1)c1ccccc1)P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: c1ccc(C(=Nc2ccc(-c3ccccc3)cc2)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
Into a reactor were introduced 0.466 g (2.00 mmol) of 4-bromobiphenyl and 4 mL of toluene under a nitrogen atmosphere. The bromobiphenyl was dissolved in the solvent. To this solution were added 0.399 g (2.2 mmol) of benzophenonimine, 0.231 g (2.4 mmol) of sodium t-butoxide, 13.5 mg (3 mol % based on the amine) of palladium acetate, and 46.9 mg (6 mmol % based on the amine) of the 1,1-diphenyl-2-(dicyclohexylphosphino)propene obtained in Example 2. The resultant reaction mixture was stirred at 100° C. for 16 hours and then cooled. Saturated aqueous ammonium chloride solution was added thereto, and this mixture was extracted with toluene. The extract was dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was purified by column chromatography to obtain 0.409 g (61%) of N-(diphenylmethylene)-4-aminobiphenyl as a yellow oily substance. The results obtained are shown in Table 20.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[CH:11]=[CH2:12])[C:3]=1[OH:10]
Reactant: O=Cc1cccc(Br)c1O
Reactant: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
After a solution of 3-bromo-2-hydroxybenzaldehyde (1.35 g, 6.7 mmol) in THF (10 ml) was cooled to 0° C., a solution of vinyl magnesium chloride in THF (2.0M, 8.05 ml, 16.1 mmol) was added thereto under a nitrogen atmosphere over 5 minutes. The mixture was gradually warmed to room temperature and stirred at room temperature for 3 hours. The mixture was cooled to 0° C. and a 20% aqueous ammonium chloride solution (30 ml) was added thereto at 0° C. After the mixture was stirred at room temperature for 30 minutes, it was poured to ice-water (30 ml). The mixture was extracted with ethyl acetate (2×50 ml). The organic layer was combined and successively washed with water (30 ml) and a saturated aqueous NaCl solution (30 ml), followed by drying with anhydrous sodium sulfate. The solid was removed by filtration and the filtrate was concentrated to obtain a pale brown oil. This oil was purified by silica gel column chromatography (use of 40 g of Wakogel C-100E, elution with hexane:ethyl acetate=5:1) to obtain 1.24 g of 2-bromo-6-(1-hydroxy-2-propenyl)phenol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:44][C:45]([NH:47][CH2:48][CH:49]1[CH2:53][O:52][C:51]([CH3:55])([CH3:54])[O:50]1)=[O:46].CN(C)C=O>O>[CH3:54][C:51]1([CH3:55])[O:50][CH:49]([CH2:48][NH:47][C:45]([CH2:44][O:36][C:35](=[O:37])[C:34]2[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]3[C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[F:42])[C@:12]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]3)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=2)=[O:46])[CH2:53][O:52]1
Reactant: CC1(C)OCC(CNC(=O)CCl)O1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)OCC(=O)NCC2COC(C)(C)O2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 50 °C
Yield: 24 %

Procedure:
In a 15 mL pressure tube, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 300 mg, 487 μmol) and 2-chloro-N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)acetamide (101 mg, 487 μmol) were combined with dry dimethyl formamide (5 mL) to give a white suspension. The tube was capped and heated at 50° C. overnight. The reaction mixture was cooled down to room temperature. It was poured into water and extracted with ethyl acetate (2×). The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified with flash chromatography (24 g pre-packed silica gel column, eluted with methanol in ethyl acetate) to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid [(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-carbamoyl]-methyl ester as an off-white solid (92 mg, 24% yield). LCMS (ES+) m/z calcd. for C39H42Cl2F2N4O7 [(M+H)+]: 787. found: 787.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:17]2[CH:22]=[C:21]([O:23]C)[CH:20]=[CH:19][C:18]=2Cl)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12.Cl.Cl.Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[NH2:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:23])[CH:22]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12
Reactant: COc1ccc(Cl)c(-n2nc3c(c2N)c(=O)[nH]c2cc(O)ccc23)c1
Reactant: CN1CCN(CCCCl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCCOc2ccc3c(c2)[nH]c(=O)c2c(N)n(-c4cccc(O)c4)nc23)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 13.8 %

Procedure:
A mixture of 3-amino-2-(2-chloro-5-methoxyphenyl)-7-hydroxy-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (75 mg), 1-(3-chloropropyl)-4-methylpiperazine dihydrochloride (70 mg), potassium carbonate (112 mg), potassium iodide (5 mg) and N,N-dimethylformamide (3 ml) was stirred at 80° C. for 4 hours. To the reaction mixture was added water, extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the concentrated residue (53 mg) was added DL-methilonine (265 mg) and methanesulfonic acid (3 ml), and the mixture was stirred at 90° C. for one night. The reaction mixture was cooled and then pH of the reaction mixture was adjusted to about 9 by adding an aqueous 20% sodium hydroxide and 5% sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified with propylaminated silica gel column chromatography to obtain the target compound (13 mg).