Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [IH:1].[Cl:2][C:3]1[C:4](N)=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]2.N([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:2][C:3]1[C:4]([I:1])=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:13]([F:16])([F:15])[F:14])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]2
Reactant: I
Reactant: CCOC(=O)C1=Cc2c(ccc(Cl)c2N)OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2c(ccc(Cl)c2I)OC1C(F)(F)F
Temperature: 0 °C
Yield: 49 %

Procedure:
To a solution of 47% aqueous HI (11 mL, 59 mmol) dissolved in DMSO (11 mL) was added dropwise at 35° C. a solution of ethyl 6-chloro-5-amino-2-(trifluoromethyl)-2H-chromene-3-carboxylate (3.8 g, 11.8 mmol) in a mixture of 11 mL of DMSO and potassium nitrite (1.63 g, 23.6 mmol) with stirring. The resulted mixture was stirred at 35° C. for 15 min, and then it was transferred into 150 mL of a solution of potassium carbonate (10 g) in ice water. The product was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium carbonate, 5% aqueous sodium hydrosulfite, and brine, dried over anhydrous magnesium sulfate. After removing the solvent, the residue was purified on silica gel column with 1:9 EtOAc/hexane. The product was obtained as 2.5 g light yellow solid. A small amount of the product was further purified on reverse phase HPLC. It gave an off-white solid. m.p=117.0-119.0° C. LC-MS (ES+): 433.2(M+1, 100); 1H NMR(CDCl3/400 MHz) 7.93(s,1H), 7.36(d, J=8.4 Hz, 1H), 6.91(d, J=8.4 Hz, 1H), 5.65(q, J=6.8 Hz, 1H), 4.33(m, 2H), 1.36(t, J=6.8 Hz, 3H). 19F NMR(CDCl3/400 Hz) −78.50(d, J=6.8 Hz). 13C NMR (CDCl3/400 MHz) 163.3, 152.3, 140.9, 133.6, 132.2, 124.7, 123.2(q, J=287.7 Hz), 119.4, 117.6, 104.5, 70.3(q, J=33.4 Hz), 62.0, 14.4. MS(EI+) 432.0(M+, 20), 363.0(M-CF3, 100). High resolution MS(EI+) m/z calc. for Cl3H9ClF3IO3: 431.9271 (M+), found: 431.9238.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](/[CH:24]=[CH:25]/[C:26]2[CH:39]=[CH:38][C:29]([C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[O:31])=[CH:28][CH:27]=2)=[N:16]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[C:70]([N:73]([CH2:75][C:76](O)=[O:77])[CH3:74])(=[O:72])[CH3:71]>>[C:70]([N:73]([CH2:75][C:76]([N:35]1[CH2:36][CH2:37][N:32]([C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26](/[CH:25]=[CH:24]/[C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:15][N:16]=3)=[CH:39][CH:38]=2)[CH2:33][CH2:34]1)=[O:77])[CH3:74])(=[O:72])[CH3:71]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN1CCOCC1
Solvent: O
Product: CC(=O)N(C)CC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 20.7 %

Procedure:
The crude product obtained using dihydrochloride of Compound 18 (300 mg, 0.741 mmol), N-methylmorpholine (0.163 mL, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (199 mg, 1.04 mmol), 1-hydroxybenzotriazole monohydrate (130 mg, 0.963 mmol) and N-acetylsarcosine (77.7 mg, 0.593 mmol) In a similar manner to Example 5, was purified by silica gel column chromatography (chloroform/methanol=90/10), followed by triturating in mixed solvent of ethyl acetate/methanol to obtain Compound 138 (54.8 mg, 25%).
Reaction SMILES: [CH:1]1([C:7]([OH:17])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CNC(=O)C1.[Br:24][Br-]Br.CCOCC>O1CCCC1>[Br:24][CH2:9][C:8](=[O:10])[C:7]([OH:17])([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C1CCCN1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CBr)C(O)(c1ccccc1)C1CCCCC1
Yield: 1158.9 %

Procedure:
1-Cyclohexyl-1-hydroxy-1-phenyl-2-propanone (2.83 g, 12.2 mmole) was added to 50 mL of dry tetrahydrofuran (THF). The solution was stirred and a solution of pyrrolidone hydrotribromide (6.08 g, 12.3 mmole) in 125 mL of dry THF was added dropwise over a period of 2 hours. After being refluxed for 4 hours, the reaction mixture was cooled. Ether was added and the solution washed twice with water and dried over magnesium sulfate. Upon evaporation of the solution to dryness, an orange oil was isolated. The product was purified by flash column chromatography (silica, hexane/ethyl acetate (99:1 followed by 95:5) to afford 3-bromo-1-hydroxy-1-cyclohexyl-1-phenyl-2-propanone (1 44 g, 37.7%). NMR (CDCl3) 1.0-2.0 (m, 10 H), 2.4 (m, 1 H), 3.5 (s, 1 H), 4.1 (s, 1 H), 7.2-7.6 (m, 5 H).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([OH:22])=[CH:8][C:7]=1Cl.C1(O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:21])[C:10]=2[C:9]([OH:22])=[CH:8][C:7]=1[O:3][CH2:2][CH2:1][OH:4]
Reactant: Nc1c(Cl)cc(O)c2c1C(=O)c1ccccc1C2=O
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Oc1ccccc1
Product: Nc1c(OCCO)cc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
47 parts of ethylene glycol, 13.7 parts of 1-amino-4-hydroxy-2-chloroanthraquinone, 24 parts of N-methylpyrrolidone, 1.2 parts of phenol and 6 parts of potassium carbonate are heated for 6 hours at 120°-125°C under nitrogen. After working up, 10.5 parts of 1-amino-2-(2'-hydroxyethoxy)-4-hydroxyanthraquinone are obtained.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][NH:16][C:17]1[N:22]=[C:21]([CH2:23][CH2:24][OH:25])[CH:20]=[CH:19][CH:18]=1.O[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[CH:30]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:15][NH:16][C:17]1[N:22]=[C:21]([CH2:23][CH2:24][O:25][C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[NH:32][C:31]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:30]3)[CH:20]=[CH:19][CH:18]=1
Reactant: CNc1cccc(CCO)n1
Reactant: COC(=O)CCc1cc2cc(O)ccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CNc1cccc(CCOc2ccc3[nH]c(CCC(=O)O)cc3c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
Diisopropyl azodicarboxylate (0.19 g, 0.94 mmol) was added to a solution of 2-[6-(methylamino)-2-pyridyl]ethan-1-ol (0.10 g, 0.66 mmol), as prepared in step e of Example 5, methyl 3-(5-hydroxyindolyl)propanoate (0.10 g, 0.46 mmol), as prepared in the preceding step, and triphenylphosphine (0.24 g, 0.92 mmol) in tetrahydrofuran (5.0 mL) at 0° C. in an ice bath. After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (20%-30% ethyl acetate in hexane) to give the title compound as a yellow oil (0.023 g, 15%). 1H-NMR (400 M Hz, CDCl3) δ 7.39 (t, J=7.3 Hz, 1H), 7.20 (d, J=8.9 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 7.07 (d, J=3.1 Hz, 1H ), 6.87 (dd, J=2.4, 8.9 Hz, 1H), 6.56 (d, J=7.2 Hz, 1H), 6.37 (d, J=3.1 Hz, 1H), 6.24 (d, J=8.2 Hz, 1H), 4.56 (br s, 1H), 3.40 (t, J=6.9 Hz, 2H), 4.34 (t, J=7.0 Hz, 2H), 3.65 (s, 3H), 3.10 (t, J=7.0 Hz, 2H), 2.89 (d, J=4.8 Hz, 2H), 2.80 (t, J=6.9 Hz, 2H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[OH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:28]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: Oc1cccnc1
Product: Clc1ccc(-c2cnc(Oc3cccnc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-hydroxypyridine according to the procedure described in Example 74 to afford 2-(3-pyridyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=428 (M++1); Rt=3.49 min; 1H-NMR 400 MHz (CDCl3): δ 7.05 (d, J=9 Hz, 2H), 7.19-7.30 (m, 4H), 7.38-7.42 (m, 2H), 7.65 (m, 1H), 8.55 (d, J=6 Hz, 1H), 8.60 (s, 1H), 8.65 (d, J=2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[NH2:13][CH2:14][CH:15]([OH:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:13]([CH2:14][CH:15]([OH:17])[CH3:16])[CH2:11]2
Reactant: CC(O)CN
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Product: CC(O)CN1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and 1-amino-2-propanol (Aldrich Cat No. 110248). LCMS (M+H)+=270.0/272.0.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)[CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17](O)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)C(C)C)C>C1COCC1.C(Cl)Cl.CO>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:6]2[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]3[NH:15][C:14]4[C:9]([C:8]=3[CH:7]=2)=[CH:10][CH:11]=[C:12]([C:17]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:18])[CH:13]=4)[CH:25]=[CH:24][CH:23]=1
Reactant: C1COCCN1
Reactant: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)O)ccc4c3c2)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCCl
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCOCC5)ccc4c3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carboxylic acid (36 mg, 0.100 mmol), morpholine (17 mg, 0.2 mmol), EDC (23 mg, 0.12 mmol), HOBt (18 mg, 0.12 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.035 mL, 0.2 mmol) in a mixture of THF (5 mL) and CH2Cl2 (1 mL) was stirred at room temperature overnight. This was diluted with MeOH and the product was isolated by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=90:10 and ending with A:B=30:70 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min) followed by removal of the solvents. This afforded 29 mg of 3-(3-methoxyphenyl)-7-(morpholine-4-carbonyl)-9H-carbazole 1-carboxamide as a solid. MS (ESI) m/z 430.2 (M+H). 1H NMR (MeOD) δ ppm 8.42 (1H, s), 8.13 (1H, d, J=7.94 Hz), 8.05 (1H, s), 7.57 (1H, s), 7.32-7.41 (2H, m), 7.29 (1H, d, J=7.63 Hz), 7.21-7.26 (1H, m), 6.85-6.93 (1H, m), 3.88 (3H, s), 3.43-3.84 (8H, m).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=O)(C)(C)C.O1CCCC1.O.[OH-].[Na+].Cl>O>[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 18 h

Procedure:
Combine (1-(t-butoxycarbonyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (3.2 g, 7.7 mmol), tetrahydrofuran/water (200 mL/200 mL). Add a 1 M aqueous solution of sodium hydroxide (8.4 mL, 8.4 mmol). Heat to reflux. After 18 hours, concentrate the reaction mixture in vacuo to form a solid. Dillute with water, adjust the pH to about 7 using a 1 M aqueous solution of hydrochloric acid, collect the solid by filtration, and dry to give (1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine: Rf=0.38 (silica gel, 20/1 ethyl acetate/methanol).
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][C:6]=2[O:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:28]12[NH:35][CH:32]([CH2:33][CH2:34]1)[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]2>CC#N.CN(C=O)C>[S:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:21]=[C:13]1[O:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:2][N:35]3[CH:28]4[CH2:34][CH2:33][CH:32]3[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]4)=[CH:4][O:5][C:6]=2[CH:11]=1
Reactant: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Reactant: CC(=O)N1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)N1CC2CCC(C1)N2Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
To a solution of 2-(3-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (120 mg, 0.31 mmol) in CH3CN/DMF (4:1, 3 mL) was added K2CO3 (169 mg, 1.2 mmol) followed by 1-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone (47 mg, 0.31 mmol) and the reaction mixture was stirred (rt, 48 h). The reaction mixture was partitioned between DCM (10 mL) and sat. NaHCO3 (5 mL). The organic layer was separated and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (47 mg, 35%). MS (ESI): mass calcd. for C23H22N4O3S, 434.14; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.7, 1H), 7.84 (d, J=8.5, 1H), 7.63-7.56 (m, 2H), 7.29 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 4.20 (dd, J=12.7, 1.5, 1H), 3.72-3.58 (m, 2H), 3.48-3.19 (m, 4H), 2.89 (d, J=12.3, 1H), 2.06 (s, J=2.8, 3H), 2.03-1.93 (m, 2H), 1.72-1.63 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([N:9]=CC2C=CC=CC=2)[CH:4]=[C:5]([CH2:7][CH3:8])[N:6]=1.[ClH:17]>>[ClH:17].[NH2:9][N:3]1[CH:4]=[C:5]([CH2:7][CH3:8])[N:6]=[C:2]1[NH2:1]
Reactant: CCc1cn(N=Cc2ccccc2)c(N)n1
Agent: Cl
Product: CCc1cn(N)c(N)n1
Temperature: 120 °C

Procedure:
A mixture of 4.29 g (0.02 mol) of 2-amino-1-benzylideneamino-4-ethyl-imidazole and 25 ml of 2N hydrochloric acid is heated to 120° C. and subjected to steam distillation for one hour. The distillation residue is cooled and then concentrated to dryness by evaporation, and the residue is crystallized from ethanol/ethyl acetate. In that manner there is obtained the title compound, m.p. 124°-125° C., 1H-NMR (DMSO/D2 0) δ=6.53 (s, 1H); 2.36 (q, 2H); 1.07 (t, 3H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[C:23]([N:42]1[CH:46]=[C:45]([CH:47]=[O:48])[N:44]=[CH:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[OH:48][CH:47]([C:45]1[N:44]=[CH:43][N:42]([C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:46]=1)[CH:15]1[CH2:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]1=[O:9]
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C(O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Lithium diisopropylamide (8 ml, 1.5M in cyclohexane, 12 mmol) was added dropwise over 5 minutes to a cooled (−78° C.) solution of tert-butyl 2-oxo-1-piperidinecarboxylate (J. Org. Chem. 1983, 48, 2424; J. Chem. Soc. I, 1989, 721) (1.99 g, 10 mmol) in tetrahydrofuran (40 ml), so as to maintain a temperature below −70° C. Once addition was complete, the solution was stirred for 20 minutes. A solution of 1-tritylimidazole-4-carboxaldehyde (J. Med. Chem. 1977, 20, 721) (4.06 g, 12 mmol) in tetrahydrofuran (60 ml) was added slowly, and once addition was complete, the reaction was stirred at −78° C. for 2 hours. Saturated aqueous ammonium chloride solution (50 ml) was added, the mixture allowed to warm to room temperature and then partitioned between water (50 ml) and ethyl acetate (300 ml). The phases were separated, the organic layer dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound, 5.3 g, 99% yield.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[Cl:35][C:36]1[N:41]=[C:40](O)[C:39]([NH:43][C:44](=[O:51])[C:45]2[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=2)=[CH:38][N:37]=1>ClCCCl>[Cl:35][C:36]1[N:37]=[CH:38][C:39]2[N:43]=[C:44]([C:45]3[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=3)[O:51][C:40]=2[N:41]=1
Reactant: O=C(Nc1cnc(Cl)nc1O)c1ccncc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Clc1ncc2nc(-c3ccncc3)oc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
12.0 g (35.9 mmol) polymer bound triphenylphosphine and 5.03 mL (35.9 mmol) triethylamine are added to 4.77 g (20.0 mmol) hexachloroethane in 40 mL 1,2-dichloroethane. The mixture is stirred for 5 min at rt. 1.00 g (4.0 mmol) N-(2-chloro-4-hydroxy-pyrimidin-5-yl)-isonicotinamide in 20 mL 1,2-dichloroethane are added and the mixture is stirred for 12 h at rt. Subsequently the mixture is concentrated in vacuo, treated with diethyl ether, filtered, and concentrated again. The residue is purified by HPLC (reversed phase; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:16]=1[CH3:33].[CH3:34][O:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[N:40][CH:41]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[F:25][C:23]1[CH:22]=[C:21]([F:26])[CH:20]=[C:19]2[C:24]=1[C:15]([NH:14][C:3]1[CH:4]=[C:5]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=1[C:38]1[CH:39]=[N:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=1)=[C:16]([CH3:33])[C:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)=[N:18]2
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1Cl
Reactant: COc1cncc(B(O)O)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cncc(-c2ccc(N3CCOCC3)cc2Nc2c(C)c(-c3ccccn3)nc3cc(F)cc(F)c23)c1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
N-(2-chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (62.7 mg, 0.13 mmol), 5-methoxypyridin-3-ylboronic acid (31.9 mg, 0.21 mmol), tricyclohexylphosphine (6.3 mg, 0.022 mmol), and tris(dibenzylideneacetone)dipalladium (0) (10.6 mg, 0.012 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (2.0 mL) and aq. 1.3M potassium phosphate tribasic (0.31 mL, 0.4 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 22 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-45% of a premixed solution of 89:9:1 DCM:MeOH:ammonium hydroxide in DCM) to afford a yellow film that was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a yellow solid as 5,7-difluoro-N-(2-(5-methoxypyridin-3-yl)-5-morpholinophenyl)-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.69 (1H, d, J=4.4 Hz), 8.42 (1H, d, J=1.7 Hz), 8.28 (1H, d, J=2.7 Hz), 7.88 (1H, td, J=7.6, 1.7 Hz), 7.82 (1H, d, J=7.8 Hz), 7.71 (1H, m), 7.43 (2H, m), 7.22 (1H, d, J=8.6 Hz), 6.93 (1H, dd, J=8.4, 2.6 Hz), 6.95 (1H, dd, J=8.6, 2.4 Hz), 6.65 (1H, dd, J=8.4, 2.3 Hz), 6.36 (1H, d, J=2.2 Hz), 3.89 (3H, s), 3.86 (4H, m), 3.21 (4H, m), 2.18 (3H, s). Mass Spectrum (pos.) m/e: 540.1 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.CC1CCCCC1N>C(O)(=O)C>[CH3:24][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: CC1CCCCC1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: CC1CCCCC1n1cnc2c(-c3ccccc3)csc2c1=O
Yield: 47.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 2-methylcyclohexanamine (0.120 ml, 0.90 mmol), and acetic acid (0.1 ml) were used to give 65.9 mg (0.20 mmol, 47.2% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15]CC2C=CC=CC=2)=[O:14])[N:10]([C:23](=[O:41])[C@@H:24]([NH:26][C@H:27]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:25])[C:9]1=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:23](=[O:41])[C@@H:24]([NH:26][C@H:27]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH3:25])[C:9]1=[O:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Yield: 89.9 %

Procedure:
2.6 g of benzyl (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylate and 100 mg of palladium black are treated in the same manner as described in Example 1-(2), whereby 1.97 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid 1/4 hydrate are obtained as colorless crystals. Yield: 89.1%
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH:7]=[CH2:8].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]>C(OCC)C>[OH:13][CH:12]([C:11]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:10]=1[F:9])[CH2:8][CH2:7][CH:6]=[CH2:5]
Reactant: O=Cc1ccc(F)cc1F
Reactant: C=CCCBr
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCC(O)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
To a stirred suspension of magnesium turnings (16.9 gm) in dry diethyl ether (1.5L) was added (argon atmosphere) a crystal of iodine and 4-bromobutene (2 ml). Soon after the reaction was initiated the remaining 4-bromobutene (101 gm) in dry diethyl ether (500 mL) was added at such a rate to maintain gentle reflux. After complete addition, the mixture was heated to reflux for 1 hour. 2,4-Difluorobenzaldehyde (100 gm) in dry diethyl ether (400 mL) was then added dropwise with a gentle reflux. The mixture was now heated for 2 hours and allowed to cool to room temperature. The entire contents of the flask were poured on 6L ice-water containing 200 ml concentrated HCl. The organic phase was separated, washed with water, saturated NaHCO3, water and dried (Na2SO4). Removal of ether in vacuo provided crude 5-hydroxy-5-(2,4-difluorophenyl)pentene as an oil (136.5 gm) which was used in the next step.