Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH2:23])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:31])[C@@H:22]([NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:19]
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N2CCC(=O)CC2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from 4-(4-oxo-piperidin-1-yl)-benzoic acid (which was obtained in Example 151) and L-glutamic acid diethyl ester hydrochloride according to the procedure of Example 154 as a yellowish gum; 1H NMR (300 MHz, CDCl3) δ 1.22 (t, J=7.1 Hz, 3 H), 1.31 (t, J=7.1 Hz, 3 H), 2.10–2.50 (m, 4 H), 2.57 (t, J=6.1 Hz, 4 H), 3.73(t, J=6.1 Hz, 4 H), 4.10–4.30(m, 4 H), 4.70–4.85(m, 1 H), 6.90 (d, J=7.5 Hz, 1 H), 7.08(d, J=8.9 Hz, 2 H), 7.78(d, J=8.9 Hz, 2 H); MS (ES) m/z: 405.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[S:25][CH:26]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:21][C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[S:25][CH:26]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1csc(-c2ccc(C(C)C)cc2)n1)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethyl]-1H-indol-4-yl}-propionic acid as light brown solid.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:36]([C:38]1[CH:39]=[C:40]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[C:41]([F:46])=[C:42]([CH:45]=1)[CH:43]=[O:44])[CH3:37]>C1COCC1>[CH2:36]([C:38]1[CH:39]=[C:40]([N:47]2[CH2:48][CH2:49][O:50][CH2:51][CH2:52]2)[C:41]([F:46])=[C:42]([CH:43]([C:9]2[N:10]([C:12]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[OH:44])[CH:45]=1)[CH3:37]
Reactant: CCc1cc(C=O)c(F)c(N2CCOCC2)c1
Reactant: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 82.2 %

Procedure:
To a solution of Intermediate 8.1 (122 mg, 0.316 mmol) in 2 mL THF at 0° C., was added BuLi (1.6 M in THF, 0.236 mL, 0.379 mmol). The mixture was stirred at 0° C. for 45 min, then a solution of Intermediate 406.1 (75 mg, 0.316 mmol) in 0.9 mL THF was added dropwise. The mixture was stirred at rt for 30 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 60% EtOAc/hexanes gradient) to afford 162 mg of Intermediate 406.2 as a colorless glass. LCMS (2 min gradient) RT=1.93 min, 624.26 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:12](\[CH:15]2[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH2:16]2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1.[CH3:32][NH2:33]>CO>[CH3:32][NH:33][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:12](\[CH:15]2[CH2:24][CH2:23][C:18]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:17][CH2:16]2)/[CH2:13][CH3:14])=[CH:7][CH:6]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC2(CC1)OCCO2
Reactant: CN
Solvent: CO
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC2(CC1)OCCO2
Temperature: 85 °C

Procedure:
A mixture of (Z)-4-(1-(4-(2-chloroethoxy)phenyl)-2-(1,4-dioxaspiro[4.5]decan-8-yl)but-1-enyl)phenol (90 mg, 0.20 mol), 30% aqueous of CH3NH2 (5 mL), and MeOH (5 mL) was heated at 85° C. in a sealed tube overnight, concentrated, and purified by column chromatography to give the desired product (90 mg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: C1COCCN1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(N2CCOCC2)c(-c2ccccc2)n1
Yield: 24.3 %

Procedure:
6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (50 mg, 20%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and morpholine (0.126 g, 1.44 mmol) according to the general procedure of Example 2.
Reaction SMILES: NC1N=CN=C2N(C(C3OC(=O)C4C(C=3C3C=CC=CC=3)=CC=CC=4)C)N=C(C3C=NC(N)=NC=3)C=12.[C:37]([N:40]1[CH2:45][CH:44]=[C:43]([C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49](=[O:56])[O:48][C:47]=2[CH:57]([N:59]2[C:63]3=[N:64][CH:65]=[N:66][C:67]([NH2:68])=[C:62]3[C:61](I)=[N:60]2)[CH3:58])[CH2:42][CH2:41]1)(=[O:39])[CH3:38].[F:70][C:71]1[CH:72]=[C:73](B(O)O)[CH:74]=[C:75]([OH:77])[CH:76]=1>>[C:37]([N:40]1[CH2:45][CH:44]=[C:43]([C:46]2[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49](=[O:56])[O:48][C:47]=2[CH:57]([N:59]2[C:63]3=[N:64][CH:65]=[N:66][C:67]([NH2:68])=[C:62]3[C:61]([C:73]3[CH:74]=[C:75]([OH:77])[CH:76]=[C:71]([F:70])[CH:72]=3)=[N:60]2)[CH3:58])[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: CC(=O)N1CC=C(c2c(C(C)n3nc(I)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Reactant: OB(O)c1cc(O)cc(F)c1
Agent: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(N)nc2)c2c(N)ncnc21
Product: CC(=O)N1CC=C(c2c(C(C)n3nc(-c4cc(O)cc(F)c4)c4c(N)ncnc43)oc(=O)c3ccccc23)CC1
Yield: 43.5 %

Procedure:
The title compound was mane in a similar way as that or the compound of example 51 from 4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-1H-isochromen-1-one (Intermediate D12, 1.08 g, 1.941 mmol), (3-fluoro-5-hydroxyphenyl)boronic acid (0.605 g, 3.88 mmol), to give the title compound (456 mg, 43.5%) as a pale grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([F:13])[S:10][C:9]=2[CH2:14][O:15]C2CCCCO2)=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([F:13])[S:10][C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(COC2CCCCO2)s1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: OCc1sc(F)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask, was placed 2-[[3-(4-chlorophenyl)-5-fluorothiophen-2-yl]methoxy]oxane (1.6 g, 4.90 mmol, 1.00 equiv), ethanol (100 mL), PPTS (120 mg, 0.48 mmol, 0.10 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 0.7 g (59%) of [3-(4-chlorophenyl)-5-fluorothiophen-2-yl]methanol as yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:21][C:3]1[C:4]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=1
Reactant: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)cccc1-c1cccc(C(F)(F)F)c1

Procedure:
In analogy to the procedure described for example 1, (3-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 2) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as dark brown amorphous solid. MS: 417.3 (MH+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[OH-].[Na+].[C:13]1(=O)[CH2:18][CH2:17][CH2:16][C:15](=[O:19])[CH2:14]1>O>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[C:13]2[CH2:18][CH2:17][CH2:16][C:15]([OH:19])=[CH:14]2)=[CH:5][CH:4]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C1CCCC(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC1=CC(=NNc2ccc(F)cc2)CCC1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
A suspension of 4-fluorophenylhydrazine hydrochloride (50 g) in water (500 ml) was treated with sodium hydroxide (12.3 g) in water (50 ml) and the resultant solution added to solution of cyclohexane-1,3-dione (97%, 35.6 g) in water (300 ml) over 2 h under nitrogen with stirring. After a further 30 min, the precipitate was filtered off, washed with water (50 ml), air dried for 1 h, and dried in vacuo over phosphorus pentoxide at 75° to give the title compound as a powder (65.3 g) m.p. 175°-176°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][NH2:18].Cl>C1(C)C=CC=CC=1>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][N:18]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCc1cccs1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1Cc1cccs1
Yield: 91.2 %

Procedure:
To a solution of commercially available phthalic anhydride 1 (500 mg, 3.38 mmol) in toluene (30 mL) at room temperature was added thiophene-2-methylamine (463 mg, 4.1 mmol) and the resulting reaction mixture was allowed to stir at reflux for 2 hours. The reaction mixture was poured onto 1N HCl and extracted with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to provide 750 mg of 11 as a pale yellow solid (812 mg theoretical, 91% yield).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[F:40])[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 40 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester (60 mg, 0.096 mmol) in MeOH (4 mL) and THF (6 mL) was added an aqueous solution (2 N) of NaOH (1.2 mL, 2.4 mmol). The reaction mixture was heated to 40° C. and stirred overnight. The crude mixture was diluted with water (5 mL), concentrated in vacuo to remove some organic solvent. The mixture was filtered, and the filtrate was acidified to “pH” 5-6. The suspension was filtered and the solid was collected, washed with water, and dried to give the desired product as a white powder (Yield, 41 mg, 66%). MS (H+), 614.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:30]3[CH2:35][CH2:34][CH:33]([O:36][C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=4[F:44])[CH2:32][CH2:31]3)=[C:20]([NH:25][CH2:26][CH:27]([F:29])[F:28])[N:21]=2)[CH:16]1[CH3:45])C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:29][CH:27]([F:28])[CH2:26][NH:25][C:20]1[N:21]=[C:22]2[CH2:23][CH2:24][NH:15][CH:16]([CH3:45])[C:17]2=[N:18][C:19]=1[N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=2[F:44])[CH2:32][CH2:31]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1c2nc(N3CCC(Oc4ccc(F)cc4F)CC3)c(NCC(F)F)nc2CCN1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1NCCc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc21

Procedure:
A solution of 6-benzyl-N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-5-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (160 mg, 0.249 mmol) and Pd(OH)2 on carbon (17.5 mg, 0.025 mmol) in THF (1.24 mL) was purged and placed under hydrogen atmosphere (balloon) overnight. The mixture was filtered through Celite™ and concentrated to give title compound as its TFA salt (136 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]2[N:18]=[CH:19][CH:20]=[CH:21][C:9]=2[N:8]=1.[H-].[Na+].[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28]Cl>>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:9]2[CH:21]=[CH:20][CH:19]=[N:18][C:10]1=2
Reactant: c1ccc(C2=Nc3cccnc3Nc3ccccc32)nc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCN1c2ccccc2C(c2ccccn2)=Nc2cccnc21

Procedure:
Following the procedure of Example 23, 6-(2-pyridinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine is reacted with sodium hydride followed by reaction with 3-dimethylaminopropyl chloride to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[CH3:34])[N:27]([CH3:35])[CH:26]=2)[C:14]1=[O:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O.[OH-].[Li+]>O1CCOCC1.O>[C:22]([C:19]1[N:18]=[C:17]2[N:13]([C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][C:4]([OH:37])=[O:3])[C:14](=[O:36])[N:15]([CH2:24][C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][C:32]=4[CH3:34])[N:27]([CH3:35])[CH:26]=3)[C:16]2=[CH:21][CH:20]=1)#[N:23]
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C#N)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc2c1c(Cn1c(=O)n([C@H](CC(=O)O)c3ccccc3)c3nc(C#N)ccc31)cn2C
Reaction time: 6 h
Yield: 38.4 %

Procedure:
To a stirred solution of (R)-3-[5-cyano-1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl]-3-phenyl-propionic acid ethyl ester (70 mg, 0.14 mmol) in dioxane (4 ml) and water (2 ml) was added lithium hydroxide monohydrate (12 mg, 0.28 mmol) at room temperature. After stirring for 6 hours the reaction appeared to be complete. The reaction was concentrated to a low volume and diluted with water. The reaction mixture was acidified using acetic acid and the resulting precipitate was collected via filtration. The solid was purified once by silica gel flash column chromatography (12 g silica gel, 0-10% MeOH/Dichloromethane) and then again by preparative TLC (2×0.5 mm silica gel, 5% MeOH/Dichloromethane) to afford 25 mg (31%) of the title compound. LCMS, M++1, m/z: 466.43.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)[O:8][CH2:7][C:6]1([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:22][CH:21]=1)[CH3:19].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C.O>ClCCl.C(OCC)(=O)C.CCCCCC>[CH3:30][S:31]([O:1][CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)[O:8][CH2:7][C:6]1([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][O:28][CH3:29])=[CH:24][CH:25]=1)[CH3:19])(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCO)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-Hydroxypropyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (280 mg, 0.70 mmol) was dissolved in dichloromethane (50 ml), methanesulfonylchloride (0.32 g) and triethylamine (0.30 g) were added thereto, and the mixture was stirred at room temperature for 1 hour After the reaction was completed, the reaction mixture was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 4-(3-methanesulfonyloxypropyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (a mixture of (3RS,4RS) and (3RS,4SR), (3RS,4RS)/(3RS,4SR)=about 6/1) (350 mg, stoichiometric yield). Then, to a solution of the product (0.59 g, 1.2 mmol) in DMF (15 ml) was added sodium azide (0.14 g), and the mixture was stirred at 60° C. for 2 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to preparative TLC (n-hexane/ethyl acetate=10/1 for twice, 5/1 for twice) to produce (3RS,4RS)-4-(3-azidopropyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-m ethylchroman (220 mg, yield 42%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[NH:7][C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([C:11](=[O:14])[CH2:12]Cl)[C:4]=2[CH:3]=1.[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH2:25][CH3:26])[CH3:23]>O1CCOCC1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[NH:7][C:8]3[CH:18]=[CH:17][CH:16]=[N:15][C:9]=3[N:10]([C:11](=[O:14])[CH2:12][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH:28]3[CH2:27][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CC1CCCCN1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2cc(Cl)ccc21
Solvent: C1COCCO1
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2cc(Cl)ccc2C(=O)Nc2cccnc21

Procedure:
5.6 g (0.0174 mole) of 9-chloro-11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one were suspended in 100 ml of anhydrous dioxane and, after addition of 6.0 g (0.035 mol) of 2-[(diethylamino)methyl]piperidine, the mixture was boiled under reflux for 12 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH:22]([C:24]1[CH:36]=[CH:35][C:27]([C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1)=[O:23]>>[NH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:22]([C:24]1[CH:36]=[CH:35][C:27]([C:28]([N:30]([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:29])=[CH:26][CH:25]=1)[OH:23]
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(Br)c1
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(N)c2)cc1
Yield: 25.2 %

Procedure:
The protected aniline (23.64 g, 0.101 mol) was treated with n-butyllithium (1.5M in hexane, 66 mL, 0.101 mol) and 4-formyl-N,N -diethylbenzamide (20.70 g, 0.101 mol) as in Example11. Chromatography of the crude product on silica gel (Waters Prep 500, dichloromethane:ethanol/100:1-3) gave 7.59 g (25%) of 4-(3-amino-α-hydroxybenzyl)-N,N-diethylbenzamide as a light yellow hygroscopic solid.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)([O-:8])=[O:7]>O1CCCC1>[CH:13]([C:12]1[CH:15]=[CH:16][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1)=[CH:4][CH2:3][CH2:2][CH2:1][CH2:11][CH2:10][CH2:9][CH2:16][CH3:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC=Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
Phosphonium salt (141 g) obtained from n-nonyl bromide (115 ml) and triphenylphosphine (78.5 g) was dissolved in dry tetrahydrofuran (500 ml) and thereto was dropwise added n-butyl lithium (372 ml, 1.6M hexane solution) over not less than 1 hour at 0° C. After the dropwise addition, the reaction mixture was stirred at said temperature for 30 minutes and at room temperature for 1 hour. A solution of 4-nitrobenzaldehyde (45.3 g) in tetrahydrofuran (150 ml) was dropwise added thereto at 0° C. over 1 hour. The reaction mixture was stirred at room temperature for 10 hours and filtered. The residue was washed with ether. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate=100:1) to give 70.9 g of 4-(1-decenyl)-nitrobenzene (cis/trans=7:3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][NH2:18])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][C:32](Cl)=[O:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][NH:18][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1cc(CCCN)ccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)NCCCc2ccc(OCc3ccccc3)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 28 h
Yield: 65.3 %

Procedure:
A solution of 3-(4-benzyloxy-3-methoxy-phenyl)-propylamine (6.06 g, 22.36 mmol) and TEA (3.5 ml, 25.14 mmol) in anhydrous THF (25 ml) was cooled to 0° C. and (3,4-dimethoxy-phenyl)-acetyl chloride (4.80 g, 22.36 mmol) in THF (10 ml) was added dropwise. After stirring at RT for 28 h under nitrogen, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted three times with AcOEt. The organic phase was dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. A subsequent washing of the crude solid with toluene gave the title compound (6.57 g, 14.61 mmol, 65%) as a beige solid.