Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:38][C:35]1[N:34]=[CH:33][C:32]([CH2:31][CH2:30][N:7]2[C:8]3[CH2:16][CH:15]4[N:11]([CH2:12][CH2:13][CH2:14]4)[CH2:10][C:9]=3[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)=[CH:37][CH:36]=1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4cccnc42)CN2CCCC2C3)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (70 mg, 0.328 mmol) in DMF (1 mL) was added a suspension of NaH (40.0 mg, 0.986 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (287 mg, 0.986 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h at RT. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (MeOH-DCM) to yield 11-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9](=O)[NH:10][CH:11]=[N:12]2)[CH3:5].[CH3:20][C:21]1[S:22][C:23]([CH2:26][N:27]2[C:35]3[C:30](=[CH:31][C:32]([NH2:36])=[CH:33][CH:34]=3)[CH:29]=[N:28]2)=[CH:24][N:25]=1>>[CH3:1][N:2]([CH3:19])[C:3](=[O:18])[C@H:4]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[C:9]([NH:36][C:32]1[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=1)[N:27]([CH2:26][C:23]1[S:22][C:21]([CH3:20])=[N:25][CH:24]=1)[N:28]=[CH:29]3)=[N:10][CH:11]=[N:12]2)[CH3:5]
Reactant: Cc1ncc(Cn2ncc3cc(N)ccc32)s1
Reactant: C[C@@H](Oc1cccc2nc[nH]c(=O)c12)C(=O)N(C)C
Product: Cc1ncc(Cn2ncc3cc(Nc4ncnc5cccc(O[C@H](C)C(=O)N(C)C)c45)ccc32)s1
Yield: 61.5 %

Procedure:
Using the same procedure as in Example 18, (2R)—N,N-dimethyl-2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]propanamide (261 mg, 1 mmol) and 1-[(2-methyl-1,3-thiazol-5-yl)methyl]-1H-indazol-5-amine (269 mg, 1.1 mmol) were reacted to give the title compound as a white solid (300 mg, 61%); NMR Spectrum (CDCl3) 1.73 (d, 3H), 2.62 (s, 3H), 3.07 (s, 3H), 3.15 (s, 3H), 5.43 (q, 1H), 5.71 (s, 2H), 6.82 (d, 1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.61 (m, 2H), 7.86 (dd, 1H), 8.05 (s, 1H), 8.42 (s, 1H), 8.62 (s, 1H); Mass spectrum 488.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:12][N:11]=1)=[O:9])([CH3:3])[CH3:2].C([N:34](CC)CC)C.ClC(OCC(C)C)=O.[OH-].N>C1COCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][CH2:25][C:26]([NH2:34])=[O:28])=[CH:12][N:11]=1)=[O:9])([CH3:3])[CH3:2]
Reactant: COc1cc2c(CCC(=O)O)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2c(CCC(N)=O)cnc(C(=O)c3cccc(OC(C)C)c3)c2cc1OC
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
The above carboxylic acid (70.3 mg) was dissolved in 6 ml of THF. Then at −30° C., triethylamine (0.055 ml) was added followed by isobutyl chloroformate (0.034 ml). The mixture was stirred at −20° C. for 30 minutes. Then 30% ammonia hydroxide solution (0.15 ml) was added. The mixture was stirred at room temperature overnight and then purified through a reverse preparative HPLC to give 3-[1-(3-Isopropoxy-benzoyl)-6,7-dimethoxy-isoquinolin-4-yl]-propionamid as a fluffy solid (47.2 mg). ES-MS calcd for C24H26N2O5 (m/e) 422.5, obsd 423.4 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(O[BH-](O[C:24](=[O:26])[CH3:25])OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:6][C:5]2[O:26][C:24]3[C:25](=[N:8][CH:3]=[CH:2][CH:7]=3)[CH:4]=2)[CH2:10][CH2:9]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: Fc1ccccc1N1CCN(Cc2cc3ncccc3o2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-(2-Fluorophenyl)piperazine (0.18 g, 1.0 mmol) and sodium triacetoxyborohydride (0.32 g, 1.5 mmol) in dichloroethane (2 mL) were treated with the product from Example 35B (2 mL, 1.0 mmol) as a 0.5M solution in dichloroethane dropwise. The mixture was allowed to stir at room temperature for 17 hours. The mixture was diluted with dichloromethane (10 mL) and washed with 1N NaOH. The organic layer was dried over magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica (dichloromethane to 2% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3, 400 MHz) δ 2.81 (br, 4H), 3.19 (br, 4H), 3.85 (s, 2H), 6.89 (s, 1H), 7.00 (m, 4H), 7.20 (dd, J=4.75, 8.14 Hz, 1H), 7.74 (d, J=8.48 Hz, 1H), 8.52 (d, J=4.75 Hz, 1H); MS (DCI/NH3) m/z 312.2 (M+H)+; Anal. Calcd for C18H18FN3O: C, 69.44; H, 5.83; N, 13.50. Found: C, 69.36; H, 5.59; N, 13.28.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([CH3:44])[CH:38]=1)([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[C:26]([CH3:36])[CH:25]=1)[CH2:22][CH3:23])[CH3:20]>O1CCCC1>[CH2:19]([C:21]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([CH3:44])[CH:38]=1)([C:24]1[CH:29]=[CH:28][C:27]([C:30]#[CH:31])=[C:26]([CH3:36])[CH:25]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#C[Si](C)(C)C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (78.3 mL, 78.3 mmol) was added to a solution of 4-[1-ethyl-1-(3-methyl-4-trimethylsilanylethynyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(2); 19.03 g, 52.19 mmol) in tetrahydrofuran (520 mL) at room temperature. The mixture was stirred at 0.5 hour and concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane/ethyl acetate=10/1) to give the title compound (15.6 g, 94%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:2][N:3]([CH2:4][CH2:5][CH2:6][S:16][C:13]1[CH:14]=[CH:15][C:10]([Br:9])=[CH:11][CH:12]=1)[CH3:8]
Reactant: CN(C)CCCCl
Reactant: Sc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCSc1ccc(Br)cc1
Temperature: 60 °C
Yield: 95.7 %

Procedure:
3-(Dimethylamino)propyl chloride hydrochloride (3.48 g, 22 mmol) was added in portions to a suspension of 4-bromothiophenol (3.78 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in DMF (40 ml) and the reaction mixture heated to 60° C. for 15 minutes. The mixture was allowed to cool to ambient temperature and poured into water (100 ml) and extracted with EtOAc (2×100 ml). The extracts were combined, washed with brine (3×100 ml), dried (Chemelut column 1010) and evaporated to give the title compound (5.25 g, 96%) as a pale yellow oil. NMR 1.76 (m, 2H), 2.20 (s, 6H, 2.35 (t, 2H, 2.93 (t, 2H), 7.18 (d, 2H, 7.38 (d, 2H); m/z 276.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:4][CH:3]=1.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(I)cc1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(I)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To a solution of trans-2-(4-iodophenyl)cyclopropanamine (420 mg, 1.621 mmol) in methanol (7 mL) were added methyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (466 mg, 1.783 mmol), sodium cyanoborohydride (204 mg, 3.24 mmol), and acetic acid (0.028 mL, 0.486 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was then quenched with saturated NaHCO3 aqueous solution (2 ml) and concentrated. The residue was treated with water (4 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 10% MeOH/EtOAc) to give 241 mg of product as pale yellow solid. MS: (M+H)+=505.3 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.97-1.16 (m, 2H), 1.19-1.38 (m, 2H), 1.46-1.63 (m, 1H), 1.71-1.92 (m, 3H), 2.00-2.10 (m, 2H), 2.29 (ddd, J=7.45, 4.42, 3.28 Hz, 1H), 2.56-2.65 (m, 2H), 2.86-2.98 (m, 2H), 3.56-3.66 (m, 2H), 3.89-3.98 (m, 3H), 6.80-6.92 (m, 2H), 7.43-7.62 (m, 4H), 7.94-8.05 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[O:10][CH2:11][C@@H:12]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[Cl:39])=[O:29])[CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[N:6][CH:7]=1.NN>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:41])[O:10][CH2:11][C@@H:12]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[Cl:39])=[O:29])[CH2:13][CH2:14][CH2:15][NH2:16])=[N:6][CH:7]=1
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN1C(=O)c2ccccc2C1=O)COC(=O)Nc1ccc(Cl)cn1
Agent: NN
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(1,3-dioxoisoindolin-2-yl)pentyl 5-chloropyridin-2-ylcarbamate (280 mg, 0.47 mmol) in MeOH (5.0 mL) was added NH2NH2 (0.13 mL, 4.7 mmol). The reaction mixture was stirred at RT for 2 h. The mixture was concentrated and re-dissolved in MeOH. The resulting solution was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 5-chloropyridin-2-ylcarbamate (162 mg, 73%). LRMS (M+H+) m/z 472.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)=[C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1>CCO.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:20]3[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=3)=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:11][CH:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1
Reactant: CCOC(=O)/C=C/c1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1scc(-c2ccc(Cl)cc2OC)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
To a solution of (E)-ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)acrylate (280 mg, 0.61 mmol) in EtOH (5 mL) was added Pd/C (50 mg). After the mixture was stirred at room temperature under H2 atmosphere for 4 hours, the mixture was filtered and concentrated in vacuo to give ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(4-hydroxyphenyl)thiophen-2-yl)propanoate (Scheme II, 11, X1=4-hydroxyphenyl, X2=4-chloro-2-methoxyphenyl) (220 mg, yield 78%). 1H NMR (DMSO-d6 400 MHz): δ 9.34 (s, 1H), 7.26 (s, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.0 Hz, 2H), 6.64 (d, J=8.4 Hz, 2H), 4.04 (q, J=7.2 Hz, 2H), 3.40 (s, 3H), 2.96 (t, J=7.6 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:7]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])=[O:8].Cl.[NH2:25][OH:26].C([O-])(=O)C.[K+]>CO>[OH:26][N:25]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[S:7]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])=[O:8]
Reactant: O=C1CCCCC1S(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=S(=O)(C1CCCCC1=NO)N1CCN(c2ccc(F)cc2)CC1
Temperature: 70 °C
Yield: 96.5 %

Procedure:
A mixture of 1-(cyclohexanone-2-sulfonyl)-4-(4-fluorophenyl)piperazine (50 mg, 0.14 mmol), hydroxylamine hydrochloride (51 mg, 0.73 mmol) and potassium acetate (72 mg, 0.73 mmol) in methanol (5 ml) was heated at 70° C. for 4 h. The solvents were evaporated. After partitioning between EtOAc and water, the organic layer was washed with brine and dried over MgSO4 to give 1-[2-(N-hydroxyimino)cyclohexane-1-sulfonyl]-4-(4-fluorophenyl)piperazine as a white solid (48 mg, 94%): MS (ESI): 356 (MH+).
Reaction SMILES: C([NH:4][CH2:5][CH2:6][C:7]1[CH:49]=[CH:48][CH:47]=[CH:46][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1)(=O)C.[H-].[Na+].CI>CN(C)C=O>[C:8]([CH2:46][NH:4][CH2:5][CH2:6][C:7]1[CH:49]=[CH:48][CH:47]=[CH:46][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])=[CH:23][CH:24]=2)[CH2:17][CH2:16][N:15]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:14]1)(=[O:9])[CH3:7]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNC(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCNCC(C)=O)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.099 g of tert-butyl 3-{2-[2-(2-acetylaminoethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 14a) in 3 ml of N,N-dimethylformamide is admixed with stirring at room temperature with 0.023 g of sodium hydride dispersion (55%). After 30 minutes at room temperature, a solution of 0.055 ml of methyl iodide in 0.4 ml of N,N-dimethylformamide is added dropwise. The reaction mixture is stirred at 75° C. over 18 hours, cooled, poured onto water and extracted with tertbutyl methyl ether (2×). The combined organic phases are dried with sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.09 (1.5:1 EtOAc-heptane); Rt=5.84.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7](OC)=[O:8])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.C1(C)C=CC=CC=1>[OH:8][C:7]1[C:6]2[C:5](=[CH:14][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:12][CH:11]=2)[NH:4][C:1](=[O:3])[CH:2]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1cc(O)c2ccc(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 64.6 %

Procedure:
To a solution of the product of step 2 (3.0 g) in THF (60 ml) was added 0.5 M KHMDS in toluene (108 ml) dropwise at −78° C. After the addition was completed, the mixture was kept at −78° C. for 40 minutes, then it was allowed to warm up slowly at room temperature. The mixture was quenched with H2O and the product was extracted twice with water. The combined aqueous layers were washed with ethyl acetate twice and then acidified with 6N HCl. The solid was filtered and the filter cake was washed with water and dried by vacuum aspiration to get a beige solid which was triturated into ethyl acetate to get a white solid (1.7 g). LRMS (ES+) m/z 230.05 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:28]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=[C:25](Cl)[N:24]=3)=[O:22])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(OCC)(=O)C.C(N(CC)CC)C.[Pd]>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:28]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=[CH:25][N:24]=3)=[O:22])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(N2CCOCC2)nc(Cl)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a mixture of 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide (95 mg) and 10% Pd/C (10 mg) in ethyl acetate (4 ml) is added a few drops of triethylamine. The mixture is then shaken at room temperature under hydrogen at 50 psi for 8 h. The solvent is then removed under reduced pressure and the residue purified by column chromatography on silica gel eluted with ethyl acetate:hexane (1:1) to 100% ethyl acetate to provide 6-morpholin-4-yl-pyrimidine-4-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide as a solid (22 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[O:10][CH3:11].C([Li])CCC.[I:17]I.OS([O-])=O.[Na+]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([I:17])=[C:4]([F:9])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(F)cc(F)cc1Cl
Reactant: II
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1c(Cl)cc(F)c(I)c1F
Temperature: -72.5 °C
Reaction time: 1.25 h
Yield: 92.6 %

Procedure:
2-Chloro-4,6-difluoroanisole (2.0 g, 11 mmol) was dissolved in 20 mL anhydrous THF and cooled to −70 to −75° C. 2.5M n-Butyl lithium in hexanes (6.7 mL, 17 mmol) was added dropwise. After stirring for 75 minutes at −75° C., the mixture was treated dropwise with a solution of iodine (5.1 g, 20 mmol) in 10 mL THF. After stirring for 20 minutes, the reaction solution was allowed to warm to 25° C. over 40 minutes. The reaction mixture was diluted with Et2O (50 mL) and stirred with dilute NaHSO3 solution to destroy excess iodine. The separated aqueous phase was extracted with 20 mL Et2O. The combined ether phases were washed with saturated NaCl, dried, and evaporated to give 1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene (3.1 g, 91% yield): mp 62-64° C.; GC-MS (m/z=304).
Reaction SMILES: C([O:3][C:4](=[O:28])[CH:5]([O:24][CH2:25][CH2:26][CH3:27])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[CH:10]2)C.[OH-].[Li+]>O1CCOCC1>[CH2:25]([O:24][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[CH:11]=[CH:10]2)[C:4]([OH:28])=[O:3])[CH2:26][CH3:27]
Reactant: CCCOC(Cc1ccc2c(ccn2COCC[Si](C)(C)C)c1)C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCOC(Cc1ccc2c(ccn2COCC[Si](C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.6 %

Procedure:
1.23 g rac-2-propoxy-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-5-yl]-propionic acid ethyl ester were dissolved in 40 ml dioxane, then treated with 7.6 ml lithium hydroxide solution (1 molar in water) and stirred for 16 hours at ambient temperature. Extraction of the reaction mixture with H2O/HCl and dichloromethane, followed by drying of the organic phase with sodium sulfate and evaporation, gave 1.27 g crude product, which was purified by chromatography (silicagel, eluent: gradient of n-heptane/EtOAc) yield to 0.98 g rac-2-propoxy-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-5-yl]-propionic acid as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([CH:16]([CH3:18])[CH3:17])[CH:12]([CH3:14])[CH3:13])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CC(C)N(C(=O)c1ccc(Br)cc1F)C(C)C

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and diisopropylamine.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[C:4](=O)[C:3]1=[O:16].O.NN>O1CCOCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][C:7]3=[CH:6][C:5]=2[CH2:4][C:3]1=[O:16]
Reactant: CN1C(=O)C(=O)c2cc3c(cc21)OCCO3
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1C(=O)Cc2cc3c(cc21)OCCO3
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To a solution of 6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione (3.00 g, 13.7 mmol) in 1,4-dioxane (25 mL) was added hydrazine monohydrate (25 mL). The reaction mixture was stirred at reflux for 4 h, allowed to cool to ambient temperature, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to afford 6-methyl-2,3,6,8-tetrahydro-7H-[1,4]dioxino[2,3-f]indol-7-one (2.46 g, 87%): 1H NMR (300 MHz, CDCl3) δ 6.75 (s, 1H), 6.49 (s, 1H), 4.19-4.12 (m, 4H), 3.36 (s, 2H), 3.00 (s, 3H); MS (ES+) m/z 206.2 (M+1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:58][O:59][C:60]([C:62]1([NH2:67])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61]>CN(C=O)C>[CH3:58][O:59][C:60]([C:62]1([NH:67][C:23]([C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]=2[O:12][CH2:11][CH:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)=[O:24])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61]
Reactant: COC(=O)C1(N)CCCC1
Reactant: O=C(O)c1ccc2ccccc2c1OCC1COc2ccccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCC2COc3ccccc3O2)CCCC1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 84 mg 1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carboxylic acid in 1 ml abs. DMF under inert atmosphere 42 mg 1-hydroxybenzo-triazole and 60 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.65 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 42 mg of 1-amino-cyclopentanecarboxylic acid methyl ester hydrochloride, followed by 0.65 μl of N,N-diisopropylethylamine were added. After 48 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 96 mg of 1-{[1-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethoxy)-naphthalene-2-carbonyl]-amino}-cyclopentanecarboxylic acid methyl ester.