Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[C:4]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=[C:4]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(CCc2ccccc2)nc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCC(C(=O)O)c1c(C)nc(CCc2ccccc2)nc1-c1ccccc1
Yield: 27.3 %

Procedure:
A solution of methyl 2-(4-methyl-2-phenethyl-6-phenylpyrimidin-5-yl)pentanoate (91 mg; 0.235 mmol) in ethanol (1.5 mL), tetrahydrofuran (0.5 mL) and 2N sodium hydroxide solution (1.5 mL; 3.0 mmol) was stirred for 24 h at room temperature. The reaction mixture was concentrated under reduced pressure, diluted with water and acidified with a 6N hydrochloric acid. The suspension was extracted twice with ethyl acetate and the organic layers were washed with water and dried by filtration over a phase separater filter (PS1). The crude material was first purified by flash chromatography on silica gel using a linear gradient of methanol (1-10%) in dichloromethane and then by preparative thick layer chromatography on silica gel eluting with 10% methanol in dichloromethane to give 24 mg (26%) of the title compound as a colorless oil. ESI/APCI(+): 375 (M+H). ESI/APCI(−): 373 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:16]([O:23][CH2:24][CH2:25][C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:27](O)=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:34]([O:33][C:31](=[O:32])[NH:30][C@H:26]([C:27](=[O:28])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:25][CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)Nc1ccc(F)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
A mixture of 4-fluoro-N2-phenylbenzene-1,2-diamine (614 mg, 3.04 mmol), (S)-4-benzyloxy-2-tertbutoxycarbonylaminobutyric acid (1.0 g, 3.3 mmol), HOAt (0.450 g, 3.3 mmol), 4-methylmorpholine (0.7 mL, 6.7 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.63 g, 3.3 mmol) in DCM (15 mL) was stirred at RT for 18 h. The reaction mixture was partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic fraction was washed with brine, dried (MgSO4), concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a yellow oil (1.22 g, 82%). LCMS (Method J): RT 4.17 min [M+H]+ 494.1.
Reaction SMILES: [CH2:1]([S:9][P:10]([Cl:13])([Cl:12])=[S:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.S(CC1C=CC=CC=1)CC1C=CC=CC=1.S(CCCCCCCC)CCCCCCCC>>[C:2]1([CH2:1][S:9][P:10]([Cl:12])([Cl:13])=[S:11])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCSP(=S)(Cl)Cl
Agent: CCCCCCCCSCCCCCCCC
Agent: c1ccc(CSCc2ccccc2)cc1
Product: S=P(Cl)(Cl)SCc1ccccc1
Yield: 53 %

Procedure:
Following the procedure and employing the reaction temperature and reactants of Example 7 with the exception that 53.5 grams (0.25 mole) of (C6H5CH2)2S were employed as a reactant instead of (n-C8H17)2S, 68 grams (53% yield)of C6H5CH2SP(S)Cl2 was obtained. The product had the following properties:
Reaction SMILES: N1C2CCCCC=2C=[C:2]1C=O.C[C:13]1[C:21]2[C:20](=O)[C:19]([CH3:24])([CH3:23])[CH2:18][CH2:17][C:16]=2[NH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:2][C:14]1[NH:15][C:16]2[CH2:17][CH2:18][C:19]([CH3:23])([CH3:24])[CH2:20][C:21]=2[CH:13]=1
Reactant: O=Cc1cc2c([nH]1)CCCC2
Reactant: Cc1c[nH]c2c1C(=O)C(C)(C)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c([nH]1)CCC(C)(C)C2
Yield: 98 %

Procedure:
Using a procedure closely analogous to the preparation of 4,5,6,7-tetrahydroindole-2-carboxaldehyde, 3,5,5-trimethyl-4-oxo-4,5,6,7-tetrahydroindole 1.65 g (9.31 mmol) was reduced by 36-hour reflux with lithium aluminum hydride 2.0 g in anh. THF (100 mL) to provide 1.50 g (98%) of 2,5,5-trimethyl-4,5,6,7-tetrahydroindole (light tan crystalline solid) that was formylated with a mixture of anhydrous DMF 20 mL and POCl3 1.5 mL to provide the title aldehyde product 1.669 g (93% overall) as a tan solid. 1H-NMR (d6-DMSO, 400 MHz): 11.31 (br s, 1H), 9.43 (s, 1H), 2.51 (m, 2H), 2.14 (s, 3H), 2.13 (s, 2H), 1.49 (t, 6.6 Hz, 2H), 0.94 (s, 6H)
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16]>C(Cl)Cl.[I-].[K+]>[O:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[N:3]1
Reactant: NCCCCO
Reactant: Clc1noc2ccccc12
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Product: OCCCCNc1noc2ccccc12
Temperature: 80 °C
Reaction time: 96 h
Yield: 93.3 %

Procedure:
A mixture of 3-chloro-1,2-benzisoxazole (0.08 mol), 4-amino-1-butanol (0.24 mol) and potassium iodide (1 g) was stirred for 4 days at 80° C. The reaction mixture was cooled, dissolved in CH2Cl2 and purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 15.4 g (93%)of 4-(1,2-benzisoxazol-3-ylamino)-1-butanol (interm. 7). b) SOCl2 (0.048 mol) was cooled to 0° C. A solution of intermediate 7 (0.048 mol) in CHCl3 (20 ml) was added dropwise and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated. The residue was washed with water. The reaction mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered, and the solvent was evaporated, yielding 10.4 g of N-(4-chlorobutyl)-1,2-benzisoxazol-3-amine (interm. 8).
Reaction SMILES: N1CCCC1.C(O)(=O)C.[C:10]1([CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=[CH:24][C:25]1[CH:33]=[CH:32][C:29]([O:30][CH3:31])=[C:27]([OH:28])[CH:26]=1.Cl>C(OCC)C.C(OCC)(=O)C>[OH:28][C:27]1[CH:26]=[C:25]([CH:24]=[CH:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:33]=[CH:32][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(=O)CCCCc1ccccc1
Agent: Cl
Solvent: C1CCNC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(C=CC(=O)CCCCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14.3 %

Procedure:
Pyrrolidine (2.42 g, 34.0 mMol) is added to acetic acid (2.04 g, 34.0 mMol), and the mixture is stirred at room temperature for 20 minutes. After this time, 6-phenyl-2-hexanone (4.00 g, 22.6 mMol) as a solution in diethyl ether (20 ml) is added, and the mixture is allowed to stir for an additional 15 minutes. An ethereal solution of iso-vanillin (3.45 g, 22.5 mMol) is then added dropwise. The reaction mixture is stirred for 48 hours. HCl (1.0 N, 30 ml) is then added to the reaction mixture, and the contents stirred for 20 minutes. The mixture is then taken up into an equal volume of ethyl acetate, and the phases separated. The organic layer is washed with saturated aqueous sodium bicarbonate, dried (sodium sulfate), and concentrated. The residue is chromatographed (silica gel; hexane/ethyl acetate 3:1) to afford 1.0 g (28%) of 1-(3-hydroxy-4-methoxyphenyl)-7-phenyl-1-hepten-3-one, mp=70°-75° C. C, H analysis Calcd. for C20H22O3 (77.39, 7.14); Found (77.68, 6.94). The procedure of Example 1 is within that described in the above cited reference by Itokawa H. et al in the Chem. Pharm. Bull. Similarly prepared are Examples 2-12 using the procedure of Example 1.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38](=[O:39])[C:37]5[CH:36]=[CH:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:42][CH:41]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1ccc(N2CCOCC2)cc1

Procedure:
The title compound, white solid (120 mg, 92%), MS (ISP) m/z=520.6 [(M+H)+], mp 241.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-morpholin-4-yl-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1>CCO.[NH4+].[Cl-].CCOC(C)=O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2cc([N+](=O)[O-])cn2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(N)cn2)cc1
Temperature: 105 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of 1-(4-methoxybenzyl)-4-nitro-1H-pyrazole (1031 mg, 4.42 mmol) in EtOH (25 mL) and sat. aq. NH4Cl (15 mL) in a sealed tube (125 mL) was treated with iron (1234 mg, 22.10 mmol, Aldrich, St. Louis, Mo.). The mixture was stirred at 105° C. for 1 h, then cooled to room temperature. The mixture was diluted with EtOAc (200 mL) and filtered through a plug of Celite® (diatomaceous earth). The filtrate was separated and the organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was filtered through a plug of silica gel (eluting with DCM:EtOAc: MeOH=25:25:1) to give 1-(4-methoxybenzyl)-1H-pyrazol-4-amine (560 mg, 2.76 mmol, 62.3% yield) as a brown solid. m/z (ESI, positive ion) 204 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.C[Zn]C.[C:11]([O:14][C:15](=[O:17])[CH3:16])(=O)[CH3:12].[C:18]1(=O)[CH2:32][CH2:31]C[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1(C)C=CC=CC=1>[C:15]([O:14][C:11]1[CH2:31][CH2:32][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C@@H:28]([CH3:29])[CH:12]=1)(=[O:17])[CH3:16]
Reactant: O=C1C=CCCCCCCCCCCCC1
Reactant: CC(=O)OC(C)=O
Agent: [Cu+2]
Agent: C[Zn]C
Agent: O=C1/C=C/CCCCCCCCCCCC1
Solvent: Cc1ccccc1
Product: CC(=O)OC1=C[C@H](C)CCCCCCCCCCCC1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 107 %

Procedure:
Under a nitrogen atmosphere 55 mg (0.121 mmol) of an optically active ligand 4-(cis-2,6-dimethylpiperidine)-(R)-ditetrahydronaphthodioxaphosphepin, 14.5 mg (0.04 mmol) of Cu(OTf)2, 2.55 ml (4.8 mmol) of a dimethylzinc toluene solution (1.88 mol/L), and 5 ml of toluene were added to a 30-ml reaction flask and cooled to −20° C. Then, a mixed solution containing 410 mg (4 mmol) of acetic anhydride, 889 mg (4 mmol) of (2E)-cyclopentadecenone and 5 ml of toluene was added thereto dropwise over 5 minutes, and the resultant mixture was stirred additionally for 4 hours until completion of the reaction was determined by gas chromatographic analysis. The reaction was terminated by addition of an aqueous 5% sulfuric acid solution after completion of the reaction to give 1.2 g of crude (R)-3-methyl-1-cyclopentadecenyl acetate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=[O:16])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(CCN)=CC=1)(OC)=O.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[NH2:47])=[CH:41][CH:40]=1)([O:37][CH3:38])=[O:36]>>[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([NH:47][CH2:17][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([N+:19]([O-:21])=[O:20])[CH:11]=2)[OH:16])[CH3:48])=[CH:41][CH:40]=1)([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1ccc(CC(C)N)cc1
Reactant: O=CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1

Procedure:
The title compound was prepared as a mixture of diastereoisomers by the process of Example 25, replacing phenyl glyoxal by 4-benzyloxy-3-nitrophenyl glyoxal and 2-(4-carbomethoxyphenyl)ethanamine by 2-(4-carbomethoxyphenyl)-1-methylethanamine. τ (CDCl3) 8.93 (3H, d, J=6 Hz), 6.70-7.80 (7H, m), 6.14 (3H, s), 5.40 (1H, m), 4.81 (2H, s) 2.30-3.10 (10H, m), 2.02 (2H, d, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:19])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1.Cl.Cl.[NH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C(N(CC)CC)C>O1CCOCC1.CN(C=O)C.C(OCC)(=O)C>[C:32]([C:30]1[CH:29]=[CH:28][C:27]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:26]([O:25][CH2:24][CH2:23][NH:22][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:7]3[C:6]([Cl:19])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[CH2:13][CH2:12]2)=[O:16])[CH:31]=1)#[N:33]
Reactant: CCOC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: CCOC(=O)CCc1ccc(C#N)cc1OCCN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(C#N)cc1OCCNC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Temperature: 95 °C
Reaction time: 4 h

Procedure:
2.0 g (6.5 mmol) of ethyl 1-(3,5-dichloropyridine-4-yl)-4-piperidinecarboxylate was stirred in 5 ml of dioxane. 5 ml of 2 N hydrochloric acid was added to the obtained mixture, and they were stirred at 95° C. for 4 hours. The solvent was evaporated, and the obtained crude product was dissolved in 10 ml of DMF. 612 mg (2.27 mmol) of ethyl 3-[2-(2-aminoethoxy)-4-cyanophenyl]propionate hydrochloride, 575 mg (3.40 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.9 ml (6.8 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([OH:12])[CH:5]=1.[CH2:14](Br)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([O:12][CH2:16][CH:15]=[CH2:14])[CH:5]=1
Reactant: C=CCBr
Reactant: COC(=O)c1cc(O)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(OC)cc(C(=O)OC)c1

Procedure:
3-Hydroxy-5-methoxybenzoic acid methyl ester is reacted with allyl bromide in the presence of potassium carbonate to give 3-allyloxy-5-methoxybenzoic acid methyl ester. B.p. 128°-30°C/0.4 mmHg. The ester is hydrolized to the corresponding acid with 20% potassium hydroxide in aqueous ethanol. The acid (m.p. 85°-7°C) when heated for 2 hours at 230°C undergoes Claisen rearrangement and cyclization to the title compound which melts at 195°-7°C.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]([CH2:16][CH3:17])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>CO>[CH3:18][N:2]([CH3:1])[CH:3]([CH2:16][CH3:17])[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)[OH:5]
Reactant: CCC(C(=O)c1ccc(NC(C)=O)cc1)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(C(O)c1ccc(NC(C)=O)cc1)N(C)C
Temperature: 25 °C

Procedure:
A solution of N-(4-(2-(dimethylamino)butanoyl)phenyl)acetamide (3.80 g, 15.30 mmol) in 40 mL MeOH was cooled in an ice bath under N2 and treated with NaBH4 (725 mg, 19.12 mmol), added in one portion. The reaction vessel was removed from the ice bath and stirred at rt over the weekend. The reaction was quenched with acetone, then concentrated in vacuo and partitioned between DCM and half-saturated NaHCO3. The aqueous phase was extracted four times with DCM and the organic extracts were combined and dried over Na2SO4. The solution was decanted and concentrated in vacuo. The solid residue was purified by silica gel column chromatography eluting with 10%-12% MeOH (2N NH3)/DCM to provide the syn-isomer of N-(4-(2-(dimethylamino)-1-hydroxybutyl)phenyl)acetamide as a white amorphous solid and the anti-isomer as a straw colored oil. MS ESI: m/z 251.17 [M+1+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32](=[O:34])[NH2:33])=[CH:31][C:25]=3[N:24]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:32]([NH2:33])=[O:34])=[CH:31][C:25]=3[N:24]=2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc2[nH]c(-c3ccc(OCCC4CCCCN4)cc3)nc2c1
Temperature: 25 °C
Yield: 133.3 %

Procedure:
To an ice-cold solution of 2-{2-[4-(5-carbamoyl-1H-benzoimidazol-2-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (0.65 g, 1.4 mmol) in CH2Cl2 (15 mL) was slowly added TFA (3.8 mL). The solution was stirred and gradually warmed to rt over 2 h. All solvent was removed via toluene azeotrope to provide the 0.68 g (100%) of the product as a yellow solid. HPLC (Method C): Rt=3.87. MS (ESI+): mass calcd. for C21H24N4O2, 364.19; m/z found, 365.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 6.20 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 7.79 (d, J=10.7 Hz, 1H), 7.73 (d, J=10.7 Hz, 1H), 7.20 (d, J=8.7 Hz, 2H), 4.23-4.19 (m, 2H), 3.31-3.28 (m, 2H), 3:03-2.89 (m, 1H), 2.17-2.11 (m, 1H), 2.10-1.98 (m, 2H), 1.83-1.76 (m, 2H), 1.64-1.44 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: N#Cc1ccc(Br)cc1
Product: CCCCCCNc1ccc(C#N)cc1
Yield: 71.7 %

Procedure:
Using the general procedure, 4-bromobenzonitrile (182 mg, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (6:1) as eluent afforded the desired product as a light yellow solid (145 mg, 72% yield). Rf=0.6 (hexane/ethyl acetate=3:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[CH:12][CH:13]=4)[C:4]=2[CH:3]=1.Cl[C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:22][C:15]1([CH3:23])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([C:28]5[CH:29]=[CH:30][CH:25]=[CH:26][C:27]=5[C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[CH:12][CH:13]=2
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cccc1c32
Reactant: CCOC(=O)c1cc(Cl)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccccc1-c1ccc2c(c1)c1cccc3c1n2-c1ccccc1C3(C)C

Procedure:
39.8 g (110.0 mmol) of 3-bromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine (Br-1), 30 g (110.0 mmol) of [4-chloro-2-(ethoxycarbonyl)phenyl]boronic acid and 9.7 g (92 mmol) of sodium carbonate are suspended in 350 ml of toluene, 350 ml of dioxane and 500 ml of water. 913 mg (3.0 mmol) of tri-otolylphosphine and then 112 mg (0.5 mmol) of palladium(II) acetate are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness. The residue is recrystallised from toluene. The yield is 44 g (94 mmol), corresponding to 86% of theory.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([NH:18][CH:19]([CH:27]([OH:54])[CH:28]([NH:36][C:37](=[O:53])[C@H:38]([CH:50]([CH3:52])[CH3:51])[NH:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(C(C)C)C(C)C)C.[CH3:64][O:65][CH2:66]Cl>ClCCl>[C:40]([NH:39][C@H:38]([C:37]([NH:36][CH:28]([CH:27]([O:54][CH2:64][O:65][CH3:66])[CH:19]([NH:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:53])[CH:50]([CH3:52])[CH3:51])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]
Reactant: COCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC(C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Yield: 10 %

Procedure:
A solution of 22 mg of the resultant compound of Example 70 in 1 ml of dichloromethane was treated with 0.07 ml of ethyldiisopropylamine and 0.03 ml of chloromethyl methyl ether. The resulting solution was heated at reflux for 1 h. The cooled solution was concentrated in vacuo to give 26 mg of a crude solid which was recrystallized from ethyl acetate/chloroform to provide 15 mg of the desired compound (Rf 0.6, 10% methanol in chloroform) as a white solid, m.p. 197°-198° C. Mass spectrum: (M+H)+ =781.
Reaction SMILES: Br[C:2]1[C:29](Cl)=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:27][CH2:26]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([Cl:31])[CH:3]=1.C(N(CC)CC)C.[C]=O.[C:41]([O:44][CH2:45]C)(=[O:43])C>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:45][O:44][C:41](=[O:43])[C:29]1[C:2](=[CH:3][C:4]([Cl:31])=[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH:25]3[CH2:26][CH2:27]3)[CH2:17][CH2:16]2)=[O:14])[CH:28]=1)[C:41]([O:44][CH3:45])=[O:43]
Reactant: CCOC(C)=O
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(Br)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1C(=O)OC
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 1.0 g (1.93 mmol) [4-(4-bromo-2,5-dichloro-phenoxy)-pyridin-3-yl]-(4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-methanone in 25 mL methanole and 25 mL ethyl acetate were added 0.40 mL (2.89 mmol) triethylamine and 0.094 g (0.12 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct (commercially available, CAS RN 851232-71-8). Then, a 70 bar carbon monoxide atmosphere was installed and the reaction mixture was stirred at 120° C. for 20 hours. After cooling down, the reaction mixture was filtered and the filtrate was treated with silica gel and evaporated. The resulting powder was then purified by silica gel chromatography using a MPLC system (50 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 50:50) to give a first batch of each compound. The remaining fractions containing impurities were combined and again chromatographed (20 g silica gel column, CombiFlash Companion, Isco Inc.) using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) to give a second batch of the desired compounds.