Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][C@@H:4]1[CH2:8][O:7][C@@:6]([C@@H:10]2[C@:18]3([CH3:19])[C@H:13]([C@@H:14]([OH:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)([CH3:9])[CH2:5]1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[OH:1][C:2]([CH3:22])([CH3:21])[CH2:3][C@@H:4]1[CH2:8][O:7][C@@:6]([C@@H:10]2[C@:18]3([CH3:19])[C@H:13]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11]2)([CH3:9])[CH2:5]1
Reactant: CC(C)(O)C[C@@H]1CO[C@](C)([C@H]2CC[C@H]3[C@@H](O)CCC[C@@]32C)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(O)C[C@@H]1CO[C@](C)([C@H]2CC[C@H]3C(=O)CCC[C@@]32C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.3 %

Procedure:
A solution of 13a (123 mg, 0.4 mmol) in dry CH2Cl2 (10 mL) was treated with PDC (pyridinium dichromate, 0.6 g, 1.6 mmol). The mixture was stirred at room temperature for 20 h. The mixture was filtered and concentrated in vacuum. The residue was purified by flash chromatography (SiO2, 3×5.5 cm, 20% EtOAc-hexanes) to give 1S (120 mg, 98%, white solid, mp: 87° C.). Elemental analysis C=73.80%, H=10.51%.
Reaction SMILES: [C:1]([N:5]1[C:13]2[N:12]3[N:14]=[CH:15][CH:16]=[C:11]3[N:10]=[C:9](Cl)[C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO.[Pd](Cl)Cl>[C:1]([N:5]1[C:13]2[N:12]3[N:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9][C:8]=2[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCc2c(Cl)nc3ccnn3c21
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)N1CCc2cnc3ccnn3c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
In a mixed solvent of 300 ml of tetrahydrofuran and 150 ml of methanol were dissolved 11.30 g of 8-tert-butyl-5-chloro-6,7-dihydro-8H-pyrrolo[3,2-e]pyrazolo-[1,5-a]pyrimidine, and the reaction system was cooled to 0° C. To the solution were gradually added 3.75 g of palladium chloride and 7.83 g of sodium borohydride, and the mixture was stirred for 30 minutes at 0° C. Furthermore, 7.50 g of palladium chloride and 5.66 g of sodium borohydride were gradually added, and the resultant mixture was stirred for 30 minutes at 0° C. and for 2 hours at room temperature. The reaction solvent was distilled off under reduced pressure, and the resultant crude product was subjected to column chromatography on silica gel (ethyl acetate→ethyl acetate:methanol=10:1) to obtain 3.94 g (yield: 40.4%) of the intended product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.[ClH:35]>CO>[ClH:35].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]3[O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: c1ccc2cc(COC3CNCCC3c3ccc4c(c3)OCO4)ccc2c1
Yield: 73 %

Procedure:
A solution of 190 mg (0.41 mmol) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(naphthalen-2-ylmethoxy)-piperidine-1 -carboxylate in a mixture of 5 ml of methanol and 25% aqueous hydrochloric acid was heated under reflux for 1 hour. Subsequently, the solvent mixture was distilled off under reduced pressure. After recrystallization of the residue from a mixture of methanol and ether there were obtained 130 mg (73% of theory) of (3RS,4RS)-4-(1,3-benzodioxol-5-yl)-3-naphthalen-2-ylmethoxy-piperidine hydrochloride as a white powder; MS: 362 (M+H)+.
Reaction SMILES: C(OC([C:11]1[NH:25][C:24]2[C:26]3[C:12]=1[CH2:13][C@@H:14]1[C@@H:19]([C:20]=3[CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]([NH:27][C:28]([N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:29])[CH2:16][N:15]1[CH3:35])=O)C1C=CC=CC=1.N>C(O)CO>[CH2:33]([N:30]([CH2:31][CH3:32])[C:28](=[O:29])[NH:27][C@H:17]1[CH2:18][C@H:19]2[C@@H:14]([CH2:13][C:12]3[C:26]4[C:24](=[CH:23][CH:22]=[CH:21][C:20]2=4)[NH:25][CH:11]=3)[N:15]([CH3:35])[CH2:16]1)[CH3:34]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C(=O)OCc5ccccc5)c(c34)C[C@H]2N(C)C1
Agent: N
Solvent: OCCO
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Yield: 85.3 %

Procedure:
150 mg (0.31 mmol) of 8α-(3,3-diethylureido)-6-methylergoline-2-carboxylic acid benzyl ester is heated in 3 ml of a saturated solution of ammonia in ethylene glycol for 3 hours to 100° C. After dilution with water, the mixture is extracted with ethyl acetate and the organic phase washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The residue is chromatographed over silica gel with methylene chloride/ethanol=8:1. After trituration in ethanol/hexane/ether, 90 mg of 8α-(3,3-diethylureido)-6-methylergoline)-2-carboxylic acid amide is obtained, mp 171°-173° C.
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.Cl.C(OCC)(=O)C>[CH3:15][N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:9]
Reactant: CCOC(=O)[C@H](C)Nc1ccccc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](C)N(C)c1ccccc1
Temperature: 70 °C
Yield: 34 %

Procedure:
To a solution of ethyl N-phenylalaninate (2 g, 10.3 mmol) in DMF (103 mL) was added powdered potassium carbonate (2.6 g, 18.5 mmol) followed by iodomethane (1.03 mL, 16.6 mmol) and the resulting mixture was heated at 70° C. over 3 days. The reaction mixture was cooled to room temperature and diluted with 1 M HCl and ethyl acetate. The product was extracted 3 times with ethyl acetate and the combined organics washed with brine, dried (MgSO4), and concentrated in vacuo. Purification by flash chromatography (8:1 hexanes/EtOAc) yielded the title compound as a colorless oil (725 mg, 34%). MS (ES+) m/z 208 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH2:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)cnc1CNCCCCN(C)C(=O)OC(C)(C)C
Reactant: O=Cc1nccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(CCCCN(C)C(=O)OC(C)(C)C)Cc1nccc2ccccc12

Procedure:
Using General Procedure B: Reaction of {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester, isoquinoline-1-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-butyl}-methyl-carbamic acid tert-butyl ester as a light brown solid. 1H NMR (CDCl3): δ 1.29 (br, 2H), 1.41 (s, 9H), 1.50 (br, 2H), 2.01 (s, 3H), 2.59 (t, 2H, J=7.0 Hz), 2.68 (s, 3H), 3.02 (br, 2H), 3.78 (s, 2H), 4.19 (s, 2H), 7.35 (s, 1H), 7.45 (t, 1H, J=7.0 Hz), 7.55 (d, 1H, J=7.0 Hz), 7.62 (t, 1H, J=7.0 Hz), 7.78 (d, 1H, J=7.0 Hz), 8.05 (d, 1H, J=7.0 Hz), 8.29 (s, 1H), 8.42 (d, 1H, J=5.8 Hz). Deprotection with TFA using General Procedure F gave N-(5-chloro-3-methyl-pyridin-2-ylmethyl)-N1-isoquinolin-1-ylmethyl-N-methyl-butane-1,4-diamine.
Reaction SMILES: [O:1]([CH2:8][CH2:9][S:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>C1COCC1>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:13]=2)=[CH:19][CH:20]=1)=[O:25]
Reactant: O=C(O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Reactant: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (2-dimethylamino-ethyl)-amide was synthesized as described for 41-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (0.80 g, 2.19 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.36 g, 2.23 mmol, 1.02 eq.) and N,N-dimethylethylenediamine (0.23 g, 2.63 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving a yellow oil that later solidified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[N:10]=[C:11]4[N:15]([CH:16]=3)[N:14]=[C:13]([O:17][CH3:18])[S:12]4)=[CH:6][C:5]2=[C:19]([OH:21])[CH:20]=1.[C:22]1([C:28]2[S:29][CH:30]=[C:31]([CH2:33]O)[N:32]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:33][C:31]2[N:32]=[C:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[S:29][CH:30]=2)[C:5]2[CH:6]=[C:7]([C:9]3[N:10]=[C:11]4[N:15]([CH:16]=3)[N:14]=[C:13]([O:17][CH3:18])[S:12]4)[O:8][C:4]=2[CH:3]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COc1nn2cc(-c3cc4c(O)cc(Cl)cc4o3)nc2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nn2cc(-c3cc4c(OCc5csc(-c6ccccc6)n5)cc(Cl)cc4o3)nc2s1
Reaction time: 1.5 h
Yield: 51.3 %

Procedure:
A flame-dried 100 mL round-bottom flask containing 6-chloro-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol (Example 37I, 25 mgs, 0.078 mmol) and (2-phenylthiazol-4-yl)methanol (Example 3B, 37.2 mgs, 0.194 mmol) in dry THF (4 mL) was added tributylphosphine (0.050 mL, 0.194 mmol). The resulting solution was charged with a solution of ADDP (49.0 mgs, 0.194 mmol) in THF (1 mL) added dropwise over 30 minutes via syringe pump. After stirring for 1.5 hours the reaction mixture was diluted with EtOAc then washed with 1N HCl, sat. NaHCO3, water and brine. The organic phase was dried (MgSO4) then concentrated to dryness. The residue was purified by ISCO using 0 to 10% diethyl ether in DCM. Fractions containing the desired product were concentrated to give the title material as a beige solid (20 mgs, 0.040 mmol, 52.0% yield). LC (Method A): 2.534 min. LCMS (APCI) calcd for C23H16ClN4O3S2 [M+H]+ m/z 495.03, found 495.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.49 (s, 1H), 7.99-7.96 (m, 2H), 7.93 (s, 1H), 7.55-7.50 (m, 3H), 7.40 (dd, J=0.8, 1.6 Hz, 1H), 7.15 (dd, J=0.4, 1.6 Hz, 1H), 7.14 (d, J=0.8 Hz, 1H), 5.43 (s, 2H), 4.21 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C=O.[C:18](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:8][C@H:6]1[N:7]([CH3:18])[C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:5]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of 1,1-dimethylethyl (3R,5S)-3,5-dimethyl-1-piperazinecarboxylate (2.04 g, 9.5 mmol) in dichloromethane (25 mL) at 0° C. was added formaldehyde (1.075 mL, 37% water solution, 14.3 mmol) followed by sodium triacetoxyborohydride (2.628 g, 12.4 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2 h before being diluted with dichloromethane and washed with 1N NaOH solution. The organics were then washed with brine, dried (MgSO4) and evaporated to yield 1,1-dimethylethyl (3R,5S)-3,4,5-trimethyl-1-piperazinecarboxylate (2.06 g, 95%). LCMS: (M+H)+: 229.2.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:17][C:13]1[CH:12]=[C:11]([CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:18]([N:26]([C:25]2[CH:28]=[CH:29][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH3:27])=[O:20])[CH:16]=[CH:15][CH:14]=1
Reactant: CNc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(Br)c1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)[C@H](Cc1cccc(Br)c1)NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
Boc-L-3-BromoPhe (5 g, 14.5 mmol) was dissolved in 50 mL of DMF and to it were added 4-chloro-N-methylaniline (2.1 mL, 17.4 mmol) and N,N-diisopropylethylamine (7.6 mL, 43.5 mmol). The reaction mixture was cooled to 0° C. and to it was added HATU portion wise (6.6 g, 17.4 mmol). The reaction mixture was allowed to stir at ambient temperature overnight and then was partitioned between ethyl acetate and water. The organic layer was separated and washed with 5% aqueous LiCl, saturated aqueous NaHCO3 and brine. The mixture was then dried over MgSO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford 5.6 g of (S)-tert-butyl 3-(3-bromophenyl)-1-((4-chlorophenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate as a white solid. MS (m/z): 469.1 [M+H]+; HPLC retention time 4.39 min (5-99% acetonitrile:water with 0.05% formic acid).
Reaction SMILES: O=[C:2]([NH:8][CH2:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>O=P(Cl)(Cl)Cl>[F:21][C:18]([F:19])([F:20])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]2[O:22][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=O)NCC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(-c2ccc(OC(F)(F)F)cc2)o1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
A solution of ethyl 2-oxo-2-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethylamino)acetate (7.8 g, 24.4 mmol) in POCl3 (50 mL) was heated at 110° C. for 3 h, and then cooled to RT. The mixture was concentrated under reduced pressure, diluted with ice—H2O (100 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (2×50 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=5:1 to 2:1) to give the title compound as a light yellow solid (6.4 g, 87%). MS (ES+) C13H10F3NO4 requires: 301. found: 302 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[N:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:8][C:7]=2[C:31]=1[CH3:32].[NH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18]3[C:17]4[CH:16]=[N:15][CH:14]=[CH:13][C:12]=4[C:11](=[O:19])[C:10]=3[C:9]([NH:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[N:8][C:7]=2[C:31]=1[CH3:32]
Reactant: COc1ccc2c3c(c(OS(=O)(=O)c4ccc(C)cc4)nc2c1C)C(=O)c1ccncc1-3
Reactant: NCCN1CCCC1
Product: COc1ccc2c3c(c(NCCN4CCCC4)nc2c1C)C(=O)c1ccncc1-3

Procedure:
This compound was prepared from toluene-4-sulfonic acid 3-methoxy-4-methyl-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (Example 18c-1) and 1-(2-aminoethyl)pyrrolidine in a similar manner to Example 18d. The desired product was obtained as a reddish powder. ESI−MS: m/z 389 (MH+); 1H-NMR (CDCl3): δ1.86 (4H, m), 2.50 (3H, s), 2.72 (4H, m), 2.90 (2H, t, J=6.5 Hz), 3.89 (2H, quartet like, J=ca 6.5 Hz), 4.02 (3H, s), 7.12 (1H, d, J=9 Hz), 7.18 (1H, brt, J=ca 5 Hz), 7.54 (1H, dd, J=4.5 Hz, 1 Hz), 8.04 (1H, d, J=9 Hz), 8.80 (1H, d, J=4.5 Hz), 9.27 (1H, brs).
Reaction SMILES: [ClH:1].Cl.[C@H:3]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CC[CH2:4]1.Cl.Cl.Cl.NC1CCN(C[C@@H]([N:58]2[CH2:63][CH2:62][CH:61]([OH:64])[CH2:60][CH2:59]2)C)CC1>>[ClH:1].[ClH:1].[OH:64][CH:61]1[CH2:62][CH2:63][N:58]([C@@H:3]([CH3:4])[CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([CH3:44])[C:41]([CH3:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:59][CH2:60]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Reactant: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c2cc1C
Agent: Cl
Product: Cc1cc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@H](C)N6CCC(O)CC6)CC5)cc34)c2cc1C

Procedure:
This compound is synthesized from 4-(5,6-dimethyl-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (127, see example 104) and amine 50 analogously to the method described in example 1.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]Cl)[C:5]=2[O:4][CH2:3][CH2:2]1.[C-:13]#[N:14].[Na+].CS(C)=O>C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:13]#[N:14])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: ClCc1cccc2c1OCCO2
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1cccc2c1OCCO2
Temperature: 65 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
Add (2,3-Dihydrobenzo[1,4]dioxin-5-yl)chloromethane (1.9 g, 10.2 mmol) and sodium cyanide (655 mgs, 13.3 mmol) to dimethylsulfoxide (20 mL). Stir under nitrogen at 65° C. for 18 hours. Dilute the reaction with ethyl acetate, wash with 0.1 molar aqueous sodium carbonate and aqueous saturated sodium chloride. Dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexane to 50% ethyl acetate in hexane to obtain 1.23 g (68%) of the desired compound as a white solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]1[CH:15]2[CH2:16][NH:17][CH2:18][CH2:19][N:14]2[CH2:13][C:12](=[O:20])[O:11]1.FC(F)(F)C(O)=O.[Cl:28][C:29]1[CH:30]=[C:31]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][C:43]([O:52][CH2:53][CH2:54]Br)=[C:44]([O:47][CH2:48][CH:49]4[CH2:51][CH2:50]4)[CH:45]=3)[N:40]=[CH:39][N:38]=2)[CH:32]=[CH:33][C:34]=1[F:35].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[Cl:28][C:29]1[CH:30]=[C:31]([NH:36][C:37]2[C:46]3[C:41](=[CH:42][C:43]([O:52][CH2:53][CH2:54][N:17]4[CH2:18][CH2:19][N:14]5[CH:15]([CH2:10][O:11][C:12](=[O:20])[CH2:13]5)[CH2:16]4)=[C:44]([O:47][CH2:48][CH:49]4[CH2:51][CH2:50]4)[CH:45]=3)[N:40]=[CH:39][N:38]=2)[CH:32]=[CH:33][C:34]=1[F:35]
Reactant: O=C1CN2CCNCC2CO1
Reactant: Fc1ccc(Nc2ncnc3cc(OCCBr)c(OCC4CC4)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN2CCN(CCOc3cc4ncnc(Nc5ccc(F)c(Cl)c5)c4cc3OCC3CC3)CC2CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.25 ml of diisopropylethylamine and 260 mg of perhydro-pyrazino[2,1-c][1,4]oxazin-3-one x 2 trifluoroacetic acid are added to 150 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopropylmethoxy-7-(2-bromoethoxy)-quinazoline in 15 ml of acetonitrile. The reaction mixture is stirred for one hour at ambient temperature and then refluxed for two hours. Then 70 mg of potassium carbonate and 75 mg of sodium iodide are added. The reaction mixture is refluxed for about another 14 hours, during which time a total of another 175 mg of perhydro-pyrazino[2,1-c][1,4]oxazin-3-one x 2 trifluoroacetic acid and 300 mg of potassium carbonate are added successively until the reaction is complete. For working up the inorganic salts are filtered off and the filtrate is evaporated down in vacuo. The flask residue is chromatographed over a silica gel column with methylene chloride/methanol (95:5) as eluant. The desired product is obtained as a light brown resin. Yield: 27 mg (16% of theory),
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>O1CCOCC1.O>[C:34]1([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc(COc2ccc(-c3cccc4ccccc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of intermediate 1; 74 mg, 0.2 mmol) in dioxane/water (10:1, 4.4 mL) was degassed for 20 min and then added to a reaction vial containing potassium carbonate (82 mg, 0.6 mmol) and 1-naphthaleneboronic acid (0.6 mmol; available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). The solution was degassed for a further 2 min and then bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 14 mg, 0.02 mmol) was added. The mixture was degassed for 30 seconds and then heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica and the silica washed with dioxane (1 mL), dimethylacetamide (1 mL), and 20% methanol in dichloromethane (1 mL). The filtrate was placed in a vial and 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl was added until a solid formed (approxiamtely 2 mL). The vial was centrifuged and the solvent was removed. The product was dried overnight in the oven to give 3-(4-naphthalen-1-yl-phenoxymethyl)-benzoic acid. Mass spectrum MH+=355.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([CH3:13])=[N:8]2)C=CC=CC=1.[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:13]1([C:9]2[C:10]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:11]([NH2:12])[N:7]([CH3:1])[N:8]=2)[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: O=C1CCCCC1
Product: Cn1nc(-c2ccccc2)c(C2CCCCC2)c1N

Procedure:
It is obtained by following essentially the procedure of example 1, reacting 1-phenyl-3-methyl-5-pyrazolamine with cyclohexanone (1:2, molar ratio) at a temperature of about 45° C. for about 8 hours. M.p. 212°-214° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1F)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[CH3:34][O:35]C1C=C(C=C(OC)C=1OC)C=O>>[CH3:1][O:2][C:3](=[O:33])[N:4]=[C:5]([S:31][CH3:32])[C:6](=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:35][CH3:34])[CH:21]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)c(OC)c1

Procedure:
The same procedure was carried out as in Examples (1a) to (1d), except that 3,4,5-trimethoxybenzaldehyde was used instead of 2-fluoro-4,5-dimethoxybenzaldehyde in Example (1a), to give the title compound.