Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH2:33][N:34]=[CH:35]S(O)(=O)=O>CN(C=O)C>[NH2:33][N:34]=[CH:35][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([O:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:17])=[O:18])[CH:12]=[CH:13][CH:14]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Oc1cccc(OCC2CCNCC2)c1)c1ccccc1Cl
Reactant: NN=CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NN=CN1CCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-[(piperidin-4-yl)methoxy]phenyl ester (191 mg, 0.5 mmol), as prepared in the preceding step, in DMF (10 mL) containing triethylamine (0.2 mL) and aminoiminomethanesulfonic acid (124 mg, 1.0 mmol) was stirred at room temperature overnight. The DMF was concentrated in vacuo and the residue was purified by flash column chromatography (90: 10 methylene chloride:methanol saturated with NH3) to give the title compound as a white foam (105 mg, 49%). 1H-NMR (300 MHz, CDCl3 /DMSO)-d6) δ 1.38 (m, 2H), 1.88 (d, 2H), 2.08 (m, 1H), 3.00 (t, 2H), 3.79 (d, 2H), 4.05 (dd, 2H), 6.61 (dd, 1H) 6.77 (t, 1H), 6.79 (dd, 1H), 7.20 (t, 1H), 7.37 (bs, 3H), 7.50 (m, 1H), 7.92 (d, 2H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C19H22 N3O4SCl: 424.1(M+H), 446.1 (M+Na), Found: 424.3, 446.6
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]1(C(O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[C:20]([O-])([O-:22])=[O:21].[K+].[K+].CN1C(=O)CCC1>O>[N+:8]([C:7]1[C:2]([N:11]2[CH2:12][CH2:13][CH:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=C(O)N1CCCCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)C1CCN(c2ncccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 634 mg of 2-chloro-3-nitropyridine, 620 mg of piperidine carboxylic acid, 820 mg of potash and 3 ml of NMP was stirred at 80° C. for 2 hours. After allowing to cool, 30 ml of water of water were added and the crude product was extracted with 30 ml of ethyl acetate. After drying the organic phase with sodium sulfate, it was concentrated under reduced pressure.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:21])[C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[OH:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>>[CH:1]1([NH:4][C:5](=[O:21])[C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:33](=[O:34])[C:32]4[CH:31]=[CH:30][C:29]([N:26]5[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]5)=[CH:37][CH:36]=4)=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(C(=O)NC3CC3)cc2)cc1
Product: O=C(Nc1ccc(C(=O)c2ccc(C(=O)NC3CC3)cc2)cc1)c1ccc(N2CCC(O)CC2)cc1

Procedure:
Compound 687 was prepared according to the procedure described in Scheme IV from N-cyclopropyl-4-(4-aminobenzoyl)benzamide and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C29H30N3O4: 484.22; found: 484.08.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[C:3]=1[CH:14]([O:16][Si](C(C)(C)C)(C)C)[CH3:15].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([F:13])[C:3]=1[CH:14]([OH:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(Cl)c(C(C)O[Si](C)(C)C(C)(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1ccc(Cl)c(C(C)O)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
Ethyl 4-chloro-2-fluoro-3-(1-t-butyldimethylsilyloxyethyl)benzoate (25 g) and tetrabutylammonium fluoride (210ml of 1.0 M solution in THF) were dissolved in THF and stirred for 4 hours at room temperature. The mixture was diluted with ether and washed with water. The organic extract was dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding ethyl 4-chloro-2-fluoro-3-(1-hydroxyethyl)benzoate (16.8 g) as a clear oil, NMR (CDCl3) 1.3(t,3H), 1.5(d,3H), 2.5(bs,1H), 4.3(q,2H), 5.3(q,1H), 7.1(d,1H), 7.7(t,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([O:19][CH3:20])=[CH:7][C:8]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:56][C:57]1[CH:62]=[CH:61][C:60]([CH:63]2[CH2:68][CH2:67][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:65][CH2:64]2)=[CH:59][CH:58]=1>>[CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([O:19][CH3:20])=[CH:7][C:8]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:56][C:57]3[CH:62]=[CH:61][C:60]([CH:63]4[CH2:64][CH2:65][N:66]([CH2:69][C:70]([NH2:72])=[O:71])[CH2:67][CH2:68]4)=[CH:59][CH:58]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: COc1cc(-c2ccc3cnc(O)nn23)c(OC)nn1
Reactant: NC(=O)CN1CCC(c2ccc(N)cc2)CC1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc3cnc(Nc4ccc(C5CCN(CC(N)=O)CC5)cc4)nn23)c(OC)nn1
Yield: 15.4 %

Procedure:
7-(3,6-Dimethoxy-pyridazin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (70 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (95.1 mg, 0.266 mmol), N,N-Diisopropylethylamine (0.126 mL, 0.726 mmol), and N,N-Dimethylformamide (2 mL, 30 mmol) and stir at room temperature for half an hour. Add 2-[4-(4-Amino-phenyl)-piperidin-1-yl]-acetamide (90.3 mg, 0.387 mmol) and stir at 60° C. overnight. An LCMS showed product. The reaction was concentrated, DMSO added, filtered and placed onto the Gilson for purification. The most pure fractions were collected, free based with saturated sodium bicarbonate, extracted with DCM, filtered and concentrated to give 2-(4-{4-[7-(3,6-Dimethoxy-pyridazin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperidin-1-yl)-acetamide as a yellow solid (15 mg, 10%). MP 249-251° C. LCMS (E/I+) 489 (M+H). NMR 1H (DMSO-d6)-9.56 (s, 1H), 9.1 (s, 1H), 8.27 (s, 1H), 7.60 (d, 2H, J=8.30 Hz), 7.40 (d, 2H, J=4.82 Hz), 7.21 (bs, 1H), 7.18 (d, 1H, J=8.42 Hz), 7.13 (bs, 1H), 6.97 (d, 1H, J=4.87 Hz), 4.06 (s, 3H), 4.04 (s, 3H), 2.87-2.96 (m, 4H), 2.40-2.48 (m, 1H), 2.14-2.25 (m, 2H), 1.70-1.78 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[C:17](Cl)(=[O:21])[CH2:18][CH2:19][CH3:20]>C(Cl)Cl>[C:17]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: COC(=O)c1sccc1N
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccsc1C(=O)OC
Temperature: 0 °C

Procedure:
To a flame dried flask equipped with stir bar was added methyl 3-aminothiophene-2-carboxylate (2.06 g, 13.1 mmol) and anhydrous methylene chloride (10.0 mL). The resulting solution was cooled to 0° C., and treated successively with pyridine (1.11 mL, 13.7 mmol) and butyryl chloride (1.44 mL, 13.7 mmol) while stirring under N2. The ice bath was removed, and the reaction warmed to 25° C. and stirred 3 h. The reaction was then poured into 1N HCl and extracted with methylene chloride. The combined organics were dried over magnesium sulfate, filtered and concentrated to provide methyl 3-(butyrylamino)thiophene-2-carboxylate (1-2). MS 228 found, 227.3 required.
Reaction SMILES: [C:1]1([P:17]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[OH:32]O>C(Cl)(Cl)Cl>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([P:17](=[O:32])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:1]2[C:14]3[C:15]4=[C:16]5[C:11](=[CH:12][CH:13]=3)[CH:10]=[CH:9][CH:8]=[C:7]5[CH:6]=[CH:5][C:4]4=[CH:3][CH:2]=2)=[CH:19][CH:20]=1
Reactant: OO
Reactant: COc1ccc(P(c2ccccc2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(P(=O)(c2ccccc2)c2ccc3ccc4cccc5ccc2c3c45)cc1
Reaction time: 0.08 h
Yield: 97 %

Procedure:
Pyrenylphenyl-4-methoxyphenylphosphine [Va] (1.68 g, 4.03 mmol) was dissolved in 25 mL of chloroform, and 5 mL of hydrogen peroxide was slowly added dropwise to the solution. The mixture was stirred for 5 minutes and then the reaction was quenched with 25 mL of 10% sodium thiosulfate. The mixture was extracted with chloroform (20 mL×3). The organic layer was dried over sodium sulfate and concentrated on an evaporator to give white crystals in 97% yield. The white crystals obtained were identified by 1H-NMR, 31P-NMR and 13C-NMR.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)COc1cccc(CCCO)c1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1cccc(CCCOS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl [3-(3-hydroxypropyl)phenoxy]acetate (107.4 g) in DCM (1.07 L) was added TEA (113 mL) at ambient temperature. Methanesulfonyl chloride (45.4 mL) was added dropwise to the mixture at 0° C. The mixture was stirred for 1 hour at ambient temperature and water (1 L) was added to the mixture at the same temperature. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford ethyl (3-{3-[(methylsulfonyl)oxy]propyl}phenoxy)acetate (155.5 g) as a yellow oil.
Reaction SMILES: C[O:2][C:3]([P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])=O.[CH3:11][N:12]([CH3:17])[C:13]([NH:15][CH3:16])=[NH:14]>O1CCCC1>[CH3:11][N:12]([CH3:17])[C:13](=[N:14][C:3]([P:5](=[O:10])([O:8][CH3:9])[O:6][CH3:7])=[O:2])[NH:15][CH3:16]
Reactant: COC(=O)P(=O)(OC)OC
Reactant: CNC(=N)N(C)C
Solvent: C1CCOC1
Product: CNC(=NC(=O)P(=O)(OC)OC)N(C)C

Procedure:
A solution of 54 parts of dimethyl methoxycarbonylphosphonate and 33 parts of 1,1,3-trimethylguanidine in 1000 parts of anhydrous tetrahydrofuran was refluxed for one hour. The solvent was removed under reduced pressure to yield 71 parts of dimethyl 1-dimethylamino-1-methylaminomethyleneaminocarbonylphosphonate, nD25 = 1.4989.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][N:37]3[CH:38]=[C:34]([C:33]([F:43])([F:32])[F:44])[CH:35]=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cn1cc(C(F)(F)F)cn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C(F)(F)F)cn3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79.1 μmol), (4-trifluoromethyl-pyrazol-1-yl)-acetic acid (20.7 mg, 106.9 μmol) and DIPEA (48 μL, 276.8 μmol) in THF (3 mL), T3P (166 μL, 276.8 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as an off white solid (71%, 35 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15](Br)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41]([S:43]([C:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1)(=[O:45])=[O:44])[CH3:42]>O1CCOCC1.C(OCC)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:32]=[CH:31][C:21]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:20][CH:19]=3)=[C:15]([C:49]3[CH:48]=[CH:47][C:46]([S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])=[CH:51][CH:50]=3)[S:14][C:13]=2[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1sc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Dissolve 1-{2-[4-(6-benzyloxy-2-bromo-benzo[b]thiophen-3-yloxy)-phenoxy]-ethyl}-piperidine (700 mg, 1.3 mmol) in dioxane (13 mL) and 10% aqueous sodium carbonate (6.9 mL, 6.5 mmol) and add 4-(ethanesulphonyl)benzene boronic acid (430 mg, 2 mmol) and Pd(PPh3)4 (150 mg, 0.13 mmol). Heat to 70° C. and stir overnight. Dilute with diethyl ether (25 mL) and water (25 mL), filter through Celite, and separate layers. Extract the aqueous layer with diethyl ether (50 mL). Combine the organic layers and wash with water (50 mL) and brine (50 mL). Dry with sodium sulfate, filter, and concentrate in vacuo. Chromatograph residue on a SiO2 column eluting with methanol in dichloromethane (0 to 5%) to give 400 mg of the title compound (49%): mass spectrum (ion spray): m/z=628.3 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([O:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Reactant: Oc1ccc2[nH]ccc2c1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCN1CCCCC1
Yield: 442.6 %

Procedure:
Using an analogous procedure to that described in Example 67, 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (10 mg), (prepared as described for the starting material in Example 67), was reacted with 5-hydroxyindole (48 mg, 0.36 mmol) to give 4-(indol-5-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (57 mg, 45%).
Reaction SMILES: [CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][Cl:16])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.CC(C)=O>C(O)C>[ClH:16].[CH2:1]([N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: Nc1ccncc1
Reactant: CC(C)CCn1c(CCl)nc2ccccc21
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)CCn1c(CNc2ccncc2)nc2ccccc21
Product: Cl

Procedure:
1-isoamyl-2-chloromethylbenzimidazole (2.9 g, 12.2 mmol) prepared in the preceding step (b), 4-aminopyridine (3.9 g, 22.5 mmol) and ethanol (24 ml) were refluxed. After concentration of the reaction mixture in vacuo, the product was crystallized from acetone (2.9 g, 9.0 mmol) and recrystallized from ethanol, than the objective compound (1.5 g, 4.5 mmol) was obtained.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:18]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH2:54]([O:56][C@@H:57]([CH2:61][C:62]1[CH:67]=[CH:66][C:65](O)=[CH:64][CH:63]=1)[C:58]([OH:60])=[O:59])[CH3:55]>ClCCl>[CH2:17]([O:60][C:58](=[O:59])[C@@H:57]([O:56][CH2:54][CH3:55])[CH2:61][C:62]1[CH:67]=[CH:66][C:65]([O:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:9][CH:10]=2)=[CH:64][CH:63]=1)[CH3:18]
Reactant: CCO[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: OCCc1ccc(Sc2ccccc2)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(Sc3ccccc3)cc2)cc1)OCC
Temperature: 25 °C
Yield: 47 %

Procedure:
2-[4-(Phenylsulfanyl)phenyl]-1-ethanol (1.22 g; 5.12 mmole), triphenylphosphine (2 g; 7.6 mmole) and 1,1′-(azodicarbonyl)dipiperidine were dissolved in dichloromethane (15 ml). After 10 minutes a solution of (S)-2-ethoxy-3-(4-hydroxyphenyl)propanoic acid (described in Example 40b) in dichloromethane (15 ml) was added and the reaction mixture was stirred over night at room temperature. The solid material was filtered off and the solvent evaporated. Chromatography of the residue on siliga gel using ethyl acetate:petroleum ether (40-60° C.), (1:99, 5:95 and 10:90) gave 1.24 g (yield 47%) of (S)-2-ethoxy-3-(4-{2-[4-(phenylsulfanyl)phenyl]ethoxy}phenyl)propanoic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2].[CH3:42][NH:43][CH3:44].O.CN(C)C=O>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]([C:15]([N:43]([CH3:44])[CH3:42])=[O:17])[C:13](=[O:27])[N:12]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=3)[C:11]3[CH2:38][CH2:39][C:40](=[O:41])[C:10]2=3)=[CH:5][CH:4]=1)#[N:2]
Reactant: CNC
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1

Procedure:
A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 4, 60 mg, 0.11 mmol) in acetonitrile (1.5 mL) is treated with dimethylamine (2.0 M in tetrahydrofuran, 270 μL, 0.53 mmol) and the mixture is stirred at room temperature for 30 min Water and N,N-dimethylformamide are added and the mixture is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield 28 mg, ESI mass spectrum [M+H]+=469; Retention time HPLC: 0.87 min (Z018_S04).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([C:18](O)=[O:19])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1([NH2:35])[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)=[O:25])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:19])[NH:35][C:26]2([C:24]([O:23][CH2:21][CH3:22])=[O:25])[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)O)C1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 3,4-dihydro-1H-isoquinoline-2,5-dicarboxylic acid 2-tert-butyl ester (2 g, 7.2 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (1.5 g, 7.2 mmol), HATU (3.27 g, 8.6 mmol) in anhydrous DMF (20 mL) is added DIPEA (1.42 mL, 8.6 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (150 mL) and washed with water (1×20 mL) and brine (2×20 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by HPLC to give a pure product (71) as white solid (1.02 g, 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH2:33]([O:35][C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38][NH2:39])[CH3:34]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:39][CH2:38][C:37]1[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=1[O:35][CH2:33][CH3:34])=[O:31]
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Reactant: CCOc1ccccc1CN
Reactant: O=C(Br)CBr
Product: CCOc1ccccc1CNC(=O)CN1CCc2c(cc(OC)c(OC)c2OC)C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-ethoxy-benzyl-amine
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:3]4[N:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1cccnn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 43.1 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (200 mg, 0.793 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (182 mg, 0.739 mmol), diisopropylethylamine (0.129 ml, 0.739 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration. This was recrystallized from ethyl acetate to obtain the desired product (117 mg, 43.0%) as a solid. mp 185-186° C.