Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].N[CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[OH-].[Na+].O1CCCC1>O>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: NCCCCC(=O)O
Reactant: CCN(CC)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(S(=O)(=O)CCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
2.5 g of 4-diethylaminobenzenesulphonyl chloride are added to a solution comprising 1.17 g of 5-aminovaleric acid and 1.2 g of sodium hydroxide dissolved in 12 cm3 of water, followed by the addition of 12 cm3 of tetrahydrofuran in order to obtain a solution. The mixture is kept stirring for 2 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid and extracted with chloroform, the organic phase is dried and the solvents are removed under reduced pressure. 2.2 g of expected product are obtained. M.p. 106°-108° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 109°-110° C., is obtained.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)=[NH:4].[CH2:15]([N:17]([CH2:28][CH3:29])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([CH3:27])[N:26]=1)[C:21](O)=O)[CH3:16]>>[CH2:28]([N:17]([CH2:15][CH3:16])[C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=3)[N:4]=2)[CH:24]=[C:25]([CH3:27])[N:26]=1)[CH3:29]
Reactant: CCN(CC)c1cc(C(=O)O)cc(C)n1
Reactant: N=C(NO)c1ccc(CC(=O)O)cc1
Product: CCN(CC)c1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cc(C)n1

Procedure:
The title compound is prepared in analogy to Example 5 starting from [4-(N-hydroxycarbamimidoyl)-phenyl]-acetic acid and 2-diethylamino-6-methyl-isonicotinic acid; LC-MS: tR=0.78 min; [M+1]+=367.13.
Reaction SMILES: S(Cl)(Cl)=O.C1(C2C=CC(C(O)=O)=CC=2)C=CC=CC=1.C1(C2C=CC(C(Cl)=O)=CC=2)C=CC=CC=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][CH:41]=[C:40]2[O:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][C:51]=1[F:57].[C:58]1([C:64]2[CH:69]=[CH:68][C:67]([C:70]([N:72]=[C:73]=[S:74])=[O:71])=[CH:66][CH:65]=2)[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][CH:41]=[C:40]2[O:49][C:50]1[CH:56]=[CH:55][C:53]([NH:54][C:73]([NH:72][C:70](=[O:71])[C:67]2[CH:68]=[CH:69][C:64]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[CH:65][CH:66]=2)=[S:74])=[CH:52][C:51]=1[F:57]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(-c2ccccc2)cc1
Agent: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C(O)c1ccc(-c2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(-c5ccccc5)cc4)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-phenylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-phenyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-phenyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-phenyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (76 mg, yield 92%). Mass spectrometry value (ESI-MS, m/z): 554 (M++1)
Reaction SMILES: [C:1]([C:6]1([CH2:21][CH2:22][CH2:23][C:24]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)([CH:27]([CH3:29])[CH3:28])[C:25]#[N:26])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3]CC)=[O:2].[ClH:40]>>[Cl-:40].[C:1]([C:6]1([CH2:21][CH2:22][CH2:23][C:24]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)([CH:27]([CH3:29])[CH3:28])[C:25]#[N:26])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][NH+:7]1[CH3:20])([OH:3])=[O:2]
Reactant: CCOC(=O)C1(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)Cc2cc(OC)c(OC)cc2CN1C
Reactant: Cl
Product: COc1ccc(C(C#N)(CCCC2(C(=O)O)Cc3cc(OC)c(OC)cc3C[NH+]2C)C(C)C)cc1OC
Product: [Cl-]

Procedure:
The resulting alkylated ester of formula 32 is then hydrolyzed by warming it in 6N HCl to produce a carboxylic acid/ammonium salt of formula 33 (step 4). For example, 3-carboethoxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (32) is heated at 35° C. in 6N HCl to produce 3-carboxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinolinium chloride (33).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28]Br>CN(C=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc2CCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in DMF (6 ml) were added potassium carbonate (415 mg, 3.00 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (302 mg, 1.65 mmol), and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 ml) was added to the residue and the resulting mixture was washed with water (5 ml×2) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure, hexane was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with hexane and was then dried under reduced pressure to obtain methyl 2-[3,5-bis(trifluoromethyl)benzyloxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (524 mg, 1.22 mmol, 81%).
Reaction SMILES: COC1C=CC(CO)=CC=1.CC1(C)C2(C)C(O)CC1CC2.C(O)C1C=CC=CC=1.[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32][OH:33].COC1C=CC(C[O:43][C:44]([NH:46][CH:47]2[C:50](=[O:51])[N:49]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH3:62])[CH:48]2[C:63]([O:65][CH3:66])=[O:64])=O)=CC=1.C(OC(NC1C(=O)N(CC2C=CC(OC)=CC=2OC)C1C(OC)=O)=O)C1C=CC=CC=1>C(O)(C)(C)C>[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32][O:33][C:44]([NH:46][CH:47]1[C:50](=[O:51])[N:49]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[CH:48]1[C:63]([O:65][CH3:66])=[O:64])=[O:43]
Reactant: OCC(Cl)(Cl)Cl
Reactant: COC(=O)C1C(NC(=O)OCc2ccc(OC)cc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: CC1(C)C2CCC1(C)C(O)C2
Agent: COC(=O)C1C(NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: COc1ccc(CO)cc1
Solvent: CC(C)(C)O
Solvent: OCc1ccccc1
Product: COC(=O)C1C(NC(=O)OCC(Cl)(Cl)Cl)C(=O)N1Cc1ccc(OC)cc1OC

Procedure:
When p-methoxybenzyl alcohol, isoborneol, benzyl alcohol, or 2,2,2-trichloroethanol is substituted for t-butanol in Example 3, methyl 3-(p-methoxybenzyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(isobornyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(benzyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, or methyl 3-(2,2,2-trichloroethoxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH:39][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]3[C:12]([CH3:24])=[CH:11][CH:10]=[C:9]([NH:8][C:6]([C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)=[O:7])[CH:14]=3)=[CH:20][CH:19]=2)=[O:22])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
5′-(3-Furoylamino)-2′-methyl-1,1′-biphenyl-4-carboxylic acid (50 mg, 0.156 mmol), 1-t-butyloxycarbonyl-4-aminomethylpiperidine (33.3 mg, 0.156 mmol), HATU (59.2 mg, 0.156 mmol), HOBT (21 mg, 0.156 mmol) and DIPEA (27 μl, 0.156 mmol) in DMF (2 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with water (2×30 ml) and dried (magnesium sulphate). The solvent was evaporated under vacuum and the residue chromatographed on a silica flash column eluting with DCM/methanol/triethylamine (96:2:2). Concentration of the product fractions under vacuum N-[4′-({[(1-t-butyloxycarbonylpiperidin-4-yl)methyl]amino}carbonyl)-6-methyl-1,1′-biphenyl-3-yl]-3-furamide (45 mg, 56%). NMR; δH [2H6]-DMSO 9.91,(1H, s), 8.56,(1H, t), 8.35,(1H, s), 7.91,(2H, d), 7.78,(1H, t), 7.66,(1H, dd), 7.59,(1H, d), 7.43,(2H, d), 7.27,(1H, d), 6.98,(1H, m), 3.93,(2H, m), 3.17,(2H, t), 2.68,(2H, b), 2.19,(3H, s), 1.74,(1H, b), 1.67,(2H, m), 1.38,(9H, s), 1.03,(2H, m). LCMS: retention time 3.50 min, [MH-BOC]+418.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:22].[C:23]([C:31]1[CH:32]=[C:33]([CH:37]([CH3:41])[C:38]([O-:40])=[O:39])[CH:34]=[CH:35][CH:36]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:40][C:38](=[O:39])[CH:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:32]=2)[CH3:41])=[O:7])=[CH:4][C:3]=1[Br:22]
Reactant: CC(C(=O)[O-])c1cccc(C(=O)c2ccccc2)c1
Reactant: CCN(CC)Cc1cc(C(=O)OCCCCCl)cc(Br)c1N
Agent: [Na+]
Product: CCN(CC)Cc1cc(C(=O)OCCCCOC(=O)C(C)c2cccc(C(=O)c3ccccc3)c2)cc(Br)c1N

Procedure:
This compound was prepared from 4-(4-amino-3-bromo-5-diethylaminomethyl-benzoyloxy)-n-butyl chloride and sodium 3-benzoyl-α-methyl-phenylacetate analogous to Example 8.
Reaction SMILES: C(OC([N:8](C1CC2C=C(OCC(O)=O)C=CC=2CCC1)[CH2:9][C@H:10](O)[CH2:11][O:12]C1C=CC=CC=1)=O)(C)(C)C.CN(C)CCCN=C=NCC.O[N:48]1C2C=CC=CC=2[N:50]=[N:49]1.O.[NH2:58]C1NN=NN=1>ClCCl>[NH:48]1[C:9]([CH2:10][C:11]([NH2:58])=[O:12])=[N:8][N:50]=[N:49]1
Reactant: On1nnc2ccccc21
Reactant: Nc1nnn[nH]1
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: O
Product: NC(=O)Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 210.1 %

Procedure:
To a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (100 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (61 mg) and 1-hydroxybenzotriazole (33 mg) in dichloromethane (10 ml) was added 5-aminotetrazole monohydrate (19.3 mg). The resulting mixture was stirred at room temperature for 18 hours and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel and treated with 4N hydrogen chloride in ethyl acetate to afford 2-[8-[(2S)-2-hydroxy-3-phenoxypropyl)-amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-2-(tetrazol-5-yl)acetamide (50 mg).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:12][NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].[C:20]([O:24][C:25]([N:27]1[CH2:31][C@@H:30]([O:32][C:33]2[C:42]3[C:37](=[C:38]([Cl:45])[C:39]([O:43][CH3:44])=[CH:40][CH:41]=3)[N:36]=[C:35]([N:46]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[N:47]3)[CH:34]=2)[CH2:29][C@H:28]1[C:55](O)=[O:56])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(C)C([C@@H]1C[C@@H](O)CN1C(OC(C)(C)C)=O)=O)CCCC=C>>[Cl:45][C:38]1[C:39]([O:43][CH3:44])=[CH:40][CH:41]=[C:42]2[C:37]=1[N:36]=[C:35]([N:46]1[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[N:47]1)[CH:34]=[C:33]2[O:32][C@@H:30]1[CH2:31][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:26])[C@H:28]([C:55](=[O:56])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[CH3:12])[CH2:29]1
Reactant: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Reactant: C=CCCCCNC
Agent: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-n3ccc(C(F)(F)F)n3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Yield: 87 %

Procedure:
Compound 114 was synthesized from compounds 32a and 113 as white foam in 87% yield, following the procedure as described for compound 48.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:25]2[O:26][C:27]([CH2:30][CH3:31])=[N:28][N:29]=2)([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:30]([C:27]1[O:26][C:25]([C:11]2([N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:29][N:28]=1)[CH3:31]
Reactant: [H][H]
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCNCC1
Reaction time: 24 h
Yield: 99.5 %

Procedure:
A mixture of 1-benzyl-4-(ethyl-1,3,4-oxadiazolyl)-4-(N-phenylpropionamido)piperidine (8.20 g, 19.6 mmol) and 10% palladium on charcol (2.0 g) in methanol (100 ml) was reacted with hydrogen (50 psi) in a Parr shaker. After 24 hours, the resulting mixture was filtered and the filtrate was concentrated in vacuo. A foamy residue (6.42 g, 19.5 mmol) was obtained. It was used for reactions without further purification. ##STR30##
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.[CH2:32]=[O:33].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[OH:1][C:2]1[C:3]([C:11]2([CH2:32][OH:33])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:30]=[CH:29][CH:28]=[CH:27][C:22]=3[C:23]([O:25][CH3:26])=[O:24])[C:12]2=[O:31])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: COC(=O)c1ccccc1CN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A solution of methyl 2-{[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]methyl}benzoate (17.1 g, 40.0 mmol) and paraformaldehyde (10.3 g, 330 mmol) in THF (500 mL) was degassed by bubbling through argon for 2 hours. To this solution was added lithium diisopropylamide solution (45.1 mL, 2 M solution, 90.0 mmol) slowly at −78° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonium chloride solution. The mixture was concentrated in vacuo to remove THF followed by the addition of ethyl acetate (500 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was recrystallized from ethyl acetate/hexanes to give the title compound (13.7 g, 75%): 1H NMR (300 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.95 (dd, 1H), 7.53-7.33 (m, 3H), 7.08-6.82 (m, 4H), 6.53 (d, 1H), 6.25 (s, 1H), 5.93-5.86 (m, 2H), 5.31-5.07 (m, 3H), 4.26-4.17 (m, 1H), 4.00-3.92 (m, 1H), 3.88 (s, 3H); MS (ES+) m/z 448.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19](O)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.Cl.[OH:24][C:25]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:29]3[CH2:28][CH2:27][C:26]4[C:31](=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:25]=4[OH:24])[CH2:30]3)=[O:20])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: CN(C)c1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(N(C)C)cc3)nc3ccccc13)C2
Yield: 20 %

Procedure:
Reaction of 2-(4-(dimethylamino)phenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 32 (20% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 2.64 and 2.89 (2t, 2H), 3.04 (s, 6H), 3.47 and 4.02 (2t, 2H), 3.74 and 3.80 (2s, 3H), 4.37 and 4.90 (2s, 2H), 6.31-6.92 (m, 4H), 7.55-7.65 (m, 1H), 7.74-7.86 (2d, 1H), 7.96-8.01 (m, 2H), 8.32-8.38 (m, 2H), 8.68 and 8.71 (2s, 1H); MS (ESI) m/z 455 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.[C:12]([CH2:17][NH2:18])(=[O:16])[CH:13]([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)CNC(=O)c1ccc(Cl)cc1
Yield: 99 %

Procedure:
4.5 g of 4-chlorobenzoyl chloride are added dropwise to a mixture of 4 g of isobutyrylmethylamine hydrochloride, 9.8 g of sodium bicarbonate, 200 ml of ethyl acetate and 100 ml of water at 5° C. to 10° C. under stirring. The mixture is further stirred at room temperature for 3 hours. The ethyl acetate layer is collected, and said layer is washed with water, dried and then condensed under reduced pressure to remove solvent. 6.1 g of N-(4-chlorobenzoyl)isobutyrylmethylamine are obtained. Yield: 87.5%.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:6]2[C:5]([C:17]([OH:19])=O)=[CH:4][C:3]=1[Cl:20].[CH2:21]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24]>>[NH2:1][C:2]1[N:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:10]=[C:6]2[C:5]([C:17]([NH:32][CH2:31][CH:28]2[CH2:29][CH2:30][N:25]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]2)=[O:19])=[CH:4][C:3]=1[Cl:20]
Reactant: CCCCN1CCC(CN)CC1
Reactant: Nc1c(Cl)cc(C(=O)O)c2nc(-c3ccccc3)cn12
Product: CCCCN1CCC(CNC(=O)c2cc(Cl)c(N)n3cc(-c4ccccc4)nc23)CC1

Procedure:
The title compounds were prepared according to the procedure described in the step 3 in EXAMPLE 5 from 5-amino-6-chloro-2-phenylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 22, Step 2) and 1-(1-butyl-4-piperidinyl)methanamine (EXAMPLE 1, METHOD A, Step 5).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].O.[NH2:14][NH2:15].Cl>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:14][NH2:15])=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: NN
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(NN)nnc1Cl
Yield: 61.3 %

Procedure:
To a solution of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (2.0 g, 9.76 mmol) in ethanol (30 ml) was added hydrazine hydrate (0.34 ml, 10.9 mmol) dropwise. The reaction mixture was heated at reflux for 18 h under an atmosphere of nitrogen. The solvent was removed under high vacuum to leave a residue to which was added 5N hydrochloric acid (50 ml). The solution obtained was washed with dichloromethane (20 ml) and the aqueous layer was poured on to a mixture of ice and aqueous ammonia. The resultant solid was collected by filtration and dried under vacuum to yield the title compound (1.2 g). Data for the title compound: 1H NMR (360 MHz, DMSO) δ1.39 (3H, t, J=7.3 Hz), 4.35 (2H), 7.07 (1H, s), 8.07 (1H, s); MS (ES+) m/e 201, 203 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:18]=1.CN1CCOCC1.C(Cl)(=O)C(Cl)=O.[N:38]1([C:43]2[CH:44]=[C:45]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=2)[NH2:46])[CH:42]=[CH:41][N:40]=[CH:39]1.NC1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:38]1([C:43]2[CH:44]=[C:45]([NH:46][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]4[CH:14]=[N:15][CH:16]=[C:17]([CH2:19][N:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[CH:18]=4)[CH:4]=3)[CH:47]=[C:48]([C:50]([F:52])([F:53])[F:51])[CH:49]=2)[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cncc(CN2CCCC2)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Nc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1C#Cc1cncc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-methyl-3-{[5-(pyrrolidin-1-ylmethyl)pyridin-3-yl]ethynyl}benzoic acid (18 mmol) is dissolved in methylene chloride (100 mL). To this solution is added 3 equivalents of 4-methylmorpholine (NMM) followed by 1.05 equivalents of oxalyl chloride. After stirring at ambient temperature for 30 minutes, 0.8 equivalents of 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (prepared as above) is added along with 5 mole % of DMAP. After initially stirring at ambient temperature, the mixture is brought to reflux and stirred overnight. After 16 h an additional 0.2 equivalents of the aniline is added, bringing the total charge to 1 equivalent. The mixture can then be stirred for an additional 2 h, quenched with water, and the layers separated. The aqueous layer can be extracted with methylene chloride (2×50 mL) and the combined extracts can be washed with water. The combined methylene chloride layers can then be evaporated and the residue dissolved in 100 mL of ethyl acetate (20 mL). After standing for 1 h, the product is allowed to crystallize. The mixture is cooled, e.g. to 0° C., filtered, and the solid product is washed with cold ethyl acetate.