Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24](Br)=[CH:23][C:12]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[CH2:1]([O:8][C:9]1[C:24]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:23][C:12]([C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]2[OH:22])=[O:14])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ccccc2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCc2ccccc2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a solution of 6-benzyloxy-5-bromo-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (85 mg) in 1,2-dimethoxyethane (1.6 ml) was added tetrakis(triphenyl-phosphine)palladium(0) (24.5 mg). The mixture was stirred for 10 min. 4-chlorophenyl-boronic acid (37.2 mg) was dissolved in 0.7 ml EtOH and added to the reaction mixture. A solution of Na2CO3 (190 mg) in water (1 ml) was added. The reaction mixture was stirred at 85° C. for 3 h. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with brine. The org. phase was dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, CH2Cl2=>CH2Cl2MeOH 4:1) to give 6-benzyloxy-5-(4-chloro-phenyl)-N-((1R,2R)-2-hydroxy-cyclohexyl)-nicotinamide (50.6 mg) as a white solid. MS (ISP) 437.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][C@@H:2]1[N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][CH:9]=[N:10][C:11]=2[NH2:15].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C(Cl)Cl.CO.CO>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH2:3][C@@H:2]1[N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][CH:9]=[N:10][C:11]=2[NH:15][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16]
Reactant: Nc1ncnc2c1ncn2[C@H]1CC=CO1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ncnc2c1ncn2[C@H]1CC=CO1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a suspension of the product of Step C (196 g, 0.97 mole), 4-dimethylaminopyridine (5.9 g, 0.048 mole) in dry pyridine (970 mL) at 26° C. was added dropwise over 1 hr trimethylacetylchloride (145 mL, 142.1 g, 1.18 mole, 1.2 equiv.). A slight 3° C. exotherm was noted. The reaction mixture was then heated to 55° C. for 4 hr becoming a pale yellow-orange solution. Analysis by TLC (methylene chloride: methanol (90:10), Rf (product) 0.75) showed the reaction was complete. The reaction solution was cooled to 25° C. and methanol (40 mL) was slowly added. The reaction solution was then stirred for 30 min, then concentrated in vacuo to a thick orange syrup. The residue was dissolved in methylene chloride (1.5 liters) and washed with 0.5N sodium bisulfate (3×500 mL), 1N sodium bisulfate (2×500 mL), then brine (1×500 mL). All aqueous washes were combined and extracted with methylene chloride (1×500 mL). All methylene chloride extracts were combined and dried over anhydrous sodium sulfate, then filtered and concentrated in vacuo light orange oil. The oil was suspended in toluene (200 mL) and concentrated in vacuo. The product solidified to a pale yellow solid weighing 262 g for a yield of 94%.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:61]([CH3:63])C)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4].[CH3:64][O:65]C(N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@H:61]([O:65][CH3:64])[CH3:63])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[C:26](=[C:27]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[C@H:47]([NH:54][C:55](=[O:58])[O:56][CH3:57])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:38][CH:37]=6)=[CH:32][C:28]5=[CH:29][CH:30]=4)[O:25][CH2:24][C:23]=3[CH:60]=2)=[CH:17][N:18]=1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc([C@@H]5CCCN5C(=O)[C@H](NC(=O)OC)c5ccccc5)[nH]4)ccc23)[nH]1)[C@@H](C)OC

Procedure:
This compound was made in an analogous manner to methyl (R)-2-((S)-2-(5-(8-(2-((S)-1-((S)-2-methoxycarbonylamino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)-6H-dibenzo[c,h]chromen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate, substituting (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid in the first amide coupling. LCMS-ESI+: calculated for C48H50N8O8: 866.96; observed [M+1]+: 867.58.
Reaction SMILES: ClCCl.Cl.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[NH:19])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:29])[CH3:28]>O>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=[N:19][C:27](=[O:29])[CH3:28])=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: N=c1ccccn1Cc1ccc(Cl)nc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N=c1ccccn1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17 %

Procedure:
Anhydrous dichloromethane (20 mL) was added to 118 mg (0.46 mmol) of 1-[(6-chloropyridin-3-yl)methyl]pyridine-2(1H)-imine hydrochloride obtained by the alternative method described in Synthesis Example 14, following which 159 μL (1.16 mmol, 116 mg) of triethylamine and 33 μL of acetyl chloride were added and the mixture was stirred at room temperature for 15 minutes. The reaction was stopped by adding water to the reaction mixture, and liquid-liquid extraction was carried out with chloroform and water. The organic phase was washed with a saturated aqueous solution of ammonium chloride, then concentrated. With the addition of hexane thereto, a solid settled out. The solid was collected by filtration and washed, then thoroughly dried, giving 21 mg of the target compound (yield, 17%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=S)[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.Cl.[NH:18]1[CH2:22][CH2:21][C@@H:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19]1>C1(C)C=CC=CC=1.ClCCl>[CH2:1]([NH:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:19]3)[O:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C1CCN([C@@H]2CCNC2)CC1
Reactant: CCNC(=O)c1ccc2[nH]c(=S)oc2c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)oc2c1
Temperature: 130 °C

Procedure:
N-Ethyl-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (Example 93A, 56 mg, 0.253 mmol) and (R)-1-(pyrrolidin-3-yl)piperidine (Reference Example 5c, 39 mg, 253 mmol) were combined in toluene (1 mL) and heated to 130° C. for one hour. The reaction mixture was diluted with dichloromethane, washed with a 1 N aqueous solution of sodium hydroxide, and the organic layer was absorbed on silica gel. The crude mixture was purified using silica gel chromatography (12 g column) eluting with a gradient of methanol/dichloromethane (1-18%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.34 Hz, 3 H) 1.40-1.53 (m, 2 H) 1.59-1.69 (m, 4 H) 1.89-2.07 (m, 1 H) 2.22-2.35 (m, 1 H) 2.36-2.60 (m, 4 H) 2.89-3.03 (m, 1 H) 3.42-3.58 (m, 3 H) 3.59-3.68 (m, 1 H) 3.82-3.92 (m, 1 H) 3.97 (dd, J=10.11, 7.34 Hz, 1 H) 5.98-6.11 (m, 1 H) 7.31 (d, J=8.33 Hz, 1 H) 7.53 (dd, J=8.33, 1.59 Hz, 1 H) 7.78 (d, J=1.59 Hz, 1 H); MS (ESI+) m/z 343.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:20]=[C:21]([NH:24][CH2:25][C:26]5[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=5)[S:22][CH:23]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(OC)(O[CH3:42])(=O)=O.[H-].[Na+].C(OC(C)C)(C)C>CN(C)C=O.O>[CH:1]1([C:7]2[CH:37]=[CH:36][C:10]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:20]=[C:21]([N:24]([CH2:25][C:26]5[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=5)[CH3:42])[S:22][CH:23]=4)=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CNc2nc(-c3ccc(OCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(OCc4ccc(C5CCCCC5)cc4)cc3)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Under an argon atmosphere, a suspension of methyl 4-(4-(4-(4-cyclohexylbenzyloxy)phenyl)-2-thiazolylaminomethyl)benzoate (65.0 g, 0.127 mol) obtained in Example 2(3) in N,N-dimethylformamide (130 ml) and dimethyl sulfate (15.0 ml, 0.159 mol) were successively added dropwise to a suspension of sodium hydride (content 60%, 6.09 g, 0.152 mol) in N,N-dimethylformamide (130 ml) at 10° C. or below and the mixture was stirred at room temperature for 1 hr. Diisopropyl ether (195 ml) and water (130 ml) were successively added dropwise at 10° C. or below, and the mixture was stirred at room temperature for 30 min. The precipitated crystals were collected by filtration, washed successively with diisopropyl ether (195 ml) and water (130 ml) and dried to give the title compound (56.0 g, 83.7%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:35])[CH:33]=O)[CH3:30].N1C=CC=CC=1C.B.C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:29]([O:31][C:32](=[O:35])[CH2:33][NH:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:18][N:17]=[C:16]([CH2:15][C:12]3[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][CH:11]=3)[CH:20]=2)=[C:22]([NH2:28])[N:23]=1)[CH3:30]
Reactant: CCOC(=O)C=O
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccn1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CNc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reaction time: 8 h
Yield: 8 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridin-2,6-diamine (40 mg, 0.11 mmol) described in Example 25 and N,N-dimethylformamide (0.5 mL) were added glyoxylic acid ethyl ester polymer foam (16 mg, 0.16 mmol), α-picoline-borane (14 mg, 0.13 mmol), and acetic acid (40 mL), which was stirred overnight at the same temperature. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (4.9 mg, 8%) as a trifluoroacetic acid salt.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:42]=[C:41]([C:43]([NH:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([O:53][Si](C(C)(C)C)(C)C)[CH:48]=2)=[O:44])[CH:40]=[C:39]([CH3:61])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:23]>O1CCCC1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:42]=[C:41]([C:43]([NH:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([OH:53])[CH:48]=2)=[O:44])[CH:40]=[C:39]([CH3:61])[C:21]=1[C:22]([NH:24][C@H:25]([C:35]([O:37][CH3:38])=[O:36])[CH2:26][NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[O:23]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of tetra-n-butylammonium fluoride in tetrahydrofuran (1 M; 1.78 mL, 1.78 mmol) was added in two portions to a solution of N-[2-chloro-4-[[[[3-[[(1,1-dimethylethyl) dimethylsilyl]oxy]phenyl]methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (1.03 g, 1.62 mmol) in dry tetrahydrofuran (20 mL). The solution was stirred at room temperature for 30 min, then diluted with ethyl acetate (100 mL) and washed with water (25 mL) and brine (25 mL). The solution was dried (MgSO4), filtered, evaporated, held under high vacuum for 2.5 h, and then chromatographed (60-70% ethyl acetate/petroleum ether) to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-[[(1,1-dimethylethoxy)carbonyl]amino]-L-alanine, methyl ester (0.82 g, 97%) as a white foam.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[S:26][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1)=[O:4].[C:27]([O-:30])(=[O:29])[CH3:28].[K+].O>C(O)(=O)C>[C:27]([O:30][CH2:2][C:3]([C:5]1[S:26][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1)=[O:4])(=[O:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OCC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2

Procedure:
To a suspension of 3.2 g of 9-chloroacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one obtained in Example 47 in 40 ml of acetic acid is added 6.0 g of potassium acetate and the mixture is refluxed under heating for 3 hours with stirring. After cooling, to the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The resulting residue is subjected to column chromatography on silica gel and eluted with a mixed solvent of choloroform and methanol (99:1). The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 9-acetyloxyacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 172°-174° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:13]2[CH:12]=[CH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]([C:30]4[CH:31]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)[C:32]([C:38]([O:40]CCC#N)=[O:39])=[C:33]([CH3:37])[NH:34][C:35]=4[CH3:36])=[O:29])[CH2:20][CH2:19]3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl>CO>[CH:14]1[C:10]2[CH:11]=[CH:12][C:13]3[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[C:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][O:27][C:28]([C:30]4[CH:31]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)[C:32]([C:38]([OH:40])=[O:39])=[C:33]([CH3:37])[NH:34][C:35]=4[CH3:36])=[O:29])[CH2:22][CH2:23]3)[C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: CC1=C(C(=O)OCCC#N)C(c2cccc(Cl)c2)C(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)=C(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)=C(C)N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5 ml of methanol and 0.434 ml of 1 N aqueous sodium hydroxide solution were added to 244 mg (0.36 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester 5-(3-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene) piperidine-1-yl )propan-1-yl) ester and stirred at room temperature for 5 hours. After adding 1 N hydrochloric acid, precipitates were taken by the filtration and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]#[CH:12])[CH:8]=2)[C:3]1=[O:13].[C:14]([NH2:22])(=[S:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[BrH:1].[C:11]([C:7]1[CH:6]=[CH:5][C:4]2[C:3]3([OH:13])[N:22]=[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[S:21][CH:2]3[CH2:10][C:9]=2[CH:8]=1)#[CH:12]
Reactant: NC(=S)c1ccccc1
Reactant: C#Cc1ccc2c(c1)CC(Br)C2=O
Product: Br
Product: C#Cc1ccc2c(c1)CC1SC(c3ccccc3)=NC21O

Procedure:
This compound is prepared analogously to the process described in Example 1c using 2-bromo-5-ethynylindan-1-one and thiobenzamide; melting point: 133-134° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1.Cl[CH2:41][C:42](=[O:44])[CH3:43]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:23][CH2:24][N:25]([CH2:41][C:42](=[O:44])[CH3:43])[CH2:26][CH2:27]3)=[O:21])[C:10]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=3[O:36][CH:37]([CH3:39])[CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCNCC2)c(OC(C)C)c1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)N2CCN(CC(C)=O)CC2)c(OC(C)C)c1

Procedure:
The compound was prepared by the treatment of [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]piperazin-1-yl-methanone (example 10 g) with chloroacetone and triethylamine at 40° C. overnight. HR-MS (ES, m/z) calculated for C33H36N4O4Cl2[(M+H)+]623.2187, observed 623.2194.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[C:31]([F:36])[CH:30]=3)[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:46]([C:48]1([C:51]([OH:53])=O)[CH2:50][CH2:49]1)=[O:47].C(N(C(C)C)CC)(C)C.[F:63][C:64]1[CH:70]=[CH:69][C:67]([NH2:68])=[CH:66][CH:65]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:1]([O:5][C:6](=[O:37])[N:7]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[S:27][C:26]3[C:21](=[N:22][CH:23]=[CH:24][C:25]=3[O:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][C:46]([C:48]4([C:51](=[O:53])[NH:68][C:67]5[CH:69]=[CH:70][C:64]([F:63])=[CH:65][CH:66]=5)[CH2:50][CH2:49]4)=[O:47])=[C:31]([F:36])[CH:30]=3)[CH:20]=2)=[CH:17][CH:18]=1)[CH2:8][CH2:9][O:10][CH3:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C1(C(=O)Cl)CC1
Reactant: Nc1ccc(F)cc1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)c(F)c4)c3s2)nc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)c3s2)nc1)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To aniline 20 (40 mg, 0.076 mmol, Scheme 6) and triethylamine (0.20 mL, 1.4 mmol) in THF (10 mL) at r.t. was added a solution of 63 (1.0 mL, 0.26 mmol) in THF and the resulting mixture was stirred for 3 h. The reaction mixture was then quenched with water (1.0 mL) and concentrated. The residue was partitioned between ethyl acetate and water, and the organic phase was washed with water and brine, dried (MgSO4), filtered and concentrated. The residue was dissolved in DMF (10 mL) and diisopropylethylamine (0.2 mL, 0.14 g, 1.1 mmol), 4-fluoroaniline (50 mg, 0.45 mmol), and HATU (75 mg, 0.20 mmol) were sequentially added. The mixture was stirred for 4 h at r.t. and partitioned between ethyl acetate and water. The organic phase was separated, washed with water, sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Silica gel chromatography of the residue (eluent ethyl acetate) provided 64 (34 mg, 61%). MS (m/z)=730.5 (M+H).
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[C:23]([O:25]C)=[O:24])=[CH:17][C:16]=2[O:28][CH3:29])=[C:8]([CH2:32][CH2:33][C:34]([F:37])([F:36])[F:35])[C:7]=1[OH:38])(=[O:5])[CH3:4].Cl>CO>[C:3]([C:6]1[CH:31]=[CH:30][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[O:28][CH3:29])=[C:8]([CH2:32][CH2:33][C:34]([F:36])([F:35])[F:37])[C:7]=1[OH:38])(=[O:5])[CH3:4]
Reactant: COC(=O)C(=O)Nc1ccc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NC(=O)C(=O)O)ccc1OCCCOc1ccc(C(C)=O)c(O)c1CCC(F)(F)F

Procedure:
18 ml of N sodium hydroxide solution are added to a solution of 7.95 g of methyl N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy]-3-methoxy-phenyl}}-oxamate in 100 ml of methanol and the mixture is refluxed for 1 hours. The hot solution is then poured into 200 ml of 0.1N hydrochloric acid. The product which has precipitated out is filterred off, washed with water and dried over phosphorus pentoxide in a drying cabinet. The N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-3-methoxy-phenyl}}-oxamic acid thus obtained is dissolved hot again in 100 ml of methanol, and one equivalent of triethanolamine in 10 ml of methanol is added. After addition of 400 ml of ether, crystallisation starts. The treithanolammonium salt of N-{{4-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-3-methoxy-phenyl}}-oxamic acid is thus obtained.
Reaction SMILES: [H-].[Na+].CO[C:5](=[O:8])[O:6][CH3:7].[CH2:9]1[C:13]2([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][CH2:11][CH2:10]1.CC(O)=O>C1COCC1>[O:19]=[C:18]1[CH:17]([C:5]([O:6][CH3:7])=[O:8])[CH2:16][CH2:15][CH2:14][C:13]21[CH2:9][CH2:10][CH2:11][CH2:12]2
Reactant: COC(=O)OC
Reactant: O=C1CCCCC12CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CCCC2(CCCC2)C1=O
Temperature: 80 °C

Procedure:
In a flask containing NaH (4.73 g, 118.20 mmol) in THF (30 mL) was added dimethylcarbonate (8.30 mL, 98.52 mmol). The mixture was heated at 80° C. To the mixture was added a solution of spiro[4.5]decan-10-one, 59, (6.00 g, 39.41 mmol) in THF dropwise (25 mL). The reaction was heated for 6 hrs at 80° C. The mixture was cooled to room temperature and hydrolyzed with AcOH. The solvent was evaporated and the crude residue was diluted with water and extracted with EtOAc. The organic layer was washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo.