Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[N:40]([CH3:44])[N:41]=[N:42][CH:43]=2)[OH:38])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[N:40]([CH3:44])[N:41]=[N:42][CH:43]=2)=[O:38])=[CH:33][CH:32]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1nncc1C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1nncc1C(=O)c1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Dess-Martin periodinane (8 g, 19 mmol) was added to a solution of 3.2 (˜15.5 mmol) in DCM (80 mL). After 1 hour, the reaction mixture was concentrated with silica gel and chromatographed (silica gel, 1:2 EtOAc/hexane) to obtain compound 3.3 (4.3 g, 14.7 mmol). MS ESI (pos.) m/e: 294.1 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]3[CH:16]=[C:17]([F:21])[CH:18]=[CH:19][C:20]=3[C:12]=2[CH2:11][CH:10]([CH3:22])[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:9]2[CH:10]([CH3:22])[CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][C:17]([F:21])=[CH:16][C:15]=4[NH:14][C:13]=3[C:7]([C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8]2)=[O:29])=[CH:26][CH:25]=1
Reactant: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1cc(F)ccc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)C(C)Cc2c1[nH]c1cc(F)ccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 2-methyl-8-fluoro-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester and 4-fluorobenzoyl chloride; 1H NMR (CDCl3) δ 10.47 (1H, s), 7.96 (1H, s), 7.61-7.65 (2H, m), 7.41 (1H, m), 7.17 (2H, t), 7.05 (1H, dd), 6.90 (1H, t), 5.63 (1H, m), 4.17 (2H, m), 4.05 (2H, m), 3.38 (1H, dd), 3.07 (1H, dd), 1.55 (2H, m), 1.07 (3H, d), 0.77 (3H, t); MS (ES): 425 (MH+).
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]([CH3:21])[N:4]=1.[CH3:22][NH2:23]>CO>[CH3:20][CH:14]1[C:13]([C:9]2[CH:8]=[C:7]3[C:12]([C:3]([NH:23][CH3:22])=[N:4][C:5]([CH3:21])=[N:6]3)=[CH:11][CH:10]=2)=[N:18][NH:17][C:16](=[O:19])[CH2:15]1
Reactant: COc1nc(C)nc2cc(C3=NNC(=O)CC3C)ccc12
Reactant: CN
Solvent: CO
Product: CNc1nc(C)nc2cc(C3=NNC(=O)CC3C)ccc12
Reaction time: 4 h
Yield: 76 %

Procedure:
In 20 ml of 40% methylamine solution in methanol was suspended 0.50 g of Compound 63 obtained in Example 65. The suspension was heated under reflux with stirring for 4 hours and then concentrated. The residue was subjected to partition between water and chloroform, and the organic layer was dried and concentrated. The residue was crystallized from a mixture of dimethylformamide and water to give 0.38 g (76%) of 4,5-dihydro-5-methyl-6-(4-methylamino2-methylquinazolin-7-yl)-3(2H)-pyridazinone (Compound 64).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCCC3
Temperature: 60 °C
Yield: 78.9 %

Procedure:
To a solution of methyl [2-methyl-4-(4-chlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.196 g; 0.459 mmol) in methanol (4.6 mL) was added a solution of sodium hydroxide 5 N (0.95 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.150 g (76%) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:14][C:13](=O)[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.C(Cl)(=O)C([Cl:30])=O>ClCCl>[Cl:30][C:13]1[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Temperature: 50 °C

Procedure:
To a solution of methyl 6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.90 g, 2.2 mmol) from Example 51, Step A in dichloromethane (5 mL) was added oxalyl chloride (1.0 mL, 11.4 mmol) and the reaction was heated at 50° C. for 24 h. The reaction was concentrated in vacuo and the residue was dissolved in methylene chloride and washed with aq. sodium bicarbonate. The organic layer was washed with a portion of brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 5 to 10% ethyl acetate in hexanes to yield methyl 2-chloro-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carboxylate.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][SH:6].Cl[CH2:8][CH:9]=[C:10]([CH3:52])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43].O>O1CCCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:52][C:10]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:51])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:50])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:49])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:48])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:47])[CH2:31][CH2:32][CH:33]=[C:34]([CH3:46])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:45])[CH2:39][CH2:40][CH:41]=[C:42]([CH3:44])[CH3:43])=[CH:9][CH2:8][S:6][CH2:5][CH2:4][NH2:3]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCl
Reactant: NCCS
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCSCCN
Yield: 61.3 %

Procedure:
Under an atmosphere of argon, sodium hydride (1.43 g, 35.8 mmol, 60% dispersion in mineral oil) was added to a solution of 2-aminoethanethiol (2.76 g, 35.8 mmol) in 90 ml of tetrahydrofuran. The mixture was heated at reflux temperature for 15 minutes and cooled in an ice bath. To the reaction mixture, 18-crown-6 (20 mg, 0.08 mmol) was added and then a solution of 1-chloro-3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,22,26,30,34-hexatriacontanonaene [23.2 g, 35.7 mmol, prepared as described in Item a) given above] in 90 ml of tetrahydrofuran was added in dropwise for 10 minutes. The reaction mixture was heated at reflux temperature for 4 hours and then cooled. After addition of water (1 ml), the solvent was evaporated in vacuo to dryness. The remaining residue was partitioned between water and n-hexane. The aqueous layer was extracted with n-hexane to combine the n-hexane layers. The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to dryness. The remaining residue was chromatographed on silica gel, eluting with CH2Cl2 /MeOH (50:1-20:1) to afford 15.1 g (61.3%) of the desired compound, as a pale brown oil.
Reaction SMILES: [CH2:1]([Cl:5])[C:2]([OH:4])=[O:3].[C:6]1([CH:12]=[CH:13][C:14]2[CH:15]=[C:16]([OH:24])[C:17]([CH2:21][CH2:22][CH3:23])=[C:18](O)[CH:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:5][CH2:1][C:2]([O:4][C:18]1[CH:19]=[C:14]([CH:13]=[CH:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:15]=[C:16]([O:24][C:2](=[O:3])[CH2:1][Cl:5])[C:17]=1[CH2:21][CH2:22][CH3:23])=[O:3]
Reactant: CCCc1c(O)cc(C=Cc2ccccc2)cc1O
Reactant: O=C(O)CCl
Product: CCCc1c(OC(=O)CCl)cc(C=Cc2ccccc2)cc1OC(=O)CCl
Yield: 72 %

Procedure:
This material was synthesized from anhydrous chloroacetic and 5-(2-Phenylethenyl)-2-1-propyl-1,3-benzenediol obtained in Example 11 in 72% yield by the same procedure as described in Example 12. 1HNMR (CDCl3, ppm): δ 1.30 (d, J=7.0 Hz, 6H), 3.08 (hept, J=7.0 Hz, 1H), 4.39 (s, 4H), 6.96 (d, J=17 Hz, 1H), 7.14 (d, J=17 Hz, 1H) 7.17 (s, 2H), 7.2-7.5 (m, 5H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[H-].[Na+].[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][CH2:34][NH2:35])=[CH:31][CH:30]=1>>[CH2:23]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:35][CH2:34][CH2:33][C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:14][CH2:15][CH3:16]
Reactant: NCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Product: CCCCOC(=O)N1CCN(c2cc(NCCc3ccc(F)cc3)nc3cc(Cl)ccc23)CC1

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.41 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.58 mmol), and 4-fluorophenethylamine (0.22 mL, 1.65 mmol) are treated according to method E yielding 4-[4-(butoxycarbonyl)piperazin-1-yl]-7-chloro-2-[2-(4-fluorophenyl)ethylamino]quinoline, which is deprotected with TFA in CH2Cl2 and transformed into the title product according to method C using 4-fluorophenyl isocyanate (18 μL, 0.16 mmol) and triethylamine (110 μL, 0.79 mmol) to give a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:9]=[CH:10][C:3]=12.C([Li])(CC)C.[Br:26]C(Br)(Br)Br>C1COCC1>[Br:26][C:7]1[C:2]([F:1])=[C:3]2[CH:10]=[CH:9][N:8]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])[C:4]2=[N:5][CH:6]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)ccnc21
Reactant: BrC(Br)(Br)Br
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Br)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
4-Fluoro-1-(tri isopropyl silyl)-1H-pyrrolo[2,3-b]pyridine (28.0 g, 95.7 mmol) in THF (600 mL) at −78° C. was treated dropwise with sec-butyllithium (150 mL, 211 mmol; 1.4M in cyclohexane). The reaction was stirred at −78° C. for 30 minutes. Perbromomethane (79.4 g, 239 mmol) in THF (100 mL) was then added dropwise. The reaction was stirred at −78° C. for 1 hour and then quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with hexanes. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The oil obtained was purified by flash chromatography on silica gel eluting with hexanes to provide 5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (30 g, 84% yield) as an oil, which solidified upon standing. 1H NMR (400 MHz, CDCl3) δ 8.28 (d, 1H), 7.26 (s, 1H), 6.62 (d, 1H), 1.86-1.78 (m, 3H), 1.11 (d, 18H).
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])([O-:9])=[O:8].[Cl:18][CH:19](Cl)[C:20]([O:22][CH3:23])=[O:21]>C(O)(=O)C>[Cl:18][CH:19]([C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[C:11]([O:16][CH3:17])[CH:12]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C(Cl)Cl
Reactant: COc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C(Cl)c1ccc([N+](=O)[O-])c(OC)c1

Procedure:
A suspension of potassium t-butoxide (1.44 kg) in dimethylformamide(6.61) cooled to −5° C. to −10° C., was treated with a mixture of 2-nitroanisole (690 g) and methyl dichloroacetate (915 g) over 4 hours, whilst maintaining the temperature below −5° C. The reaction mixture was then treated with acetic acid (770 ml) and then with water (6.61) and then e extracted three times with tert-butyl methyl ether (5.51). The combined extracts were washed with water (5.51), then with saturated sodium bicarbonate solution (5.51), then with saturated brine (5.51) and then dried over magnesium sulphate to give a solution of methyl α-chloro-3-methoxy-4-nitrophenylacetate.
Reaction SMILES: [C:1]1([CH3:51])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][N:13]([S:41]([C:44]2[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:14][CH2:15][CH2:16][N:17]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:54][N:55]([CH2:59][CH2:60]Cl)[CH2:56][CH2:57]Cl>CN(C=O)C>[CH3:54][N:55]1[CH2:59][CH2:60][N:10]([S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:51])=[CH:2][CH:3]=2)(=[O:8])=[O:9])[CH2:11][CH2:12][N:13]([S:41]([C:44]2[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=2)(=[O:43])=[O:42])[CH2:14][CH2:15][CH2:16][N:17]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:32])=[O:33])[CH2:18][CH2:19][N:20]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:57][CH2:56]1
Reactant: CN(CCCl)CCCl
Reactant: Cc1ccc(S(=O)(=O)NCCN(CCCN(CCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(C)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a stirred solution of 1,4,8,11-tetra(p-toluenesulfonyl)-1,4,8,11-tetraazaundecane prepared in Example 16A (80.7 g, 0.104 mole) in anhydrous DMF (1 l) was added sodium hydride (6.24 g-80% in mineral oil, 0.208 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under a dry argon atmosphere. The solution was then heated to 100° C. and a solution of N-methylbis(2-chloroethyl)amine freshly prepared as in Example 15A (16.2 g, 0.104 mole) in anhydrous DMF (200 ml) was added dropwise over a 45 minute period, maintaining the temperature at 100° C. After stirring, an additional 45 minutes at 100° C., the solution was concentrated in vacuo to a volume of 900 ml. H2O (1200 ml) was added at room temperature to crystallize the product. The solid was dried in vacuo over P2O5 to give 83.2 g (93% yield) of the crude product as a brown solid. A portion (50 g) of the crude product was purified by flash chromatography (silica gel, CHCl3 -95:5 (v/v)-CHCl3 -MeOH gradient) to give 16.8 g (34% yield) of the product as a light yellow solid. An analytical sample was recrystallized from CH2Cl2 -hexane: mp 183°-5° C.; Rf =0.60, silica gel-95:5 (v/v) CHCl3 -MeOH; 1H NMR (CDCl3) δ 1.91 (quint, J=6.0 Hz, 2H), 2.19 (s, 3H), 2.44 (s, 12H), 2.52 (t, J=6.2 Hz, 4H), 3.18 (m, 12H), 3.31 (m, 4H), 7.33 (m, 8H), 7.68 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=[O:5].Cl[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][O:1][C:2]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:21][CH2:20]1
Reactant: ClCC1CC1
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Product: COc1cc(OCC2CC2)c(C=O)cc1-c1cccs1
Yield: 18 %

Procedure:
Ex-32A: 2-Cyclopropylmethoxy-4-methoxy-5-thiophen-2-yl-benzaldehyde was prepared in a similar manner as described in Ex-29C from 2-hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex. 29B) and chloromethyl-cyclopropane, 18% yield. 1H-NMR (CDCl3) δ 10.41 (s, 1H), 8.24 (s, 1H), 7.43 (d, 1H), 7.29 (d, 1H), 7.06 (t, 1H), 6.45 (s, 1H), 3.95 (m, 5H), 1.31 (m, 1H), 0.68 (m, 2H), 0.40 (q, 2H).
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[N:40]=[CH:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[CH:55]=[C:54]2[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])[CH2:53]2)=[CH:48][CH:47]=1)=[O:45]>C(#N)C>[CH2:27]([O:34][C:35]1[N:40]=[CH:39][N:38]([CH2:43][C:44](=[O:45])[C:46]2[CH:55]=[C:54]3[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:58])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=c1cc(OCc2ccccc2)nc[nH]1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Solvent: CC#N
Product: O=C(Cn1cnc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2

Procedure:
6-Benzyloxy-3-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-3H-pyrimidin-4-one is prepared following preparation 15b from 850 mg (4.20 mmol) 6-benzyloxy-3H-pyrimidin-4-one and 1.35 g (4.41 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone in acetonitrile as solvent (purification via reversed HPLC chromatography).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:46].[Li+]>O1CCCC1>[Br:46][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:33])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:13]=1
Reactant: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CO)c1
Reactant: [Br-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cccc(CC(=O)Nc2ccccc2CBr)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.1 %

Procedure:
To a solution of 4 g of N-[2-(hydroxymethyl)phenyl]-3-(tetradecyloxy)benzeneacetamide in 75 ml of tetrahydrofuran is added 1.19 g of triethylamine and 1.34 q of methanesulfonyl chloride, followed by stirring at room temperature for 1.5 hours. Added 7.66 g of lithium bromide with stirring continued for an additional 2.5 hours. The solvent is evaporated and the residue partitioned between chloroform and saturated sodium bicarbonate. The organic layer is dried and evaporated to a residue which is crystallized from hexane to give 2.6 g of the desired product as a white solid, m.p. 103°-106° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@@H:14]([C:15]2[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=2[F:23])[CH2:13][CH2:12][C@H:11]([N:24]2[CH2:31][C:30]3[C:29]([NH:32]C(=O)OCC4C=CC=CC=4)=[N:28][NH:27][C:26]=3[CH2:25]2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[OH-].[OH-].[Pd+2]>[NH2:32][C:29]1[C:30]2[CH2:31][N:24]([C@@H:11]3[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C@@H:14]([C:15]4[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=4[F:23])[CH2:13][CH2:12]3)[CH2:25][C:26]=2[NH:27][N:28]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3[nH]nc(NC(=O)OCc4ccccc4)c3C2)CC[C@@H]1c1cc(F)c(F)cc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3[nH]nc(N)c3C2)CC[C@@H]1c1cc(F)c(F)cc1F
Reaction time: 1 h

Procedure:
To 31 mg (0.05 mmol) of the product from Step A in 4 mL of methanol was added 10 mg of 20% palladium hydroxide on carbon. The reaction mixture was purged with hydrogen gas and held under 1 atmosphere of hydrogen for 1 h. The mixture was filtered through a pad of Celite and the filter cake was successively washed with three portions of 4 mL of methanol. The combined filtrate and washings were concentrated and used without further purification in Step C. LC/MS 452.2 (M+1).
Reaction SMILES: N1(C(N)=O)CC=CCC1.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]([N:21]2[CH2:26][CH2:25][C:24](=[CH:27][CH:28]3[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:29]3)[CH2:23][CH2:22]2)=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>[Pd].C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]([N:21]2[CH2:22][CH2:23][CH:24]([CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:29]3)[CH2:25][CH2:26]2)=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CCN1CCCC(C=C2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: [Pd]
Agent: NC(=O)N1CC=CCC1
Solvent: CCO
Product: CCN1CCCC(CC2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 4 h
Yield: 62.2 %

Procedure:
A mixture of the alkenes N-(3,4-dichlorophenyl)-4-[1-ethylpiperidin-3-yl)methyl]-3,6-dihydropyridine-1(2H)-carboxamide and N-(3,4-dichlorophenyl)-4-[(1-ethylpiperidin-3-yl)methylene]piperidine-1-carboxamide (3:1) (40 mg) and 10% palladium on charcoal (30 mg) in ethanol (5 mL) was evacuated and purged with hydrogen. The mixture was left under an atmosphere of hydrogen for 4 hrs and then filtered through celite. The celite pad was washed with ethanol and the filtrate evaporated. The residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water and then by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane to give the title compound as a white solid (25 mg, 62%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[C:23]([C:25]4[NH:26][C:27]([C:30]5[O:31][C@@H:32]([CH3:35])[CH2:33][N:34]=5)=[CH:28][CH:29]=4)[CH:22]=[C:21]([O:36][C@@H:37]([CH3:41])[CH2:38][O:39][CH3:40])[CH:20]=3)=[CH:14][N:13]=2)(=[O:11])=[O:10])=CC=1>FC(F)(F)C(O)=O>[CH3:40][O:39][CH2:38][C@H:37]([CH3:41])[O:36][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]2[NH:26][C:27]([C:30]3[O:31][C@@H:32]([CH3:35])[CH2:33][N:34]=3)=[CH:28][CH:29]=2)[CH:22]=1)[O:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([NH2:8])(=[O:10])=[O:11])=[N:13][CH:14]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(N)(=O)=O)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
N,N-Bis(4-methoxybenzyl)-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenoxy)pyridine-2-sulfonamide (160 mg, 0.24 mmol) synthesized in Example (120c) was dissolved in trifluoroacetic acid (2 mL), and stirring was carried out at 40° C. for 8 hours. The solvent was distilled off under reduced pressure, methylene chloride and triethylamine were added in small portions to the residue, and the solvent was distilled off again under reduced pressure. The resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-5%) to afford the desired compound (106 mg, yield 99%) as a white solid.