Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH2:29]([NH:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:53][CH3:54])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[C:36]([NH2:55])[N:35]=1)[CH2:30][CH2:31][CH3:32].ICC>>[CH2:29]([NH:33][C:34]1[N:42]=[C:41]2[C:37]([N:38]=[C:39]([O:53][CH3:54])[N:40]2[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]2[CH2:48][CH2:49][N:50]([CH2:1][CH3:2])[CH2:51][CH2:52]2)=[C:36]([NH2:55])[N:35]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Solvent: CCI
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from N2-butyl-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purine-2,6-diamine and 2-iodoethane.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][O:40][CH2:41]OC)=[CH:34][CH:33]=2)=[C:29]([CH3:44])[CH:28]=[C:27]([CH3:45])[N:26]=1)(=O)C.[OH-:46].[Na+].[CH3:48]O>>[C@@H:6]1([O:24][C:25]2[C:30]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([CH2:38][CH:39]([O:46][CH3:48])[O:40][CH3:41])=[CH:36][CH:37]=3)=[C:29]([CH3:44])[CH:28]=[C:27]([CH3:45])[N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CO
Reactant: COCOCCc1ccc(Cc2c(C)cc(C)nc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reactant: [OH-]
Agent: [Na+]
Product: COC(Cc1ccc(Cc2c(C)cc(C)nc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-3-[4-(2-methoxymethyloxyethyl)benzyl]-4,6-dimethylpyridine (0.13 g) in methanol (4.0 mL) was added 2 mol/L aqueous sodium hydroxide solution (0.50 mL), and the mixture was stirred for 30 minutes at room temperature. After the reaction mixture was concentrated under reduced pressure, the residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=9/1) to give 2-(β-D-glucopyranosyloxy)-3-[4-(2-methoxy-methyloxyethyl)benzyl]-4,6-dimethylpyridine (0.086 g).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([OH:22])=[CH:17][CH:18]=3)[C:13]2=[O:23])[CH:6]=1)[CH3:2].Br[CH2:26][CH2:27][Cl:28].[C:29](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:28][CH2:27][CH2:26][O:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=3[CH3:11])[C:4]([NH:3][CH:1]3[CH2:29][CH2:2]3)=[O:24])[C:13]2=[O:23])=[CH:18][CH:17]=1
Reactant: CCNC(=O)c1ccc(C)c(-n2ccc3ccc(O)cc3c2=O)c1
Reactant: O=C([O-])[O-]
Reactant: ClCCBr
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccc2ccc(OCCCl)cc2c1=O

Procedure:
N-Ethyl-3-(7-hydroxy-1-oxoisoquinolin-2(1H)-yl)-4-methylbenzamide (0.65 g), 1-bromo-2-chloroethane (0.8 ml) and potassium carbonate (2.6 g) were stirred in DMF (26 ml) at 50° C. for 23 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×5), brine (×2), dried (magnesium sulfate) and concentrated to give 3-[7-(2-chloroethoxy)-1-oxoisoquinolin-2(1H)-yl]-N-cyclopropyl-4-methylbenzamide as a foam (577 mg); NMR Spectrum: (DMSO d6) 1.17 (t, 3H), 2.16 (s, 3H), 3.34 (m, 2H), 4.05 (t, 2H), 4.45 (m, 2H), 6.80 (d, 1H), 7.30 (d, 1H), 7.53 (m, 2H), 7.74 (d, 1H), 7.82 (m, 2H), 7.94 (d, 1H), 8.51 (t, 1H); Mass Spectrum: M+H+ 385.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[CH2:10][CH2:11][CH:12]([C:30](N1C(C2C=CC=CC=2)COC1=O)=[O:31])[CH:13]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C>C(O)(=O)C>[Si:1]([O:8][CH:9]([C:44]1[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=1)[CH2:10][CH2:11][CH:12]1[C:30](=[O:31])[N:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:13]1[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1cccc(C#N)c1)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [F-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(C)(C)[Si](C)(C)OC(CCC1C(=O)N(c2ccc(F)cc2)C1c1cccc(C#N)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Under argon, a mixture of 13 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-fluorophenylamino)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentyl]benzonitrile 12, 50 ml of bistrimethylsilylacetamide, 0.5 g of tetrabutylammonium fluoride and 100 ml of tert-butyl methyl ether is stirred at room temperature for 10 h. After the reaction has ended, 5 ml of acetic acid are added slowly with ice-cooling, and the mixture is concentrated. The residue is separated by silica gel chromatography (ethyl acetate/heptane=1/8). This gives 13:
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[C:2]1([CH:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:14]2[CH2:19][CH2:18][N:17]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
71.7 g (284 mmol) benzhydrylpiperazine, 45 g (361 mmol) 2-(2-chloroethoxy)-ethanol, 43.2 g (312 mmol) potassium carbonate and 9.4 g (57 mmol) potassium iodide are stirred in 400 ml absolute DMF for 8 hours at 75° C. After cooling, the solution is concentrated under vacuum. The residue is distributed between acetic acid ethyl ester and water. The aqueous phase is extracted twice with acetic acid ethyl ester and the combined organic phases are washed three times with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (90/10): Yield 104 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18]([OH:20])=O.[C:21]1([NH2:31])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][C:18]([NH:31][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: Nc1cccc2ccccc12
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCC(=O)Nc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(7-bromo-2-(ethoxycarbonyl)-1H-indol-3-yl)propanoic acid (0.68 g), naphthalen-1-amine (0.294 g), DMAP (0.363 g) and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (0.576 g) was stirred for 3 days at room temperature. The product precipitated and was filtered, washed with dichloromethane, and dried under vacuum.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11](O)=[O:12])[CH:8]=[CH:7][C:6]=1[N+:14]([O-])=O)([CH3:3])[CH3:2].C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:47]([NH:49][C:50]3[CH:51]=[CH:52][C:53]([C:60]([O:62][CH3:63])=[O:61])=[N:54][C:55]=3[O:56][CH:57]([CH3:59])[CH3:58])=[O:48])=[N:41][C:42]=2[O:43][CH:44]([CH3:46])[CH3:45])=[O:35])=[N:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[NH2:14][C:6]1[CH:7]=[CH:8][C:9]([C:11]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:34]([NH:36][C:37]3[CH:38]=[CH:39][C:40]([C:47]([NH:49][C:50]4[CH:51]=[CH:52][C:53]([C:60]([O:62][CH3:63])=[O:61])=[N:54][C:55]=4[O:56][CH:57]([CH3:59])[CH3:58])=[O:48])=[N:41][C:42]=3[O:43][CH:44]([CH3:46])[CH3:45])=[O:35])=[N:28][C:29]=2[O:30][CH:31]([CH3:32])[CH3:33])=[O:12])=[N:10][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)Oc1nc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(NC(=O)c3ccc(N)c(OC(C)C)n3)c(OC(C)C)n2)c(OC(C)C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2ccc(NC(=O)c3ccc(NC(=O)c4ccc(N)c(OC(C)C)n4)c(OC(C)C)n3)c(OC(C)C)n2)c(OC(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
6-Isopropoxy-5-nitro-2-pyridinecarboxylic acid (24.0 mg, 0.105 mmol), (COCl)2 (0.268 g, 2.12 mmol, 20 eqv), and DMF (cat.) were dissolved in 3 ml of CH2Cl2. The solution was allowed to stir for 2 h at rt and was then concentrated in vacuo. A solution of Methyl 5-{[(5-{[(5-amino-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinyl)carbonyl]amino}-6-isopropoxy-2-pyridinecarboxylate (6-1b) (30.0 mg, 0.052 mmol, 0.5 eqv) and DIEA (27.3 mg, 0.21 mmol, 2.0 eqv) in 3 ml of CH2Cl2 was added to the crude acid chloride. The solution was stirred for 12 h at rt. The precipitate was filtered, and washed several times with cold CH2Cl2. The nitro-derivative and 10% Pd/C (5 mg) were added to 5 ml of 1:1 MeOH/CH2Cl2 and the suspension was stirred for 20 min at rt under 1 atm H2. The solution was filtered through celite and the filtrate was concentrated in vacuo to give 36 mg of a white solid (92%): 1H NMR (500 MHz, CDCl3) d 1.45 (d, J=6.5 Hz, 6H), 1.50 (d, J=6.5 Hz, 6H), 1.54 (d, J=6.0 Hz, 12H), 3.94 (s, 3H), 5.55 (m, 1H), 5.68 (m, 3H), 7.00 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 2H), 8.92 (d, J=8.0 Hz, 1H), 9.03 (dd, J1=8.0 Hz, J2=8.0 Hz 2H), 10.24 (s, 1H), 10.27 (s, 1H), 10.28 (s, 1H); 13C NMR (125 MHz, CDCl3) d 22.17, 22.17, 22.20, 22.20, 52.35, 68.56, 69.23, 69.33, 69.36, 117.32, 117.42, 117.86, 119.03, 120.02, 125.03, 125.83, 126.12, 126.63, 126.81, 127.25, 134.52, 135.33, 137.88, 138.71, 139.22, 149.67, 150.81, 150.87, 151.93, 162.78, 162.80, 163.46, 165.47; HRMS (FAB) Submitted.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[N:14]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[C:12]([CH2:24][N:25](C)[C:26](=O)[O:27][C:28]([CH3:31])(C)C)[CH:11]=1.[C:34]([O:37]CC)(=[O:36])[CH3:35].Cl.C[OH:42]>>[C:28]([OH:42])(=[O:27])/[CH:31]=[CH:35]/[C:34]([OH:37])=[O:36].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]1[N:14]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:13]=[C:12]([CH2:24][NH:25][CH3:26])[CH:11]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc(F)c1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Reactant: CO
Agent: Cl
Product: CNCc1cc(-c2c(F)cccc2OC)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 51 %

Procedure:
tert-Butyl {[5-(2-fluoro-6-methoxyphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (100 mg) was dissolved in methanol (20 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added and the mixture was stirred at 70° C. for 20 min. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (6 mL), fumaric acid (49 mg) was added, and the obtained crystals were collected by filtration to give the title compound as colorless crystals (yield 53 mg, 51%).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[Cl:11][CH2:12][Cl:13]>>[Cl-:11].[Cl:13][CH2:12][N+:2]([CH3:10])([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: ClCCl
Reactant: COC(=O)CCCN(C)C
Product: COC(=O)CCC[N+](C)(C)CCl
Product: [Cl-]
Yield: 44 %

Procedure:
A solution of methyl 4-(dimethylamino)butanoate (4) (3.39 g, 23.35 mmol) in anhydrous dichloromethane (50 ml) was stirred for 3 days at ambient temperature and 3 days under reflux. The reaction mixture was evaporated and the oily solid was triturated with diethyl ether (30 ml) in an ultrasound bath. The crystals were filtered, washed with diethyl ether and dried in vacuo over P2O5 to afford 2.36 g (44%) of N-(chloromethyl)-4-methoxy-N,N-dimethyl-4-oxobutan-1-aminium chloride.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].N1C=CC=CC=1>C(Cl)Cl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][C:33](=[O:35])[CH3:34])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Yield: 91 %

Procedure:
A solution of Example 39H (0.050 g, 0.105 mmol), acetic anhydride (0.011 mL, 0.116 mmol), and pyridine (0.068 mL, 0.840 mmol) in methylene chloride (2 mL) was stirred at 25° C. for 4 hours. The solution was concentrated in vacuo and the residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give the desired product (0.046 g, 90%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.43 (m, 1H) 0.77 m, 7 H) 1.33 m, 1 H) 1.56 m, 3 H) 2.06 m, 4 H) 2.23 m, 1 H) 7.53 (m, 1 H) 7.66 m, 1 H) 7.77 m, 3 H) 8.16 m, 1 H) 8.29 m, 1 H) 10.38 m, 1 H) 13.84 (m, 1 H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]=O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][NH2:18].[C-:19]#[N:20].[K+]>O.CO>[Si:1]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH:12]([CH:15]([NH:20][CH3:19])[C:17]#[N:18])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(C=O)C1
Reactant: CN
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNC(C#N)C1CCC(CO[Si](C)(C)C(C)(C)C)C1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To 3-((tert-butyldimethylsilyloxy)methyl)-cyclopentanecarbaldehyde (5.8 g, 23.94 mmol) in H2O (8 mL) and methanol (10 mL) was added methylamine (0.0755 g, 23.94 mmol) at 0° C. This mixture was then added at 0° C. to KCN (1.56 g, 23.94 mmol) in H2O (3 mL). The resulting reaction mixture was stirred at 23° C. for 18 hours. The organic material was extracted with ethyl acetate (3×100 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo. 1H NMR (400 MHz, CDCl3) δ ppm 4.27-4.38 (2 H, m), 3.49-3.60 (1 H, m), 2.55 (3 H, s), 2.00-2.35 (4 H, m), 1.65-1.96 (2 H, m), 1.42-1.54 (2 H, m), 1.22 (1 H, ddd, J=13.4, 9.3, 3.8 Hz), 0.89 (9 H, s), 0.05 (6 H, m). LCMS (+ESI, M+H+) m/z 283.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].C1(C#C)C=CC=CC=1.[NH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)C#N>C(#N)C1C=CC=CC=1>[NH2:15][C:16]1[CH:17]=[CH:18][CH:21]=[C:22]([C:4]#[C:3][C:2]([CH3:6])([CH3:5])[CH3:1])[CH:23]=1
Reactant: C#CC(C)(C)C
Reactant: N#Cc1cccc(N)c1
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CC(C)(C)C#Cc1cccc(N)c1
Reaction time: 45 h
Yield: 48 %

Procedure:
The procedure was identical to Example 2, with the exception that 3,3-dimethyl-1-butyne (0.488 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-aminobenzonitrile (0.236 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 45 h at 65° C. showed the presence of 0.96 mmol (48% yield) of 1-amino-3-(3,3-dimethyl-1-butynyl)benzene and 1.00 mmol of 3-aminobenzonitrile remaining in the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][CH2:12][CH2:13][O:14][Si:25]([C:22]([CH3:24])([CH3:23])[CH3:21])([CH3:27])[CH3:26])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(COCCO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of the product of Example 5A (544.5 mg, 2.59 mmol) in anhydrous DMF (26 mL) was added imidazole (264 mg, 3.89 mmol) and TBDMS-Cl (586 mg, 3.89 mmol). The reaction mixture stirred at room temperature overnight and was quenched with water. The aqueous layer was extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to provide the desired product (677.5 mg, 2.19 mmol) in 84% yield. 1H(CDCl38.01, 600 MHz): δ (2H, d, J=8.3 Hz), 7.42 (2H, d, J=8.4 Hz), 4.63 (2H, s), 3.91 (2H, s), 3.82 (2H, t, J=5.0), 3.58 (2H, t, J=5.1 Hz), 0.91 (9H, s), 0.07 (6H, s); 13C (CDCl3166.5, 143.5, 129.2, 128.8, 126.5, 72.1, 71.6, 150 MHz): δ 62.3, 51.5, 25.4, 17.9, −5.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15](OCC)(=[O:18])[NH:16][NH2:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:15](=[O:18])[NH:16][N:17]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)NN
Reactant: Clc1ccc(-c2ccc(Br)cc2)nn1
Solvent: CCCCO
Product: O=c1[nH]nc2ccc(-c3ccc(Br)cc3)nn12

Procedure:
A mixture of 2.69 g. of 6-(p-bromophenyl)-3-chloropyridazine (U.S. Pat. No. 4,092,311), 3.12 g. of ethyl carbazate and 50 ml. of n-butanol is heated at reflux for 16 hours, then cooled and filtered giving an orange solid which is saved. The filtrate is heated at reflux for 23 hours, then chilled in an ice bath and filtered giving more orange solid. The two crops are combined and recrystallized from dimethylformamide, giving 0.65 g. of the desired product as orange crystals, m.p. 348°-350° C. (dec.).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].[CH3:6][C:7]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:10])[C:8]#[N:9].C(O)(=O)C.[NH2:22][C:23]#N>C(O)C>[C:23]([N:9]=[C:8]([O:1][CH2:2][CH3:3])[C:7]([CH3:6])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10])#[N:22]
Reactant: CC[O-]
Reactant: CC(C)(C#N)Oc1ccccc1
Reactant: N#CN
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=NC#N)C(C)(C)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of sodium ethoxide in ethanol, freshly prepared from sodium (0.02 mol) and ethanol (50 mL), was added 2-methyl-2-phenoxypropanenitrile from Step D (0.05 mol). The mixture was stirred overnight at room temperature, and then acetic acid (0.07 mol) was added, followed by addition of NH2CN (0.05 mol). The mixture was stirred for 3 hours and the solvent was removed. The residue was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate=4:1˜1:1) to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.27 (t, J=8.0 Hz 2H), 7.05 (t, J=7.2 Hz 1H), 6.88˜6.90 (m, 2H), 4.38 (q, J=7.2 Hz, 2H), 1.61 (s, 6H), 1.39 (t, J=7.2 Hz, 3H); LCMS (ESI+) m/z 233 (M+H)+.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.[CH2:18](S)[CH2:19][CH2:20]C>>[CH2:1]([S:2][CH:3]([C:4]1[CH:5]=[CH:6][C:7]([Cl:10])=[CH:8][CH:9]=1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCS
Reactant: CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCCCSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
The procedure described for making bis(p-chlorophenyl)methyl methyl sulfide was followed except that n-butyl mercaptan was used. The product obtained was greater than 90 percent pure.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:25]=[CH:24][C:15]3[CH:16]=[C:17]([C:19]([O:21]CC)=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:25]=[CH:24][C:15]3[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[S:18][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cc2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc3cc(C(=O)O)sc3c2)nc1Cl
Temperature: 50 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
Ethyl 6-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1-benzothiophene-2-carboxylate obtained in Example (184a) (74.4 mg) was dissolved in methanol (3 ml) and THF (6 ml). A 2 N aqueous lithium hydroxide solution (4 ml) was added, and the mixture was stirred at 50° C. for two hours. The organic solvent was evaporated under reduced pressure, followed by neutralization with 1 N hydrochloric acid. The resulting solid was collected by filtration, washed with distilled water, and dried under reduced pressure at 45° C. to obtain 64 mg of the title compound as a solid.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:35])=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:27]3[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]=3[CH3:35])[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1ccc(Cl)cc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3cc(Cl)ccc3C)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(5-chloro-2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:14])([CH3:13])C(O)=O)[CH:6]=[CH:7][CH:8]=1.C([N:17]([CH2:20]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:29])C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:17]([C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:13])[CH3:14])=[C:20]=[O:29]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: COc1cccc(C(C)(C)C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cccc(C(C)(C)N=C=O)c1
Temperature: 0 °C

Procedure:
2-(3-methoxy-phenyl)-2-methyl-propionic acid (24.40 g) is dissolved in toluene (120 mL) and cooled to 0° C. Triethylamine (16.61 mL) and diphenylphosphorylazide (24.37 g) are added. After 0.5 h the mixture is heated to 110° C. After 3 h the reaction mixture is diluted with EtOAc, cooled to 0° C., extracted with NaHCO3 solution and NaCl solution (H2O, 10%), dried on magnesium sulphate, filtered off from the desiccant and the solvent is eliminated in vacuo. The residue is used in the next reaction step without any further purification.