Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@@H:17]([CH3:20])[CH2:18][OH:19])([CH3:4])([CH3:3])[CH3:2].[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:15][CH2:14][CH2:13][C@@:12]2([CH3:16])[C@H:8]1[CH2:9][CH2:10][C@@H:11]2[C@@H:17]([CH3:20])[CH2:18][O:19][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@]12C
Temperature: 0 °C
Yield: 66.3 %

Procedure:
198 mg (0,606 mmol) of (R)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propan-1-ol was dissolved in pyridine (3 ml) and cooled to 0° C. DMAP (18,5 mg; 0,152 mmol) was added followed by a slow addition of pivaloyl-chloride (97 ml; 0,79 mmol). The mixture was allowed to react for half an hour at 0° C. and half an hour at room temperature. The reaction mixture was poured in a cold aqueous HCl (25%) solution. Extraction with ether, washing with brine, drying over Na2 SO4 and solvent removal gave a dark oil which was purified by column chromatography on silica gel (eluent: n-hexane/ethyl-acetate 97:3) affording 215 mg (86,3%) of 2,2-Dimethyl-propionic acid (R)-2-[(1R,3aR,4S,7aR)-4-(tert-butyl-dimethyl-silanyloxy)-7a-methyl-octahydro-inden-1-yl]-propyl ester (J1) as a yellow oil.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][OH:7]
Reactant: BrCCCc1ccccc1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(3-phenyl-propyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 151 mmol). and 1-bromo-3-phenylpropane (20 g, 101 mmol). Yield 21.31 g, (95%); yellow oil; MS: 223.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N:10]#[C:11]Br>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:11]([NH2:10])[NH:9][C:4]=2[CH:3]=1
Reactant: N#CBr
Reactant: Nc1ccc(Br)cc1N
Solvent: CO
Product: Nc1nc2ccc(Br)cc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 144.5 %

Procedure:
4-bromobenzene-1,2-diamine (1.02 g, 5.45 mmol) was taken into 50% aqueous methanol (25 mL) followed by slow addition of cyanogen bromide (1.73 g, 16.35 mmol) and the mixture was allowed to stir at room temperature over 12 h. The mixture was then concentrated to approximately 50% volume, diluted with water and brought to neutral pH by addition of 2 M aqueous sodium hydroxide. The aqueous mixture was then partitioned with ethyl acetate and the organic solution washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 6-bromo-1H-benzimidazol-2-amine (1.67 g) as a red amorphous residue. MS (EI) for C7H6BrN3: 213 (MH+).
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]([CH2:22][CH3:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:11]([F:21])[CH:10]=1)=[O:7])[CH3:4].[CH3:24][O:25][C:26](=[O:36])[CH:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:24][O:25][C:26](=[O:36])[CH:27]([N:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[CH:5]([CH2:3][CH3:4])[CH2:22][CH3:23])=[CH:10][C:11]=2[F:21])[CH2:20][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)OC)c3cccc(F)c3)CC2)c(F)c1
Reaction time: 20 h
Yield: 77.7 %

Procedure:
A mixture of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide dihydrochloride (0.26 g, 0.70 mmol), bromo-(3-fluoro-phenyl)-acetic acid methyl ester (0.23 g, 0.91 mmol), and anhydrous K2CO3 (0.34 g, 2.45 mmol) in DMF (10 mL) was stirred for 20 h. The mixture was diluted with water (100 mL) and extracted with DCM (2×30 mL). The combined organic layers were washed with water, dried (Na2SO4), and concentrated. The residue was purified (SiO2; acetone/DCM) to give the title compound (0.25 g, 78%). MS: mass calcd. for C25H31F2N3O3, 459.23. m/z found, 460.3 [M+H]+. 1H NMR (CDCl3): 7.48-7.43 (m, 1H), 7.35-7.28 (m, 1H), 7.25-7.20 (m, 2H), 7.17 (br s, 1H), 7.12-7.07 (m, 1H), 7.05-6.99 (m, 1H), 6.86 (t, J=9.0, 1H), 4.07 (s, 1H), 3.71 (s, 3H), 3.11-3.04 (m, 4H), 2.70-2.59 (m, 4H), 2.03-1.95 (m, 1H), 1.75-1.66 (m, 2H), 1.59-1.49 (m, 2H), 0.93 (t, J=7.4, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>N1C=CC=CC=1.[Cl-].[Na+].O>[CH2:13]([O:12][C:10](=[O:11])[NH:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:14]
Reactant: CCOC(=O)Cl
Reactant: Nc1cccnc1Br
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Nc1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
3-Amino-2-bromopyridine described in Preparation Example S-1 (1.4 g, 8.1 mmol) was dissolved in pyridine (10 mL), ethyl chloroformate (0.93 mL, 9.7 mmol) was added dropwise on an ice bath, and the solution was stirred for 2 hours at room temperature. After the reaction was completed, the reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4), and the title compound (0.56 g, 2.3 mmol, 28%) was obtained.
Reaction SMILES: CP(=O)(OC)OC.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[Cl:13][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:23]=1)[O:20]CCC2=O.[NH4+].[Cl-].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CCCCCC.O>[CH2:11]=[C:10]1[C:16]2[C:21](=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:23]=[C:14]([Cl:13])[CH:15]=2)[O:20][CH2:8][CH2:9]1
Reactant: O=C1CCOc2c(OC(F)F)cc(Cl)cc21
Reactant: [Li]CCCC
Agent: COP(C)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C1CCOc2c(OC(F)F)cc(Cl)cc21
Temperature: 120 °C
Yield: 47 %

Procedure:
To a solution of dimethyl methylphosphonate (8.9 g, 71.1 mmol) in dry THF (55 mL) under N2 was added, dropwise over 1 h at −70° C., n-butyllithium in hexane (1.6M, 49.2 mL). The mixture was stirred for 30 minutes at −70° C., whereafter a solution of 6-chloro-8-difluoromethoxychroman-4-one (6.8 g, 27.35 mmol, from step (v) above) in dry THF (15 mL) was added, dropwise over 30 minutes at −70° C. The reaction mixture was stirred for 2 h at −70° C., whereafter NH4Cl (aq., sat., 110 mL) was added, and then water (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated. The residue was dissolved in DMF (85 mL). To the solution was added anhydrous potassium carbonate (27.4 g, 201.0 mmol) and water (3.6 ml). The mixture was warmed for 2 h at 120° C. (oil-bath). After the mixture had reached room temperature water (80 mL) was added. The mixture was extracted with EtOAc. The combined organic layers were washed with citric acid (aq., 10%) and with brine, dried (Na2SO4) and evaporated. The crude product was chromatographed on silica gel, eluting with heptane:methylene chloride (8:2), to afford 3.2 g (47%) of the sub-title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:6]([O:13][CH3:14])[CH:5]=[C:4]([O:15][CH3:16])[C:3]=1[C:17](=[O:32])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][O:30][CH3:31])[CH:21]=1.[H-].[Na+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([O:15][CH3:16])[C:3]([C:17](=[O:32])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH2:29][O:30][CH3:31])[CH:21]=2)=[C:2]([O:1][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C:7]=1[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)CBr
Reactant: COCOc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2O)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(CCC(=O)c2c(OC)cc(OC)c(CCC(C)C)c2OCC(=O)OC)ccc1OC
Reaction time: 0.5 h

Procedure:
Then, 20 ml of dimethylformamide was dropped into a mixture of 1-(2-hydroxy-4,6-dimethoxy-3-isopentylphenyl)-3-(4-methoxy-3-methoxymethoxyphenyl)-1-propanone and 0.4 g of sodium hydride at 0° C., and the mixture was stirred for 30 minutes. Then, 1.0 ml of methyl α-bromoacetate was added to the mixture at 0° C. and the mixture was stirred for 30 minutes. After the reaction, the solvent was removed from the reaction liquid mixture by distillation and the residue was dried under a reduced pressure to obtain substantially quantitatively 1-(4,6-dimethoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-methoxy-3-methoxymethoxyphenyl)-1-propanone in the form of a colorless transparent oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH2:35][CH2:36][OH:37]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH2:35][CH2:36][OH:37])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Reactant: NCCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)NCCCO)c(F)c1
Yield: 47 %

Procedure:
4-(2-Fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in a mixture of anhydrous THF and anhydrous DMF and treated with 3-amino-1-propanol as for example 34. After workup, the residue was further purified by flash chromatography on silica gel (5% MeOH/CH2Cl2—10% MeOH/CH2Cl2 gradient elution) yielding 4-(2-fluoro-4-methylanilino)-N-(3-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (47%) as a pale cream solid; m.p. (EtOAc/Hexane) 142-145° C. 1H NMR [400 MHz, (CD3)2SO] δ 9.86 (br s, 1H), 8.36 (t, J=5.4 Hz, 1H), 8.21 (s, 1H), 7.30 (t, J=8.4 Hz, 1H), 7.16 (d, J=11.8 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 5.40 (s, 1H), 4.48 (t, J=5.1 Hz, 1H), 3.47 (dd, J=11.5, 6.2 Hz, 2H), 3.35 (s, 3H), 3.27 (dd, J=12.8, 6.8 Hz, 2H), 2.32 (s, 3H), 1.67 (p, J=6.7 Hz, 2H). LCMS (ACPI−) 332 (100%). Anal. Calcd for C17H20FN3O3: C, 61.3; H, 6.1; N, 12.6. Found C, 61.0; H, 6.3; N, 12.7.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].[C:32]([C:35]1[S:36][C:37](Br)=[CH:38][CH:39]=1)(=[O:34])[CH3:33]>CCCCCC.C(OCC)(=O)C>[C:32]([C:35]1[S:36][C:37]([C:9]2[C:10]3[O:14][CH2:13][CH:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:17][CH:16]=4)[C:11]=3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:30])[CH3:31])[C:8]=2[CH3:29])=[CH:38][CH:39]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)s1
Yield: 65 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-acetyl-5-bromothiophene, the title compound was synthesized in the same manner as in Example 107. Yield: 65%. Melting point: 157-158° C. (hexane-ethyl acetate).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:8]2[CH2:15][C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1.CN(C)CCN(C)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:28]=1[CH2:36]Br>>[Cl:6][C:7]1[C:8]2[C:15]3([CH2:36][C:28]4[C:27](=[CH:32][CH:31]=[C:30]([N+:33]([O-:35])=[O:34])[CH:29]=4)[CH2:26]3)[C:14](=[O:16])[NH:13][C:9]=2[N:10]=[CH:11][N:12]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: O=[N+]([O-])c1ccc(CBr)c(CBr)c1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Product: O=C1Nc2ncnc(Cl)c2C12Cc1ccc([N+](=O)[O-])cc1C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyllithium (2.5 M in hexanes, 0.29 ml, 0.74 mmol) was added to a stirred solution of 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one from Step B (50 mg, 0.295 mmol) at −78° C. in THY (30 mL). After complete addition of butyllithium, N,N,N′,N′-tetramethylethane-1,2-diamine (0.31 mL, 0.77 mmol) was added. After 1 h at −78° C., 1,2-bis(bromomethyl)-4-nitrobenzene (91 mg, 0.295 mmol, described in Intermediate 2) was added and the reaction warmed to ambient temperature. After 8 h, the reaction was quenched with H2O and the mixture was partitioned between EtOAc and H2O. The aqueous solution was extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=317 (M+1).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[CH:18]=[C:17]([O:19][CH:20]([F:22])[F:21])[N:16]([CH3:23])[N:15]=2)=[C:9]([F:24])[CH:8]=1.C(=O)([O-])O.[Na+]>ClC(Cl)(Cl)Cl>[Cl:4][C:18]1[C:14]([C:10]2[CH:11]=[C:12]([CH3:13])[C:7]([Cl:6])=[CH:8][C:9]=2[F:24])=[N:15][N:16]([CH3:23])[C:17]=1[O:19][CH:20]([F:22])[F:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Reaction time: 16 h

Procedure:
22 g (0.16 mol) of sulfuryl chloride were added dropwise to a solution of 43 g (0.15 mol) of 3-(4-chloro-2-fluoro-5-methylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 250 ml of tetrachloromethane. After the reaction solution had subsequently been stirred for 16 hours, 200 ml of saturated aqueous sodium hydrogen carbonate solution was added dropwise. The organic phase was then separated off, washed using saturated sodium chloride solution, dried over magnesium sulfate, then filtered and finally concentrated. Yield: 46 g.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(CN2CCc3ncccc3C2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1cnc2c(c1)CNCC2
Reaction time: 10 h

Procedure:
6-Benzyl-5,6,7,8-tetrahydro-[1,6]naphthyridine (3.10 g, 13.82 mmol) is dissolved in acetic acid (40 ml). To the solution is added Pd—C (10%, 500 mg). The resulting mixture is hydrogenated under 40-50 psi at 55-60° C. for 10 hr. The solid catalyst is removed by filtration, and the filtering cake is washed with MeOH (20 ml×2). The combined organic phase is evaporated to dryness. The residue is taken up into water (25.0 ml), basified with saturated sodium carbonate solution, and extracted with EtOAc (30 ml×3). The combined organic phase is dried with sodium sulfate, and concentrated to give the title compound. MS (+VE) m/z 135.1 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([SH:11])[CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[CH3:1][C:2]1[C:7]2[C:8](=[O:10])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccn1
Reactant: Cc1cccc(S)c1C(=O)O
Solvent: c1ccncc1
Product: Cc1cccc2sc(-c3ccccn3)nc(=O)c12
Temperature: 135 °C
Yield: 19.9 %

Procedure:
A mixture of 6-methyl-2-mercaptobenzoic acid (1.70 g, 10.1 mmol), 2-cyanopyridine (1.06 g, 10.2 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 18 hrs as described in Example 9. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with ethyl acetate. The resultant product was recrystallized from ethanol to give the titled compound (0.51 g, 20%).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1.O>CCOCC>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Li]c1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC(c1ccccc1)c1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Temperature: -78 °C

Procedure:
To a solution of 2.35 g (4.90 mmol) of N-[(6-{2-[(tert-butylamino)methyl]-1-naphthyl}pyridin-2-yl) methyl]-2,6-diisopropylaniline in 50 ml of THF 20.0 ml (14.8 mmol) of 0.74 M PhLi in ether was added by vigorous stirring at −78° C. The reaction mixture was heated to room temperature and stirred for 10 minutes. Further on, 2 ml of water was added, and the resulting mixture was poured into 50 ml of water. The crude product was extracted with 3×30 ml of ether. The organic extract was washed by 2×50 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:10:1, vol.). Yield 2.38 g (86%) of orange oil. Anal. calc. for C39H45N3: C, 84.28; H, 8.16; N, 7.56. Found: C, 84.41; H, 8.17; N, 7.38. For 1H NMR (in CDCl3) see FIG. 1—Bottom spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[C:25]([F:26])=[CH:24]C=[CH:22][C:21]=2F)=[N:16][CH:17]=1.FC1C=[N:37]C=CC=1C(Cl)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[C:12]1[N:13]=[CH:14][C:15]([NH:18][C:19](=[O:28])[C:20]2[CH:21]=[CH:22][N:37]=[CH:24][C:25]=2[F:26])=[N:16][CH:17]=1
Reactant: O=C(Cl)c1ccncc1F
Reactant: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1c(F)cccc1F
Product: O=C(Nc1cnc(-c2cc(C(F)(F)F)ccc2Cl)cn1)c1ccncc1F

Procedure:
Compound 2 was prepared in an analogous fashion to Compound 1 except that 3-fluoro-isonicotinoyl chloride was used instead of 2,6-difluoro-benzoyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27]C1C=CC=CC=1C1CCC2C(=CC=C(O)C=2)O1>>[F:27][C:26]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:12]=2)[O:17]1
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1F)O2
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2F)O3)nc1

Procedure:
2-[2-(2-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 390 mg of 2-(2-fluorophenyl)chroman-6-ol. The product was purified by column chromatography using heptane-ethyl acetate (4:1) as an eluant. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.56 (m, 1H), 7.43 (m, 1H), 7.30-7.22 (m, 2H), 7.20 (d, 1H, J 9.1 Hz), 7.02 (d, 1H, J 2.8 Hz), 6.98 (dd, 1H, J 8.7, 2.8 Hz), 6.91 (d, 1H, J 8.7 Hz), 5.37 (dd, 1H, J 10.4, 2.3 Hz), 3.04 (ddd, 1H, J −17.0, 11.5, 6.0 Hz), 2.82 (ddd, 1H, J −17.0, 5.1, 2.8 Hz), 2.18 (m, 1H), 2.08 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH2:14])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32](=[O:43])/[CH:33]=[CH:34]/[C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH3:30].C(OCC)(=O)C>C(OCC)C>[C:1]([O:5][C:6](=[O:28])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:27])[C@H:13]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:14][C@H:33]([C:32]([O:31][CH2:29][CH3:30])=[O:43])[CH2:34][C:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:42])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/C(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)[C@H](CC(=O)c1ccccc1)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.0 g (20 mmoles) of Nε -t-butoxycarbonyl-(S)-lysyl-(S)-proline-t-butylester are dissolved in 100 ml of diethyl ether and 4.48 g (22 mmoles) of E-ethyl-3-benzoyl-acrylate are added to the solution. The reaction mixture is stirred at room temperature for 5 hours. After evaporation of the solvent the title product is isolated on a Kieselgel column in the form of transparent oil. Rf =0.49 i(in a 7:3 eluent mixture of ethyl acetate and ether).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC>>[N:1]1([CH2:8][CH2:9][NH:10][CH3:11])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1
Reactant: CCN1CCC[C@H]1CN
Reactant: C1=CCNCC1
Product: CNCCN1CC=CCC1

Procedure:
By using 1,2,3,6-tetrahydropyridine (960.2 mg) as a starting material, the title compound (855 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([NH:22]C(=O)C)[CH2:16]3)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2].[ClH:26]>>[ClH:26].[CH:1]([C:4]1[S:8][C:7]([NH:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([NH2:22])[CH2:16]3)(=[O:12])=[O:11])=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)NC1Cc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2C1
Agent: Cl
Product: CC(C)c1nnc(NS(=O)(=O)c2ccc3c(c2)CC(N)C3)s1

Procedure:
N-[5-(5-Isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-indan-2-yl]-acetamide (96 mg) was heated and stirred for 27 hours in 10 ml 2N hydrochloric acid at 100° C. After completion a clear solution occurred. This was evaporated to dryness and the solid residue was used without further purification.
Reaction SMILES: [H-].[Na+].[CH:3](OC)=[O:4].[CH3:7][C:8]([C:10]1([CH3:16])[CH2:13][CH:12]([CH2:14][CH3:15])[CH2:11]1)=[O:9].CO>CCCCCC.CCOCC>[OH:4][CH:3]=[CH:7][C:8]([C:10]1([CH3:16])[CH2:13][CH:12]([CH2:14][CH3:15])[CH2:11]1)=[O:9]
Reactant: CCC1CC(C)(C(C)=O)C1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC1CC(C)(C(=O)C=CO)C1

Procedure:
Sodium hydride (1.25 g of 50% mineral oil dispersion, 50 mmol) was washed with dry hexane and then stirred under an argon atmosphere with 12.5 ml of dry ether. A solution of 5 ml of methyl formate and 2.4 g of (1-methyl-3-ethylcyclobutyl) methyl ketone (prepared in Example 3A) in 5 ml of ether was then added to the reaction mixture along with about 0.5 ml of methanol. As a voluminous precipitate formed, sufficient ether was added to make the reaction mixture more easily stirred. The resultant mixture was stirred for 1 hr and then quenched by the addition of water. The ether phase was separated and extracted three times with 1 M sodium hydroxide. The combined aqueous extraction phases were acidified with concentrated hydrochloric acid and extracted three times with ether. The combined ether extract was evaporated in vacuo. Traces of water were removed by twice addition of benzene which was removed by evaporation in vacuo. The title compound had the following physical characteristics: