Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH3:27])=[CH:21][CH:20]=2)=[CH:12]\[C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:19]2[NH:24][C:23](=[O:25])[C:22]([O:26][CH3:27])=[CH:21][CH:20]=2)[CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[NH:14]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O

Procedure:
An (R,S) mixture of the title compound was obtained by performing substantially the same reaction as in Examples 4-207 and 4-208(2) except for using 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}-3-methoxypyridin-2(1H)-one obtained in Example 4-164. This was preparatively isolated by a chiral HPLC column (CHIRALCEL OD-H, hexane:ethanol=50:50 v/v, 40° C., 7.0 mL/min, 210 nm) to give one diastereomer (A) of the title compound as a colorless amorphous (9.5 mg) and the other diastereomer (B) of the title compound as a colorless powder (11.9 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:3](=[O:6])[CH:4]=[CH2:5].[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17].C(N(CC)CC)C>CO>[CH3:29][C:26]([C:21]1[CH:22]=[C:23]([S:25][CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[O:6])[CH:24]=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[C:20]=1[OH:30])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)N(C)CCc1ccccn1
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methyl-N-[2-(2-pyridinyl)ethyl]-2-propenamide (0.95 g, 0.005 mole) was dissolved in methanol (200 ml) containing 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole). After addition of triethylamine (0.5 ml), the solution was stirred at room temperature overnight. The solvent was removed by a nitrogen stream to give a residue which was purified by chromatography on silica to give the title compound, m.p. ca. 82°-84° C.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14]C)=O)(=[O:4])=[O:3].O.[NH2:17][NH2:18]>C(O)C>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:17][NH2:18])=[O:14])(=[O:4])=[O:3]
Reactant: NN
Reactant: COC(=O)Cc1ccccc1S(N)(=O)=O
Solvent: CCO
Solvent: O
Product: NNC(=O)Cc1ccccc1S(N)(=O)=O
Yield: 76.7 %

Procedure:
To a suspension of 30 g of methyl 2-(aminosulfonyl)benzeneacetate in 125 ml of absolute ethanol was added 7.8 g of hydrazine monohydrate. The suspension was heated at reflux for about 16 hours, then cooled in an ice-water bath. A viscous oil formed which solidified on continued stirring and cooling. The suspension was filtered and suction-dried to give 23 g of the subject compound; m.p. 116°-125° C. Anal. Calc. for: C8H11N3O3S; C,41.9; H,4.8; N,18.3. Found: C,41.5; H,4.9; N,18.0.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[O:5][CH2:4]1.C([O-])(=O)C.[Na+].[CH2:31]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][CH2:48][CH2:49][C:50](=O)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:43][CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[CH2:31]([O:38][C:39]([N:41]1[CH2:42][CH2:43][CH:44]([CH2:47][CH2:48][CH2:49][C@@H:50]([NH:2][C@@H:3]2[C:9](=[O:10])[N:8]([CH2:11][C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[C:7]3[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=3[O:5][CH2:4]2)[C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:45][CH2:46]1)=[O:40])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(=O)CCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
A mixture of benzyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate hydrochloride (2.5 g), ethanol (30 ml), sodium acetate (0.57 g), acetic acid (0.4 g), ethyl 5-(1-benzyloxycarbonyl-4-piperidyl)-2-oxovalerate (2.5 g) and molecular sieves 3A (10 g) is stirred for 10 minutes at room temperature. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.4 g) in ethanol (50 ml) for 2 hours. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (300 ml) and ethyl acetate (300 ml). The resulting mixture is agitated thoroughly and filtered. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is dissolved in a mixture of ethyl acetate (20 ml) and oxalic acid (2 g). This solution is diluted with petroleum ether (300 ml), and the supernatant layer is removed by decantation. To the precipitate are added water (100 ml), ethyl acetate (200 ml) and excess sodium bicarbonate. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is subjected to silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction gives benzyl 3(S)-[4-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylbutyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1O.[F:13][C:14]([F:21])([F:20])[C:15]1[NH:19][CH:18]=[N:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC)=O)=NC(OC)=O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)C.O>[CH3:1][C:2]1([CH3:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[N:19]1[C:15]([C:14]([F:21])([F:20])[F:13])=[CH:16][N:17]=[CH:18]1
Reactant: CC1(C)Cc2ccccc2C1O
Reactant: FC(F)(F)c1cnc[nH]1
Agent: COC(=O)N=NC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)Cc2ccccc2C1n1cncc1C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethyl-indan-1-ol, prepared as described in Example 10, (400 mg, 2.47 mmol) in THF (30 mL) at 0° C. is added 5-trifluoromethyl-1H-imidazole (510 mg, 3.75 mmol), triphenylphosphine (982 mg, 3.75 mmol) and a 40 wt % solution of dimethyl azodicarboxylate in toluene (1.4 mL, 3.75 mmol). The reaction is then placed at room temperature and permitted to stir for 1 hour, at which time it is diluted with diethyl ether and water, and is then charged with Na2CO3 (1.9 g, 17.9 mmol). The reaction is permitted to stir for 10 minutes and the layers are separated. The organic layer is washed with brine and the aqueous layers are combined and back-extracted with diethyl ether. The organic layers are combined, dried with MgSO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-hexanes, 15:85 to 1:1) to afford 1-(2,2-dimethyl-indan-1-yl)-5-trifluoromethyl-1H-imidazole; HRMS: (ESI) m/z 281.1266 [(M+H)+; calcd for C15H15F3N3: 281.1276]. The HCl salt of the title compound can be prepared by dissolution in diethyl ether, followed by treatment with an excess of 1N HCl in diethyl ether. The resulting heterogeneous solution is concentrated to furnish the HCl salt of 1-(2,2-dimethyl-indan-1-yl)-5-trifluoromethyl-1H-imidazole; 1H NMR (400 MHz, CD3OD) δ ppm 0.91 (s, 3 H), 1.29 (s, 3 H), 2.83-3.24 (m, 2 H), 5.46 (s, 1 H), 7.25-7.50 (m, 4 H), 8.12 (s, 1 H), 8.18 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]1([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:37]1[CH:38]=[CH:39][C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccc(-c2ccccc2)cc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-phenylphenylboronic acid (109 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-biphenyl-4-yl-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([NH:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[O:14])=[C:6]([CH2:17][CH2:18][CH3:19])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: NCCCCCCc1cccnc1
Reactant: CCCc1c(OCCCC(=O)O)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCC(=O)NCCCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butanoic acid was allowed to react with 3-pyridine hexanamine according to procedure A and the product was purified by chromatography on silica gel to give 4-(4-acetyl-3-hydroxy- 2-propylphenoxy)-N-[6-(3-pyridinyl)hexyl]butanamide, the title compound, mp 69°-71° (from ether-hexane) in 84% yield.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].C(N(CC)CC)C.[OH:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:16][CH2:17][C:18]([CH3:35])([CH3:34])[C@@H:19]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:30])([CH3:29])[CH3:31])/[CH:20]=[CH:21]/[C:22]([O:24][CH3:25])=[O:23])(=[O:7])=[O:6]
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Reactant: O=S(=O)(Cl)CCCCl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 84.3 %

Procedure:
Following the general procedure for the preparation of neopentyl sulfonylester intermediates of Description 10, 25.7 mL (37.4 g, 211.4 mmol) of 3-chloropropylsulfonyl chloride in 500 mL of anhydrous dichloromethane (DCM) in the presence of 25.8 g (211.4 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) and 29.5 mL (21.4 g, 211.4 mmol) of triethylamine (Et3N, TEA) was reacted at ca. 0° C. with 40.5 g (133.9 mmol) of methyl (2E)(4S)-6-hydroxy-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (4). After work-up and isolation, the crude material was purified by silica gel column chromatography using methyl tert-butyl ether (MTBE) and hexane (Hxn) mixtures (MTBE/Hxn=1:6 MTBE/Hxn=1:5→MTBE/Hxn=1:4) as eluent to provide 50.0 g (84% yield) of the title compound (15a) as a pale-yellow oil. Rf=0.46 (MTBE/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.01 (s, 3H), 0.09 (s, 3H), 0.93 (s, 9H), 0.97 (s, 3H), 0.98 (s, 3H), 2.30-2.38 (m, 2H), 3.27-3.33 (m, 2H), 3.68-3.73 (m, 2H), 3.77 (s, 3H), 3.98 (d, J=9.6 Hz, 1H), 4.10 (d, J=9.2 Hz, 1H), 4.11 (dd, superimposed, J=6.4, 1.6 Hz, 1H), 5.97 (dd, J=15.6, 1.2 Hz, 1H), 6.90 (dd, J=15.6, 6.8 Hz, 1H) ppm. MS (ESI) m/z 442.9 (M+H)+, 464.9 (M+Na)+. The analytical data was consistent the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:16]=2[N:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Product: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH:5]=[CH2:6].[CH:7]1[CH:12]=[CH:11][C:10]([O-:13])=[CH:9][CH:8]=1.[Na+].C1(C2C(I=O)=C(S([O-])(=O)=O)C(C)=CC=2)C=CC=CC=1.[N-](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[Na+]>ClCCl.Cl[Ti](Cl)(Cl)Cl.CC(CC)=O.C(O)(=O)C>[O:13]([CH2:6][CH2:5][O:4][CH:3]=[CH2:2])[C:10]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1
Reactant: [O-]c1ccccc1
Reactant: C=COCCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cc1ccc(-c2ccccc2)c(I=O)c1S(=O)(=O)[O-]
Agent: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: C=COCCOc1ccccc1

Procedure:
The compound phenoxyethylvinylether is prepared by reacting chloroethylvinylether with sodium phenate, followed by polymerization in dichloromethane initiated with TiCl4 at -10° C. By reacting 8.2 g of the polymer with 9.8 g of phenyliodosotoluene sulfonate in 40 mL of a mixture of an equal volume of acetic acid and dichloromethane. A polyiodonium is obtained which is precipitated with ether. The ionic exchange reaction is carried similarly to that of example 3 between 12 g of polymer and 7 g of sodium bis(trifluoromethanesulfonyl)imide. After precipitation and washing with water, there is obtained a sticky mass which is used in a 50% solution of methylethylketone.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[C:18](=[O:23])[NH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1>>[NH:35]1[CH:34]=[C:33]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([CH:20]([CH3:21])[CH3:22])[C:18](=[O:23])[NH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:24]=2)[CH:37]=[N:36]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)n1c(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n[nH]c1=O
Product: CC(C)n1c(-c2cc3c(s2)-c2ccc(-c4cn[nH]c4)cc2OCC3)n[nH]c1=O

Procedure:
Following the procedure of Example 44, 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4-isopropyl-1H-1,2,4-triazol-5(4H)-one and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were reacted to give 264. MS: (ESI+) 394.2
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1C(=O)CC(CC(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.500 g, 1.35 mmol), methyl bromoacetate (0.247 g, 1.62 mmol), and potassium carbonate (0.56 g, 4.05 mmol) in DMF (6 mL) was stirred at 60° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=50:50 to 0:100) to provide methyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (0.474 g, 79%) as a white amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:4][C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:30][NH2:31]>C(O)C>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:31][NH:30][C:13](=[O:14])[C:6]=2[C:5]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[N:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1c(-n2ccnc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1c(-c2ccccc2)nc(-n2ccnc2)c2c(=O)[nH][nH]c(=O)c12

Procedure:
In 10ml of ethanol was dissolved 0.342 g of 3-amino-4,5-diethoxycarbonyl-6-(imidazol-1-yl)-2-phenylpyridine, and 0.5 ml of hydrazine monohydrate was added to the solution. The mixture was heated under reflux for 7 hours. After the reaction mixture was concentrated, the residue was acidified with acetic acid. The resulting precipitate was collected with. filtration and washed with water, followed by reprecipitation from DMF/H2O, to give 0.2 g of the title compound as yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH2:1])=[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:4]([CH3:19])=[N:5]2)(=[O:27])[CH3:26]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3)c2c1N
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@@H]3CCCN3C(C)=O)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-2-methyl-5-(pyrrolidin-2-ylmethoxy)-quinoline-3-carboxylate (Example 89b) and acetic anhydride as brown solid (31%). MS 372 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10]NC(=O)CCC(N)=O.S(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: c1ccc2[nH]ccc2c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c[nH]c2ccccc12
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 110.2 %

Procedure:
To a 3 L round bottom flask equipped with a mechanical stirrer, thermometer and a Gooch tube was added sieve-dried dimethylformamide (1.2 L) and indole (200 g). The solution was stirred under an atmosphere of nitrogen and cooled to about 10° C. N-Chlorosuccinamide (216.6 g) was added via the Gooch tube at a rate such as to maintain a reaction temperature of 10° -18° C. After the addition was complete, a second charge of N-chlorosuccinamide (34.2 g) was added. When the reaction was found to be >97% complete by high performance liquid chromatography, the reaction mixture was poured into a well-stirred, cold solution of aqueous sodium bisulfite (5.2 L of 0.1% sodium bisulfite in water and 640 g of ice). After about 15 min, the precipitate was collected and washed with water (2×1 L). The filtrate was partitioned between dichloromethane (1.3 L) and 0.1% aqueous sodium bisulfite solution (1 L). The phases were separated and the aqueous solution was extracted with dichloromethane (300 ml). The organic fractions were combined, washed with water (800 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated (at about 25° C. and about 50 mm Hg). The residue was dried in a vacuum oven at 25° C. and about 125 mm Hg for 2 to 4 hrs to yield 240.3 g (92.9%) of product, 3-chloroindole (91.6% pure).
Reaction SMILES: [Na].Cl[C:3]1[C:8]([O:9][CH:10]([F:12])[F:11])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:13][OH:14]>>[F:11][CH:10]([F:12])[O:9][C:8]1[C:3]([O:14][CH3:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)Oc1cccnc1Cl
Reactant: CO
Agent: [Na]
Product: COc1ncccc1OC(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 56 %

Procedure:
As shown in step 3(a)-ii of Scheme 3(a), an excess of sodium metal was dissolved into 20 mL anhydrous methanol and 2-chloro-3-(difluoromethoxy)pyridine (2.0 g, 11.1 mmol) in anhydrous methanol was added. The reaction mixture was stirred in a sealed vessel at 100° C. for 6 hours. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and brine. The brine was extracted with EtOAc and the combined organics were dried over Na2SO4, filtered, and the volatiles removed under reduced pressure. The product was purified by silica gel chromatography (DCM) to yield 3-(difluoromethoxy)-2-methoxypyridine as a colorless oil (Compound 2007, 1.1 g, 56% yield: ESMS (M+H) 176.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C@@H:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([NH:23][CH3:24])=[O:22]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:19][C@@H:20]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:21]([NH:23][CH3:24])=[O:22])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-N,4-dimethyl-pentanamide monohydrochloride (CAN 99145-71-8) as starting materials, MS (D): m/e=360.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:32][NH:33][C:34]([NH:36][OH:37])=[NH:35].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:32][NH:33][C:34](=[NH:35])[NH:36][OH:37])[CH2:10]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1cccc(Cl)c1Cl)C2
Temperature: 85 °C
Reaction time: 2 h
Yield: 188.2 %

Procedure:
A mixture of 7-(2,3-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (306 mg), 1-amino-3-hydroxyguanidine p-toluenesulfonate (320 mg) and concentrated hydrochloric acid (0.2 ml) in ethanol (6 ml) was stirred at 85° C. (bath temperature) for 2 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (30 ml), tetrahydrofuran (20 ml) and 0.2 N sodium hydroxide (25 ml). The mixture was shaken, and the separated upper layer was washed with 0.2 N sodium hydroxide (10 ml) and water (10 ml, thrice). To the upper layer was added 2 N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure. The residue was recrystallized form ethanol and dried to give 7-(2,3-dichlorophenyl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 95) (390 mg) as yellow crystals.