Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:23])([CH2:17][O:18]S(C)(=O)=O)[CH2:10]OC(=O)C(C)C.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:23][CH2:10]1)[CH2:17][OH:18]
Reactant: CC(C)C(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC[C@@]1(c2ccc(F)cc2F)CO1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
In 14 ml of methanol was dissolved 4.06 g of (S)-2-(2,4-difluorophenyl)-1-isobutyryloxy-3-methanesulfonyloxy-2-propanol obtained in Example 44. After a temperature of the resulting liquid was kept at 5° C., 14 ml of aqueous solution of 2N sodium hydroxide was added dropwise thereto with cooling at 15° C. or below. After dropping, the resulting liquid was stirred at a temperature of 10° to 15° C. for 2 hours. Thereto 1N hydrochloric acid was added until the liquid was adjusted to pH 7 and methanol was removed under reduced pressure. To the residue was added ethyl acetate to extract. The resulting organic layer was washed with saturated aqueous solution with sodium chloride. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 2.04 g of oily (S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 9.24 minutes ((S)-form) and 10.7 minutes ((R)-form)).
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[S:19][C:18]3=[CH:20][N:21]=[CH:22][N:17]3[CH:16]=2)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[S:19][C:18]3=[CH:20][N:21]([CH3:2])[CH:22]=[N+:17]3[CH:16]=2)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4cncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4cn(C)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (1.2 ml) is added to 113.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 23-a), and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature overnight. The excess reagent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 84.6 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(6-methylimidazo[5,1-b]thiazolium-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a yellow viscous material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13](OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[N:10]1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>CCOC(C)=O.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.C1(C)C=CC=CC=1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:13]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:10]=[C:11]([CH:22]3[CH2:27][C:26]([CH3:29])([CH3:28])[O:25][C:24]([CH3:31])([CH3:30])[CH2:23]3)[CH:12]=2)=[CH:35][CH:34]=1
Reactant: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 43.2 %

Procedure:
A flask is charged with trifluoromethanesulfonic acid 2-(2-methoxy-phenyl)-5-(2,2,6,6-tetramethyl-tetrahydro-pyran-4-yl)-2H-pyrazol-3-yl ester (1.10 g, 3.70 mmol), 4-chlorophenyl boronic acid (0.630 g, 4.07 mmol), Pd(PPh3)4 (0.24 g, 5 mol %), 2 M Na2CO3 (16 mL), EtOH (16 mL) and toluene (32 mL) and heated at 80° C. for 6 h. The reaction was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL), and the organic layer dried over Na2SO4 and evaporated. The crude product was purified by flash silica gel chromatography eluting with 10% EtOAc/hexanes to give 0.68 g (66%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7][CH2:8][S:9]([CH3:11])=[O:10])=[CH:3][CH:2]=1.[H-].[Na+].[C:15](#[N:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)Cl>C1COCC1.O>[CH3:11][S:9]([C:8]([S:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:12])=[CH:2][CH:3]=1)=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10]
Reactant: Cc1ccc(SCS(C)=O)cc1
Reactant: N#Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(SC(=C(N)c2ccccc2)S(C)=O)cc1
Temperature: 25 °C

Procedure:
1.20 Grams of methyl p-tolylthiomethyl sulfoxide was dissolved in 15 ml of THF, and added with 165 mg of sodium hydride under cooling with ice, followed by stirring for an hour at room temperature. Then 1 ml of benzonitrile was added to the solution, and stirred for 16.5 hours at room temperature and for 5 hours at 60°C., followed by addition of methylene chloride and 2 ml of water. After drying with Glauber's salt and filtration, the filtrate was concentrated under reduced pressure. The residue was washed with cyclohexane to obtain 1.212 g of 1-methylsulfinyl-1-(p-tolylthio)-2-amino-2-phenylethylene.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20]Cl)[CH:14]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:14]=1
Reactant: ClC[C@@H]1CCCN1c1cncc(Br)c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Brc1cncc(N2CCC[C@H]2Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of NaH (0.011 g, 0.272 mmol) in DMF (1 mL) was added 1H-1,2,4-triazole (0.016 g, 0.236 mmol) and the reaction mixture was stirred at room temperature for 30 min. Then, 3-bromo-5-((S)-2-chloromethyl-pyrrolidin-1-yl)-pyridine (0.05 g, 0.181 mmol) in DMF (0.5 mL) was added to the reaction mixture which was heated to 80° C. over night. The mixture was diluted with DCM, poured into aq. NaHCO3 (5 mL) and the aqueous layer was extracted with DCM (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.04 g, 72%) as a yellow oil. MS: 308.0, 310.0 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.C1COCC1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:41]=[CH:42][CH:43]=1)[CH2:29][O:30][CH2:31][C:32]([CH3:40])([CH3:39])[C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].[Cl-].[Na+]>>[C:34]([C:33]1([OH:38])[C:32]([CH3:40])([CH3:39])[CH2:31][O:30][CH:29]1[C:28]1[CH:41]=[CH:42][CH:43]=[C:26]([O:25][CH3:24])[CH:27]=1)([CH3:36])([CH3:37])[CH3:35]
Reactant: COc1cccc(COCC(C)(C)C(=O)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2OCC(C)(C)C2(O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
In nitrogen atmosphere, 1.50 ml (11.4 mmol) of diisopropylamin and 6.60 ml (10.6 mmol) of 1.6 M butyllithium hexane were added to 15 ml of THF anhydride at a room temperature, and the mixture was stirred for 30 minutes. Adding 10 ml of THF dissolving 1.48 g (5.32 mmol) of 1-(3-methoxybenzyloxy)-2,2,4,4-tetramethyl-3-pentanon (Compound [49]) at −78° C., the mixture was stirred for 2 hours. The reaction mixture was stirred for 200 minutes with increasing the temperature to a room temperature gradually. The mixture was added to saturated aqueous solution of sodium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, then dried with magnesium sulfate anhydride and concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=1:2) to obtain 1.30 g of 3-t-butyl-3-hydroxy-2-(3-methoxyphenyl)-4,4-dimethyl-2,3,4,5-tetrahydrofuran (Compound [50]). Yield 87.8%.
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10](I)=[C:9]([F:14])[CH:8]=1.[C:15](=[C:18]1[C:23](=[O:24])[O:22][C:21]([CH3:26])([CH3:25])[O:20][C:19]1=[O:27])([CH3:17])[CH3:16]>C1COCC1.C1(C)C=CC=CC=1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:15]([CH:18]2[C:19](=[O:27])[O:20][C:21]([CH3:25])([CH3:26])[O:22][C:23]2=[O:24])([CH3:17])[CH3:16])=[C:9]([F:14])[CH:8]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CC(C)=C1C(=O)OC(C)(C)OC1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(C(C)(C)c2ccc(Br)cc2F)C(=O)O1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution (183 mL, 182.79 mmol) of 1M isopropylmagnesium chloride in THF was added dropwise to a solution of 4-bromo-2-fluoro-1-iodobenzene (50.0 g, 166.17 mmol) in anhydrous THF (96 mL) over 20 min at −20° C. under argon atmosphere. The reaction mixture was stirred at −20° C. for 30 min, and added dropwise to a solution of 5-isopropylidene-2,2-dimethyl-1,3-dioxane-4,6-dione in anhydrous toluene (84 mL) over 20 min at −20° C., and then the used container was washed with THF (24 mL). The reaction mixture was stirred at 0° C. for 3 hr, 10% aqueous citric acid solution (200 mL) was added thereto at 0° C., and the mixture was extracted with toluene (200 mL). The organic layer was concentrated under reduced pressure to give 5-(2-(4-bromo-2-fluorophenyl)propan-2-yl)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale-yellow oil.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32](Br)[C:31]([F:38])=[CH:30][N:29]=1>CN1C(=O)CCC1.CCOC(C)=O>[Br:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([N:15]2[CH2:16][CH2:17][CH:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[O:11])[CH2:13][CH2:14]2)[C:31]([F:38])=[CH:30][N:29]=1
Reactant: O=[N+]([O-])c1c(Br)ncc(F)c1Br
Reactant: CN1CCN(C(=O)C2CCNCC2)CC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C2CCN(c3c(F)cnc(Br)c3[N+](=O)[O-])CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A round-bottomed flask was charged with (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (16.45 g, 57.89 mmol) and DIPEA (23.20 g, 31.27 mL, 179.5 mmol) in NMP (160 mL). 2,4-Dibromo-5-fluoro-3-nitro-pyridine (17.36 g, 57.89 mmol) was added and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Additional (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (1.65 g, 0.1 eq) and DIPEA (1 mL, 0.1 eq) was added and stirred at room temperature for a further 3 h. The mixture diluted with EtOAc, washed with water (3×). The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were combined, washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (330 g SiO2, 0 to 5% MeOH (containing 10% ammonium hydroxide)/DCM) to afford product as a yellow solid (20.24 g, 81%). MS (ES+) 432.0.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([N+:22]([O-:24])=[O:23])[CH:3]=1.[CH3:25][N:26](C)C=O>[C-]#N.[Zn+2].[C-]#N.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.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:8]2[C:7]3=[C:2]([C:25]#[N:26])[CH:3]=[C:4]([N+:22]([O-:24])=[O:23])[CH:5]=[C:6]3[O:11][C:10]([CH3:13])([CH3:12])[C:9]2=[O:14])=[CH:16][CH:17]=1
Reactant: CC1(C)Oc2cc([N+](=O)[O-])cc(Br)c2N(c2ccc(F)cc2)C1=O
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CC1(C)Oc2cc([N+](=O)[O-])cc(C#N)c2N(c2ccc(F)cc2)C1=O
Temperature: 175 °C

Procedure:
A mixture of 5-bromo-4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 53(6), 2.00 g), zinc cyanide (0.60 g), tetrakis(triphenylphosphine)palladium(0) (0.60 g) and N,N-dimethylformamide (30 mL) was heated at 175° C. under microwave irradiation for 5 minutes under argon atmosphere. After cooling, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=95/5→65/35) to give 4-(4-fluorophenyl)-2,2-dimethyl-7-nitro-3-oxo-3,4-dihydro-2H -1,4-benzoxazin-5-carbonitrile (1.42 g) as a pale yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[CH:15]=2)=[CH:8][C:7]=1[CH3:40].O.[OH-].[Li+].O>O1CCOCC1>[F:27][C:26]([F:28])([F:29])[C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([CH:15]=[C:16]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:37])[F:38])=[CH:32][CH:31]=3)[CH:17]=2)[CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:41])=[O:2])=[C:7]([CH3:40])[CH:8]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)COc1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)cc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(OCc2cc(-c3ccc(C(F)(F)F)cc3)cc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
The crude [4-(3,5-bis(4-trifluoromethylphenyl)-benzyloxy)-2-methyl-phenoxy]-acetic acid methyl ester from Step A above is dissolved in dioxane (2 mL). Solid lithium hydroxide monohydrate (18 mg, 0.44 mmol, excess) is added, followed by water (0.2 mL). After 1 hour, the mixture is concentrated to dryness. Purification by reversed-phase HPLC yields [4-(3,5-bis(4-trifluoromethylphenyl)-benzyloxy)-2-methyl-phenoxy]-acetic acid A1 as a solid. 1H-NMR (400 MHz, CDCl3) δ=7.67 (m, 9H), 7.61 (s, 2H), 6.82 (d, J=2.8 Hz, 1H), 6.72 (dd, J=9.0, 2.8 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 5.08 (s, 2H), 4.58 (s, 2H), 2.22 (s, 3H). 19F-NMR (376 MHz, CDCl3) δ=−62.4. No MS could be obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:33]=[CH:32][C:20]2[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:23][O:24][C:19]=2[CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:33]=[CH:32][C:20]3[N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:22][CH2:23][O:24][C:19]=3[CH:18]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(N)ccc21
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3C(=O)OC(C)(C)C)nc1Cl
Yield: 54.2 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (100 mg, 0.59 mmol), thionyl chloride (5 mL), pyridine (10 mL) and tert-butyl 7-amino-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate obtained in Example (95b) (0.3 g, 1.20 mmol), to obtain 0.13 g of the title compound as a pale yellow solid (56%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[N:2]1.[CH:9](=[C:16]([C:19]#[N:20])[C:17]#[N:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>CCO>[NH2:20][C:19]1[N:2]2[N:1]=[CH:5][CH:4]=[C:3]2[C:6]([C:7]#[N:8])=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]=1[C:17]#[N:18]
Reactant: N#CCc1cc[nH]n1
Reactant: N#CC(C#N)=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)c(C#N)c2ccnn2c1N
Yield: 14.3 %

Procedure:
To a stirred solution of (1H-Pyrazol-3-yl)-acetonitrile (100 mg, 0.93 mM) from Step C of Preparative Example 3, in absolute EtOH (4.7 mL) at 25° C. was added benzylidene malononitrile (144 mg, 0.93 mM) and piperidine (0.009 mL, 0.09 mM). The mixture then refluxed for 1.0 hr. The solvent evaporated. Chromatography on silica gel (60×2.5 cm) with CH2Cl2 afforded 7-Amino-5-phenyl-pyrazolo[1,5-a]pyridine-4,6-dicarbonitrile (34.6 mg, 14%) LCMS: MH+=260; HRMS: m/z 260.0938 (MH+), Calcd. C15H9N5: m/z 260.0936; δC (DMSO) CH: 99.0, 128.5, 128.5, 128.8, 128.8, 129.8, 145.4; C: 75.4, 86.9, 115.5, 116.0, 134.8, 138.9, 148.1, 149.4.
Reaction SMILES: [NH3:1].[Cl:2][CH:3]([C:8](=O)[CH2:9][CH3:10])[C:4](OC)=[O:5].[CH:12]([NH2:14])=O>>[Cl:2][C:3]1[C:4]([OH:5])=[N:1][CH:12]=[N:14][C:8]=1[CH2:9][CH3:10]
Reactant: CCC(=O)C(Cl)C(=O)OC
Reactant: N
Reactant: NC=O
Product: CCc1ncnc(O)c1Cl
Temperature: 50 °C

Procedure:
NH3 gas is passed with cooling (max. 50° C.) through a solution of 99.7 g (0.6 mol) of methyl 2-chloro-3-oxo-valerate in 130 ml of formamide until the mixture takes up no more NH3 (about 1 h). The ammonia residues are removed by blowing out with nitrogen and applying a vacuum. The reaction solution is subsequently added dropwise to 450 ml of a 30% NaOMe solution in methanol at 50° C. Addition of a further 50 ml of formamide is followed by heating at 50° C. for 3 h. The volatile constituents are evaporated in vacuo, and subsequently the mixture is added to water and the pH is adjusted to 6 with HCl. Extraction with ethyl acetate and evaporation provide 91.2 g of crude product, which is recrystallized from cold acetone. Yield: 66.3 g (70%)
Reaction SMILES: Cl.O[C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]3[C:13](=[C:14]([C:17]([OH:19])=[O:18])[C:15]=2[CH:16]=1)[CH:12]=[C:11]1[CH:20]=[CH:21][CH:22]=[CH:23][C:10]1=[CH:9]3.[C:24](=[O:27])([O-])[O-].[Cs+].[Cs+].Br.[CH3:31][N:32]([CH2:34][CH2:35]Br)[CH3:33]>CS(C)=O>[CH3:31][N:32]([CH2:34][CH2:24][O:27][C:16]1[C:15]2[C:14]([C:17]([O:19][CH2:35][CH2:34][N:32]([CH3:33])[CH3:31])=[O:18])=[C:13]3[C:8]([CH:9]=[C:10]4[CH:23]=[CH:22][CH:21]=[CH:20][C:11]4=[CH:12]3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:33]
Reactant: O=C([O-])[O-]
Reactant: CN(C)CCBr
Reactant: O=C(O)c1c2cc(O)ccc2nc2cc3ccccc3cc12
Agent: Br
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Product: CN(C)CCOC(=O)c1c2cc3ccccc3cc2nc2cccc(OCCN(C)C)c12
Temperature: 60 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
To a solution of 2-hydroxy-benz[b]acridine-12-carboxylic acid hydrochloride (360 mg, 1.108 mmol) in methyl sulfoxide (11 ml) were added cesium carbonate (3.61 g, 11.08 mmol) and N,N-dimethylaminoethyl bromide hydrobromide (1.03 g, 4.432 mmol). After 15 hours of stirring at 60° C. under nitrogen, the reaction mixture was diluted with methyl sulfoxide (20 ml) and filtered to remove the insoluble impurities. The filtrate was concentrated under reduced pressure to a small volume, which was separated on a preparative-TLC plate (2 mm silica gel) by developing with chloroform/methanol/water (47:48:5). The desired orange band was collected and extracted with 25% methanol/chloroform. Removal of the solvents under reduced pressure gave N,N-dimethylaminoethyl 2-(N,N-dimethylamino)ethoxy-benz[b]acridine-12-carboxylate (86 mg, 18%). Rf 0.6 (silica gel, chloroform/methanol/water 65:25:4). MS (FAB, Glycerol Matrix): m/z 432 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=[CH:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:32](P(C(C)(C)C)C(C)(C)C)(C)(C)[CH3:33].C([Sn](CCCC)(CCCC)C=C)CCC>O1CCOCC1>[CH:32]([C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=[CH:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1)=[CH2:33]
Reactant: Ic1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Reactant: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1ccc(N=C(C=COc2ccccc2)Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
Phenyl N-(4-iodophenyl)-3-(phenoxy)acrylimidate (0.50 g), bis(benzylideneacetone)palladium (0) (0.023 g) and cesium carbonate (0.82 g) were suspended to dioxane (15 ml). Tri-t-butylphosphine (10 wt % in hexane: 0.24 g) and tributyl (vinyl) tin (0.44 g) were added thereto and it was stirred for four hours at room temperature and 60° C. for five hours. The unsolved matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain phenyl N-(4-vinylphenyl)-3-(phenoxy)acrylimidate (0.29 g) as yellow oil.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)#[N:2].[NH3:12].[H][H]>>[NH:2]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:1]1.[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH2:12]
Reactant: [H][H]
Reactant: N
Reactant: N#CCCC1CCCCC1=O
Product: C1CCC2NCCCC2C1
Product: NCCCC1CCCCC1N

Procedure:
Through a tubular reactor (diameter 16 mm, packing height 50 cm, oil-heated double jacket), installed up-stream of the hydrogenation reactor and packed with 67.2 g (96 ml) of γ-aluminum oxide in the form of 1.5 mm extrudates, there were pumped upwardly, per hour, 22.6 g of 2-(2-cyanoethyl)-cyclohexanone (purity 96%, 0.144 mole) and 1,086 ml of liquid ammonia (652 g, 38.3 moles) at a pressure of 250 bar and a temperature of 70° C. Hydrogen was then added to the stream at a rate of 60 standard liters (2.7 moles) per hour, and the effluent from the in-line imination reactor was passed upwardly through the hydrogenation reactor at a pressure of 250 bar and a temperature of 120° C. Following separation and distillation of the product obtained after an on-stream period of 16.3 hours there were obtained, besides 43.5 g of decahydroquinoline, 291.7 g of 2-(3-aminopropyl)-cyclohexylamine. The yield of 2-(3-aminopropyl)-cyclohexylamine was 79.8% of theory.
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH:3]1[CH:11]=[CH:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([N:18]2[C:1](=[O:13])[CH2:2][C:3]3[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=3[C:5]2=[O:7])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CC1C=CCCC1C(=O)O
Reactant: Nc1cccc(Cl)c1
Product: O=C1CC2=C(CCCC2)C(=O)N1c1cccc(Cl)c1

Procedure:
A mixture of tetrahydrohomophthalic acid (46.0 g., 0.25 mole) and m-chloroaniline (31.8 g., 0.25 mole) is heated by an oil bath until molten for two hours. When removed from the oil bath, the reaction mixture solidifies and is recrystallized twice from ethanol/ethyl acetate, giving 2-(m-chlorophenyl)-5,6,7,8-tetrahydroisoquinoline-1,3(2H,4H)-dione.