Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6](OCC)=[O:7].O.[NH2:24][NH2:25]>C(O)C>[Cl:1][C:2]1[CH:14]=[C:13]([C:15]2[CH:16]([CH3:22])[NH:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([NH:24][NH2:25])=[O:7]
Reactant: NN
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1Cl
Solvent: CCO
Solvent: O
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NN)c(Cl)c1
Reaction time: 4 h
Yield: 76.3 %

Procedure:
A solution of 1.0 g of ethyl α-[2-chloro-4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 5) and 0.39 g of 80% hydrazine hydrate in 10 ml of ethanol was stirred on an oil bath kept at 105° C. for 4 hours. The mixture was then cooled, after which the crystals which precipitated were collected by filtration and recrystallized from ethanol, to give 0.73 g of the title compound as white crystals melting at 252°-254° C.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].C(O)C.[O-]CC.[Na+].[Br:14][C:15]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]2[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=2[C:16]=1[CH2:33]Br>C(O)C>[Br:14][C:15]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]2[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=2[C:16]=1[CH:33]=[O:2]
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Reactant: CC(C)[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(Br)c(C=O)c2c(=O)[nH]ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To 370 mg (4.2 mmol) of 2-nitropropane were added 10 ml of dehydrated ethanol and 1.43 g (4.2 mmol) of 20% sodium ethoxide ethanol solution, then, 500 mg (0.84 mmol) of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(f) was added to the mixture at 5° C., and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 167 mg of the title compound as a white solid. (Yield: 32%)
Reaction SMILES: [CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].C([Mg]Cl)(C)C.C(C(CC=C)CO[SiH2]C1C=CC([Mg]Cl)=CC=1)C=C.C(O[B:45]1[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]1)(C)C>O.C1COCC1>[CH2:1]([CH:4]([CH2:15][CH:16]=[CH2:17])[CH2:5][O:6][SiH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:45]2[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(I)cc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: C=CCC(CC=C)CO[SiH2]c1ccc([Mg]Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CC=C)CO[SiH2]c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A THF solution (2 mL) of the 4-(diallylethoxysilyl)iodobenzene (171 mg, 0.48 mmol) obtained in Example 2 was added dropwise with 2 mol/L of i-PrMgCl (0.50 mL (solvent: THF), 1.0 mmol) at −30° C. Then, the resultant solution was stirred under a nitrogen atmosphere at −30° C. for 1.5 hours to obtain a THF solution containing 4-(diallylethoxysilyl)phenylmagnesium chloride (Grignrad solution). Subsequently, the obtained Grignrad solution was cooled to −78° C., and added dropwise with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (204 μL, 1.0 mmol) to obtain a reaction mixture. Thereafter, the obtained reaction mixture was stirred under a nitrogen atmosphere at −78° C. for one hour, and further stirred at room temperature for 14 hours. After that, the reaction mixture was added with distilled water to terminate the reaction, and 10% by mass of an HCl solution was further added thereto until the salt thus formed disappeared. Then, the organic layer was separated therefrom, and the aqueous layer was extracted with ether to collect the organic layer. Subsequently, the organic layer thus collected was washed with sat.NaHCO3 and sat.NaCl, dried with MgSO4, filtered, and concentrated to obtain a crude product. Thereafter, the crude product thus obtained was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1), and thereby 1-(diallylethoxysilyl)-4-(4,4,5,5-tetramethyl-1,3,2-di oxaborolan-2-yl)benzene was obtained (128.3 mg, 75% yield).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1.[F:33][C:34]([F:49])([F:48])[C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:38](O)=[O:39]>>[F:33][C:34]([F:48])([F:49])[C:35]1[CH:36]=[C:37]([C:38]([NH:12][C@@H:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C@H:14]2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[O:39])[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](c2cccc(Cl)c2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2cccc(Cl)c2)C1

Procedure:
Using the compound obtained in step 1 and 3,5-bis(trifluoromethyl)benzoic acid, and by the reaction and purification in the same manner as in Reference Example 44, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH2:32])=[CH:27][CH:26]=2>>[CH3:22][C:23]1[NH:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([NH:32][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([N:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]4)=[O:12])[S:10][C:3]=13)=[CH:27][CH:26]=2
Reactant: CC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: CC(=O)N1CCN(C(=O)c2cc3nccc(Nc4ccc5[nH]c(C)cc5c4)c3s2)CC1

Procedure:
The title compound was prepared from 1-[4-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-piperazin-1-yl]-ethanone and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 434 (MH+); HPLC Rf: 3.52; HPLC purity: 99%.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:20]1([CH2:19][O:18][C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=2)[C:3]([OH:26])=[O:2])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 96.2 %

Procedure:
A solution of 41.4 g (0.12 mol) of 3,5-bis(phenylmethoxy)benzoic acid methyl ester and 59 ml (0.36 mol) of 6N NaOH in 700 ml of methanol and 350 ml of dioxane was stirred at reflux for 17 hours. The solvents were removed at reduced pressure and the residue was dissolved in water and acidified to pH 3 with 6N HCl. The resultant solid was filtered and recrystallized from methylene chloride-methanol to give 38.6 g (97% yield, mp 211°-213°) of 3,5-bis(phenylmethoxy)benzoic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2([O:15][C:14](=[O:16])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](I)[CH3:22].Cl>O.CN(C)C=O>[CH2:21]([N:13]1[CH2:12][C:11]2([CH2:17][CH2:18][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)[O:15][C:14]1=[O:16])[CH3:22]
Reactant: CCI
Reactant: O=C1NCC2(CCN(Cc3ccccc3)CC2)O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CC2(CCN(Cc3ccccc3)CC2)OC1=O

Procedure:
A mixture of 16.5 g 8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, 6.6 g, 50% suspension of sodium hydride in mineral oil, 15 g ethyl iodide and 70 ml N,N-dimethylformamide is heated at 90° for one hour. The mixture is poured into 150 ml water and the resulting mixture acidified with 10 N hydrochloric acid. The mixture is extracted with two 100 ml portions of hexane. The aqueous layer is basified with sodium hydroxide and extracted with three 75 ml portions of dichloromethane. Removal of solvent in vacuum affords a residue which when crystallized from heptane gives 3-ethyl-8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one, mp 105°-106°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:4][CH:3]=1.[F-:19].[K+].C(OCC)(=O)C.O>CS(C)=O>[F:19][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:4][CH:3]=1
Reactant: COc1ccc(Oc2ncc(Cl)nc2C#N)cc1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Oc2ncc(F)nc2C#N)cc1
Temperature: 105 °C
Reaction time: 3 h
Yield: 79.3 %

Procedure:
In 39 mL of dimethyl sulfoxide was dissolved 1.95 g of 6-chloro-3-(4-methoxyphenoxy)-2-pyrazinecarbonitrile. After adding 2.16 g of potassium fluoride, the mixture thus obtained was stirred at 100-110° C. for 3 hours. The reaction mixture was returned to room temperature, a mixture of 40 mL of ethyl acetate and 200 mL of water was added, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=5:1] to obtain 1.45 g of 6-fluoro-3-(4-methoxyphenoxy)-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: C[N:2](C)[CH2:3][CH2:4]N(C)C.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.BrC1[CH:57]=[CH:56][C:55]([C:58](=[O:60])[CH3:59])=[CH:54][C:53]=1[F:61]>CN(C)C=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:58]([C:55]1[CH:56]=[CH:57][C:4]([C:3]#[N:2])=[C:53]([F:61])[CH:54]=1)(=[O:60])[CH3:59]
Reactant: CN(C)CCN(C)C
Reactant: CC(=O)c1ccc(Br)c(F)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(C#N)c(F)c1
Temperature: 160 °C

Procedure:
N,N,N′,N′-Tetramethylethylenediamine (0.667 mL, 4.42 mmol), zinc cyanide (1.46 g, 12.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (54.05 mg, 0.059 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (124.3 mg, 0.215 mmol) was added successively to a solution of 1-(4-bromo-3-fluorophenyl)ethanone (4.34 g, 20.0 mmol) in N,N-dimethylformamide (15 mL) in a microwave tube. The tube was sealed and degassed three times, and heated to 160° C. under microwave irradiation with a 240 s hold time, and 300 Watt maximum power input. After cooling, the reaction mixture was filtered through a pad of Celite with a thin layer of silica gel in the middle using dichloromethane as the eluant. The combined filtrates were concentrated under reduced pressure. The residue was purified by chromatography on silica gel with ethyl acetate in hexanes (0-40%) to give the desired product. (3.20 g, 98.1%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].[I-]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCc1ccccn1
Yield: 23.7 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (2.4 g) and 2-chloromethylpyridine (2.6 g) are dissolved in acetone (50 ml). To the mixture are added potassium carbonate (2.8 g) and patassium iodide (0.1 g), and the mixture is refluxed for 4 hours. After acetone is distilled off, water is added to the residue and extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over sodium sulfate. After chloform is distilled off, the residue is purified by column chromatography (neutral alumina, made by Merck) and eluted with n-hexane to give 1-methyl-5-(2-pyridyl)methylthio-1,2,3,4-tetrazole (1.0 g) as colorless prisms (ethanol), m.p. 78°-81° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[N:10]=2)[N:7]=1>C1COCC1.CO.[Pd]>[N:10]1[C:9]([C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:7]2
Reactant: N#Cc1cccc(-c2cn3nc(Cl)ccc3n2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(-c2cn3ncccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.5 mg 10% Pd-C were added to the solution of 3-(6-chloroimidazo[1,2-b]pyridazin-2-yl)benzonitrile (50 mg, 0.2 mmol) in THF/MeOH 25 ml. The reaction mixture was stirred vigorously at room temperature for 4 h under hydrogen and the Pd—C was then removed. The filtrate was concentrated in vacuo to give the 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile as a yellow-white solid.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[C:5]([CH:21]=CC)=[C:6]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:8]=[CH:7]2.N1C(C)=CC=CC=1C.[O:33]1CCOCC1>O.C(Cl)Cl.O=[Os](=O)(=O)=O>[F:24][CH:2]([F:1])[O:3][C:4]1[C:5]([CH:21]=[O:33])=[C:6]2[C:10](=[C:11]([CH3:13])[CH:12]=1)[N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH:8]=[CH:7]2
Reactant: CC=Cc1c(OC(F)F)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cc(OC(F)F)c(C=O)c2ccn(C(=O)OC(C)(C)C)c12
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 5-(difluoromethoxy)-7-methyl-4-(prop-1-en-1-yl)-1H-indole-1-carboxylate (1.83 g, 5.42 mmol) in dioxane (40 mL) and water (13.56 mL) at 0° C., 2,6-lutidine (1.26 mL, 10.85 mmol), OsO4 (1.36 mL, 0.108 mmol) (2.5% in t-BuOH) and NaIO4 (4.64 g, 21.70 mmol) were added and the reaction was stirred at room temperature. After 1 hour the reaction was diluted with DCM and the layers separated. The organics were washed with sat. NH4Cl and water, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.45 (s, 1H) 7.93 (d, J=3.54 Hz, 1H) 7.37 (d, J=3.54 Hz, 1H) 7.34 (t, J=73.6 Hz, 1H) 7.16 (s, 1H) 2.63 (s, 3H) 1.61 (s, 9H). MS (ESI+) m/z 326.2 (M+H).
Reaction SMILES: C1C=CC(P(Cl)(C2C=CC=CC=2)=O)=CC=1.C([O:19][C:20]1[C:21]([CH3:29])=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([OH:25])=O)(=O)C.[C:30]([NH:34][C:35]([C@@H:37]1[C:41]([CH3:43])([CH3:42])[S:40][CH2:39][N:38]1[C:44](=[O:58])[C@@H:45]([OH:57])[C@@H:46]([NH2:56])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CCOC(C)=O>[C:30]([NH:34][C:35]([C@@H:37]1[C:41]([CH3:42])([CH3:43])[S:40][CH2:39][N:38]1[C:44](=[O:58])[C@@H:45]([OH:57])[C@@H:46]([NH:56][C:23](=[O:25])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([OH:19])[C:21]=1[CH3:29])[CH2:47][C:48]1[CH:49]=[CH:50][C:51]([O:54][CH3:55])=[CH:52][CH:53]=1)=[O:36])([CH3:31])([CH3:32])[CH3:33]
Reactant: COc1ccc(C[C@H](N)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1C
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(C[C@H](NC(=O)c2cccc(O)c2C)[C@H](O)C(=O)N2CSC(C)(C)[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 1 h
Yield: 80.4 %

Procedure:
DPP-Cl (43 μl) and TEA (31 μl) were added to a solution of 3-acetoxy-2-methylbenzoic acid (41 mg) in EtOAc (2 ml), and the mixture was stirred for one hour. After the addition of the compound obtained in Step 2 (85 mg) and TEA (34 μl), the mixture was stirred overnight. The reaction mixture was washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl. After concentration, MeOH (1.5 ml) and 1N NaOH (300 μl) were added. After stirring for one hour, IN HCl was added to make the reaction mixture acidic. The resulting mixture was extracted with EtOAc. The extract was washed with 5% Na2CO3 (×2), 1N HCl, and 5% NaCl, dried over MgSO4, filtered and concentrated. The residue was recrystallized from a mixture of EtOAc and n-hexane to obtain the title compound (90 mg, 81%).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C=O.[CH:27](O)=[O:28]>>[OH:28][CH2:27][C:11]1[C:12]2[C:4]3[CH2:3][N:2]([CH3:1])[CH2:24][CH2:23][C:5]=3[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[OH:16])[C:7]=2[CH:8]=[CH:9][C:10]=1[CH3:13]
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Reactant: O=CO
Agent: C=O
Product: Cc1ccc2c(c1CO)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Yield: 7.1 %

Procedure:
2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol (350 mg, 1 mmol), formaldehyde (37%, 0.89 g, 10 mmol) and formic acid (922 mg, 20 mmol) was stirred at 100° C. for 12 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was washed with saturated sodium bicarbonate and extracted with DCM (2×25 mL). The combined organic layer was washed with water (5×25 mL) dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was subjected to preparative HPLC to obtain 25 mg of 2-(9-(hydroxymethyl)-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.56 (d, 2H), 7.29 (d, 2H), 7.12 (d, 1H), 6.98 (d, 1H), 4.9 (dd, 1H), 4.79 (q, 2H), 4.13 (m, 2H), 3.78 (d, 1H), 3.72 (d, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.67 (m, 2H), 2.49 (s, 3H), 2.32 (s, 3H). Separation by chiral HPLC provided diastereomers II-150a-d.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH2:10][CH2:11][C@@H:12]2[C@@H:19]3[C@@H:15]([O:16][C:17](=[O:20])[CH2:18]3)[CH2:14][C@H:13]2[O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C@H:9]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[CH2:10][CH2:11][C@@H:12]2[C@@H:19]3[C@@H:15]([O:16][CH:17]([OH:20])[CH2:18]3)[CH2:14][C@H:13]2[O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 135.6 %

Procedure:
(3aR,4R,5R,6aS)-4-((3R)-5-phenyl-3-((tetrahydro-2H-pyran-2-yl)oxy)pentyl)-5-((tetrahydro-2H-pyran-2-yl)oxy)hexahydro-2H-cyclopenta[b]furan-2-one (22.0 g, 46.6 mmol) was dissolved in toluene (200 mL), followed by cooling to −70° C., and DIBAL (1.0M in hexane, 60 mL, 60.0 mmol) was added dropwisely. Then the reaction was quenched by adding saturated aqueous solution of ammonium chloride (10 mL) at −70° C. The resulting mixture was poured into 200 mL of a 2M sodium bisulfate aqueous solution at room temperature and the stirring was continued for 30 minutes. After separation of the organic layers, toluene (200 mL) was added to the aqueous layer. The combined organic layers were concentrated under reduced pressure to give 30.0 g of crude title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]4[C@@H:29]4[CH2:31][C@@H:30]4[F:32])=[CH:20][C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2)=O)(C)(C)C.[ClH:38]>>[ClH:38].[NH2:8][CH2:9][C:10]12[CH2:17][N:16]([C:18]3[C:27]([F:28])=[C:26]4[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]4[C@@H:29]4[CH2:31][C@@H:30]4[F:32])=[CH:20][C:19]=3[F:37])[CH2:15][CH:14]1[CH2:13][CH2:12][O:11]2
Reactant: CC(C)(C)OC(=O)NCC12CN(c3c(F)cc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3F)CC1CCO2
Agent: Cl
Product: NCC12CN(c3c(F)cc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3F)CC1CCO2

Procedure:
In an analogous manner to Example 1B, the product from step A is reacted with half-concentrated hydrochloric acid to give 7-(1-aminomethyl-2-oxa-7-aza-bicyclo[3.3.0]oct-7-yl)-6,8-difluoro-1-(cis-2-fluorocyclopropyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride with a melting point of 220°-227° C. (with decomposition).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1>>[Cl:8][C:5]1[S:4][C:3]([CH2:2][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccc(Cl)s1
Product: CC(=O)Cc1ccc(OCc2ccc(Cl)s2)cc1

Procedure:
Prepared by the method of Example 2 (b) from 2-chloromethyl-5-chlorothiophene and 4-hydroxyphenyl acetone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=O)[C:5]([Cl:10])=[CH:4][N:3]=1.Cl.[NH2:12][OH:13]>CC(O)C.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[N:12][OH:13])[C:5]([Cl:10])=[CH:4][N:3]=1
Reactant: O=Cc1cc(Cl)ncc1Cl
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: ON=Cc1cc(Cl)ncc1Cl
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of lithium di-isopropylamide was prepared by the addition of 100 ml of 1.5 molar (M) butyllithium (in a hexane solution) to 14.2 g of di-isopropylamine in 100 ml of THF at less than -30° C. After stirring for 20 minutes the solution was cooled to below -70° C. and a solution of 20.8 g of 2,5-dichloropyridine in 56 ml of THF was added at such a rate that the temperature was maintained at below -70° C. After the addition was complete, the reaction temperature was stirred at below -70° C. for 30 minutes. A solution of 13.2 g of DMF in 30 ml THF was added at the same temperature and stirred for an additional 30 minutes. The reaction mixture was allowed to warm to room temperature then poured into a mixture containing 250 g of ice and 45 ml of concentrated HCl and stirred for 15 minutes. The acidic solution was neutralized to about pH 6-7 with 3 normal (N) NaOH. The organic layer was separated and the aqueous layer extracted with ethyl ether. The organic solutions were combined, washed with saturated NaCl solution, dried and evaporated to dryness to give about 22 g of 2,5-dichloro-4-pyridinecarboxaldehyde. This aldehyde was dissolved in 100 ml of 2-propanol, mixed with 13.8 g of hydroxylamine hydrochloride and 20 drops of concentrated HCl and heated on a steambath for 1 hour. The mixture was then poured onto 200 g of ice, stirred well and filtered leaving a solid residue. The solid was vacuum dried to give 22.8 g (85%) of the desired 2,5-dichloro-4-pyridinecarboxaldehyde oxime ##STR6##