Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:15]=2)[C:10]([N:25]2C(=O)C3C(=CC=CC=3)C2=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].NN.C(Cl)Cl.CC(C)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[CH:15]=2)[C:10]([NH2:25])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1nc(N2C(=O)c3ccccc3C2=O)c2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: NN
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(N)c2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of 6-(tert-butyl-dimethyl-silanyloxy)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-indazole-1-carboxylic acid tert-butyl ester (1.17 g, 2.37 mmol) in dry THF (20 ml), under argon atmosphere, was treated with 3.56 ml of 1M hydrazine in THF (3.56 mmol). The mixture was stirred at reflux for 1 h then more 1M hydrazine in THF was added (8 ml). After stirring for additional 2 h at reflux, the reaction mixture was cooled to r.t. and the precipitated solid filtered and washed with THF. The filtrate was evaporated to dryness and the residue purified by flash chromatography over silica gel eluting with DCM/acetone 7:3 affording 785 mg (yield: 91%) of the title compound as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1sc(Nc2ccc(C=O)cc2[N+](=O)[O-])nc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3nc(-c4ccc(Cl)cc4)c(C(N)=O)s3)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.6 %

Procedure:
To a mixture of 0.10 g (0.24 mmole) of 4-(4-chloro-phenyl)-2-(4-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.18a), 0.31 g (1.44 mmole) of sodium triacetoxyborohydride and 5 mL of dichloromethane was added 0.04 mL (0.36 mmole) of 1-methylpiperazine. The mixture was stirred at room temperature for 4 hours and then diluted with dichloromethane, washed with aqueous saturated sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-15:85) to give 0.044 g of 4-(4-chloro-phenyl)-2-[4-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.18b).
Reaction SMILES: [CH2:1]([C:5]1([N:12]([CH3:14])[CH3:13])[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=2)[NH:18][CH:17]=1.[F:29][C:30]([F:36])([F:35])S(O)(=O)=O.[OH-].[Na+]>ClCCl>[CH2:1]([C:5]1([N:12]([CH3:14])[CH3:13])[CH2:10][CH2:9][C:8]([C:17]2[NH:18][C:19]3[C:24]([C:16]=2[CH3:15])=[CH:23][C:22]([C:30]([F:36])([F:35])[F:29])=[CH:21][CH:20]=3)([C:17]2[NH:18][C:19]3[C:24]([C:16]=2[CH3:15])=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCC1(N(C)C)CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccc(C(F)(F)F)cc3c2C)(c2[nH]c3ccc(C(F)(F)F)cc3c2C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 128.3 %

Procedure:
4-butyl-4-(dimethylamino)cyclohexanone (395 mg, 2 mmol, synthesis cf. WO2008009415, ketone unit Ket-4) together with 3-methyl-5-trifluoromethyl-1H-indole (398 mg, 2 mmol, synthesis cf. WO2008009415, indole unit Ind-7) was dissolved in dichloromethane (20 ml). Trifluoromethane sulphonic acid (0.2 ml, 338 mg, 2.25 mmol) was then added. This was stirred for 3 d at RT. For work up the reaction mixture was mixed with 1N NaOH (10 ml) and stirred for 10 min. After phase separation the aqueous phase was extracted with dichloromethane (2×10 ml). The combined organic phases were dried with sodium sulphate, filtered and concentrated to low volume in a vacuum. 741 mg of light brown solid was obtained, which was separated by chromatography [silica gel 60 (80 g); ethyl acetate/methanol (15:1; 1.51); (10:1; 500 ml); 1:1; 500 ml)].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([Cl:12])[CH:3]=1.[CH3:13][N:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][C:15]1=[O:24].[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:21]2[CH:22]=[CH:23][C:18]3[O:17][CH2:16][C:15](=[O:24])[N:14]([CH3:13])[C:19]=3[CH:20]=2)=[O:11])=[C:4]([Cl:12])[CH:3]=1
Reactant: CN1C(=O)COc2ccccc21
Reactant: O=C(O)Cc1ccc(Br)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CN1C(=O)COc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21

Procedure:
In analogy to Example 1, step 1, (4-bromo-2-chloro-phenyl)-acetic acid was converted to the acid chloride and subsequently reacted with 4-methyl-2H-1,4-benzoxazin-3(4H)-one in the presence of AlCl3 to give the title compound as a light brown solid. MS (m/e, ISP neg. ion)=392.1 [M−H+].
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9]CC(O)=O.C([O-])([O-])=O.[K+].[K+].[C:20]([O:24]C(OC(OC(C)(C)C)=O)=O)(C)(C)[CH3:21]>C(OC(=O)C)C.O.O1CCOCC1>[CH2:7]([NH:2][CH:20]([OH:24])[CH3:21])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)CCCC1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 179.8 %

Procedure:
4-Piperidin-2-ylbutanoic acid Hydrochloride (10.0 g, 48.3 mmol), and K2CO3 (26.6 g, 193.1 mmol) was dissolved in dest. water (70 ml) and Dioxane (124 ml). The reaction mixture was cooled to 0° C. and at this temperature Di-tert-butyldicarbonate (11.4 g, 53.1 mmol) was added slowly. The reaction mixture was stirred for 24 h at room temperature. After completion of the reaction water and Ethylacetate were added, the two phases were separated. The aqueous Phase was extracted once with Ethylacetate. Afterwards the aqueous Phase was triturated with 2 M HCL (aqueous) to reach pH=2. At this pH the aqueous phase was extracted 4× with Dichloromethane. The combined organic layers were dried over Magnesium sulfate, filtered out and evaporated to complete dryness to give (2) (13.13 g, 100%).
Reaction SMILES: [CH2:1]([C:4]#[N:5])[CH:2]=[CH2:3].[C:6]1([SiH:12]([Cl:14])[Cl:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Pt].[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[C:4]([CH2:1][CH2:2][CH2:3][Si:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([Cl:14])[Cl:13])#[N:5]
Reactant: C=CCC#N
Reactant: Cl[SiH](Cl)c1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [Pt]
Agent: [H+]
Product: N#CCCC[Si](Cl)(Cl)c1ccccc1
Temperature: 120 °C

Procedure:
(γ-Cyanopropyl) phenyldichlorosilane was prepared by adding 67.1 grams (1.0 moles) of allylcyanide slowly to 177.1 grams (1.0 moles) of phenyldichlorosilane containing 10-4 moles of platinum as chloroplatinic acid at a temperature of 130° - 135° C. in a three-necked flask. After completion of the addition, the reaction mixture was heated at 120° C. for 16 hours. The pure (γ-cyanopropyl) phenyldichlorosilane was isolated by fractional distillation (b.p. 132° C./0.7 mm).
Reaction SMILES: Cl.C[C:3]1[N:8]=[C:7]([C:9]2[NH:10][C:11](=[O:19])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=[CH:5][CH:4]=1.C(Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:17]1([CH2:18][CH:9]([NH:10][C:11](=[O:19])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][N:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(-c2cc3ccccc3c(=O)[nH]2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NC(Cc1ccccc1)c1ccccn1)c1ccccc1

Procedure:
The amine prepared as described in (a) was dissolved in chloroform and equivalent amounts of benzoyl chloride and triethylamine were added. The reaction mixture was refluxed for two hours and then washed with water and dried with sodium sulphate. The solvent was distilled off and the residue crystallised from ethanol to yield N-[2-phenyl-1-(2-pyridyl)ethyl]benzamide.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[CH3:15][N:16]([C:41]1[S:42][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[N:44][N:45]=1)[C:17](=[O:40])[CH2:18][CH2:19][S:20]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.C(=O)(O)[O-].[Na+]>[SH:20][CH2:19][CH2:18][C:17]([N:16]([CH3:15])[C:41]1[S:42][C:43]([C:46]2[CH:47]=[N:48][CH:49]=[CH:50][CH:51]=2)=[N:44][N:45]=1)=[O:40]
Reactant: CN(C(=O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nnc(-c2cccnc2)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CCS)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Yield: 85.5 %

Procedure:
Triethylsilane (76 μL, 0.48 mmol, 5.0 equiv) and trifluoroacetic acid (710 μL, 5.7 mmol, 100 equiv) were sequentially added to a stirred solution of N-methyl-N-(5-(pyridin-3-yl)-1,3,4-thiadiazol-2-yl)-3-(tritylthio)propanamide (50 mg, 0.096 mmol, 1.0 equiv) in dichloromethane (1.3 mL) at 23° C. The resulting solution was stirred at 23° C. for 30 m. The reaction mixture was diluted with a saturated solution of sodium bicarbonate (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4), gravity-filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a white powder (23 mg, 85%): mp 149-151° C.; 1H NMR (300 MHz, CDCl3) δ 9.17 (br s, 1H), 8.71 (m, 1H), 8.29 (m, 1H), 7.44 (dd, J=8, 5 Hz, 1H), 3.87 (s, 3H), 2.91-310 (m, 4H), 1.87 (t, J=8 Hz, 1H); ESIMS m/z 281 ([M+H]+).
Reaction SMILES: [C:1]([C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:16][CH2:17][CH2:18][CH:19]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:4]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH2:16][CH2:17][CH2:18][CH:19]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)c1ccccc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(CCCC(CCCCCCC(=O)O)(C(C)=O)c1ccccc1)OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of ethyl 8-acetyl-8-phenyl-12-benzyloxyheptadecanoate (14 g., crude), sodium hydroxide (2.0 g., 0.05 mole) and methanol (150 ml.) is stirred for 48 hours. The methanol is removed in vacuo; and the residual oil is poured into H2O (100 ml.), acidified with 6 N HCl (100 ml.) extracted with ether, and the combined ether extracts dried over anhydrous Na2SO4. The ether is removed in vacuo, and the residual oil is chromatographed through a silica gel column (95% CHCH3 -5% MeOH) to obtain 8-acetyl-8-phenyl-12-benzyloxyheptadecanoic acid (1.43 g., slightly impure).
Reaction SMILES: [N:1]([C@@H:4]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][C@@H:5]1[O:6][C:7](=[O:9])[CH3:8])=[N+]=[N-].[CH3:27][C:28](OC(C)=O)=[O:29]>[Pd]>[C:28]([NH:1][C@@H:4]1[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][C@@H:5]1[O:6][C:7](=[O:9])[CH3:8])(=[O:29])[CH3:27]
Reactant: CC(=O)OC[C@@H]1O[C@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Product: CC(=O)N[C@H]1[C@@H](OC(C)=O)O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 10 h
Yield: 83 %

Procedure:
A solution of Compound 9 (0.60 g, 1.62 mmol) in Ac2O (20 mL) was hydrogenated over 70 mg of 10 percent palladium on charcoal under atmospheric pressure. After 10 hours, the solution was filtered and the filtrate was concentrated in vacuo. By flash column chromatography with EtOAc-toluene (2.5:1), 0.52 g of Compound 10 was obtained in 83 percent yield. 1H NMR (CDCl3) δ6.03 (1H, d, J1-2=1.5 Hz, H-1), 5.34 (1H, dd, J3-4=10.0 Hz, J3-2=5.0 Hz, H-3), 5.18 (1H, t, J4-5=J4-3=10.0 Hz, H-4), 4.65 (1H, ddd, J5-4=10.0 Hz, J5-6a=5.0 Hz, J5-6b=2.0 Hz, H-5), 4.29 (1H, dd, J6a-6b12.5 Hz, J6a-5b=5 Hz, H-6a), 4.06 (1H, dd, J2-3=5.0 Hz, J2-1=1.5 Hz, H-2), 4.05 (1H, dd, J6b-6a=12.5 Hz, J6b-5=2.0 Hz, H-6b), 2.18 (3H, s, acetyl), 2.10 (3H, s, acetyl), 2.07 (3H, s, acetyl), 2.07 (3H, s, acetyl), 2.01 (3H, s, acetyl). 13C NMR (CDCl3) δ170.4, 170.1, 170.0, 169.6, 168.0, 91.7, 73.4, 70.1, 65.5, 62.1, 49.3, 23.2, 20.8, 20.7, 20.7, 20.6. HRMS (FAB) calcd for C16H23NO10Na (M+Na+) 412.1220, found 412.1224.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[C:21]2/[CH:27]=[CH:28]/[C:29]([O:31]C)=[O:30])(=[O:16])=[O:15])(=[O:7])=[O:6].O1CCCC1.[ClH:38]>O.CO>[ClH:38].[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[C:21]2/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])(=[O:15])=[O:16])(=[O:6])=[O:7].[ClH:38].[ClH:38].[CH3:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][N:22]=[C:21]2/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])(=[O:15])=[O:16])(=[O:6])=[O:7]
Reactant: COC(=O)/C=C/c1n[nH]c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(/C=C/C(=O)O)c2c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
(E)-3-[5(2-Methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]acrylic acid can be obtained in the following way: 36 mg of lithium hydroxide monohydrate and 0.5 ml of distilled water are added successively to a suspension of 72 mg of methyl (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]acrylate, of 0.5 ml of tetrahydrofuran and of 0.5 ml of methanol, and the reaction mixture is stirred for 72 hours at a temperature in the region of 20° C. The medium is then diluted with 5 ml of distilled water, and acidified with 1N hydrochloric acid to a pH in the region of 2. The precipitate formed is isolated by filtration, washed with distilled water and then dried under a ventilated hood for 16 hours. 23 mg of (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]acrylic acid sesquihydrochloride are thus obtained in the form of a white solid melting at 170° C. (analysis C17H15N3O6S2.1.5 HCl % calculated C, 42.88; H, 3.49; Cl, 11.17; N, 8.83; O, 20.16; S, 13.47. % found C, 42.41; H, 3.74; N, 8.56; S, 12.83).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.Cl[CH:11]([O:13]C)Cl>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:11]=[O:13]
Reactant: COC(Cl)Cl
Reactant: Cc1ccc(F)cc1O
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C=O)c(F)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 5-fluoro-2-methylphenol (630 mg, 5 mmol) in dichloromethane (5 ml) was added titanium chloride (1890 mg, 10 mmol) dropwise at 0° C. and then (dichloromethyl)-methyl ether (689 mg, 6 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour, quenched with ice (50 g) and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, concentrated and applied to a silica gel column, eluting with hexane/ethyl acetate (10:1), to furnish the title compound (545 mg, 71% yield) as a white solid. 1H NMR (270 MHz, CDCl3) δ 2.25 (3H, s), 6.04 (1H, brs), 6.60 (1H, d, J=11.2 Hz), 7.66 (1H, d, J=7.9 Hz), 10.18 (1H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][OH:6])[CH3:2].[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([CH2:17]Cl)[CH:16]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:7])[CH2:5][O:6][CH2:17][C:15]1[CH:14]=[N:13][CH:12]=[C:11]([Br:10])[CH:16]=1)[CH3:2]
Reactant: ClCc1cncc(Br)c1
Reactant: CCOC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
Hydroxy-acetic acid ethyl ester (3.7 g, 36 mmol) is added to a suspension of 60% NaH (1.5 g, 37 mmol) in DMF (70 ml) at 0° C. and the mixture is stirred at room temperature for 15 min. Then 3-bromo-5-chloromethyl-pyridine (3.0 g, 15 mmol) is added to the mixture at 0° C. and the mixture is stirred at room temperature for 16 hrs. The reaction is quenched with saturated. NH4Cl aqueous solution, extracted with EtOAc three times. The organic layers are combined, washed with water and brine, dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography to give 1.6 g of (5-bromo-pyridin-3-ylmethoxy)-acetic acid ethyl ester. 1.0 M MeMgBr (7.5 mL, 7.5 mmol) is added dropwise to a solution of (5-bromo-pyridin-3-ylmethoxy)-acetic acid ethyl ester (1.6 g, 5.9 mmol) in THF (54 mL) at 0° C. The mixture is stirred at room temperature for 16 hrs. Then the mixture is diluted with EtOAc and washed with water and brine. The organic layer is separated, dried over Na2SO4 and concentrated. The residue is purified by flash column chromatography to give 600 mg of 1-(5-bromo-pyridin-3-ylmethoxy)-2-methyl-propan-2-ol. It is then converted to 6-[5-(2-hydroxy-2-methyl-propoxymethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester according to the procedure of Suzuki Coupling Method IV.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]([CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[C:18]([O:20]C)=[O:19])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>CO>[C:32]([O:31][C:29]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][CH:17]([CH2:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]2)[C:18]([OH:20])=[O:19])[CH2:28][CH2:27]1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)C(CC1CCN(C(=O)OC(C)(C)C)CC1)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CC(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)O)CC1
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
An aqueous 5N sodium hydroxide (5 ml; 25 mmol) was added to a solution in methanol (5 ml) of methyl 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]acetate (906 mg; 1.9 mmol) synthesized by the process described in Referential Example 3, and the mixture was stirred for 30 minutes in a bath controlled at 100° C. The reaction mixture was made acidic by addition of 6N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 861 mg (yield: 98%) of 2,2-bis[(1-tert-butoxycarbonyl-4-piperidinyl)methyl]acetic acid as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2O[C:10](=[O:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1.[NH2:21][CH2:22][C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:21]([CH2:22][C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C:10](=[O:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(-c3cccc(Cl)c3)oc(=O)c2c1
Reactant: CC(C)NC(=O)CN
Solvent: CCO
Product: COc1ccc2cc(-c3cccc(Cl)c3)n(CC(=O)NC(C)C)c(=O)c2c1
Temperature: 120 °C
Yield: 73.4 %

Procedure:
In an open, 50 mL two-necked round bottom flask, a neat mixture of compound 3-(3-chlorophenyl)-7-methoxyisochromen-1-one (1.00 g, 3.49 mmol) and 2-amino-N-isopropylacetamide (INTERMEDIATE I.1) (2.02 g, 17.4 mmol, 5 eq) was heated to 120° C. under argon for 3 days, adding absolute EtOH in aliquots (2 mL) daily to loosen up the reaction mixture. The residue was purified by chromatography on silica gel with ethyl acetate:hexane (1:3, v/v) as eluent to give 2-[3-(3-chlorophenyl)-7-methoxy-1-oxo-1H-isoquinolin-2-yl]-N-isopropylacetamide (0.985 g, 2.56 mmol, 73%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[CH:18]=1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:6]=2[CH:18]=1
Reactant: COCCOCc1c(CO)oc2ccc(F)cc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: COCCOCc1c(C=O)oc2ccc(F)cc12
Reaction time: 5 h
Yield: 50.6 %

Procedure:
To a mixture of {5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methanol (2.65 g) synthesized above, 4-methylmorpholine N-oxide (2.44 g) and acetonitrile (50 mL) was added tetrapropylammonium perruthenate (366 mg), and the mixture was stirred for 5 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30% ethyl acetate/hexane) to give the title object compound (1.33 g, 51%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH:24]([CH2:23][CH2:22][NH:21][CH3:20])[CH2:25]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: CNCCC1CNCCO1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCNC)C3)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-methylaminoethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[2-(2-methylaminoethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.