Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS([O-])(=O)=O.[Na+].O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:41])[CH2:20][CH2:19][CH:18]([C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[CH2:24]3)=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOC(C)=O.CCCCCC.CCOCC>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([OH:41])[CH2:16][CH2:17][CH:18]([CH2:21][N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([CH2:29][O:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=4)[CH2:24]3)[CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: O=C(C1CCC(O)(c2ccc(Cl)cc2)CC1)N1CCCC(COc2ccc(C(F)(F)F)cc2)C1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC1(c2ccc(Cl)cc2)CCC(CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A portion of this ketone (105 mg, 0.27 mmol) amide mixture was dissolved in 2 mL of THF at 0° C. and p-Cl-phenyl magnesium bromide (0.68 mL of a 1M solution, 2.5 equivalents) was added via syringe. After 30 minutes, 2 mL of 1M NaHSO4 solution was added, followed by 15 mL of water and 15 mL of ether. Extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel using a EtOAc-hexane gradient column, the desired Grignard adduct [4-(4-Chloro-phenyl)-4-hydroxy-cyclohexyl]-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-methanone (88 mg, 65%; MS 478=M+1 minus water). A portion of this material (41 mg, 0.083 mmol) was dissolved in 2 mL of THF and excess lithium aluminum hydride (31 mg, ca. 10 equivalents) was added. The solution was heated to reflux for 5 minutes, cooled to 0° C., and quenched by dropwise addition of 1 mL 1M NaOH. Additional THF (10 mL) was added, and the suspension was stirred at room temperature for 30 minutes and then filtered though a plug of sodium sulfate. The solution thus obtained was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 1-(4-Chloro-phenyl)-4-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-ylmethyl]-cyclohexanol (187) was obtained (28 mg, 70%). MS 482 (M++1), 464 (M++1 minus water).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:30](=[O:31])[CH2:29][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: ClCCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Cc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a mixture of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.164 g, 0.56 mmol) and 2-phenylacetyl chloride (0.96 mL, 0.724 mmol) was added 1,2-dichloroethane (2 mL). The reaction mixture was stirred at room temperature for 16 hours. The crude reaction mixture was washed with saturated aqueous sodium bicarbonate (20 mL) and brine (20 mL). The organic extract was dried over Na2SO4 and concentrated under reduced pressure to give the desired product, 1-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-phenylethanone as a brown oil (0.230 g, 100%). LCMS [M+H]: 413.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([NH:22][C:2]1[N:7]=[C:6]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])[N:5]=[C:4]([N:9]2[CH2:15][CH:14]3[CH2:16][CH2:17][CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[N:3]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Reactant: CC(C)(C)N
Product: CC(C)(C)Nc1nc(NC(C)(C)C)nc(N2CC3CCC(CC3)C2)n1

Procedure:
3-(4,6-Dichloro-s-triazin-2-yl)-3-azabicyclo[3.2.2]nonane (8.2 g.; 0.03 mole) and 25 ml. (0.24 mole) of t-butylamine is placed in a glass liner in a bomb and then heated in an oil bath maintained at 160°-180° C. for 16 hours. After cooling, the contents of the bomb are rinsed with chloroform and water into a flask and 50 ml. of 10 N NaOH is added. The solution is then evaporated in vacuo and the aqueous solution remaining is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered through Magnesol® and the Magnesol® washed with chloroform. Removal of solvent in vacuo, column chromatography on silica gel and recrystallization of the pure fractions containing the more polar component from n-heptane gives 4.8 g. of fine colorless crystals, m.p. 217°-222° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:16]([C:18]1[C:19]([CH3:27])=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22])#[N:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]#[N:17])[C:19]=2[CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1c(C#N)cccc1C(=O)O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C#N)c2C)Cc2ccccc2C1
Yield: 89.2 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (250 mg, 1.2 mmol), 3-cyano-2-methyl-benzoic acid (196 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen. Anhydrous DMF (2 mL) is added and stirring is initiated. After a few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(3-cyano-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (373 mg, 89%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]#[C:19][C:20]2[CH2:24][C:23]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]([OH:33])[CH2:25]3)[O:22][N:21]=2)[CH:15]=[CH:16][CH:17]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]#[C:19][C:20]2[CH2:24][C:23]3([C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26](=[O:33])[CH2:25]3)[O:22][N:21]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: OC1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1CC2(CC(C#Cc3cccc(Cl)c3)=NO2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A solution of oxalyl chloride (64.6 μL, 0.74 mmol) in 5 mL of anhydrous CH2Cl2 was cooled to −60° C.; DMSO (105 μL, 1.48 mmol) was added dropwise so as to keep the reaction at the same temperature. After 15 min. the compound of Example 82 (174 mg, 0.49 mmol) dissolved in 1 mL of anhydrous CH2Cl2 was added and after 30 minutes TEA (0.413 mL, 2.96 mL) was added dropwise. Turning off the cooling and heating up to r.t., the reaction mixture was stirred for 3 hours, then it was quenched with H2O, extracted with CH2Cl2 and dried on Na2SO4. The residue from evaporation was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Petroleum Ether-EtOAc from 95:5 to 1:1) to give the title compound as a brownish oil. Yield: 50%
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C([O-])([O-])=O.[Na+].[Na+]>[Pd]>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(O)cc2C=O)cc1Cl
Yield: 93 %

Procedure:
2-bromo-5-hydroxybenzaldehyde (1 mmol), 3-chloro-4-methoxyphenylboronic acid (1 mmol) and Na2CO3 (2 mmol) were dissolved in AcN/H2O (7:3). Then, palladium tetrakistriphenylphosfine (0.03 mmol) was added and the resulting mixture was refluxed until completion. After concentrating the mixture in vacuo the residue was taken up in water and extracted with AcOEt. The combined organic fractions were dried over Na2SO4, filtered, and evaporated. The crude reaction product was purified by means of flash chromatography on silica gel (hexane/AcOEt 5:1) to yield 3′-chloro-4-hydroxy-4′-methoxybiphenyl-2-carbaldehyde as a white solid (93%); m.p.: 168-170° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>>[C:1]1([C:7]2[N:8]=[C:9]([S:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:10]([CH2:18][C:19]([OH:21])=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cn1c(SCc2ccccn2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c(SCc2ccccn2)nc(-c2ccccc2)c1-c1ccccc1

Procedure:
Starting substances: 1.0 g (2.3 mmol) of Z27 from Example 126; 7.5 ml (15 mmol) of 2 N NaOH
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][C:14]1[O:18][C:17]([C:19](Cl)=[O:20])=[CH:16][CH:15]=1>ClCCl>[Br:13][C:14]1[O:18][C:17]([C:19]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:20])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Br)o1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Br)o1)N1CCN(c2ccccc2)CC1
Reaction time: 2.5 h
Yield: 77.1 %

Procedure:
N-Phenylpiperazine (1.3 ml, 8.51 mmol) is added to a mixture of 5-bromofuran-2-carbonyl chloride (1.5 g, 7.16 mmol), piperidinomethylpolystyrene (2.2 g, 3.5 mmol/g, 7.7 mmol) in anhydrous dichloromethane (30 mL) and stirred for 2.5 hr. The reaction mixture is diluted with dichloromethane and filtered through silica gel. The filtrate is concentrated to afford (5-bromo-furan-2-yl)-(4-phenyl-piperazin-1-yl)-methanone as a white solid (1.85 g, 77% yield); MS: m/e=336 (M+H). 1H-NMR (CDCl3, δ ppm) 7.03 (m, 6H); 6.45 (d, 1H); 3.96 (s, 4H); 3.28 (m, 4H).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4]CC.[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(#N)C1C=CC=CC=1>>[C:13]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[C:14][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccccc1
Reactant: C#CCCCC
Solvent: N#Cc1ccccc1
Product: CCCCC#Cc1ccccc1
Reaction time: 20 h
Yield: 95 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-hexyne (0.450 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 1.90 mmol (95% yield) of 1-hexynylbenzene and and 0.08 mmol of benzonitrile remaining in the reaction mixture.
Reaction SMILES: C(OCC)(=O)C.Cl.C(OC([NH:15][C:16]1[C:17]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])[C:32]([NH:34][C:35]3[CH:44]=[CH:43][C:38]4[O:39][CH2:40][CH2:41][O:42][C:37]=4[CH:36]=3)=[O:33])=[CH:26][N:25]=2)=[O:23])=[CH:18][S:19][CH:20]=1)=O)(C)(C)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[NH2:15][C:16]1[C:17]([NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])[C:32]([NH:34][C:35]3[CH:44]=[CH:43][C:38]4[O:39][CH2:40][CH2:41][O:42][C:37]=4[CH:36]=3)=[O:33])=[CH:26][N:25]=2)=[O:23])=[CH:18][S:19][CH:20]=1
Reactant: CN(C)CCN(Cc1ccc(C(=O)Nc2cscc2NC(=O)OC(C)(C)C)nc1)C(=O)Nc1ccc2c(c1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(C)CCN(Cc1ccc(C(=O)Nc2cscc2N)nc1)C(=O)Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
4.0M Hydrogen chloride-ethyl acetate solution (5.0 mL) was added to a solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-5-[3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-(2-dimethylaminoethyl)ureidomethyl]pyridine-2-carboxylic acid amide (Reference Compound No. 6-4, 60 mg, 0.10 mmol) in a mixed solvent of ethyl acetate (2.0 ml)—methanol (3.0 mL), and then the reaction mixture was stirred at room temperature for 2 hours. Chloroform (0.10 L) and saturated aqueous sodium hydrogen carbonate solution (0.15 L) were added to a reaction solution, and then the whole was partitioned. The organic layer was washed with brine (0.10 L). The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to give 38 mg of the title compound as an orange amorphous product. (Yield 77%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:21][CH2:22][O:23][CH3:24])[C:11](=[O:20])[C:12]([C:15]([O:17]CC)=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[I-].[Li+]>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:21][CH2:22][O:23][CH3:24])[C:11](=[O:20])[C:12]([C:15]([OH:17])=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cnc(-c2cc(F)cc(F)c2)n(CCOC)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COCCn1c(-c2cc(F)cc(F)c2)ncc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of ethyl 2-(3,5-difluorophenyl)-1,6-dihydro-1-(2-methoxyethyl)-6-oxo-5-pyrimidinecarboxylate (i.e. the product from Example 9, Step C) (1.14 g, 3.37 mmol) in ethyl acetate (10 mL) was added lithium iodide powder (1.35 g, 10.0 mmol). The reaction mixture was heated to reflux for 24 h, cooled, and then stirred at room temperature for 72 h. The reaction mixture was concentrated under reduced pressure. To the resulting residue was added water (10 mL), followed by 6 N hydrochloric acid until the pH was 2. The mixture was extracted with dichloromethane, and the organic layer was dried (MgSO4) and concentrated under reduced pressure to afford a solid, which was washed with diethyl ether and dried under reduced pressure to afford the title product as a white solid (700 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[N:13]1[CH:18]=CC=C[CH:14]=1.CNC.C1COCC1>O1CCOCC1>[NH2:1][C:2]1[C:7]([S:8]([N:13]([CH3:18])[CH3:14])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: c1ccncc1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Agent: CNC
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a cold (0 □C) suspension of 2-amino-5-bromo-3-pyridinesulfonyl chloride (92.1 mmol) in dry 1,4-dioxane (92 mL) was added pyridine (101.3 mmol) followed by a 2M solution of dimethylamine in THF (101.3 mmol). The reaction was allowed to warm to rt for 2 h, heated to 50 □C for 1 h, then cooled to rt. After standing for 2 h, the precipitate was collected by filtration and rinsed with a minimal amount of cold water. Drying the precipitate to constant weight under high vacuum provided 14.1 g (55%) of the title compound as a white solid. MS(ES)+ m/e 279.8, 282.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([N+:29]([O-])=O)=[CH:24][CH:25]=4)[NH:20][C:19]3=[O:32])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:29][C:23]1[CH:22]=[C:21]2[C:26]([C:27](=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[C:19](=[O:32])[NH:20]2)=[CH:25][CH:24]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Solvent: CC(=O)O
Product: Nc1ccc2c(=O)n(CCCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c(=O)[nH]c2c1
Yield: 96 %

Procedure:
A mixture of 30 parts of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]-butyl]-7-nitro-2,4(1H,3H)-quinazolinedione, 500 parts of acetic acid and 2 parts of a solution of thiophene in methanol 4% was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated. The residue was stirred in 80 parts of 2-propanol, 300 parts of water and 100 parts of ammonium hydroxide. The aqueous phase was decanted and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 27 parts (96%) of 7-amino-3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione; mp. 213.0° C. (8).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[N:8][O:7][N:6]=1)N.[ClH:15].[Cl-].[Na+].N([O-])=O.[Na+]>C(OCC)(=O)C.O>[OH:1][N:2]=[C:3]([Cl:15])[C:5]1[C:9]([NH:10][CH2:11][CH2:12][O:13][CH3:14])=[N:8][O:7][N:6]=1
Reactant: COCCNc1nonc1C(N)=NO
Reactant: Cl
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COCCNc1nonc1C(Cl)=NO
Temperature: 5.5 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
At room temperature N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (50.0 g, 0.226 mol) was dissolved in 6.0 M hydrochloric acid aqueous solution (250 mL, 1.5 mol). Sodium chloride (39.5 g, 0.676 mol) was added followed by water (250 mL) and ethyl acetate (250 mL). At 3-5° C. a previously prepared aqueous solution (100 mL) of sodium nitrite (15.0 g, 0.217 mol) was added slowly over 1 hr. The reaction was stirred at 3-8° C. for 2 hours and then room temperature over the weekend. LCMS indicated reaction completed. The reaction solution was extracted with ethyl acetate (2×200 mL). The combined ethyl acetate solution was dried over sodium sulfate and concentrated to give the desired product (49.9 g, 126%) as a crude white solid. LCMS for C6H10ClN4O3 (M+H)+: m/z=221.0. 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1 H), 5.85 (t, J=5.6 Hz, 1 H), 3.50 (t, J=5.6 Hz, 2 H), 3.37 (dd, J=10.8, 5.6 Hz, 2 H), 3.25 (s, 3 H).
Reaction SMILES: C[O:2]C1(F)O[C:6]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[O:5]O1.CSC>[Cl-].[Na+].O>[OH2:2].[OH2:2].[OH2:2].[F:9][C:8]([F:11])([F:10])[C:6]([C:12]([F:15])([F:14])[F:13])=[O:5]
Reactant: COC1(F)OOC(C(F)(F)F)(C(F)(F)F)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: CSC
Solvent: O
Product: O=C(C(F)(F)F)C(F)(F)F
Temperature: 0 °C
Yield: 264.8 %

Procedure:
100 g (0.38 mol) of 1-fluoro-4,4-bis(trifluoromethyl)-2,3,5-trioxolanyl methyl ether (purity: 98%) was charged in a 500-ml five-necked flask. While performing nitrogen bubbling, brine at −20° C. was passed through a Dimroth condenser. While stirring at a reaction temperature of −20° C., 23.4 g (0.38 mol) of dimethyl sulfide was added dropwise using a dropping funnel over 30 minutes. The gas obtained by the reaction was collected by a water trap cooled with ice water to 0° C., and the obtained aqueous layer was analyzed by 19F-NMR. As a result, it was confirmed that 73.8 g (yield: 89%) of hexafluoroacetone trihydrate was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][NH:23][C:24]([NH:33]C(OC(C)(C)C)=O)=[N:25]C(OC(C)(C)C)=O)[N:16]=[CH:15][CH:14]=[C:13]2[O:41][C:42]1[C:43]([CH3:52])=[N:44][C:45]2[C:50]([CH:51]=1)=[CH:49][CH:48]=[CH:47][CH:46]=2.[OH-].[Na+]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][NH:23][C:24]([NH2:33])=[NH:25])[N:16]=[CH:15][CH:14]=[C:13]2[O:41][C:42]1[C:43]([CH3:52])=[N:44][C:45]2[C:50]([CH:51]=1)=[CH:49][CH:48]=[CH:47][CH:46]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCNC(=N)N
Temperature: 0 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (1 ml) was added to N-{2-[6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinolin-7-yloxy]-ethyl}-N′,N″-diboc-guanidine (222 mg) at 0° C., and the mixture was then stirred at 0° C. for 2 hr. The reaction solution was made alkaline by the addition of a 1 N aqueous sodium hydroxide solution and was extracted with n-butanol. The n-butanol layer was washed with water and was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (150 mg, yield 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:17]([O:22][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1)[C:18]([F:21])([F:20])[F:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=COCCC1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=C(NC(C(=O)O)C(OC1CCCCO1)C(F)(F)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 2-(N-benzyloxycarbonylamino)3-hydroxy-4,4,4-trifluorobutyrate (3.3 g) in methylene chloride (33 ml) was added dihydropyran (1.1 ml) and pyridinium p-toluenesulfonate (251 mg) at room temperature. After stirring for 2 hours at room temperature, the solvent was distilled off and the residue was diluted with ethyl acetate, washed successively with aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the ethyl acetate was evaporated and the residue was diluted with methanol (20 ml). To the methanol solution was added 1N sodium hydroxide (10 ml) and the mixture was stirred for 2 hours at room temperature. The solvent distilled off and the residue was washed with ethyl acetate. The aqueous layer was acidified with citric acid to pH 4 and extracted with ethyl acetate (2 times). The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was crystallized with a mixture of diisopropylether and hexane to give 2-(N-benzyloxycarbonylamino)-3-(2-tetrahydropyranyloxy)- 4,4,4,-trifluorobutyric acid (1 g).