Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:30])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:17]2=[O:29])[CH2:3]1.B(Br)(Br)Br>C(Cl)Cl>[F:30][C:2]1([F:1])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([CH:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:17]2=[O:29])[CH2:3]1
Reactant: COc1ccc(C2CCN(C3CCN(Cc4ccc(F)cc4)C3=O)CC2(F)F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1C(N2CCC(c3ccc(O)cc3)C(F)(F)C2)CCN1Cc1ccc(F)cc1
Reaction time: 1 h
Yield: 17.5 %

Procedure:
To a solution of 3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one (200 mg, 0.48 mmol, mixture of diastereomers from step D) in DCM (15 mL) at −10° C. was added boron tribromide (0.05 mL, 0.48 mmol) and the reaction mixture was stirred under nitrogen for one hour. The mixture was then diluted with a satd. sodium bicarbonate solution and extracted with 100 mL of DCM. The organic layer was separated, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via preparative HPLC (method D) to yield 3-(3,3-difluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one (mixture of 4 diastereomers, 34 mg, 17% yield). LCMS (method N) RT 1.497 min, m/z 405.0 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[SH:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.Cl>C1COCC1>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[S:20][CH2:1][CH:2]([CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([OH:5])=[O:4]
Reactant: C=C(CCC(=O)OCC)C(=O)O
Reactant: Sc1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCC(CSc1cccs1)C(=O)O
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Under N2, a mixture of 2-methylene-4-ethoxycarbonylbutyric acid (17 g, 0.09 mol), triethylamine (4.3 g, 0.04 mol) in THF (120 ml) and 2-mercaptothiophene (11 g, 0.095 mol) was heated at reflux. After 24 hours the reaction mixture was cooled to room temperature and poured into 3N HCl (400 ml). The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were backwashed with saturated NaCl, dried, filtered and concentrated to dryness. The residue was chromatographed on a Still column and the product eluted with 15% CH3OH-CHCl3 saturated with NH3 to yield 14 g of 1 wherein R1, R2, R3 and R4 are each H.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16](Cl)(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][S:16]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:22]=2[O:21][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=S(=O)(Cl)Cc1cccc(OCc2ccccc2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CNS(=O)(=O)Cc2cccc(OCc3ccccc3)c2)c(OC)c1
Reaction time: 0.5 h

Procedure:
Under inert gas, 4.89 g of (3-benzyloxyphenyl)methanesulfonyl chloride were initially charged in 50 ml of THF, then, at a temperature of −20° C., 3.00 ml of 2,4-dimethoxybenzylamine were added dropwise and the reaction solution was allowed to come to 0° C. within 30 minutes. The reaction solution was diluted with 80 ml of ethyl acetate and washed with water, with 10% aqueous potassium hydrogensulfate solution, saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined, concentrated by rotary evaporation and dried under high vacuum. This gave the product (3.12 g) with a molecular weight of 427.5 g/mol (C23H25NO5S).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[Cl:16])([CH3:6])[CH3:5].[F:18][C:19]([F:38])([F:37])[O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[C:28][CH2:29][CH2:30][CH2:31]OS(C)(=O)=O)=[CH:23][CH:22]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:17])[C:4]([O:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH2:31][CH2:30][CH2:29][C:28]#[C:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]([F:18])([F:37])[F:38])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[Cl:16])([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)Oc1cc(Cl)c(O)cc1Cl
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: COC(=O)C(C)(C)Oc1cc(Cl)c(OCCCC#Cc2ccc(OC(F)(F)F)cc2)cc1Cl

Procedure:
In analogy to the procedure described in. example 20A], 2-(2,5-dichloro-4-hydroxy-phenoxy)-2-methyl-propionic acid methyl ester was treated with methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) in acetonitrile at the reflux temperature of the solvent for 3 h to give the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]12[CH2:10][CH:6]3[CH2:7][CH:8]([CH2:9]1)[C:4]([NH:11]C(=O)OC(C)(C)C)([CH2:5]3)[CH2:3]2.[ClH:19]>CCOC(C)=O>[ClH:19].[F:1][C:2]12[CH2:10][CH:6]3[CH2:7][CH:8]([CH2:9]1)[C:4]([NH2:11])([CH2:5]3)[CH2:3]2
Reactant: CC(C)(C)OC(=O)NC12CC3CC1CC(F)(C3)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: NC12CC3CC1CC(F)(C3)C2
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred solution of the compound obtained from step I (0.25 g, 0.98 mmol) in EtOAc (1 mL) cooled to ice bath temperature was added a solution of dry HCl in EtOAc (3N, 3 mL). After stirring the reaction mixture for 2 h, the volatiles were removed under reduced pressure. The crude product was triturated with ether several times to obtain 1-fluorotricyclo[3.3.1.03,7]nonan-3-amine, hydrochloride salt (0.19 g) in 99% yield. m/z (M+1) 156; 1H NMR (DMSO-d6) 300 MHz δ 8.45 (s (br), 2H), 2.47-2.18 (m, 4H), 1.96-1.72 (m, 6-H), 1.63 (dd, J=2.6, 9.5 Hz, 1H), 1.50-1.42 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][NH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.F[C:24](F)(F)C(O)=O>C(O)C>[CH2:1]([N:8]1[CH:24]=[C:13]2[CH:14]=[CH:15][CH2:16][C:17]3[NH:20][CH2:19][CH2:18][N:11]([C:12]=32)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NCCN1CCN(Cc2ccccc2)c2ccccc21
Agent: C=O
Solvent: CCO
Product: C1=CC2=CN(Cc3ccccc3)CCN3CCNC(=C23)C1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A solution of 1.089 g (4.07 mmol) of 2-(4-benzyl-3,4-dihydro-2H-quinoxalin-1-yl)ethylamine and 20 ml ethanol was treated with 122 mg (4.07 mmol) of formaldehyde and 511 mg (4.48 mmol) of trifluoroacetic acid and stirred over night at room temperature. The solvent was evaporated and dichloromethane was added to the crude mixture. The organic phase was washed with 1 molar sodium hydroxide solution. The organic phase was dried and purified by column chromatography on silica (eluent: starting with dichloromethane and then up to 100% methanol) to yield 448 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.O1CCC[CH2:19]1.[H-].[Na+].IC>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:19])[C:10]([N:15]([CH3:17])[CH3:16])=[N:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(=O)O
Product: CN(C)C(=N[N+](=O)[O-])N(C)Cc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a mixture of 0.24g of 1-(6-chloro-3-pyridylmethyl)-3,3-dimethyl-2-nitroguanidine (Compound No. 6) and 6ml of dry tetrahydrofuran (THF) was added 0.045g of 60% sodium hydride (in mineral oil) at room temperature, followed by stirring for 30 minutes. A solution of 0.16g of iodomethane in lml of THF was added to the reaction mixture and allowed to react for 3 days. After adding 0.lml of acetic acid, the mixture was filtered to remove insoluble materials and the filtrate was concentrated. The residue was purified by a column chromatography [developing solvent: dichloromethanemethanol (20:1)] to obtain 0.17g of 1-(6-chloro-3-pyridylmethyl)-1,3,3-trimethyl-2-nitroguanidine (Compound No. 14) as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][C:17]=1[F:30].[Cl-].[NH4+]>O1CCCC1.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:6][CH3:7])=[O:5])=[C:17]([F:30])[CH:18]=1)#[N:29]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Reaction time: 1 h

Procedure:
To a solution of methyl 3-oxoheptanoate (10.9 g) in tetrahydrofuran (100 mL) was added 60% sodium hydride (2.07 g), and the mixture was stirred for 1 hr. A solution of 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (10.0 g) in tetrahydrofuran (50 mL) was added, and the mixture was stirred for 15 hr. Ammonium chloride and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (13.0 g, 100%).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33]N>>[F:21][C:20]([F:23])([F:22])[C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[C:26]([F:25])([F:35])[F:36])[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1ccccc1C(F)(F)F
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1C(F)(F)F
Yield: 46 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-3) and o-trifluoromethyl-phenylhydrazine according to the method described for Example 1 in 46% yield. MS: M=451.1 (M+H)+
Reaction SMILES: C(N(CC)[CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=1)C.[CH:21]([CH:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])([CH3:23])[CH3:22]>>[CH:21]([C:24]1([CH2:4][CH2:5][C:6](=[O:18])[CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30])([CH3:23])[CH3:22]
Reactant: CC(C)C1C(=O)CCC1=O
Reactant: CCN(CC)CCC(=O)CCCc1cccc(OC)c1
Product: COc1cccc(CCCC(=O)CCC2(C(C)C)C(=O)CCC2=O)c1
Yield: 97.7 %

Procedure:
Condense a mixture (6 g) of 1-diethylamino-6-(m-methoxyphenyl)hexan-3-one and 6-(m-methoxhyphenyl)hex-1-en-3-one with 2-isopropylcyclopentane-1,3-dione (3 g) using a procedure similar to that described for the condensation of the 2-ethyl compound. Obtain the corresponding triketone, 2-isopropyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (7.2 g) as an uncrystallizable gum.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:26]([F:27])=[C:25]([F:28])[C:24]([C:29]([F:32])([F:31])[F:30])=[C:23]([F:33])[C:22]=2[F:34])[N:19]=[CH:18][CH:17]=1)(=[O:14])[CH3:13].O>C(O)(=O)C>[C:12]([NH:15][C:16]1[N:20]([C:21]2[C:22]([F:34])=[C:23]([F:33])[C:24]([C:29]([F:32])([F:31])[F:30])=[C:25]([F:28])[C:26]=2[F:27])[N:19]=[CH:18][C:17]=1[N+:8]([O-:11])=[O:9])(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reaction time: 4 h
Yield: 94 %

Procedure:
12.5 ml (0.13 mol) of acetic anhydride and 4.5 ml (0.105 mol) of 98 percent strength nitric acid are added in succession to 34.1 g (0.10 mol) of 5-acetamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 85 ml of glacial acetic acid at about 15° C. The temperature is allowed to rise slowly to 25° C. and the mixture is subsequently stirred for 4 hours. The reaction solution is then poured onto 250 ml of water. The precipitate is filtered off, washed neutral and dried in vacuo. 36.3 g (94% of theory) of 5-acetamido-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 138° C.-140° C. are obtained.
Reaction SMILES: [F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([OH:5])=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.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>CN(C=O)C>[F:1]/[C:2](=[CH:6]\[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)/[C:3]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[CH:28][CH:27]=1)=[O:5]
Reactant: O=C(O)/C(F)=C/c1cccnc1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(S(=O)(=O)c2ccccc2)cc1)/C(F)=C/c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
The mixture of (Z)-2-fluoro-3-(pyridin-3-yl)acrylic acid (100 mg, 0.598 mmol),4-(phenylsulfonyl)aniline (140 mg, 0.598 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (341 mg, 0.897 mmol), DIEA (232 mg, 1.795 mmol) in DMF (Volume: 10 ml) was stirred at RT for overnight, removed DMF, extracted with EtOAc, washed with 1N NaOH, brine, dried and the biotage purification afforded the product (51 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:23]([N:13]1[CH2:12][CH2:11][N:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=2)[CH2:15][CH2:14]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: N#Cc1ccc(N2CCNCC2)cc1F
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCN(c2ccc(C#N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-fluoro-4-(piperazin-1-yl)-benzonitrile (0.53 g, 2.56 mmol) and triethylamine (0.5 ml, 3.59 mmol) in CH2Cl2 (13 ml) is added dropwise to a cooled solution (0-5° C.) of acryloyl chloride (0.25 ml, 3.15 mmol) in CH2Cl2 (3 ml). After complete addition, the mixture is stirred at rt for 1 h, sat. aq. Na2CO3 solution is added and stirring is continued for 20 min. The organic layer is separated off, dried over Na2SO4 and evaporated. Upon addition of AcOEt, 4-(4-acryloyl-piperazin-1-yl)-2-fluoro-benzonitrile crystallizes out, is filtered off, washed with AcOEt and air-dried.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1>[OH-].[OH-].[Pd+2].C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCC(=Cc2cccc(F)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Fc1cccc(CC2CCNCC2)c1
Yield: 85.3 %

Procedure:
A mixture of benzyl 4-(3-fluorobenzylidene)piperidine-1-carboxylate (Intermediate 181, 1.05 g), 20% palladium hydroxide on carbon (0.227 g), IMS (30 mL) and acetic acid (10 mL) was degassed by nitrogen/vacuum purging. The mixture was placed under an atmosphere of hydrogen with rapid stirring. After 2 hours the mixture was filtered and the filtrate was diluted with water (40 mL) and neutralized with Na2CO3. The solution was saturated with sodium chloride, extracted with ethyl acetate dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in a mixture of methanol and water (20 mL, 1:1) and passed down a SCX-2 column. The product was eluted with 2M ammonia to give 4-(3-fluorobenzyl)piperidine (0.532 g)
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:12]([O:13]C(=O)C)[C@H:11]([O:17]C(=O)C)[C:8]2([CH2:10][CH2:9]2)[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]3[O:37][CH2:36][CH2:35][NH:34][C:33]=3[CH:38]=2)[CH:22]=1)(=O)C.C[O-].[Na+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@H:6]2[C@H:5]([OH:4])[C@@H:12]([OH:13])[C@H:11]([OH:17])[C:8]3([CH2:10][CH2:9]3)[O:7]2)=[CH:22][C:23]=1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]2[O:37][CH2:36][CH2:35][NH:34][C:33]=2[CH:38]=1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc3c(c2)NCCO3)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1[C@@H](O)[C@H](O)C2(CC2)O[C@H]1c1ccc(Cl)c(Cc2ccc3c(c2)NCCO3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.5 %

Procedure:
To a stirred solution of acetic acid (5S,6S,7R,8S)-6,7-diacetoxy-5-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-4-oxa-spiro[2.5]oct-8-yl ester (100 mg, 0.18 mmol) in methanol (6 mL) was added sodium methoxide (39 mg, 0.73 mmol) and stirred at room temperature for 3 h. The solvent was evaporated and crude product purified by silica gel column chromatography to give 35 mg of (5S,6R,7R,8S)-5-[4-chloro-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-4-oxa-spiro[2.5]octane-6,7,8-triol as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:11]([C:7]1[O:8][CH:9]=[CH:10][C:6]=1[CH2:4][OH:3])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1ccoc1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1occc1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-isopropyl-furan-3-carboxylic acid ethyl ester (82) (4.0 g, 21.95 mmoles) in tetrahydrofuran (70 ml) was treated portionwise during 0.5 h with lithium aluminium hydride (0.7 g, 18.4 mmoles) under a nitrogen atmosphere. When the addition was complete the mixture was stirred at room temperature for 18 hours, then quenched by the addition of excess acetone (1 ml) and then water (1 ml). After diluting with ethyl acetate (150 ml) the grey precipitate was removed by filtration. The filtrate was evaporated and the residue dissolved in diethyl ether and dried. Evaporation of the solvent afforded (2-isopropyl-furan-3-yl)-methanol. This material was used immediately in the next step.
Reaction SMILES: O.O.P([O-])(O)(O)=O.[Na+].[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:28])[F:27])[N:21]([CH3:29])[N:20]=2)=[CH:14][C:11]=1[CH:12]=[O:13].OO.Cl([O-])=[O:33].[Na+].Cl>O.C(#N)C>[Cl:9][C:10]1[CH:17]=[C:16]([F:18])[C:15]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:27])[F:28])[N:21]([CH3:29])[N:20]=2)=[CH:14][C:11]=1[C:12]([OH:33])=[O:13]
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=P([O-])(O)O
Agent: OO
Solvent: O
Solvent: CC#N
Product: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Temperature: 25 °C

Procedure:
A solution of 2.8 g (18 mmol) of sodium dihydrogen phosphate dihydrate in 28 ml of water was added at 10-15° C. to a solution of 24 g (71 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzaldehyde in 130 ml of acetonitrile. Then, 6.8 ml of 30% strength aqueous hydrogen peroxide solution and (in the course of one hour) 9.8 g (108 mmol) of sodium chlorite were added in succession. After the mixture had been stirred for a further hour, it was heated to room temperature. After it had been stirred for a further 16 hours, it was acidified using dilute hydrochloric acid. The aqueous solution was then extracted twice using ethyl acetate, whereupon the combined organic phases were washed in succession with concentrated aqueous thiosulfate solution, water and saturated sodium chloride solution, dried over magnesium sulfate and finally concentrated. Yield: 23 g; m.p.: 137-140° C.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].S(Cl)([Cl:30])=O>>[CH2:1]([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([Cl:30])=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1cnc(-c2ccc(C(=O)O)cc2)nc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCOc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
4-(5-n-Undecyloxypyrimidine-2-yl)benzoic acid (1.86 g) was heated together with excess thionyl chloride for 8 hours under reflux and thereafter, unaltered thionyl chloride was distilled off to obtain 4-(5-n-undecyloxypyrimidine-2-yl)benzoic acid chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:21]1[C:16]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)=[N:17][CH:18]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2-c2ncc(C(F)(F)F)cc2Cl)c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of 5-nitroindazole (1.63 g) in N,N-dimethylformamide (10 ml), 60% sodium hydride (0.5 g) was added, and the resultant mixture was stirred while cooling with ice. After 10 minutes, 2,3-dichloro-5-trifluoromethylpyridine (2.1 g) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-nitroindazole (1.8 g)
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][CH:29]([CH2:33][CH3:34])[C:30](O)=[O:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:30](=[O:31])[CH:29]([CH3:28])[CH2:33][CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: CCC(C)C(=O)O
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (51 mg, 49%), MS (ISP) m/z=415.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and rac-2-methylbutanoic acid