Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]2[C:10](=O)[C:11]3[C:12]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[NH:25]C(=O)C(F)(F)F)=[CH:13][CH:14]=[N:15][C:16]=3[C:17](=[O:18])[C:8]=2[N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][N:7]=[C:8]2[C:9]=1[C:10]1[N:25]=[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]3=[C:12]3[CH:13]=[CH:14][N:15]=[C:16]([C:11]=13)[C:17]2=[O:18])([O-:3])=[O:2]
Reactant: O=C1c2nccc(-c3ccccc3NC(=O)C(F)(F)F)c2C(=O)c2c([N+](=O)[O-])ccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1c2nccc([N+](=O)[O-])c2-c2nc3ccccc3c3ccnc1c23
Reaction time: 8 h
Yield: 49.8 %

Procedure:
365 mg (0.826 mmol) of the compound of Example 3 and 2 mL of trifluoroacetic acid in 20 mL of CH2Cl2 are refluxed for 3 hours. After evaporating off the solvent on a rotary evaporator, the residue is taken up in 20 mL of 1N NaOH and 20 mL of CHCl3 and the reaction medium is stirred overnight. The organic phase is recovered and the aqueous phase is extracted with CHCl3 (5 times 20 mL). After drying the organic phases over MgSO4 and evaporating off the solvent on a rotary evaporator, the residue is purified by flash chromatography on a column of RP8 grafted silica (60/40 MeOH/H2O) to give 135 mg of compound in the form of pale orange-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:14][CH2:13][N:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10]3)[O:9][C:4]=2[CH:3]=1.[Br:28]N1C(=O)CCC1=O.C(C(N=NC(C)(C)C#N)(C)C)#N>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[C:7]3[C:8]3([CH2:10][CH2:11][N:12]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:13][CH2:14]3)[O:9][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1)OC1(CCN(C(=O)C(F)(F)F)CC1)c1ccc(C#N)n1-2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc2n1-c1ccc(CBr)cc1OC21CCN(C(=O)C(F)(F)F)CC1
Temperature: 80 °C
Yield: 17.6 %

Procedure:
7′-Methyl-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (250 mg, 0.666 mmol), 1-bromopyrrolidine-2,5-dione (119 mg, 0.666 mmol) and 2-(1-cyano-1-methyl-ethyl)azo-2-methyl-propanenitrile (10.9 mg, 0.0666 mmol) were combined in carbon tetrachloride and the mixture was heated at 80° C. for 4 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography to give 7′-(bromomethyl)-1-(2,2,2-trifluoroacetyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1′-carbonitrile (53.2 mg, 18%).
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C1C(=O)N([Br:21])C(=O)C1.O>CN(C=O)C>[Br:21][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[S:2]([F:10])([F:11])([F:12])([F:13])[F:1]
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
To a solution of 3-(pentafluoro-λ6-sulfanyl)aniline (13.46 g, 61.4 mmol) in DMF (123 ml) stirred in a 500 mL round-bottomed flask in an ice bath under a nitrogen atmosphere, NBS (12.02 g, 67.6 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 4 hr. The reaction was worked up by the addition of H2O and extracted with EtOAc (2×100 mL). The combined organic layer was washed with H2O and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by CombiFlash Rf system eluted with a gradient up to 20% EtOAC/hexanes of EtOAc on a 120 g column to afford the desired 4-bromo-3-(pentafluoro-λ6-sulfanyl)aniline (11 g, 36.9 mmol, 60.1% yield).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][CH:20]([O:23][Si](C(C)(C)C)(C)C)[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CO>C1COCC1.C(Cl)Cl.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH:18]=2)=[CH:13][C:12]=1[F:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Nc1ccc(C2=CCC(O)CC2)cc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
{4-[4-(tert-Butyl-dimethyl-silanyloxy)-cyclohex-1-enyl]-2-fluoro-phenyl}-carbamic acid benzyl ester (340 mg, 0.75 mmol) was dissolved in THF (10 mL). To this solution at rt was added TBAF (1M in THF) (2 mL, 2 mmol). The reaction mixture was stirred at rt overnight. After the reaction was complete (TLC, 5% MeOH in DCM), the reaction was diluted with EtOAc (5 mL), quenched with NaHCO3 (saturated, 5 mL). The two layers were separated and the aq. layer was extracted with EtOAc (15 mL×2). The EtOAc solution was combined, washed with NaHCO3 aq, and brine (10 mL each), sequentially, and dried over K2CO3, filtered, concentrated. The crude product was purified on a silica gel column, eluted with 5% MeOH in DCM to obtain 230 mg (92% yield) of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([C:21](OCC)=[O:22])=[N:9]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:11][C:10]([CH:21]=[O:22])=[N:9]1
Reactant: CCOC(=O)c1cc(Sc2ccc(C)cn2)n(-c2ccccc2Cl)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(Sc2cc(C=O)nn2-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of ethyl 1-(2-chlorophenyl)-5-[(5-methylpyridin-2-yl)thio]-1H-pyrazole-3-carboxylate (642 mg) in tetrahydrofuran (10 mL) was added a 1.5 mol/L solution (3.4 mL) of diisobutylaluminum hydride in toluene at −78° C., and the mixture was stirred at 0° C. for 1 hr. 1 mol/L Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To a solution of the residue in toluene (8 mL) was added manganese dioxide (1.38 g) and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:1) to give the title compound as a yellow oil (yield 426 mg, yield 80%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C@:9]([CH3:28])([C:24]([F:27])([F:26])[F:25])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[N+]=[N-])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C@:9]([CH3:28])([C:24]([F:27])([F:25])[F:26])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N=[N+]=[N-])c2)CO[C@@]1(C)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cccc(N)c2)CO[C@@]1(C)C(F)(F)F

Procedure:
A solution of [(2R*,5R*)-5-(3-azido-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (0.82 g, 1.92 mmol) in EtOH (10 ml) was stirred in the presence of 10% Pd—C (0.1 g) under an atmosphere of hydrogen at 25° C. for 1.5 h. The catalyst was filtered off over Celite, evaporated and the residual oil was purified by flash-chromatography on silica gel (hexane/EtOAc 10:1 to 1:2) to provide the title compound as a colorless foam: TLC (hexane/EtOAc 1:1): Rf=0.43; HPLC RtH5=1.082 min; 1H NMR (360 MHz, CDCl3): δ 10.94 (s, 1H), 7.21 (t, 1H), 6.74 (d, 1H), 6.67 (d, 1H), 6.66 (s, 1H), 4.01 (s, 2H), 3.78 (broad s, 2H), 1.68 (s, 3H), 1.65 (s, 3H), 1.57 (s, 9H); ESIMS: 386, 388 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH2:20][CH3:21])[O:17][N:16]=3)[N:4]2[N:3]=1.ClC1C2[C:27](=[CH:28]C=CC=2)[C:26]2=NN=[C:35]([C:36]3C=C(CC)O[N:37]=3)[N:25]2N=1.ClCC1C=NC=CN=1>>[CH2:20]([C:18]1[O:17][N:16]=[C:15]([C:14]2[N:4]3[N:3]=[C:2]([O:1][CH2:28][C:27]4[CH:26]=[N:25][CH:35]=[CH:36][N:37]=4)[C:11]4[C:6]([C:5]3=[N:12][N:13]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:19]=1)[CH3:21]
Reactant: CCc1cc(-c2nnc3c4ccccc4c(O)nn23)no1
Reactant: CCc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Agent: ClCc1cnccn1
Product: CCc1cc(-c2nnc3c4ccccc4c(OCc4cnccn4)nn23)no1

Procedure:
The title-compound was prepared from 6-hydroxy-3-(5-ethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine (prepared from 6-chloro-3-(5-ethylisoxazol-3-yl)-1,2,4-triazolo[3,4-a]phthalazine, Example 105 part c, using conditions described for the preparation of Intermediate 2) and 2-chloromethylpyrazine (prepared as described in Example 15 part a) using the procedure described in Example 15 part b, 1H NMR (360 MHz, CDCl3) δ 1.42 (3H, t, J=7.6 Hz, CH3), 2.94 (2H, q, J=7.6 Hz, CH2), 5.83 (2H, s, CH2), 6.84 (1H, s, Ar—H), 7.84 (1H, m, Ar—H), 7.98 (1H, m, Ar—H), 8.30 (1H, d, J=7.9 Hz, Ar—H), 8.60-8.64 (2H, m, 2 of Ar—H), 8.70 (1H, m, Ar—H), 9.15 (1H, d, J=1.3 Hz, Ar—H); MS (ES30) m/e 374 [MH]+; Anal. Found. C, 61.16; H, 3.79; N, 26.19. C19H15N7O2 requires C, 61.12; H, 4.05; N, 26.26%.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[S:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1.Cl>>[Si:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[C:30]([C:27]2[CH:28]=[CH:29][S:25][CH:26]=2)=[O:31])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CNc2ccc(C#N)cc2)cc1
Reactant: O=C(Cl)c1ccsc1
Agent: Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CN(C(=O)c2ccsc2)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71 %

Procedure:
The procedure of Preparation Example 8 was repeated, except that 203 mg of 4-[N-(4-tert-butyldimethylsilyloxybenzyl)amino]benzonitrile was used in place of 4-[N-(4-benzyloxybenzyl)amino]phenol and 110 mg of 3-thiophenecarbonyl chloride was used in place of methanesulfonyl chloride. The resulting mixture was stirred at room temperature for 19 hours. After the reaction mixture was poured into dilute hydrochloric acid, the product was extracted with ethyl acetate. After the extract was successively washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting crude product was purified by TLC (using a 3:1 mixture of hexane and ethyl acetate as the developing solvent) to obtain 191 mg of N-(4-tert-butyl-dimethylsilyloxybenzyl)-N-(4-cyanophenyl)-3thiophenecarboxamide.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[CH:5]=1.[Br:20]Br>>[ClH:1].[ClH:1].[NH2:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[C:9]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:8]3=[C:7]([CH3:19])[C:6]=2[C:5]=1[Br:20]
Reactant: BrBr
Reactant: Cc1c2c(nc3ccc(N)cc13)CCNCC2
Agent: Cl
Product: Cc1c2c(nc3ccc(N)c(Br)c13)CCNCC2

Procedure:
9-Amino-10-bromo-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline dihydrochloride was prepared from 9-amino-1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline dihydrochloride by bromination with an equimolar quantity of bromine analogous to Example 148.
Reaction SMILES: COC1C=CC(P(=S)=[S:10])=CC=1.[S:12]1[C:16]2[C:17]([C:21]([NH2:23])=O)=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1>C1(C)C=CC=CC=1>[S:12]1[C:16]2[C:17]([C:21](=[S:10])[NH2:23])=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: COc1ccc(P(=S)=S)cc1
Reactant: NC(=O)c1cccc2nnsc12
Solvent: Cc1ccccc1
Product: NC(=S)c1cccc2nnsc12
Yield: 56.4 %

Procedure:
A suspension of 2.42 g of p-methoxyphenylthiono-phosphine sulfide and 1.79 g of benzo-1,2,3-thiadiazole-7-carboxamide in 95 ml of toluene is refluxed under a nitrogen atmosphere for 6 hours. The mixture is then evaporated in vacuo and the residue is suspended in ethyl acetate and filtered off. The filtrate is recrystallized from ethyl acetate/tetrahydrofuran with added active charcoal. 1.1 g of yellow crystals of melting point 129°-131° C. result.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.Br[C:20]1[C:21]2[C:26]([CH:27]=[C:28]3[C:33]=1[CH:32]=[CH:31][CH:30]=[CH:29]3)=[CH:25][CH:24]=[CH:23][CH:22]=2.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH:22]1[C:21]2[C:26](=[CH:27][C:28]3[C:33]([C:20]=2[C:13]2[CH:14]=[CH:15][C:10]([C:2]4[O:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:11][CH:12]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(-c2nc3ccccc3o2)cc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc2c(-c3ccc(-c4nc5ccccc5o4)cc3)c3ccccc3cc2c1

Procedure:
In a 200 mL three-neck flask, 3.7 g (15 mmol) of 4-(benzoxazol-2-yl)phenylboronic acid, 3.9 g (15 mmol) of 9-bromoanthracene, 3.3 g (31 mmol) of sodium carbonate, 60 mL of toluene, 15 mL of ethanol, and 15 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 0.16 g (0.14 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 110° C. for 6 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with saturated saline, and the organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give a solid. A toluene solution of the solid was subjected to suction filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), and the filtrate was condensed. The solid was recrystallized with ethyl acetate/hexane, so that 3.3 g of target yellow powder was obtained in a yield of 57%.
Reaction SMILES: [NH:1]([C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)C(C)=O.[OH-].[Na+]>O>[NH2:1][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 98.1 %

Procedure:
363 g (1.37 moles) of 1-acetamino-anthraquinone are warmed with 3.5 l of water and 130 ml of concentrated sodium hydroxide solution (d = 1.48) in a stainless steel autoclave for 5 hours at 150° C. After cooling to room temperature, the red suspension is filtered. The residue is washed with hot water until neutral. After drying, 300 g of 1-amino-anthraquinone are obtained (yield: 98%). Degree of purity: 97 to 98%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[O:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:13][O:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[K+]>CO>[OH:4][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]2[O:12][CH2:13][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][O:16]2)=[CH:9][CH:10]=1)=[O:2]
Reactant: CCCCCCC[C@H]1CO[C@H](c2ccc(C(=O)OC)cc2)OC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCC[C@H]1CO[C@H](c2ccc(C(=O)O)cc2)OC1
Temperature: -10 °C

Procedure:
In methanol was dissolved 5 g (0.016 mole) of trans-2-(p-methoxycarbonylphenyl)-5-heptyl-1,3-dioxane, to which 1.2 equivalents of potassium hydroxide was added, and the mixture was refluxed for 8 hours with heating. After distilling methanol under reduced pressure, 300 ml of ethyl acetate was added to the residue, and the mixture was neutralized with 10% aqueous solution of hydrochloric acid while cooling at a temperature of -10° C. Then, the organic layer was concentrated and was recrystallized from methanol to give 4.2 g of trans-2-(p-hydroxycarbonylphenyl)-5-heptyl-1,3dioxane (yield: 86%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([C:12]([O-:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([O-:9])=[O:8].S(=O)(=O)(O)O>O>[Cl:2][C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C([O-])c1ccc(Cl)cc1C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: O
Product: O=C(O)c1ccc(Cl)cc1C(=O)O

Procedure:
To a suspension of 750 g of monosodium-4-chlorophthalate and 1200 ml water was added 120 ml conc. sulfuric acid. The resulting brown solution was extracted with three 400 ml portions of ether. The combined extracts were treated with carbon black, filtered and the ether distilled. The 4-chlorophthalic acid obtained was dehydrated by heating to 170°C for two hours to give 550 g of anhydride. To a solution of the anhydride in 600 ml of toluene was added 219 g of n-butylamine diluted with an equal weight of toluene. The solution was refluxed for 16 hours and the water formed was collected in a Dean-Stark trap. After treatment with carbon black the hot toluene solution was cooled to 5°C to give 280 g of crude 4-chloro-N-butyl phthalimide. Recrystallization from 1000 ml ethanol afforded 240 g of 99% pure imide.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C:23]([F:32])([F:31])[CH:24]([CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[OH:25]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:28]3[CH2:29][CH2:30][CH:26]([CH:24]([OH:25])[C:23]([F:31])([F:32])[F:22])[CH2:27]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OC(C1CCNC1)C(F)(F)F
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC(C(O)C(F)(F)F)C1
Yield: 45.7 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 20 mg, 70.4 μmol) was reacted with 2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN of corresponding free base: 943906-23-8, 14.5 mg, 70.4 μmol) to obtain the title compound (14 mg, 46%) as colorless liquid, MS (EI): m/e=436.4 [MH+].
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([O:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:22](=[O:24])[CH2:21][O:20][C:17]2[S:18][CH:19]=[C:15]([C:12]3[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=3)[N:16]=2)[CH2:27][CH2:26]1
Reactant: O=C(O)COc1nc(-c2ccc(F)cc2)cs1
Reactant: NC1CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1nc(-c2ccc(F)cc2)cs1)NC1CC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-yloxy]-acetic acid trifluoroacetic acid salt and 31.1 mg (0.54 mmol) of cyclopropylamine. Yield: 21.5 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.I.CS[C:27]([C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)=[NH:28]>C(O)C>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:27](=[NH:28])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 99.1 %

Procedure:
A solution of compound 86 (0.45 g, 1.426 mmol) in dry ethanol (25 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.81 g, 2.853 mmol) at room temperature and resulting solution was stirred for 24 h. The solvent was evaporated, crude was diluted with sat. NaHCO3 solution (25 mL) and CH2Cl2 (50 mL). The organic layer was separated and aqueous layer was extracted into CH2Cl2 (2×25 mL). The combined organic layer was washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 3:97) to obtain compound 87 (0.6 g, quantitative) as a foam. 1H NMR (DMSO-d6) δ 1.40-1.56 (m, 11H), 1.90-1.94 (m, 2H), 2.86-2.94 (m, 3H), 4.02-4.06 (m, 2H), 6.26 (s, 1H), 6.64 (dd, 1H, J=1.2, 8.4 Hz), 6.99 (s, 1H), 7.05 (d, 1H, J=1.8 Hz), 7.09 (dd, 1H, J=3.6, 4.9 Hz), 7.27 (d, 1H, J=8.4 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.63 (s, 1H); ESI-MS m/z (%): 425 (MH+, 100).
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:4]=2[N:3]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27].[OH-].[Na+].CCOC(C)=O.CCCCCC>C(O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:4]2[N:3]=[C:2]([NH:29][CH:26]([CH3:28])[CH3:27])[N:6]([C@@H:7]3[O:19][C@H:18]([CH3:20])[C@@H:13]([OH:14])[C@H:8]3[OH:9])[C:5]=2[CH:21]=1
Reactant: CC(C)N
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Nc1nc2ccc(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](O)[C@H]1O
Yield: 28 %

Procedure:
A mixture of 2-bromo-6-chloro-1-(2,3-di-O-acetyl-5-deoxy-β-D-ribofuranosyl)-1H-benzimidazole and 10 mL of isopropylamine in 5 mL of absolute ethanol was refluxed for 18 h. To this resultant mixture was added 1 mL of 1N NaOH and the resultant solution was dry-packed in silica gel. Flash column chromatography on silica gel with EtOAc/hexane (1:1) gave 0.15 g of a still impure product. Further purification on a silica gel preparative plate using EtOAc/hexane (1:1) gave 0.06 g (28%) of the title compound as a foam. 1H NMR (DMSO-d6) δ1.18 (d, 6H, 2×CH3), 1.35 (d, 3H, CH3), 3.7-3.8 (m, 1H, CH), 3.8-3.9 (m, 1H, CH), 4 (sextet, 1H, CH), 4.3 (q, 1H, CH), 5.2-5.21 (m, 2H, 2×OH), 5.61 (d, 1H, CH), 6.38 (d, 1H, aromatic), 6.95 (d, 1H, aromatic), 7.1-7.2 (m, 2H, aromatic & NH).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([Cl:10])[C:17]([O:18][CH3:19])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: O=Cc1ccccc1Cl
Reactant: COc1ccc(N)cc1Cl
Product: COc1cc(C(=O)c2ccccc2Cl)c(N)cc1Cl

Procedure:
(2-amino-4-chloro-5-methoxyphenyl)-(2-chlorophenyl)-methanone (Xy) was prepared by reacting 2-chlorobenzaldehyde with 0.019 moles of 3-chloro-4-methoxy aniline in a manner analogous to Example 1. MH+/Z=296.