Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:22]([CH3:33])[C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[N:11]([CH3:21])[C:12]([CH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][CH3:18])=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:19][C:16]([CH3:20])([CH2:17][CH3:18])[CH2:15][C:12]1[N:11]([CH3:21])[C:10]([CH:9]([N:22]([CH3:33])[C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[CH:3][CH:4]=2)=[N:14][CH:13]=1
Reactant: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)N(C)C(=O)OCc2ccccc2)n1C
Reactant: Fc1ccc(Br)nc1
Agent: [Pd]
Agent: C[Sn](C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(-c3ccc(F)cn3)cc2)N(C)C(=O)OCc2ccccc2)n1C

Procedure:
Palladium tetrakis(triphenylphosphine) (16 mg, 0.01 mmol) was added to a degassed, ambient temperature solution of benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}methylcarbamate (72 mg, 0.14 mmol), 2-bromo-5-fluoropyridine (25 mg, 0.14 mmol) and hexamethylditin (46 mg, 0.14 mmol) in 1,4-dioxane (5 mL). After stirring at reflux overnight, the reaction mixture was diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded benzyl {1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}methylcarbamate.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6](=O)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>CO>[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=3)[C:6]2=[O:5])=[CH:28][CH:27]=1
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 14.9 %

Procedure:
[Step 2] To a solution of 3-acetyl-6-bromo-4-phenyl-isochromen-1-one (1.03 g) in methanol (100 ml) were added 4-aminomethyl-benzoic acid methyl ester hydrochloride (3.02 g) and triethylamine (4.2 ml) and the mixture was stirred at room temperature for 18 hrs. The solvent was evaporated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=19/1→3/1) to give the title compound (220 mg, 15%).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C1CCCC1
Yield: 70.6 %

Procedure:
To a solution of 4.6 g (0.2 mol) sodium in 80 mL absolute ethanol was added 30.4 mL (0.2 mol) diethyl malonate. After briefly stirring, 21.4 mL (0.2 mol) cyclopentyl bromide was added, and the resulting solution refluxed for 12 hrs. Most of the ethanol was then removed by rotary evaporation, and the reaction was quenched with 250 mL of water and extracted 3 ×, each with 100 mL ether. The extracts were dried over MgSO4, filtered, and concentrated. Distillation through a 6" Vigreaux at 6 mm Hg provided 32.232 g of a clear colorless oil at bp 122-125 C.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][CH2:5][CH:4]([C:7]2[C:11]([C:12](OCC)=[O:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[S:9][N:8]=2)[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:21][C:2]1([F:1])[CH2:6][CH2:5][CH:4]([C:7]2[C:11]([CH2:12][OH:13])=[C:10]([C:17]([F:19])([F:20])[F:18])[S:9][N:8]=2)[CH2:3]1
Reactant: CCOC(=O)c1c(C2CCC(F)(F)C2)nsc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1c(C2CCC(F)(F)C2)nsc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 100-mL round-bottom flask, was placed ethyl 3-(3,3-difluorocyclopentyl)-5-(trifluoromethyl)-1,2-thiazole-4-carboxylate (200 mg, 0.61 mmol, 1.00 equiv), ether (5 mL), LAH (46 mg, 1.21 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at 0° C. The reaction was then quenched by the addition of 10 ml of EA. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/30-1/10). This resulted in 100 mg (crude) of [3-(3,3-difluorocyclopentyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methanol as yellow oil.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]2[CH2:13][CH2:14][C:15](=[O:16])[C:5]=12>CO>[CH3:3][C:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]2[CH2:13][CH2:14][CH:15]([OH:16])[C:5]=12
Reactant: Cc1c2n(c3ccccc13)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c2n(c3ccccc13)CCC2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
Sodium borohydride (1.368 g, 36 mmole) was added portionwise to a solution of 2,3-dihydro-9-methyl-1H-pyrrolo[1,2-a]indol-1-one, prepared by the process of Example 1, Step 1, (2.22 g, 12 mmole) in methanol (200 mL). The reaction mixture was stirred at 25° C. for 2 hours, evaporated to near-dryness, and the residue suspended in water (150 mL). The product was extracted with chloroform (3×75 mL), and the combined organic layer dried over MgSO4, filtered, and evaporated to dryness. The residue was crystallized from ether to afford 1.32 g (59%) of product, m.p. 118.5°-120° C., as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:18]=2)=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=3)[CH:18]=2)=[C:13]([F:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(OC)cc(-c3cccc(F)c3)c2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CNc2c(F)ccc(OCC(=O)O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a solution of ethyl 2-[2,4-difluoro-3-[[3-(3-fluorophenyl)-5-methoxy-phenyl]methylamino]phenoxy]acetate (see example 16) (200 mg, 0.45 mmol, 1.0 eq) in THF (10 mL) was added an aqueous solution of NaOH (1 M aqueous solution, 4 mL, 4 mmol, 8.9 eq) at 0° C. The reaction mixture was stirred at room temperature for 3 h. The organic solvent was removed water added and the pH adjusted to pH 4-6 by addition of 1M HCl. The solid that precipitated was collected by filtration and dried in vacuo to give the title compound as a solid (150 mg, 80%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.C1COCC1.C(OCC)(=O)C>[CH3:20][S:21]([O:1][CH2:2][CH:3]([NH:5][C:6]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:12])[CH3:4])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (2-hydroxy-1-methylethyl)carbamate (2.8 g, 15.98 mmol), triethylamine (4.44 ml, 3.23 mmol) and 4-dimethylaminopyridine (195 mg, 1.59 mmol) were dissolved in 135 ml of THF. Methanesulfonyl chloride (1.3 ml, 16.78 mmol) was added dropwise on an ice bath, and the reaction mixture was stirred for 3 h and warmed to room temperature. Following addition of ethyl acetate and sodium bicarbonate solution, the organic phase was separated off and concentrated. Yield: 3.97 g (98%).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1.Br>C(O)(=O)C>[OH:8][C:9]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: N#Cc1ccc(C(F)(F)F)cc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1ccc(C(F)(F)F)cc1O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(Benzyloxy)-4-(trifluoromethyl)benzonitrile (~20 grams) in 350 ml. acetic acid and 100 ml. 33% HBr was stirred overnight, refluxed for four hours, and then stirred overnight again. Next the reaction mixture was stripped to a small volume and poured into ice water. The crude precipitate which formed was stirred in hexane, filtered, and was identified by NMR as the desired product, yield 9.3 grams.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH2:13][CH2:14][C:15]1[CH:19]=[C:18]([NH:20][C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][CH:23]=2)[N:17](C(OC(C)(C)C)=O)[N:16]=1>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:13][CH2:14][C:15]2[CH:19]=[C:18]([NH:20][C:21](=[O:29])[C:22]3[CH:23]=[CH:24][C:25]([I:28])=[CH:26][CH:27]=3)[NH:17][N:16]=2)[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3ccc(I)cc3)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(CCc2cc(NC(=O)c3ccc(I)cc3)[nH]n2)cc(OC)c1
Reaction time: 24 h
Yield: 24.3 %

Procedure:
Trifluoroacetic acid (3.85 mL, 50.02 mmol) was added in one portion to tert-butyl 3-(3,5-dimethoxyphenethyl)-5-(4-iodobenzamido)-1H-pyrazole-1-carboxylate (288 mg, 0.5 mmol) in DCM (10 mL) at room temperature. The resulting solution was stirred for 24 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (5 mL). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 3.5M NH3/Methanol and pure fractions were evaporated to dryness to afford a tan solid. The solid was triturated with DCM to give the title compound (58.0 mg, 24.3%) as a white solid; 1H NMR (399.9 MHz, DMSO-d6) δ 2.88 (4H, s), 3.73 (6H, s), 6.33 (1H, t), 6.42 (2H, d), 6.47 (1H, s), 7.77 (2H, d), 7.87 (2H, d), 10.73 (1H, s), 12.17 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([O-:21])=[O:20]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (355 mg) in DMF (5 mL) was added sodium hydride (110 mg of 60% in oil) and 4-nitrobenzyl bromide (596 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a light orange solid.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:28])[C@H:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:7][CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:10]([CH3:12])[CH3:11]>O.COCCOC>[CH3:11][CH:10]([CH3:12])[C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:8][NH:7][C@H:6]([C:5]([OH:28])=[O:4])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC(C)[C@@H](CN[C@@H](Cc1ccccc1)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
A solution of lithium hydroxide (1.63 g, 0.068 mole) in water (70 ml) was added to a solution of the product of Step A (7.6 g, 0.021 mole) in ethylene glycol dimethyl ether (100 ml) with cooling in an ice bath. The reaction mixture was stirred at room temperature under Ar for 2 hours, concentrated in vacuo, and extracted (2×) with ethyl acetate. The aqueous phase was neutralized with 10% of citric acid, cooled and filtered to give the product as a white solid (6.6 g), mp >193° (dec).
Reaction SMILES: C(OC([N:8]1[CH:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:11]([CH:20]([OH:24])[CH2:21][S:22][CH3:23])[O:10]C1(C)C)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[NH2:8][CH:12]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH:11]([OH:10])[CH:20]([OH:24])[CH2:21][S:22][CH3:23]
Reactant: CSCC(O)C1OC(C)(C)N(C(=O)OC(C)(C)C)C1CC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CSCC(O)C(O)C(N)CC1CCCCC1

Procedure:
29.4 mg of (4S,5R or S)-3-tert-butoxycarbonyl-4-cyclohexylmethyl-2,2-dimethyl-5-[(1RS)-1-hydroxy-2-methylthioethyl]oxazolidine was dissolved in 0.3 ml of dioxane, and 0.42 ml of a dioxane solution of 3.6M hydrogen chloride was added thereto. From the reaction solution, the solvent was distilled off under reduced pressure to obtain 22.5 mg of (2RS,3R or S,4S)-4-amino-5-cyclohexyl-1-methylthio-2,3-pentanediol hydrochloride as colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[NH:10]1[CH2:18][CH2:17][CH:13]([C:14]([NH2:16])=O)[CH2:12][CH2:11]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:10]1[CH2:18][CH2:17][CH:13]([C:14]#[N:16])[CH2:12][CH2:11]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1cncc(Cl)c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: N#CC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 33 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (0.50 g, 2.7 mmol), isonipecotamide (0.30 mg, 2.7 mmol), NMP (15 mL) and triethylamine (0.76 mL, 5.5 mmol). The crude product was purified by flash column chromatography on silica gel (CH2Cl2, MeOH, 99:1) to furnish the title compound as a white solid (228 mg, 33%), m/z (ESI) C11H12Cl2N3 requires 256.0403 found [M+H]+ 256.0409.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=1)=[C:7]2[CH3:26].[CH3:28][O:29][C:30](=[O:33])[CH2:31]Br>>[CH3:28][O:29][C:30](=[O:33])[CH2:31][O:27][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:26])=[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:16][CH:15]=1)[C:9](=[O:12])[NH:10]2
Reactant: Cc1c(Cc2ccc(C(=O)C(C)(C)C)cc2)c(=O)[nH]c2c(Cl)ccc(O)c12
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(Cl)c2[nH]c(=O)c(Cc3ccc(C(=O)C(C)(C)C)cc3)c(C)c12

Procedure:
The title compound was prepared by the method of Preparation 7a using 8-chloro-3-[4-(2,2-dimethylpropionyl)benzyl]-5-hydroxy-4-methyl-1H-quinolin-2-one and bromoacetic acid methyl ester.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>CO>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cc(CO)ccc1OCc1ccccc1
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
Under ice cooling, 75.7 g of sodium borohydride is introduced within one hour into 128.0 g of 4-benzyloxy-3-nitrobenzaldehyde in 4.2 l of methanol. After 1.5 hours of agitation at room temperature, 1.1 l of 2N HCl is added dropwise. The isolated reaction product is recrystallized from a mixture of 680 ml of diisopropyl ether and 170 ml of isopropanol, thus obtaining 103.0 g of 4-benzyloxy-3-nitrobenzyl alcohol, mp 76°-77° C.
Reaction SMILES: CC[O:3][C:4](/[CH:6]=[CH:7]/[CH2:8][P:9]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10])=[O:5].[OH-].[K+]>O>[CH2:15]([O:14][P:9]([CH2:8]/[CH:7]=[CH:6]/[C:4]([OH:5])=[O:3])([O:11][CH2:12][CH3:13])=[O:10])[CH3:16]
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOP(=O)(C/C=C/C(=O)O)OCC
Reaction time: 3 h
Yield: 89.8 %

Procedure:
To a solution of triethyl 4-phosphonocrotonate (5.53 g) in water (36 mL) was added a solution of potassium hydroxide (1.69 g) in water (36 mL) at room temperature, and the reaction solution was stirred for 3 hours. The resulting reaction solution was washed with dichloromethane, and the water layer was acidified to pH2 with concentrated hydrochloric acid and extracted with dichloromethane (550 mL). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure to give 4.41 g of 4-diethylphosphonocrotonic acid as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:25])[NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([CH2:15][NH:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc2c(c1)OCO2)C1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
2-[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (278 mg, 0.80 mmol) was dissolved in DCM:TFA (1:1, 6 mL) and stirred at room temperature for 3 hours. After this period, the solution was concentrated down under vacuum. The crude material was diluted in DCM (50 mL) and washed with 1M NaOH (aq) (50 mL) to afford the crude residue. The crude product was purified by Flash chromatography (0-10% methanol/DCM gradient) to afford 85.1 mg (43%) of pyrrolidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide. [M+H]+ 249.08.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.C(N(CC)CC)C.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[S:47](Cl)(=[O:49])=[O:48]>ClCCl>[C:12]1([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:9]2[CH:10]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:47]([C:38]3[CH:39]=[CH:40][C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:37]=3)(=[O:49])=[O:48])[N:7]=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 84.3 %

Procedure:
To a solution of the product from step c (465 mg, 1.22 mmol) and triethylamine (185 μl, 1.33 mmol) in dry dichloromethane (15 ml) was added 2-naphthalenesulfonyl chloride (227 mg, 1.22 mmol). The solution was stirred for 2 h and the solvent evaporated. Flash column chromatography (silica; 5% methanol/dichloromethane) of the residue afforded the product as a colourless foam (588 mg, 84%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH:25][CH:26](C(OC(C)(C)C)=O)[CH2:27][CH3:28])=[CH:19][CH:18]=1>>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][CH2:26][CH2:27][CH3:28])=[CH:21][CH:22]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCC(NCCc1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Product: CCCNCCc1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Using procedure 4, 4-trifluoromethoxybenzenesulfonyl chloride was added to 2-(4-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine to give the title compound as a solid, m.p. 151-154° C.
Reaction SMILES: CC(C)[C@@H:3]([N:7]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:24])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[C:8]1=[O:36])[C:4]([OH:6])=[O:5].O=C1C2C(=CC=C(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)C=2)CN1CC(OC)=O>>[O:36]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:10]=2)[CH2:15][N:7]1[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: COC(=O)CN1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Product: O=C(O)CN1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 91 %

Procedure:
The compound of example 334 was prepared analogous to compound of example 331 by hydrolysis of the compound of example 333.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Li+].[O:20]1[C:24]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30]([O-])=[O:31])=[CH:23][CH:22]=[N:21]1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:24]3[O:20][N:21]=[CH:22][CH:23]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C([O-])c1ncoc1-c1ccno1
Agent: [Li+]
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccno3)cn2)o1

Procedure:
Following general procedure Z3 followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-isoxazol-5-yl-oxazole-4-carboxylic acid lithium salt. LC-MS-conditions 01: tR=0.81 min; [M+H]+=367.95.
Reaction SMILES: [NH2:1]N.[C:3]1([S:9]([C:12](=[CH:15][N:16](C)C)[C:13]#[N:14])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCO>[C:3]1([S:9]([C:12]2[C:15]([NH2:16])=[N:1][NH:14][CH:13]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NN
Reactant: CN(C)C=C(C#N)S(=O)(=O)c1ccccc1
Solvent: CCO
Product: Nc1n[nH]cc1S(=O)(=O)c1ccccc1
Reaction time: 5 h
Yield: 29.2 %

Procedure:
2.05 ml (40.9 mmol) of NH2NH2 were added to a solution of 9.08 g (38.3 mmol) of 2-benzenesulphonyl-3-dimethylamino-acrylonitrile in 60 ml of EtOH and stirred at 40° for 5 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 10:1) yielded 2.5 g (30%) of 4-benzenesulphonyl-1H-pyrazol-3-ylamine as a beige powder, m.p. 159-161°.