Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH:12]=1>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][CH:16]2[N:18]([CH3:19])[CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: CN1C2C=C(c3ccc4ccccc4c3)CC1CC2
Solvent: CCO
Product: CN1C2CCC1CC(c1ccc3ccccc3c1)C2
Yield: 1.5 %

Procedure:
A solution of 1.3 gm (5.22 mMol) 3-(naphth-2-yl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene in 25 mL ethanol containing 1.3 gm 10% palladium on carbon was stirred at room temperature under a hydrogen atmosphere maintained by a balloon for 8 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with a gradient of dichloromethane containing 2-10% methanol and 30% of dichloromethane saturated with ammonia. Frac-tions containing product were combined and concentrated under reduced pressure to provide 0.020 gm (1.7%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:13]Br>C(Cl)(Cl)Cl>[Br:13][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[C:1]([CH:11]=[O:12])=[CH:2][CH:3]=[CH:4]2
Reactant: O=Cc1cccc2ccccc12
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=Cc1cccc2cc(Br)ccc12
Yield: 36.7 %

Procedure:
To a flask fitted with a condenser containing 1-naphthaldehyde (10 g, 64.02 mmol) was added a solution of bromine (3.3 mL, 63.83 mmol) in anhydrous chloroform (15 mL). The reaction mixture was heated under reflux for 3.5, allowed to RT and filtered. The filtrate was washed with water, brine and dried (MgSO4). After evaporation the crude product was purified on silica gel (eluant: hexanes:EtOAc, 98:2) to afford 6-bromo-1-naphthaldehyde 5.5 g (27%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH3:28])[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:4][C:3]=1[CH2:29][CH2:30][C:31]([OH:33])=[O:32]>[Pd].O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:13]2[O:17][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:15][C:14]=2[CH3:28])[CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[CH2:29][CH2:30][C:31]([OH:33])=[O:32]
Reactant: C=CCC(Oc1ccc(CCC(=O)O)c(C)c1)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(CCC(=O)O)c(C)c1)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-but-3-enyloxy}-phenyl)-propionic acid (30 mg, 0.065 mmol), 10% Palladium on charcoal (30 mg) and tetrahydrofuran (30 mL) is stirred under a hydrogen balloon 30 min. The solution is filtered over celite and concentrated in vacuo to afford the title compound, 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-butoxy}-phenyl)-propionic acid as a white solid, 30 mg 100%. MS (M++1) 462.
Reaction SMILES: C1O[C:4]2([CH2:18][CH2:17][C:7]3([CH2:15][C:14]4[C:9](=[CH:10][C:11](C)=[CH:12][CH:13]=4)[CH2:8]3)[CH2:6][CH2:5]2)[O:3]C1.Cl>CC(C)=O>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][C:7]21[CH2:17][CH2:18][C:4](=[O:3])[CH2:5][CH2:6]2
Reactant: Cc1ccc2c(c1)CC1(CCC3(CC1)OCCO3)C2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC2(CC1)Cc1ccccc1C2

Procedure:
A mixture of 4g. (0.016 M) of spiro(cyclohexane-1,2'-indan)-4-one ethylene ketal [10] (prepared in Example 20B) and 8 ml. of 2.5 N hydrochoric acid in 80 ml. of acetone is heated at reflux for about 4 hours. Most of the solvent is removed under vacuum and ether added. The organic layer is separated, washed with water and brine and evaporated to dryness. The residue is chromatographed on a 350 ml. column of silica gel with elution by methylene chloride. Those fractions similar by thin layer chromatography are combined to give spiro(cyclohexane-1,2'-indan)-4-one [11] as an amorphous gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[N:14]=[N:13]1)[C:9](O)=[O:10].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH3:52]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:12]1[CH:16]=[C:15]([CH2:17][N:18]2[C:22](=[O:23])[N:21]([CH2:24][C@H:25]([OH:30])[C:26]([F:29])([F:28])[F:27])[C:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)=[N:19]2)[N:14]=[N:13]1)[C:9]([NH2:52])=[O:10]
Reactant: N
Reactant: O=C(O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)C(c1ccccc1Cl)n1cc(Cn2nc(-c3ccc(Cl)cc3)n(C[C@H](O)C(F)(F)F)c2=O)nn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
25 mg (0.045 mmol) of the compound from Example 104 were initially charged in 1 ml of DMF, and 9 mg (0.058 mmol) of HOBt and 11 mg (0.058 mmol) of EDC were added. After 10 min of stirring at RT, 0.5 ml (0.90 mmol) of ammonia solution (35% strength in water) was added, and the reaction was stirred at RT for 16 h. The reaction mixture was then purified directly, without any further work-up, by chromatography [Method 19]. This gave 10 mg (40% of theory) of the target compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[S:17]1[C:21]2[C:22]([CH:26]=O)=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1.O>O1CCCC1>[S:17]1[C:21]2[C:22](/[CH:26]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[N:18]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cccc2nnsc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cccc2nnsc12
Reaction time: 0.33 h
Yield: 98.2 %

Procedure:
To a suspension of 55% sodium hydride (1.81 g, 41.5 mmol) in tetrahydrofuran (30 mL) was added a solution of ethyl diethylphosphonoacetate (8.31 mL, 41.5 mmol) in tetrahydrofuran (10 mL) at 0° C. and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 1,2,3-benzothiadiazole-7-carbaldehyde (6.20 g, 37.8 mmol) in tetrahydrofuran (60 mL) at 0° C. and the mixture was stirred at room temperature for 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) and recrystallization (ethyl acetate/hexane) to give the title compound (8.70 g, yield 98%).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5]2([CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)[C:4](=[O:16])[O:3]1>Cl>[O:14]=[S:11]1(=[O:15])[CH2:12][CH2:13][C:5]([C:4]([OH:16])=[O:3])([C:6]([OH:8])=[O:7])[CH2:9][CH2:10]1
Reactant: CC1(C)OC(=O)C2(CCS(=O)(=O)CC2)C(=O)O1
Agent: Cl
Product: O=C(O)C1(C(=O)O)CCS(=O)(=O)CC1
Reaction time: 0.38 h

Procedure:
3,3-Dimethyl-9,9-dioxo-2,4-dioxa-9λ6-thia-spiro[5.5]undecane-1,5-dione (200 mg; 0.763 mmol) is dispersed in 2M HCl aqueous solution (2 mL) and the vial is placed into microwave oven for 23 minutes at 100° C. After cooling, the reaction mixture is extracted with diethyl ether once. The aqueous layer is saturated with solid sodium chloride and extracted with 50% THF in ethyl acetate three times. The organics are combined and dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:29])[C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([O:24][CH:25]([F:27])[F:26])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].Cl>O1CCCC1>[CH:1]1([N:4]2[C:14]3[C:13](=[C:18]([N+:19]([O-:21])=[O:20])[C:17]([F:22])=[C:16]([F:23])[C:15]=3[O:24][CH:25]([F:26])[F:27])[C:12](=[O:29])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(OC(F)F)c(F)c(F)c1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
1.0 g (0.0024 moles) of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5-trifluoro-6-nitrobenzoyl)acrylate [(XIX), R1 =--OCHF2, R3' =NO2, R17 =C2H5, X=X'=F] [prepared as described in step (d) above] was dissolved in 10 ml of tetrahydrofuran, and 0.094 g (0.0024 moles) of a 60% w/w suspension of sodium hydride in mineral oil was added to the resulting mixture. The mixture was then stirred at room temperature for 1 hour, after which 1N aqueous hydrochloric acid was added, and the mixture was vigorously stirred to acidify the whole mixture. The crystals which precipitated were collected by filtration and washed with water and with diethyl ether, in that order, to give 0.6 g of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-5-nitro-1,4-dihydro-4-oxo-quinoline-3-carboxylate as a pale yellow powder, melting at 262°-268° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[OH-].[Na+].O.CC#N>C(O)C.O1CCCC1>[CH:1]1([N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:5][CH3:6])[CH2:2][CH2:3]1
Reactant: CCN(Cc1ccc(C#Cc2ccc(CC(=O)OC)cc2)cc1C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(Cc1ccc(C#Cc2ccc(CC(=O)O)cc2)cc1C)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure I; a solution of methyl (4-{4-[(cyclopropyl-ethyl-amino)-methyl]-3-methyl-phenylethynyl}-phenyl)-acetate (Compound 129, 140.0 mg, 0.39 mmol) in ethanol (5 mL) and tetrahydrofuran (5 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up followed by HPLC (Partisil-10 pac 10% H2O-CH3CN) afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].S(=O)(=O)(O)O.[CH:22]1([CH2:28][CH2:29]O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.S1(CCCC1)(=O)=O>CO>[Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([C:6]([O:8][CH2:29][CH2:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:7])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: OCCC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 105 °C
Reaction time: 0.5 h

Procedure:
After charging 50 parts of 4-chloro-3,5-dinitrobenzoic acid, 0.3 part of 98% sulfuric acid, 78 parts of cyclohexaneethanol and 50 parts of sulfolane into a flask, the mixture was heated to 100 to 110° C., and was maintained at the same temperature for 8 to 10 hours. After checking the disapearance of 4-chloro-3,5-dinitrobenzoic acid by HPLC, the reaction mass was cooled to room temperature under atmospheric pressure, and to the mass was 240 parts of methanol, and was stirred for 30 minutes. The resulting mixture was filtrated to obtain crystals, and the crystals were washed with 40 parts of methanol and then dried to obtain 58 parts of 2-cyclohexylethyl 4-chloro-3,5-dinitrobenzoate.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[S:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[CH2:12][C:13]([OH:15])=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[CH2:6]([O:8][C:9]([C:11]1[CH:12]=[C:13]([O:15][C:1](=[O:3])[CH3:2])[C:21]2[CH:20]=[C:19]([CH3:22])[S:18][C:17]=2[CH:16]=1)=[O:10])[CH3:7]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(=Cc1ccc(C)s1)CC(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(OC(C)=O)c2cc(C)sc2c1
Yield: 60.4 %

Procedure:
Sodium acetate (10 g, 120 mmol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-2-thienyl)but-3-enoic acid (12.3 g, 48 mmol) in 100 mL of acetic anhydride. The reaction mixture was refluxed for 3 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 250 mL of dichloromethane. The suspension was filtered. The precipitate was washed by 100 mL of dichloromethane. The combined solutions were washed by 200 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (150×100 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 8.2 g (29 mmol, 61%) of 4-(acetyloxy)-2-methyl-1-benzothiophene-6-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH2:6][N:5]([CH:13]([CH3:15])[CH3:14])[C:4]=2[N:3]=1.I[CH3:17].[H-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:17])[C:7](=[O:12])[CH2:6][N:5]([CH:13]([CH3:15])[CH3:14])[C:4]=2[N:3]=1
Reactant: CC(C)N1CC(=O)Nc2cnc(Cl)nc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)N1CC(=O)N(C)c2cnc(Cl)nc21
Reaction time: 1 h
Yield: 70 %

Procedure:
2-Chloro-8-isopropyl-7,8-dihydro-5H-pteridin-6-one (28 g; 0.118 mol) in Dimethylacetamide (100 ml) was cooled to −5° C. and iodomethane (8.839 ml; 0.141 mmol)) was quickly added. Then, NaH (7.1 g; 0.177 mmol) was added in portions. After 1 h the reaction mixture was allowed to reach room temperature and was maintained at that temperature until complete conversion of the starting material into the desired product. The reaction mixture was diluted with water and ice and the precipitate formed was filtered and dried in vacuo. 20 g (0.083 mol; 70% yield) of a white powder were obtained.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.Cl[C:7]1[CH:8]=[CH:9][C:10]2[N:11]([C:13]([CH2:20][N:21]3[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]3=[O:29])=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:12]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.C(CC(=O)C)(=O)C.[Fe+3]>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:20][N:21]4[CH2:25][CH:24]([CH2:26][CH2:27][CH3:28])[CH2:23][C:22]4=[O:29])=[C:14]([C:16]([F:17])([F:19])[F:18])[N:15]=3)[N:12]=2)[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(Cl)nn23)C1
Agent: [Fe+3]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(C4CC4)nn23)C1
Reaction time: 16 h
Yield: 25 %

Procedure:
Freshly prepared cyclopropyl magnesium bromide (as described in J. Am. Chem. Soc. (2002), 124, 13856-63; with cyclopropylbromide (48 mg, 0.4 mmol, 1.2 eq) and magnesium powder (10 mg) in 5 ml of THF) is added slowly and dropwise to a mixture of 1-{[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 30 (120 mg, 0.33 mmol) and iron (III) acetylacetone (3 mg, 0.0165 mmol, 0.05 eq) in THF (5 ml) at room temperature. The reaction is kept at room temperature for 16 h, then hydrolyzed (10 ml of 1 N HCl), neutralized with a saturated solution of NaHCO3 until alkaline pH. The crude product is extracted with ethyl acetate (3×20 ml). The cumulated organic layers are dried over MgSO4, filtered and condensed under reduced pressure. The residue is purified by preparative chromatography (CH2Cl2/MeOH/NH4OH: 98/210.2 (v/v/v)) to afford 1-{[6-cyclopropyl-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 40.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][F:37])=[CH:30][N:29]=1)[C:20]([O:22]C(C)(C)C)=[O:21])[C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:8][C@@H:9]([CH2:17][CH2:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][F:37])=[CH:30][N:29]=1)[C:20]([OH:22])=[O:21])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(OCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N[C@@H](CCC(Cc1ccc(OCCF)cn1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
To a solution of 56 mg of di-tert-butyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-{[5-(2-fluoroethoxy)pyridin-2-yl]methyl}hexanedioate (0.1 mmol) in anisol (0.7 mL) was added trifluoroacetic acid (1.5 mL), and the resulting mixture was stirred for 3 h at room temperature. Trifluoroacetic acid was removed under reduced pressure, water (approx. 2 mL) was added and separating anisol (which was expected to encumber preparative HPLC if present in large excess) was removed. The remaining aqueous solution of the crude product was directly loaded onto a preparative HPLC, method B, to give 14 mg of the target compound as white, hygroscopic lyophilisate (approx. 40% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:34][CH2:33][C:20]4([N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:23][N:22]([CH3:31])[C:21]4=[O:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:68][N:69]([CH3:73])[CH2:70][CH2:71][NH2:72]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:34][CH2:33][C:20]4([N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:23][N:22]([CH3:31])[C:21]4=[O:32])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([NH:72][CH2:71][CH2:70][N:69]([CH3:73])[CH3:68])=[O:14])=[CH:4][CH:3]=1
Reactant: CN1CN(c2ccccc2)C2(CCN(C(=O)c3cn(CC(=O)O)c4cc(Cl)ccc34)CC2)C1=O
Reactant: CN(C)CCN
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: CN(C)CCNC(=O)Cn1cc(C(=O)N2CCC3(CC2)C(=O)N(C)CN3c2ccccc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of [6-chloro-3-(3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro[4.5]decane-8-carbonyl)-indol-1-yl]-acetic acid in DMF was treated sequentially with 1 eq. of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 1 eq. of N,N-diisopropylethylamine and 1 eq. of N,N-dimethylethylenediamine. The mixture was shaken at room temperature for 12 h, concentrated and purified by prep. HPLC to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O-]CC.[Na+].[C:25]([CH2:27][C:28](OCC)=[O:29])#[N:26]>C(O)C>[NH2:26][C:25]1[N:10]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[S:12][C:11]2=[N:20][C:28](=[O:29])[CH:27]=1
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2c(-c3ccncc3)sc3nc(=O)cc(N)n23)cc1
Yield: 42.1 %

Procedure:
To a suspension of [4-(4-methoxyphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (1.0 g) in ethanol were added in turn a 20% solution of sodium ethoxide in ethanol (1.4 mL) and ethyl cyanoacetate (0.40 g). The resultant mixture was heated under reflux for 8 hours. After distilling off the solvent, water was added to the residue, the mixture was neutralized with acetic acid and the precipitate formed was filtered off. The remaining crude crystals were recrystallized from ethanol to obtain the title compound (0.52 g, yield 42%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:40])[C:17]2[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:27][CH:26]=3)[CH:18]=2)[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].F[C:43]1[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=1>>[C:1]([O:5][C:6](=[O:41])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:40])[C:17]2[CH:22]=[C:21]([O:23][C:43]3[CH:50]=[CH:49][C:46]([C:47]#[N:48])=[CH:45][CH:44]=3)[CH:20]=[C:19]([O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:27][CH:26]=3)[CH:18]=2)[CH2:14][CH2:15]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(O)cc(Oc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)CC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(CNC(=O)OC(C)(C)C)cc3)c2)CC1
Yield: 43.3 %

Procedure:
Using 1.2 g (2.1 mmol) of [2-(1-{3-[4-(tert-Butoxycarbonylamino-methyl)-phenoxy]-5-hydroxy-benzoyl}-piperidin-4-yl)-ethyl]carbamic acid tert-butyl ester and 4-fluorobenzonitrile (0.5 g, 4.2 mmol) and following the procedure of Example 42(b) afforded 0.610 g of the required product. Percentage purity (LCMS): 89.1%, (M+1)=670.3+1.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]([CH2:17][C:18]([O:20]CC)=[O:19])[N:9]=1)([CH3:7])([CH3:6])[CH3:5]>O.O1CCCC1>[C:4]([C:8]1[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:10]([CH2:17][C:18]([OH:20])=[O:19])[N:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(F)(F)F)n(CC(=O)O)n1
Reaction time: 2 h

Procedure:
At room temperature, a solution of lithium hydroxide monohydrate (2.35 g) in water (20 ml) is added dropwise to a solution of ethyl [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate (XVI-1, 7.80 g) in tetrahydrofuran (80 ml). The reaction mixture is stirred for 2 hours. After removal of the solvent under reduced pressure, the residue is, at 0° C., slowly adjusted to pH 2-3 using dilute hydrochloric acid (1M). This gives, after filtration and drying, [3-tert-butyl-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid as a white solid (7.1 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:21][N:20](S(CC5CCCC5)(=O)=O)[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.N1CC(NC2C(F)=CN=C(C3C4C(=NC=C(Cl)C=4)N(S(C4C=CC(C)=CC=4)(=O)=O)C=3)N=2)C1.[N:65]([Si](C)(C)C)=[C:66]=[O:67]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:19][N:20]([C:66]([NH2:65])=[O:67])[CH2:21]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: O=S(=O)(CC1CCCC1)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CNC4)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Product: NC(=O)N1CC(Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 79 %

Procedure:
According to the procedure for compound 469 using 61 mg (0.11 mmol) of 6c and isocyanatotrimethylsilane (15.14 μL, 0.11 mmol) afforded 87 mg (79% yield) of 512, as a white solid:
Reaction SMILES: [OH-].[K+].CC1C=CC(S([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[C:16]([O:21][CH2:22][CH:23]=[CH2:24])[CH:15]=2)(=O)=O)=CC=1>CCO.O>[CH2:22]([O:21][C:16]1[CH:15]=[C:14]([OH:13])[CH:19]=[CH:18][C:17]=1[Br:20])[CH:23]=[CH2:24]
Reactant: C=CCOc1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCOc1cc(O)ccc1Br
Temperature: 90 °C
Yield: 84.1 %

Procedure:
Potassium Hydroxide (11.2 g, 200 mmoles) was added to a solution of the product from Example 63A (3.5 g, 9.14 mmoles) in EtOH (180 mL) and H2O (180 mL). The reaction was heated to 90° C. for 2 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by flash chromatography on a prepacked Biotage colum (hexane to 4:1 hexane:ethyl acetate) on silica gel to provide the title compound (1.76 g, 84%).