Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]2[O:8][CH2:7]2)=[CH:4][CH:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][CH2:12]1
Reactant: Clc1ccc(C2CO2)cc1
Reactant: NC1CC1
Product: OC(CNC1CC1)c1ccc(Cl)cc1
Yield: 54.5 %

Procedure:
4-Chloro styrene oxide (1.24 g, 8.0 mmol) and 3 ml of cyclopropylamine in methanolic solution were charged into a flask. The flask was sealed and put in a refrigerator for 5–7 days. The solution was concentrated and the residue crystallized from ether, the title compound was obtained as white needle crystals, mp. 100.2–102° C., yield 54.5%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:8])[O:5][C:6]=1[CH3:7].[Se](=O)=[O:10]>O1CCOCC1>[CH3:7][C:6]1[O:5][C:4](=[O:8])[O:3][C:2]=1[CH2:1][OH:10]
Reactant: O=[Se]=O
Reactant: Cc1oc(=O)oc1C
Solvent: C1COCCO1
Product: Cc1oc(=O)oc1CO

Procedure:
A solution of 4,5-dimethyl-2-oxo-1,3-dioxolene (1 mmole) and selenium dioxide (2.5 mmole) in dioxane was heated at reflux for 1 h. Evaporation, extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: Rf=0.5, 5% MeOH-dichloromethane.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:14])[C:11]#[C:12][CH3:13]>O=[Mn]=O>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1[C:10](=[O:14])[C:11]#[C:12][CH3:13]
Reactant: CC#CC(O)C1=C(C)CCCC1(C)C
Agent: O=[Mn]=O
Product: CC#CC(=O)C1=C(C)CCCC1(C)C
Yield: 81 %

Procedure:
A mixture of 1.277 g. (66.3 mMole) of the acetylenic carbonyl compound prepared according to the description of paragraph (b) above, 12 g. of activated MnO2 and 100 ml. of petroleum-ether (30°-40°) were stirred for 15 minutes at room temperature. The solid was removed by filtration and the liquid was dried over molecular sieves then it was concentrated and distilled under reduced pressure. 1.02 g. (81%) of 2,6,6-trimethyl-1-tetrolyl-1-cyclohexene were thus obtained, the analytical measurements thereof gave the following results: nD20 =1.5107; d420 =0.957. IR spectrum (liquid phase): 2210 (νC↓C), 1640 (νC=0)cm-1. NMR spectrum (CCl4): 1.08 (3 H, s), 1.68 (3 H, s), 2.02 (3 H, s) ppm (δ). Mass spectrum: 190 (28), 175(100), 67 (63), 123 (37), 41 (25), 81 (24), 135 (22), 28 (21), 91 (20), 147 (20).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: Cc1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Product: Cc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-methyl-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1.C1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-:22])(=[O:1])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCC1CCc2ccccc2O1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 25 h
Yield: 84.5 %

Procedure:
To a stirred and cooled (0° C.) solution of 32.8 g of 3,4-dihydro-2H-1-benzopyran-2-methanol in 71 ml of pyridine and 135 ml of benzene was added dropwise a solution of 41.9 g of 4-methyl-benzenesulfonyl chloride in 72.5 ml of benzene. Upon completion, stirring was continued for 25 hours. The reaction mixture was washed successively with a hydrochloric acid solution (10%), with water and with a sodium carbonate solution (10%). The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 100%). The eluent of the desired fraction was evaporated, yielding 28.3 g of 3,4-dihydro-2H-1-benzopyran-2-methanol 4-methylbenzenesulfonate (ester) as a solid residue, mp. 59.4° C. (interm. 1). In a similar way there was also prepared: 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol 4-methylbenzenesulfonate (ester) (interm. 2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][CH2:11][CH2:12][CH2:13][OH:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:1][C:2]1[N:7]=[C:6]([O:14][CH2:13][CH2:12][CH2:11][O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: COCCCO
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1ccnc(Cl)n1
Temperature: 80 °C
Yield: 32.9 %

Procedure:
2,4-Dichloropyrimidine (250 mg, 1.678 mmol), 3-methoxy-1-propanol (0.193 ml, 2.014 mmol), and cesium carbonate (929 mg, 2.85 mmol) were combined in DMF (5 ml). The suspension was heated to 80° C. for 15 h. The mixture was allowed to cool to room temperature, diluted with brine and extracted with EtOAc (3×). The organic layer was dried over Na2SO4 and concentrated in vacuo. Purification via flash chromatography (5-15% EtOAc:Hexanes) gave 2-chloro-4-(3-methoxypropoxy)pyrimidine (112 mg, 33%) as a colorless oil. MS ESI: [M+H]+ m/z 203.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][CH:21]=[C:20]2O>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[N:22][CH:21]=[C:20]2[Cl:3]
Reactant: COc1ccc2nncc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COc1ccc2nncc(Cl)c2c1
Yield: 59 %

Procedure:
Phosphorous oxychloride (5 ml) was added to a mix of dimethylaniline (157 mg, 1.3 mmol) and 6-methoxy-4-hydroxycinnoline (208 mg, 1.2 mmol). The reaction was heated at reflux for 15 min, then cooled and concentrated under vacuum. The residue was partitioned between chloroform (100 ml) and water (30 ml), then the organic layer was washed with brine and dried (Na2SO4). Chromatography of the residue adsorbed onto silica gel (3 g) on silica gel (15 g) eluent CH2Cl2 to 10% Ethylacetate/CH2Cl2 gave 6-methoxy-4-chlorocinnoline (135 mg, 0.7 mmol) in 59% yield as white yellow solid. δH (CDCl3)=4.03 (s, 3H); 7.28 (d, 1H); 7.51 (dd, 1H); 8.41 (d, 1H) and 9.22 (br s, 1H). MS (ESI) (M+H)+ 195.
Reaction SMILES: [CH2:1]([O:3][P:4]([NH:9][C@H:10]1[C@H:15]([F:16])[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H][H]>CO.[Pd]>[F:16][C@@H:15]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[NH:9][P:4](=[O:5])([O:6][CH2:7][CH3:8])[O:3][CH2:1][CH3:2]
Reactant: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1F)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOP(=O)(N[C@@H]1CNCC[C@H]1F)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.3 %

Procedure:
A mixture of trans-benzyl 3-(diethoxyphosphorylamino)-4-fluoropiperidine-1-carboxylate (0.54 g, 1.4 mmol) and 10% Pd/C (0.074 g, 0.070 mmol) in methanol (30 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 6 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give diethyl trans-4-fluoropiperidin-3-ylphosphoramidate (0.35 g, 99%) as oil.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([OH:12])[CH2:9][CH2:10][CH3:11]>O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C1(C)C=CC=CC=1>[CH2:6]([O:7][C:1]1([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:1][CH2:2][CH3:3]
Reactant: CCCCO
Reactant: O=C1CCCCC1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOC1(OCCCC)CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 185.8 %

Procedure:
In a 300-ml three-necked flask, 98 g (1 mole) of cyclohexanone, 148 g (2 moles) of n-butanol, 50 g of molecular sieve 4A, 2 mg of cerium chloride hexahydrate and 40 g of toluene were charged. The resulting mixture was stirred at 25° C. under atmospheric pressure for 12 hours in a nitrogen atmosphere. After the removal of the molecular sieve 4A, the solvent (toluene) and unreacted starting materials were distilled off under reduced pressure. Distillation of the residue under reduced pressure gave 212.2 g of cyclohexanone dibutyl acetal (yield: 93.1%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[N:5]=[C:4]([C:13]([F:16])([F:14])[F:15])[CH:3]=1
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1nc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.1 %

Procedure:
A solution of ethyl 5-chloro-3-(trifluoromethyl)-1H-pyrazole-1-acetate (218 mg, 0.85 mmol) in tetrahydrofuran (1 mL) was treated with sodium hydroxide (0.2 mL, 50% aqueous solution) in water (0.6 mL), and stirred at ambient temperature for 4 h. The reaction mixture was then diluted with water (15 mL) and was concentrated under reduced pressure. The reaction mixture was acidified with concentrated hydrochloric acid to pH 1. The resulting mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated to give 140 mg of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]([CH3:19])[O:16][C:15]2[CH:20]=[C:21](Br)[CH:22]=[N:23][C:14]1=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C([O:28][B:29](OC(C)C)[O:30]C(C)C)(C)C>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH:17]([CH3:19])[O:16][C:15]2[CH:20]=[C:21]([B:29]([OH:30])[OH:28])[CH:22]=[N:23][C:14]1=2)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1CN(C(=O)OC(C)(C)C)c2ncc(Br)cc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)c2ncc(B(O)O)cc2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Butyl lithium (2.5 M in THF, 6.08 mL, 2.5 equiv.) was added dropwise into a stirring solution of 7-bromo-2-methyl-2,3-dihydro-pyrido[3,2-b][1,4]oxazine-4-carboxylic acid tert-butyl ester (2.0 g, 6.08 mmol, 1.0 equiv.) and triisopropylborate (2.86 g, 15.19 mmol, 2.5 equiv.) in anhydrous THF (20 mL) at −78° C. under nitrogen. The reaction was stirred at −78° C. and monitored with LCMS. After 2 hr, LCMS indicated the reaction complete. The reaction was quenched with water (20 mL) and concentrated under reduced pressure. The residue was washed with ether (2×10 mL) and the aqueous layer was placed in an ice-water bath. While stirring, 10 N HCl aqueous solution was carefully added dropwise until pH˜7. Filtration and washing with ice-water (3×5 mils) gave the desired product as a white solid (923 mg).
Reaction SMILES: S([O-])(O[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=O)=O.[Na+].[CH3:19][NH:20][CH2:21][C@@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:23].[OH-].[Na+]>O>[CH2:5]([N:20]([CH3:19])[CH2:21][C@@H:22]([C@H:24]([C@@H:26]([C@@H:28]([CH2:30][OH:31])[OH:29])[OH:27])[OH:25])[OH:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCN(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 160 °C

Procedure:
Sodium lauryl sulphate 90% (w/w) (493.4g, 1.67m), N-methyl-D-glucamine (611.1 g, 3.15 m), and sodium hydroxide (60 g, 1.5 m) in 1055.7 g water were charged into a 5 liter autoclave vessel. After pressure testing with nitrogen at 200 psi the autoclave was then heated for 2 hours at 160° C. (maximum steam pressure generated was 88 psi). The reaction mixture was then cooled to give a white spongy material which was washed with water and methanol to remove impurities, and dried in a desiccator to give a white powder. Base value=96% pure.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]([CH3:46])[C:44]#[N:45])[CH:42]=2)O1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:38]3[CH:39]=[N:40][N:41]([CH:43]([CH3:46])[C:44]#[N:45])[CH:42]=3)[C:23]2=[CH:22][N:21]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4cnn(C(C)C#N)c4)n[nH]c3n2)c1F

Procedure:
This compound was prepared as a TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile. LCMS (M+H)+=412.0.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2([C:16]3[S:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=3)[CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH:1]1([CH2:4][O:5][C:6]2([C:16]3[S:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=3)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: c1ccc(-c2csc(C3(OCC4CC4)CCC4(CC3)OCCO4)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(OCC2CC2)(c2nc(-c3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.6 %

Procedure:
8.3 g of 2-(8-cyclopropylmethoxy-1,4-dioxaspiro[4.5]dec-8-yl)-4-phenylthiazole and 5.5 g of p-toluenesulfonic acid were dissolved in 137 ml of acetone and 14 ml of water. The mixture was stirred at room temperature for 4 days, then poured onto 100 ml of a saturated aqueous sodium hydrogencarbonate solution. The acetone was distilled off and the residue extracted three times with 100 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 5.9 g of the title compound were obtained as an amorphous solid.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:10])=O)[N:6]=1.O1CCCC1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1.O>C(OCC)(=O)C>[SH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:10])=[S:25])[N:6]=1
Reactant: NC(=O)Cc1csc(S)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)Cc1csc(S)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 197.8 %

Procedure:
To a mixture of 2-mercaptothiazol-4-yl-acetamide (174 mg) and tetrahydrofuran (10 ml) was added Lawesson's reagent (202 mg) at room temperature. After stirring at room temperature overnight, the solution was poured into a mixture of water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate) to give 2-mercaptothiazol-4-yl-thioacetamide (188 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9]C)[CH:5]=[C:6]([F:8])[CH:7]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1cc(F)cc(Cl)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cc(F)cc(Cl)c1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A solution of 3-chloro-5-fluoroanisole (10 g, 62 mmol) in CH2Cl2 (50 mL) was cooled in a stream of argon to −70° C. under stirring. BBr3 (11.8 mL, 124 mmol) was added dropwise under vigorous stirring at −70° C. in 15 min. The reaction mixture was heated to room temperature and alkalized with the saturated NaHCO3 solution to pH ˜6. The layers were separated, and the water layer was extracted with CH2Cl2 (2×50 mL). The combined organic layer was washed with brine, dried over Na2SO4 and evaporated in vacuo to give the title compound (8 g, 88%, 54.6 mmol) as a yellow oil. 1H NMR data (dmso-d6): 10.36 (s, 1H, OH), 6.73-6.79 (m, 1H, H—Ar), 6.64-6.68 (m, 1H, H—Ar), 6.53-6.59 (m, 1H, H—Ar).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[N:8]1([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: C#CC(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C=CN1CCCC1
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 29.43 g of ethyl propiolate (0.30 mol) in 200 ml of benzene was held at 25° in a water bath with magnetic stirring. A solution of 21.34 g of pyrrolidine in 50 ml of benzene was added dropwise over a period of 45 minutes, during which time the temperature rose to 35°. The clear brown solution was stirred overnight and the solvent removed under reduced pressure at 55°. The residue was distilled under pressure to give 35.05 g of yellow oil, boiling point 110° (0.4 torr), which crystallized upon standing. The yellow solid was recrystallized from petroleum ether to give 31.36 (62%) of yellowish platelets, m.p. 37.5°-39.5°.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7]C)=[O:6])[CH3:3].[OH-].[Na+]>>[OH:1][CH:2]([CH:4]([CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([OH:7])=[O:6])[CH3:3]
Reactant: COC(=O)C(CCCc1ccccc1)C(C)O
Agent: [Na+]
Agent: [OH-]
Product: CC(O)C(CCCc1ccccc1)C(=O)O

Procedure:
Analogously to Example 29A, 4.00 g (16.9 mmol) of methyl 2-(1-hydroxyethyl)-5-phenylpentanoate are reacted with 34.0 ml of a 1 M sodium hydroxide solution to give 2-(1-hydroxyethyl)-5-phenylpentanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:26]([CH:23]1[CH2:25][CH2:24]1)=[O:27]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine (22.3 g, 79.1 mmol) and triethylamine (16.53 mL, 118.6 mmol) in CH2Cl2 (200 mL) was added cyclopropanecarbonyl chloride (8.68 mL, 94.9 mmol) dropwise over 15 minutes, and the reaction was stirred at room temperature for 2 hours. The mixture was partitioned between CH2Cl2 and H2O, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to give cyclopropanecarboxylic acid (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:11](=[O:23])[CH:10]=1.Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]([CH:15]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:11](=[O:23])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Cn1ccc(-c2cc(Cl)ccc2Br)cc1=O
Reactant: BrCc1ccncc1
Agent: Br
Product: CC(C)(C)OC(=O)C(Cc1ccncc1)n1ccc(-c2cc(Cl)ccc2Br)cc1=O

Procedure:
1.3 g (purity 94%, 3.0 mmol) of tert-butyl [4-(2-bromo-5-chlorophenyl)-2-oxopyridin-1(2H)-yl]acetate and 1.2 g (4.5 mmol) of 4-(bromomethyl)pyridine monohydrobromide were reacted according to General Method 7A. Yield: 1.7 g (purity 89%, quant.)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](Cl)=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.Cl>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[CH:8]=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(Cl)c12
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of [4,8-dichloro-3-(4-chlorobenzyl)-2-methylquinolin-5-yloxy]acetic acid methyl ester (0.12 g), palladium, 5 wt. % on activated carbon (0.010 g), ethanol, and 1.0 M aqueous hydrochloric acid (1.0 mL) was stirred at room temperature for 17 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washing with ethanol and water and the solvent removed under reduced pressure to afford title compound, 0.11 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].N1CCCCC1.[OH:20][CH2:21][CH2:22][N:23]([C:25]1[CH:32]=[CH:31][C:28](C=O)=[CH:27][CH:26]=1)[CH3:24]>>[OH:20][CH2:21][CH2:22][N:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN(CCO)c1ccc(C=O)cc1
Solvent: C1CCNCC1
Product: CN(CCO)c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A one liter three-necked flask fitted with a dropping funnel, mechanical stirrer and condenser is charged with 34.35 g of 4-nitrophenylacetic acid, and piperidine (16.2 g) is added dropwise over a period of 30 minutes. At the end of the addition, a 33.62 g quantity of 4-[N-(2-hydroxyethyl)-N-methylamino]benzaldehyde is added.
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:28][C@H:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:30]([CH3:32])[OH:31].Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([NH:28][C@H:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
1.14 g (3 mmol) of Boc-Lys(Z)-OH, 0.51 g (3 mmol) of H-Thr-OMe.HCl, 0.68 g of (3.6 mmol) of EDCI, 0.58 g (3.6 mmol) of HOBT and 0.66 ml (6 mmol) of NMM are dissolved at -10° C. in 10 ml THF and stirred at room temperature for 15 hours. The THF is distilled off under vacuum, the residue dissolved in 50 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5 N HCl, 10% NaHCO3 solution and water respectively. The organic phase is dried with MgSO4 and the solvent distilled off under vacuum. 1.36 g (92%) of thin-layer chromatographically identical Boc-Lys(Z)-Thr-OMe are obtained as a colourless foam.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][NH:14][C@@H:13]([CH2:16][O:17][C:18]2[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:37]([C@H:34]2[CH2:33][CH2:32][C@H:31]([C:30]([F:29])([F:40])[F:41])[CH2:36][CH2:35]2)=[O:38])[C@@H:13]([CH2:16][O:17][C:18]2[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using ethyl 3-(((2R,4R)-4-(benzyloxymethoxy)pyrrolidin-2-yl)methoxy)picolinate (EXAMPLE 79 Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.