Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][C:14]=1[C:25]1[C:26]([S:31]([N:34]([C:41]2[O:45][N:44]=[C:43]([CH3:46])[C:42]=2[CH3:47])COCCOC)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.CC1C(C)=C(NS(C2C(C3C=CC(C4N=CC=CN=4)=CC=3C=O)=CC=CC=2)(=O)=O)ON=1>CN(C)C=O.O>[CH3:46][C:43]1[C:42]([CH3:47])=[C:41]([NH:34][S:31]([C:26]2[C:25]([C:14]3[CH:15]=[CH:16][C:17]([C:19]4[N:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:18][C:13]=3[CH2:12][N:4]3[CH2:5][CH2:6][C:2]([CH3:8])([CH3:1])[C:3]3=[O:7])=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:33])=[O:32])[O:45][N:44]=1
Reactant: COCCOCN(c1onc(C)c1C)S(=O)(=O)c1ccccc1-c1ccc(-c2ncccn2)cc1CBr
Reactant: CC1(C)CCNC1=O
Agent: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2C=O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncccn3)cc2CN2CCC(C)(C)C2=O)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a solution of the 3,3-dimethyl-2-pyrrolidinone so prepared (0.033 g, 0.29 mmol) in 1 mL of dimethylformamide ("DMF"), NaH (60% suspension in mineral oil, 0.015 g, 0.36 mmol) was added and the mixture was stirred at room temperature under argon for 10 minutes. 2'-(Bromomethyl)-N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide (prepared as described in Step A of Example 14, except that the title compound of Step F of Example 11 was employed in place of N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-pyrimidinyl)[1,1'-biphenyl]-2-sulfonamide; 0.085 g, 0.145 mmol) was then added and the mixture was stirred for 3 hrs. The mixture was then added to 50 mL water and the solution was extracted with 3×25 mL EtOAc. The combined organic extracts were washed with water and dried and evaporated to afford 0.086 g (95%) of the title compound of this step as a colorless gum.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26][CH:27]=[CH2:28])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:31][C:32]1[CH:33]=[C:34](Br)[CH:35]=[CH:36][C:37]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N1CCOCC1)C>C(#N)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26]/[CH:27]=[CH:28]/[C:34]1[CH:35]=[CH:36][C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:31])[CH:33]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)C
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Agent: CCN1CCOCC1
Solvent: CC#N
Product: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 75.5 %

Procedure:
By the method of Preparation 3 a), tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)hex-5-enoate (2.085 g, 5.0 mmol) was reacted with 3-methyl-4-phenylbromobenzene (1.855 g, 7.5 mmol) under palladium catalysis, using N-ethylmorpholine as base at reflux in acetonitrile for 16.5 h. Work-up as before followed by purification by repeated flash chromatography (first column hexane:ether=4:1; second column toluene:ether=20:1) gave mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a pale yellow gum (2.205 gm, 75%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below). δH (400 MHz, CDCl3) 0.95 (9H, s), 1.42 (9H, s), 2.26 (3H, s), 2.35 (1H, m), 2.45 (1H, dd, 3 and 17 Hz), 2.54 (1H, dt, J=15 and 6.5),2.69 (1H, dd, J=9 and 17 Hz), 2.77 (1H, m), 4.52 (1H, d, J=10 Hz), 4.97 (1H, d, J=12 Hz), 5.06 (1H, d, J=12 Hz), 6.16 (1H, dt, J=18 and 7 Hz), 6.42 (2H, m), 7.29 (13H, complex).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:25])[CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](O)=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(Cl)[Cl:27]>O1CCCC1.S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH3:25])[CH2:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20]([Cl:27])=[O:21])=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: ClCCl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(Cc1ccc(OCC(=O)Cl)cc1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
1.15 g 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetic acid are dissolved in a mixture of 7 ml of methylene chloride and 7 ml of tetrahydrofuran, and 2.2 ml of thionyl chloride are added thereto. After the mixture is refluxed for 2 hours, the solvent is distilled off to give 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetyl chloride as ocherous oil. The product obtained above is dissolved in 10 ml of tetrahydrofuran. The solution and 6 ml of 0.6N an aqueous sodium hydroxide solution are added dropwise to a mixture of 787 mg of 6-aminohexanoic acid, 11 ml of 0.6N an aqueous sodium hydroxide solution, 20 ml of ethanol and 10 ml of ether under stirring at the same time. After the mixture is stirred at room temperature overnight, 50 ml of water and 50 ml of ether are added thereto. The aqueous layer is made acidic with 10% hydrochloric acid, extracted with ethyl acetate, washed, dried, filtered, and evaporated to remove the solvent. Thus obtained pale yellow caramel is purified by silica gel column chromatography (solvent; chloroform, then chloroform: methanol=9:1) to give 1.50 g of 6-{ 4-[2-(4-chlorophenyl)sulfonylaminopropyl]phenoxyacetylamino}-n-hexanoic acid as colorless oil.
Reaction SMILES: Cl.Cl.[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH2:11])[CH2:7]1)([CH3:5])[CH3:4].[CH3:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:3]([C@:6]1([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:10][CH2:9][C@@H:8]([NH:11][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[CH3:30])[CH2:7]1)([CH3:5])[CH3:4]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Reactant: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine dihydrochloride (135.0 mg, 0.29 mmol), 3-methyltetrahydro-4H-pyran-4-one (100 mg, 0.88 mmol) and triethylamine (0.1.6 mL, 1.2 mmol) in methylene chloride (10 mL) was added sodium triacetoxyborohydride (190 mg, 0.88 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4), concentrated. The residue was purified by flash chromatography on silica gel (EtOAc to EtOAc/Et3N=10:0.1) to give desired product as a mixture of two isomers. The two isomers were separated by chiral HPLC to give isomer 1 and isomer 2. MS calculated for C24H36F3N5O2: (M+H) 484; found 484.1.
Reaction SMILES: [CH3:1][C:2]1[N:3](CC(OC(C)(C)C)=O)[C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[C:8](C1SC=CC=1)[CH:7]=[CH:6][CH:5]=2.Cl.[Br:36]C1C=CC(NN)=CC=1>>[Br:36][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[S:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1c(Sc2ccc(S(C)(=O)=O)cc2)c2c(-c3cccs3)cccc2n1CC(=O)OC(C)(C)C
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Product: Cc1[nH]c2ccc(Br)cc2c1Sc1ccc(S(C)(=O)=O)cc1

Procedure:
The sub-title compound was prepared by the method of Example 3 part (i) using the product from Example 26 part (i) (2.5 g) and 4-bromophenyl hydrazine hydrochloride (2.3 g). The reaction mixture was evaporated to half volume and the resulting precipitate filtered off, washed with ether and dried to yield the sub-title compound (2.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:15])([CH3:14])[CH:9]3[O:13][CH:10]32)=[CH:5][CH:4]=1)#[N:2].C(OCC)(=O)C.[OH-].[NH4+:23]>C(O)C>[NH2:23][C@@H:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:12]=2)[CH2:7][C:8]([CH3:15])([CH3:14])[C@H:9]1[OH:13]
Reactant: CC1(C)Cc2ccc(C#N)cc2C2OC21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)Cc2ccc(C#N)cc2[C@@H](N)[C@@H]1O

Procedure:
A solution of 7-cyano-1,2-epoxy-3,3-dimethyl-1,2,3,4-tetrahydronaphthalene (3.5 g) in ethanol (50 ml) and ammonium hydroxide solution (100 ml) was stirred at room temperature for 10 days. Ethyl acetate (50 ml) was added and the mixture extracted with dilute hydrochloric acid. The acidic extracts were made basic with sodium hydroxide solution, and extracted with ethyl acetate. The organic extracts were washed with water, then brine, and dried over sodium sulphate.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([Cl:21])[C:3]=1[OH:22].[N+]([O-])(O)=[O:24].O>C(O)(=O)C>[Cl:21][C:4]1[C:3](=[O:22])[C:2](=[O:24])[C:7]2[C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:9][O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(=O)c2coc3cc(Cl)c(O)c(Cl)c23)cc1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C(Cl)=C3)cc1
Temperature: 60 °C

Procedure:
To a suspension of compound 10d (100 mg, 0.29 mmol) in glacial acetic acid (1.5 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 30 min, allowed to cool to room temperature, and poured into cold water. The resulting precipitate was filtered and recrystallized (CH2Cl2-pet. ether) to furnish compound SKC-BF-04 (50 mg, 53%) as a red solid. TLC Rf=0.4 (petroleum ether-EtOAc, 7:3); 1H NMR (CDCl3) δ 7.86-7.80 (m, 3H), 7.54 (s, 1H), 6.95 (d, J=9.0 Hz, 2H), 3.88 (s, 3H); MS (ES) m/z 317 (M+H)+.
Reaction SMILES: COC(=O)C([N:6]1[C@H:9]([S:10][C:11](=[O:13])[CH3:12])[C@@H:8]([O:14][CH3:15])[C:7]1=[O:16])=O>CO.C(Cl)Cl>[C:11]([S:10][C@H:9]1[NH:6][C:7](=[O:16])[C@@H:8]1[O:14][CH3:15])(=[O:13])[CH3:12]
Reactant: COC(=O)C(=O)N1C(=O)[C@H](OC)[C@H]1SC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1C(=O)N[C@@H]1SC(C)=O

Procedure:
A solution of 71.20 mg of 2[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl-2-oxoacetic acid methyl ester (crude product) in 10 ml of 1% aqueous methanol is stirred overnight at room temperature. The reaction mixture is diluted with methylene chloride, washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields the title compound.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:40][CH:26]1[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]1)[CH2:40][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)C1CCC(OCC2CO2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COC2CCC(C(=O)O)CC2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(ethoxycarbonyl)-cyclohexyloxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Br:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].I[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[Li]CCCC.CCCCCC>C1COCC1>[Br:10][C:7]1[N:8]=[CH:9][C:4]([C:1]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)([OH:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: Ic1cccnc1
Reactant: CC(=O)c1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1ccc(Br)nc1
Temperature: 25 °C

Procedure:
A solution of 5-acetyl-2-bromopyridine (Aldrich) (1.2 g, 5.82 mmol) and 3-iodopyridine (EGA-Chemie) (1.193 g, 5.82 mmol) in THF (10 ml) was immersed in a dry ice-acetone bath. n-BuLi (1.6M) in hexane (4.00 ml, 6.40 mmol) was added slowly by a syringe at −70° C. (exothermic reaction!). The reaction was allowed to warm up slowly to room temperature and was stirred over night. The reaction mixture was cooled to −20° C. and quenched with H2O before dilution with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo and dried to obtain title compound as off-white solid.
Reaction SMILES: CO.[C:3]1([C:9]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH2:23](O)/[CH:24]=[CH:25]\[CH2:26][OH:27]>>[C:11]([C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:27][CH2:26][CH:25]=[CH:24][CH2:23][O:10]1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC/C=C\CO
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)C1(c2ccccc2)OCC=CCO1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
60.8 g (1.9 mols) of methanol were added with stirring to a suspension of 105 g (0.5 mol) of benzil in 107.1 g (0.9 mol) of thionyl chloride, with cooling to a temperature below 10° C. The mixture was initially stirred until room temperature was reached, and then it was stirred for 2 hours at 50° C. 52.8 g (0.6 mol) of cis-2-butene-1,4-diol were added to the clear, pale yellow solution, and volatile products were distilled off at 10 torr and 50° C. The mixture was then stirred for 3 hours at from 60° to 65° C. under normal pressure, 15 g of potassium carbonate and 200 ml of isopropanol were added, and the reaction product was precipitated by the dropwise addition of 100 ml of water. 110.4 g of 2-benzoyl-2-phenyl-4,7-dihydro-1,3-dioxepin were obtained, having a melting point of from 115° to 119° C. After recrystallizing from isopropanol, the melting point was from 118° to 119° C.
Reaction SMILES: OCCO[C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1.OC1C=CC(C2C=CN=C(NC3C=[C:48]([O:50]C)[C:47]([O:52]C)=C(OC)C=3)N=2)=CC=1.C1(=O)OCCO1.[H-].[Na+]>>[OH:50][CH2:48][CH2:47][O:52][C:10]1[CH:5]=[CH:6][C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)[N:12]=2)=[CH:8][CH:9]=1
Reactant: COc1cc(Nc2nccc(-c3ccc(O)cc3)n2)cc(OC)c1OC
Reactant: COc1cc(Nc2nccc(-c3cccc(OCCO)c3)n2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: O=C1OCCO1
Product: COc1cc(Nc2nccc(-c3ccc(OCCO)cc3)n2)cc(OC)c1OC

Procedure:
The compound was prepared in a manner analogous to the preparation of the compound of Example 47 from the compound of Example 49 (250 mg, 0.71 mmol), ethylene carbonate (70 mg, 6.78 mmol) and 60% sodium hydride (dispersion in oil) (30 mg, 0.78 mmol) to give the title compound (140 mg) as a yellow solid m.p 145-146°. MS m/z 398 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=[CH:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[CH:27][NH:28]2.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:1]([O:8][CH2:9][C@@H:10]([C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[CH:32][C:24]=2[CH3:23])[NH:28][CH:27]=1)[CH2:11][CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC=CCOCc1ccccc1
Reactant: Cc1cccc2[nH]ccc12
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C(O)c1ccccc1
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1cccc2[nH]cc([C@@H](CC=O)COCc3ccccc3)c12
Yield: 97.6 %

Procedure:
Prepared according to the general procedure from benzoic acid 4-benzyloxy-but-enal (143 mg, 0.750 mmol), 4-methyl-1H-indole (80.5 mg, 0.500 mmol), 2,4-dinitrobenzoic acid (21.2 mg, 0.100 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −60° C. for 2.5 h to provide, after silica gel chromatography (15:85 EtOAc/hexanes), the title compound as a colorless oil (150 mg, 94% yield, 94% ee) after silica gel chromatography in 15% EtOAc/hexanes. IR (film) 3406, 2947, 2923, 2843, 2738, 1717, 1620, 1604, 1584, 1451, 1411, 1383, 1344, 1315, 1271, 1178, 1114, 1066, 1226, 969 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.82 (dd, J=2.1, 2.1 Hz, 1H, CHO), 8.14 (s, 1H, NH), 8.02 (dt, J=1.5, 7.2 Hz, 2H, ArH), 7.58 (tt, J=1.5, 6.6 Hz, 1H, ArH), 7.45 (tt, J=1.2, 6.9 Hz, 2H, ArH), 7.24-7.08 (m, 3H, ArH, NCH), 6.91 (dt, J=0.9, 7.2 Hz, 1H, ArH), 4.74 (dd, J=4.2, 10.5 Hz, 1H, CH2O), 4.52-4.43 (m, 1H, ArCH), 4.32 (dd, J=8.4, 10.8 Hz, 1H, CH2O), 3.05 (ddd, J=2.1, 6.9, 16.8 Hz, 1H, CH2CO); 2.95 (ddd, J=2.1, 7.8, 16.8 Hz, 1H, CH2CO), 2.82 (s, 3H, ArCH3); 13C NMR (75 MHz, CDCl3) δ 201.3, 166.3,136.5, 133.2, 130.5, 130.0, 129.7, 128.5, 125.1, 122.6, 122.1, 121.7, 115.8, 109.4, 68.9, 47.8, 31.7, 21.0; HRMS (CI) exact mass calcd for (C20H19NO3) requires m/z 321.1365, found m/z 321.1353. [α]D=−26.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (10:90 ethanol/hexanes, 1 mL/min); S isomer tr=47.8 min and R isomer tr=42.4 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([OH:15])=O)=[CH:8]2.P(C#N)(OCC)(OCC)=O.[CH2:26]([N:28](CC)[CH2:29]C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][C:9]([C:13]([N:28]([CH3:29])[CH3:26])=[O:15])=[CH:8]2
Reactant: CCN(CC)CC
Reactant: COc1cccc2c1OCC(C(=O)O)=C2
Agent: CCOP(=O)(C#N)OCC
Product: COc1cccc2c1OCC(C(=O)N(C)C)=C2

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 4 using 8-methoxy-2H-chromene-3-carboxylic acid (8.0 g), triethylamine (14.0 ml) and diethyl cyanophosphate (8.2 ml), the title compound (3.2 g) was obtained as a brown oil.
Reaction SMILES: [NH2:1]CCC[Si](OC)(OC)OC.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].[CH:17]([OH:20])(C)[CH3:18]>C(OCCCC)(=O)C>[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].[NH2:1][C:12]([O:20][CH2:17][CH3:18])=[O:16]
Reactant: CC(C)O
Reactant: CO[Si](CCCN)(OC)OC
Agent: C=CC(=O)O
Solvent: CCCCOC(C)=O
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 9.94 g of 3-aminopropyltrimethoxysilane and 15.4 g of hexanedioldiacrylate is stirred at room temperature for 3 hours. To the mixture, 28.5 g of PM glycol ether is added. The resulting mixture is stirred at room temperature for 1 minute. Then, 1.73 g of acrylic acid is added, and the mixture is stirred for 5 minutes. The mixture is diluted by adding 106.7 g of isopropanol. Next, 84.4 g of OG401-31 and 34.7 g of NALCO 1034A are added under vigorous agitation. The resulting mixture is stirred at room temperature for 1 hour. 0.74 g of a solution of EBECRYL 1360 (50% by weight in PM glycol ether), 3.98 g of DAROCUR 1173, and 64.8 g of n-butyl acetate are added. The resulting coating composition is stirred for an additional 30 minutes to ensure mixing.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=2[O:2]1.[I:12]I>C(Cl)(Cl)Cl>[I:12][C:8]1[C:5]([CH2:6][OH:7])=[CH:4][C:3]2[O:2][CH2:1][O:11][C:10]=2[CH:9]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: II
Solvent: ClC(Cl)Cl
Product: OCc1cc2c(cc1I)OCO2
Temperature: -5 °C
Yield: 53.9 %

Procedure:
To a solution of 3,4-(methylenedioxy)benzyl alcohol (1.8 g, 12 mmol) and CF3COOAg (3.434 g, 15.5 mmol) in dry CHCl3 (55 mL) at −5° C. was added I2 (3.9 g, 15.5 mmol) in portion. The resulting yellow mixture was maintain at −5° C. for 5 min, then filtered. The filtrate was washed with 20% Na2S2O3, dried and evaporated. The crude was purified by column chromatography on silica gel (petroleum ether) to obtain (6-iodobenzo[d][1,3]dioxol-5-yl)methanol (1.8 g, 56%) as a white solid. LCMS: 279[M+1]+; 1H NMR (DMSO-d6) δ 4.31 (d, 2H, J=4.2 Hz), 5.40 (t, 1H, J=4.2 Hz), 6.03 (s, 2H), 7.03 (s, 1H), 7.34 (s, 2H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:47][C:48]1[N:52]([CH3:53])[C:51]([CH3:54])=[N:50][N:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:47][C:48]3[N:52]([CH3:53])[C:51]([CH3:54])=[N:50][N:49]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1nnc(CCl)n1C
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cc1nnc(Cn2nnc3c(N4CC(F)(F)C(F)(F)C4)nc(C(C)(C)C)nc32)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS (m/e): 428.3 (MH+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:7]=[N:8][C:9]=1[CH2:10][O:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:4].C[O:30][C:31](=[O:62])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38]C(C2C(COC3C=CC=CC=3)=NN(C3C(Cl)=CC=CC=3Cl)N=2)=O)[CH:33]=1>>[C:12]12([O:11][CH2:10][C:9]3[N:8]=[N:7][N:6]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[C:5]=3[C:3]([NH:38][C:34]3[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=3)[C:31]([OH:62])=[O:30])=[O:4])[CH2:19][CH:18]3[CH2:20][CH:14]([CH2:15][CH:16]([CH2:17]3)[CH2:21]1)[CH2:13]2
Reactant: COC(=O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Reactant: COC(=O)c1c(COC23CC4CC(CC(C4)C2)C3)nnn1C1CCCCCC1
Product: O=C(O)c1cccc(NC(=O)c2c(COC34CC5CC(CC(C5)C3)C4)nnn2C2CCCCCC2)c1

Procedure:
5-(Adamantan-1-yloxymethyl)-3-cycloheptyl-3H-[1,2,3]triazole-4-carboxylic acid methyl ester was converted to the corresponding acid (as in Example 28, step c) which was then coupled to methyl 3-aminobenzoate (as in Example 28, step d). Hydrolysis of the methyl ester (as in Example 28, step e) resulted in the preparation of 3-{[5-(adamantan-1-yloxymethyl)-3-cycloheptyl-3H-[1,2,3]triazole-4-carbonyl]-amino}-benzoic acid. 1H NMR (d6-DMSO) 13.02 (1H, s), 10.64 (1H, s), 8.29 (1H, s), 7.89 (1H, d, J=9 Hz), 7.73 (1H, d, J=6 Hz), 7.54-7.49 (1H, m), 4.96-4.92 (1H, m), 4.73 (2H, s), 2.10-2.02 (7H, m), 1.78-1.45 (20H, m). The material was further analysed as its N-methyl D-glucamine salt.