Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.C[O-].[Na+].[C:14](OCC)(=[O:16])C.O>CO>[F:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([O:16][CH3:14])=[N:7][CH:6]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc(F)nc1C#N
Temperature: 0 °C

Procedure:
In 25 mL of methanol was dissolved 2.5 g of 3,6-difluoro-2-pyrazinecarbonitrile. Then, 2.4 g of 28% methanolic solution of sodium methoxide was dropwise added at 5-15° C., and the mixture thus formed was stirred at an ice-cooled temperature for 2 hours. The reaction mixture was poured into a mixture of 50 mL of ethyl acetate and 50 mL of water, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=10:1] to obtain 0.45 g of 6-fluoro-3-methoxy-2-pyrazinecarbonitrile as a colorless oily product.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([OH:17])=O)[CH2:11][C:12]([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22].C(#N)C.[OH-].[Na+]>O>[CH3:18][O:19][C:20](=[O:30])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][C:15](=[O:17])[C@H:10]([CH2:11][C:12](=[O:13])[OH:14])[NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)c1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
1.19 g (5.0 mmol) of N-benzoyl-L-aspartic acid and 1.79 g (10.0 mmol) of L-phenylalanine methyl ester were added to a flask which contained 50 ml of 50% acetonitrile in water containing 5 mM CaCl2. The pH of the solution was adjusted to 6.0 with 10M NaOH. The solution was admixed with 4 g of suction filtered immobilized enzyme prepared above. Thereafter, the reaction were carried out with stirring for 4 hours at 40° C. After completion of the reaction, the immobilized enzyme was separated by filtration. The pH of the filtrate was then adjusted to 3.7 by 10 molar hydrochloric acid. Resulting slurry was filtered and washed with water to give N-benzoyl-L-aspartyl-L-phenylalanine methyl ester.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:24]>>[CH2:23]([N:25]([CH2:31][CH3:32])[C@@H:26]1[CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:27]1)[CH3:24]
Reactant: CCN(CC)[C@@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CCN(CC)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)—N,N-diethylpyrrolidin-3-amine (1.2 equiv) to give 202 (M+1 438.0)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:24][CH:21]3[CH2:23][CH2:22]3)=[O:20])=[CH:16][CH:17]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(Cc2ccc(N=C=O)cc2)c1
Reactant: NC1CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2ccc(NC(=O)NC3CC3)cc2)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-isocyanato-benzyl)-1H-pyrazole-4-carboxylic acid ethyl ester (99 mg, 0.365 mmol) in THF (2 ml) was added cyclopropylamine (41.7 mg, 0.730 mmol). The resulting solution was stirred for 30 min at 23° C. The solvent was evaporated, and the residual white solid was triturated in diethyl ether, filtered, washed with diethyl ether and ethanol, and dried under vacuum to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](C2C=NC=CN=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(-c2ccc(C)cc2C(=O)O)nc1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, using 2-bromo-5-methylpyridine. ESI-MS (m/z): 228 [M+1]+.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cc2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-benzyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (56%, white crystals). HPLC-MS m/z=318.1 (M+l), Rt: 5.05 min.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[N:14](C=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:18])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CC(C)=O.CCO>[Cl:1][C:2]1[C:15]2[NH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Cl:18])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=CN1c2c(Cl)cccc2Sc2cccc(Cl)c21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: Clc1cccc2c1Nc1c(Cl)cccc1S2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The mixture of the crude 1,9-dichloro-10H-phenothiazine-10-carbaldehyde was dissolved in acetone (8 mL) and a solution of KOH (330 mg, 5.88 mmol) in EtOH (5.0 mL) was added. The mixture was stirred for 12 h at room temperature and then was evaporated to dryness to give a residue. The residue extracted with EtOAc and washed with 1M H3PO4. The organic layers were combined and dried over MgSO4, filtered and evaporated to give a residue. The residue was purified by flash silica gel chromatography to give 300 mg of a light yellow solid. LC/MS confirmed M+1=269.
Reaction SMILES: [CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[NH:5]1)[CH:2]=[CH2:3].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([C:31]3[CH:30]=[CH:29][C:28]([F:27])=[CH:33][C:32]=3[F:34])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[NH:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reactant: OB(O)c1ccc(F)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)N1
Yield: 58.9 %

Procedure:
A mixture of (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (188 mg, 0.452 mmol), 2,4-difluorophenylboronic acid (86 mg, 0.581 mmol), Pd(Ph3P)2Cl2 (20 mg) and aqueous Cs2CO3 solution (0.5 mL, 2 M) in 1,4-dioxane (10 mL) was stirred and heated at reflux for 2 h. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to give (R)-4-allyl-1-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (120 mg, 59%).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=O)[CH2:3][CH2:2]1.[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22][NH2:23]>CO.C(O)(=O)C>[CH3:12][N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[NH:22]/[N:23]=[C:4](/[CH:1]1[CH2:3][CH2:2]1)\[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Cn1c(NN)nc2ccccc21
Reactant: O=C(c1ccccn1)C1CC1
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(N/N=C(\c2ccccn2)C2CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of cyclopropyl-(2-pyridyl)-methanone (1,00 g, 7,40 mmol) and 1-methyl-2-hydrazinobenzimidazole (1.20 g, 7.40 mmol) in 20 ml of methanol is stirred for 3 days at room temperature after the addition of 6 drops of glacial acetic acid. Monitoring is effected by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored in the refrigerator at approximately 5° C. for 24 hours. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.97 g (45% of theory).
Reaction SMILES: [CH2:1]1[C:5]2[CH2:6][NH:7][CH2:8][C:4]=2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].Br[C:17]1[S:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:25]([O:24][C:22]([C:19]1[S:18][C:17]([N:7]2[CH2:6][C:5]3[CH2:1][N:2]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:4]=3[CH2:8]2)=[N:21][CH:20]=1)=[O:23])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC2=C(CNC2)C1
Reactant: CCOC(=O)c1cnc(Br)s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N2CC3=C(CN(C(=O)OC(C)(C)C)C3)C2)s1
Yield: 64.3 %

Procedure:
tert-Butyl 3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (1.2 g, 5.7 mmol), ethyl 2-bromothiazole-5-carboxylate (1.69 g, 7.17 mmol) and triethylamine (1.09 ml, 7.84 mmol) were stirred at 100° C. in 70 ml of DMF for 7 h. The residue was filtered off, the filtrate was concentrated and the remaining residue was extracted with ethyl acetate. 1.34 g of crude product were obtained, which were reacted without further purification (M+H+: 366.14).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N+:10]([O-:12])=[O:11])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH3:13][Li]>[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:13])[C:7]([N+:10]([O-:12])=[O:11])=[CH:8][N:9]=1
Reactant: O=Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: [Li]C
Agent: Cl[Ti](Cl)(Cl)Cl
Product: CC(=O)c1cc(Cl)ncc1[N+](=O)[O-]

Procedure:
A route to prepare 4-hydroxy 6-chloro 1,7 napthyridine is depicted in Scheme III. Starting with 2-chloro-4-methyl-5-nitropyridine, condensation with dimethylformamidedimethylacetal and subsequent oxidative cleavage yields 2-chloro-5-nitroisonicotinaldehyde. Chemoselective methyl addition to the aldehyde with methyllithium and titaniumtetrachloride at −50° C. followed by oxidation yields 1-(2-chloro-5-nitropyridin-4-yl)ethanone. Nitro reduction with iron in acetic acid, followed by a two step monotosylation yields N-(4-acetyl-6-chloropyridin-3-yl)-4-nitrobenzenesulfonamide. Upon heating with dimethylformamidedimethylacetal and diisopropylethylamine in DMF at 105° C. and subsequent treatment with thiophenol at room temperature, 6-chloro-1,7-naphthyridin-4-ol is obtained IV. Conversion of IV to the corresponding triflate or benzyl ether using standard conditions yields bifunctional intermediates which can be taken through the chemical transformation depicted in Schemes 1 and 2 to yield 4,6 disubstituted 1,7 naphthyridines V.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])=[O:6].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([NH:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][C:5]([NH:7][CH2:8][CH2:9][S:10]([OH:13])(=[O:12])=[O:11])=[O:6])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N[C@@H](CCC(=O)NCCS(=O)(=O)O)C(=O)O
Product: O=C(CC[C@H](NC(=O)c1ccccc1)C(=O)O)NCCS(=O)(=O)O

Procedure:
25.4 mg. (0.1 mmoles) of gamma-L-glutamyl-taurine are treated with 13 μl. of benzoyl chloride as described in Example 12. The reaction mixture is processed as described in Example 12 to obtain N-benzoyl-gamma-L-glutamyl-taurine, which is purified by paper electrophoresis using a pH 6.5 buffer solution. Relative motility (related to cysteinic acid): 1.06. Rf =0.47 (in a 15:10:3:12 mixture of n-butanol, pyridine, glacial acetic acid and water).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][OH:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]([F:24])[F:23])=[C:14]([CH2:25][O:26][CH2:29][CH3:30])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCBr
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(CO)c(C(F)F)nc3N21
Agent: [H-]
Agent: [Na+]
Product: CCOCc1cc2c(nc1C(F)F)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1, intermediate d) from (4R,9aR)-6-difluoromethyl-7-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 26, intermediate b), sodium hydride and ethyl bromide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH3:17][C:18]1([CH3:34])[O:23][CH:22]([C:24]([NH:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:25])[C:21]([CH3:33])([CH3:32])[CH2:20][O:19]1>>[CH3:17][C:18]1([CH3:34])[O:23][CH:22]([C:24]([NH:26][CH2:27][CH2:28][C:29]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:16])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:30])=[O:25])[C:21]([CH3:33])([CH3:32])[CH2:20][O:19]1
Reactant: CCCCCCCCCC(=O)NCCCO
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 98.1 %

Procedure:
N-(3-Hydroxypropyl)decanamide (2.29 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 4.61 g of the title compound (yield: 98%)
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:40](=[O:42])[CH3:41])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic anhydride, pyridine and dimethylaminopyridine in methylene chloride to give the title compound.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22]Br)([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:13]([O:17][C:18](=[O:24])[NH:19][CH2:20][CH2:21][CH2:22][N:10]1[CH2:11][CH2:12][CH:7]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(N2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A mixture of 4-piperidinopiperidine (Aldrich) (2.0 g, 11.88 mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester [Eur. J. Med. Chem. Chim. Ther. 37 (2002) 573-584] (3.96 g, 16.63 mmol), dimethyl formamide (130 mL) and potassium carbonate (1.64 g, 11.88 mmol) was stirred at room temperature overnight, then concentrated in vacuo. The residue was dissolved in water (150 mL), extracted with dichloromethane (3×150 mL), the combined organic layers were washed with brine (150 mL), dried over sodium sulfate, filtered and concentrated. The crude product was submitted to column chromatography using Kieselgel 60 (0.040-0.063 mm) (Merck) as adsorbent, and chloroform:methanol:NH4OH=10:1:0.1 as eluent to yield 2.27 g (59%) of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 98.4 %

Procedure:
2,4-Dibenzyloxybenzaldehyde [V] (20 g) was dissolved in methanol (700 ml) and then, thereto was added sodium borohydride (3.6 g) and this was left to stand at room temperature (20° C.) for 1.5 hour. To the reaction mixture was added water (1.5 liter) and the resulting precipitate was collected by filtration and recrystallized from ethanol to obtain 2,4-dibenzyloxybenzyl alcohol [VI] (19.8 g, yield 98%). Melting point: 84°-85° C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cc2c(I)n[nH]c2cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc2c(I)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cn1
Yield: 47.3 %

Procedure:
To a solution of 5.8 g of 3-iodo-1H-pyrazolo[3,4-c]pyridine-5-carbonitrile in 70 mL of dichloromethane were added 13.1 mL of diisopropylethylamine, 2.4 g of tetra-n-butylammonium iodide and 12.0 g of trityl chloride at room temperature, and stirred at this temperature for a day. The solution was evaporated, diluted with ethyl acetate, washed successively with saturated ammonium chloride and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10), to afford 5.2 g of the title compound as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:14]([OH:16])=[O:15])=[CH:8]2)=[O:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[CH:1]([C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[CH:8]2)=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(O)ccc2cc(C(=O)O)ccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(O)ccc2cc(C(=O)OCc3ccccc3)ccc12
Reaction time: 72 h

Procedure:
To a suspension of 5-formyl-6-hydroxy-2-naphthoic acid (1.12 g, 5.18 mmol) in 7.3 mL DMF at rt under N2 was added 569 mg (5.69 mmol) of KHCO3 and 1.11 mL (9.32 mmol) of benzyl bromide. The mixture was stirred for 3 days, at which point it was diluted with H2O and extracted with EtOAc. The extract was washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel, using 85:15 hexanes-EtOAc as the eluent, to give 410 mg (25%).
Reaction SMILES: [O:1]1CCC[O:3][CH:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](O)([CH:31]=[CH2:32])[CH2:14][O:15][CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=1.Cl>CC(C)=O.O>[F:29][C:27]([F:28])([F:30])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=1)[CH2:16][O:15][CH2:14][C:13]1([CH:31]=[CH2:32])[C:8]2[C:7](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]([OH:1])[O:3]1
Reactant: C=CC(O)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1C1OCCCO1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: C=CC1(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-(1,3-dioxan-2-yl)phenyl)-1-(3,5-bis(trifluoromethyl)benzyloxy)but-3-en-2-ol (800 mg, 1.68 mmol) in acetone (20 mL) and water (1 mL) was added concentrated hydrochloric acid (0.2 mL) at room temperature. The resulting reaction was stirred at room temperature for 2 h. The reaction was quenched by addition of saturated sodium bicarbonate, and concentrated to remove most of the acetone. The mixture was poured into diethyl ether, washed with water, then brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%-->50% EtOAc/Hex) gave 475 mg (68%) as a colorless oil. Mass spec.: 401.32 (M-OH)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[C:13](=O)([O-])[O-].[Na+].[Na+].IC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 1H-indazole-6-carboxylic acid (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room temperature overnight. The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100% ethyl acetate/heptanes) to afford methyl 1H-indazole-6-carboxylate as a yellow solid (2.95 g, 90%). 1H NMR (400 MHz, CDCl3, δ): 10.40 (br. s., 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).