Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)CCCCCCCC(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A stirred mixture of nonanedioic acid (18.8 g; 0.10 mol), benzyl alcohol (10.8 g; 0.10 mol), and p-toluenesulphonic acid (0.2 g) in toluene (200 mL) was refluxed through a Dean-Stark trap overnight. The mixture was cooled to ambient temperature and extracted with 10% aqueous N-methyl-D-glucamine (4×25 mL). The last extract was a milky emulsion. The first three extracts were combined, acidified with 1 M HCl (50 mL), and filtered to give recovered nonanedioic acid (3.8 g). The emulsion was acidified with 1 M HCl and allowed to separate overnight. The organic layer was evaporated and the residue dissolved in hexane (200 mL) and diethyl ether (50 mL). The solution was extracted with 10% N-methyl-D-glucamine (2×50 mL) (emulsions broken by adding a little ethanol). The organic solution was washed with water (1×25 mL) and the combined aqueous solution was acidified with 1 M HCl (150 mL). After extraction with dichloromethane-tetrahydrofuran (4:1) (5×10 mL), the combined extracts were dried (Na2SO4), filtered, and evaporated. 13.0 g (47%) product was obtained (oil that solidified on standing).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: Clc1ncccn1
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCO[C@@H]1CN(c2ncccn2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 22.3 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), 2-chloropyrimidine (51 mg, 0.45 mmol) and sodium carbonate (157 mg, 1.48 mmol) were suspended in DMF (1 mL). The suspension was subjected to the same operation as in Example (131b) to obtain 25.1 mg of the title compound as a white solid (22%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[CH2:29][C:30]1([NH2:33])[CH2:32][CH2:31]1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:33][C:30]2([CH2:29][C:28]3[CH:34]=[CH:35][CH:36]=[C:26]([CH3:25])[CH:27]=3)[CH2:32][CH2:31]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1cccc(CC2(N)CC2)c1
Agent: O=C([O-])C(F)(F)F
Product: Cc1cccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 161 mg (1 mmol) 1-(3-methyl-benzyl)-cyclopropylamine. Yield: 179 mg (37%, trifluoroacetate); mass spectroscopy: [M+H]+=369.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[C:7]2=[O:13].[F:26][C:27]1[CH:28]=[C:29]([CH2:37][C:38](O)=[O:39])[CH:30]=[CH:31][C:32]=1[C:33]([F:36])([F:35])[F:34].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[F:26][C:27]1[CH:28]=[C:29]([CH2:37][C:38]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:7]3=[O:13])=[O:39])[CH:30]=[CH:31][C:32]=1[C:33]([F:35])([F:36])[F:34]
Reactant: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1N
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(=O)n([C@H]3CCN(C(=O)OC(C)(C)C)C3)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with (S)-tert-butyl 3-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)pyrrolidine-1-carboxylate (150.00 mg, 0.043678 mmol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (116.4 mg, 0.05241 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (420 mg, 1.1 mmol), N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) and N,N-dimethylformamide (2 mL, 20 mmol) and the reaction was stirred at 45° C. overnight. The solvent was removed under reduced pressure and the residue purified by flash chromatography to afford the product as light yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.CN(C)C(=O)C.[N:28]1([CH2:33][C:34](Cl)=[O:35])[CH:32]=[N:31][N:30]=[N:29]1.C(=O)([O-])O.[Na+]>ClCCl>[N:28]1([CH2:33][C:34]([NH:1][C@@H:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]23)=[O:35])[CH:32]=[N:31][N:30]=[N:29]1
Reactant: O=C(Cl)Cn1cnnn1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cn3cnnn3)[C@H]2SC1

Procedure:
In dichloromethane (10 ml) was suspended 7β-amino-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid (942 mg), followed by the addition of N,N-dimethylacetamide (1 ml). Then, under ice-cooling and stirring, a solution of (1H-tetrazol-1-yl)acetyl chloride (441 mg) in dichloromethane (3 ml) was added. The mixture was further stirred at room temperature for 30 minutes, after which it was poured in an aqueous solution of sodium hydrogen carbonate. The water layer, i.e. aqueous extract, was purified by column-chromatography on Sephadex LH-20. The fractions rich in the desired product were pooled, concentrated, made acidic with phosphoric acid and extracted with ethyl acetate. The extract was dried, concentrated and treated with ether. The procedure provided 7β-[2-(1H-tetrazol-1-yl)acetamido]-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]2[S:11][C:12]([CH3:14])=[CH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Br:15]Br>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]2[S:11][C:12]([CH3:14])=[C:13]([Br:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2cc(C)sc12
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cccc2c(Br)c(C)sc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
A solution of 2-methyl-benzo[b]thiophene-7-carboxylic acid methyl ester (0.50 g, 2.44 mmol) in CHCl3 (10 mL) is cooled to 0° C., treated with a solution of Br2 (0.13 mL, 2.44 mmol) in CHCl3 (5 mL). The reaction is stirred at 0° C. for 30 min, then at RT overnight. The reaction is diluted with CH2Cl2 (50 mL), washed with 10% Na2S2O3 (2×20 mL); dried with Na2SO4, filtered and concentrated to give the title compound (0.69 g, 2.43 mmol, 100%). 1H NMR (CDCl3): δ 2.58 (s, 3H), 4.02 (s, 3H), 7.50 (t, J=7.9 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 8.08 (d, J=7.5 Hz, 1H).
Reaction SMILES: [N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]([NH2:12])[CH2:3][C:2]=1[NH2:13].CS(C)=O.[CH3:18][N:19]1[CH2:24][CH2:23]N[CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:12]([C:4]2[CH2:3][C:2]([N:13]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[N:1][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=2)[CH2:21][CH2:20]1
Reactant: NC1=Nc2ccccc2N=C(N)C1
Reactant: CN1CCNCC1
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CCN(C2=Nc3ccccc3N=C(N3CCN(C)CC3)C2)CC1
Temperature: 120 °C
Yield: 74 %

Procedure:
3H-[1,5]Benzodiazepine-2,4-diamine (32.50 g, 160 mmol, 86%) was added to a solution of dimethyl sulfoxide (220 ml), toluene (220 ml) and 1-methylpiperazine (165 ml). The mixture was heated for 16 h at 120° C. After cooling the product precipitated. It was filtered off and washed with isopropyl ether (80 ml) to give 40.1 g (74%) of the title compound as off-white needles. The second crop was obtained by adding isopropyl ether (410 ml) to the filtrate. The mixture was allowed to stand overnight at 4° C., the crystallised product was filtered off to give additional 4.25 g (8%) of the title compound. For analytical purposes the product was recrystallised from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=O.[N:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:14]=[O:15].[H-].[Na+].Cl>O.O1CCCC1>[CH2:16]([N:13]1[C:7](=[O:9])[C:6]2[CH:5]=[C:4]([CH2:11][CH3:12])[S:3][C:2]=2[NH:1][C:14]1=[O:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCc1cc(C(=O)OC)c(N)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(Cc3ccccc3)c(=O)[nH]c2s1
Temperature: 60 °C
Reaction time: 5 h
Yield: 25 %

Procedure:
To a mixture of methyl 2-amino-5-ethylthiophene-3-carboxylate (5 g), (isocyanatomethyl)benzene (3.33 mL) and tetrahydrofuran (50 mL) was added sodium hydride (1.18 g), and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was diluted with water, and the mixture was adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound as colorless crystals (2.1 g, 25%).
Reaction SMILES: [CH2:1]([NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]1(=O)[O:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([N:19]1[CH2:20][CH2:21][CH2:22][C:23]1=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCCO1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Product: CCCCCCCC/C=C\CCCCCCCCN1CCCC1=O

Procedure:
Oleylamine (125 g, tech grade, 80% pure, 0.374 mole) was heated with γ-butyrolactone (27 ml, 0.35 mole) at 180° C. under nitrogen for 24 hours. The product was purified via vacuum distillation as a light yellow waxy solid. Mass Spectra: m/e (relative intensity) 335 (M+, 28.40).
Reaction SMILES: [C:1]([N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:3][CH2:2][C:1]([N:5]([CH3:15])[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[O:4])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Reactant: C1CCNCC1
Product: CN(C(=O)CCN1CCCCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from N-acryloyl-N-methyl-4-nitro-aniline and piperidine
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(N(CC)CC)C>C(O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][CH2:7][C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1ccc([N+](=O)[O-])c(CCl)c1
Reactant: COC(CN)OC
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(CNCc1cc(C)ccc1[N+](=O)[O-])OC

Procedure:
A solution of 43 g of 5-methyl-2-nitrobenzyl chloride in 200 ml of ethanol is added drop-wise to a solution of 40 g of aminoacetaldehyde dimethylacetal and 40 g of triethylamine in 300 ml of ethanol at reflux temperature, and the solution is heated for 18 hours at reflux. It is then evaporated in a vacuum until dry and the residue is dissolved in ethyl acetate, and extracted several times with water. After the organic phase is dried and evaporated, the heading compound remains as a reddish oil.
Reaction SMILES: [BH4-].[Li+].[C:3]1([S:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12](OC)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O>O1CCCC1>[C:3]1([S:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:11]=2[CH2:12][OH:13])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1Sc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc(C(F)(F)F)ccc1Sc1ccccc1
Temperature: 2 °C

Procedure:
21.5 g of lithium borohydride are suspended in 375 ml of tetrahydrofuran under a nitrogen atmosphere and heated to reflux. This suspension is treated dropwise under reflux over a period of 20 minutes with a solution of 130 g of methyl 2-(phenylthio)-5-trifluoromethyl-benzoate in 600 ml of tetrahydrofuran. The mixture is stirred under reflux for 2 hours and subsequently cooled to 2° C. The mixture is treated over a period of 10 minutes with 450 ml of 2-N aqueous hydrochloric acid in such a manner that the temperature does not exceed 10° C. After the addition of 750 ml of water, the mixture is extracted with 1000 ml of ether. The organic phase is washed twice with 300 ml of water each time, dried over sodium sulphate, filtered and evaporated. There is obtained 2-(phenylthio)-5-trifluoromethyl-benzyl alcohol as a light-yellow oil which crystallises spontaneously; melting point 84° C.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Na].[N+](C1C=CC(S[C:17]2[C:22]([C:23]#[N:24])=[CH:21][C:20]([CH:25]=[CH:26][C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])=[CH:19][N:18]=2)=CC=1)([O-])=O.C(OCC)C>C(O)(C)(C)C>[NH2:4][C:3]1[N:5]=[C:23]([NH2:24])[C:22]2[CH:21]=[C:20]([CH:25]=[CH:26][C:27]3[C:28]([Cl:34])=[CH:29][CH:30]=[CH:31][C:32]=3[Cl:33])[CH:19]=[N:18][C:17]=2[N:2]=1
Reactant: N#Cc1cc(C=Cc2c(Cl)cccc2Cl)cnc1Sc1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: Nc1nc(N)c2cc(C=Cc3c(Cl)cccc3Cl)cnc2n1
Temperature: 24 °C

Procedure:
To a solution of 2.24 g (23.4 mM) of guanidine hydrochloride in 30 ml of tert.-butanol were added 0.538 g (23.4 mM) of sodium metal. The mixture was heated at 50° C. for 90 minutes, at which time 2.0 g (4.67 mM) of the 2-(4-nitrophenylthio)-3-cyano-5-(2,6-dichlorophenyl)ethenylpyridine from above were added in one portion. The mixture was heated at reflux for three hours, then cooled to 24° C., diluted by addition of 200 ml of diethyl ether, and filtered. The filter cake was washed with 30 ml of water and dried. The solid product was next washed with 20 ml of acetone and dried to afford 1.45 g (93.5% yield)
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[CH2:16](I)[CH:17]=[CH2:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2)[CH:17]=[CH2:16]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2[nH]c(C(=O)OCC)cc12
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
50 mg (0.24 mmol) of ethyl 4-hydroxyindole-2-carboxylate (U.S. Pat. No. 3,705,907), 48 mg (0.29 mmol) of allyl iodide, and 33 mg (0.24 mmol) of potassium carbonate were added to 0.5 ml of N,N-dimethylformamide, and the mixture was stirred for 1 hour and 45 minutes at 50° C. After the reaction, the solvent was evaporated. The residue was dissolved in chloroform, washed with saturated aqueous solution of sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 63 mg of a crude product, which was purified by separation thin layer chromatography (silica gel, chloroform: methanol=30:1) to obtain 42 mg (yield: 70.2%) of the target compound. This compound was recrystallized from a mixture of chloroform and n-hexane to obtain light brown needles of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.Br[CH2:25][CH2:26][CH2:27][OH:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:25][CH2:26][CH2:27][OH:28])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: OCCCBr
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCCO)(c1ccccc1)C(=O)N2
Temperature: 60 °C
Yield: 40.8 %

Procedure:
A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-phenylindolin-2-one (1.5 g, 5 mmol), 3-bromopropan-1-ol (1.3 g, 10.0 mmol), potassium iodide (0.16 g, 1 mmol) and potassium carbonate (1.3 g, 10.0 mmol) in THF (50 mL) was heated at 60° C. for 5 hours in a capped pressure tube. The mixture was then cooled to room temperature and diluted with ethyl acetate (20 mL) and extracted with water (2×20 mL) and brine (20 mL). Aqueous layers were back washed with ethyl acetate (20 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product (0.74 g, 41%). 1H NMR (400 MHz, DMSO-d6): δH 10.65 (s, 1H), 7.23-7.36 (m, 7H), 7.00 (d, J=8.0 Hz, 1H), 4.39 (m, 1H), 3.31-3.33 (m, 2H), 2.37 (s, 3H), 2.18-2.28 (m, 2H), 2.16 (s, 3H), 1.21-1.27 (m, 1H), 1.02-1.06 (m, 1H) MS (ESI) m/e [M+1]+ 363.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([O:13]C(C)(C)C)=O)[C:5]2=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:22]>FC(F)(F)C(O)=O>[F:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]([NH2:22])=[O:13])[C:5]2=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)c1n[nH]c2nc(F)ccc12
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1n[nH]c2nc(F)ccc12
Reaction time: 2 h
Yield: 89.1 %

Procedure:
t-Butyl 6-fluoro-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (8.90 g, 37.5 mmole) was dissolved in 30 mL of trifluoroacetic acid and allowed to stand undisturbed for 2 hours. The solvent was then evaporated and the residue was dissolved in 30 mL of DMF. N,N'-Carbonyldiimidazole (7.0 g, 43.2 mmol) was added and the reaction mixture was stirred overnight. Ammonium acetate (8.7 g, 113 mmol) was then added to the resulting suspendion and stirring was continued for 4 hours. The solvent was evaporated under high vacuum and the residue was triturated well with H2O to give 6.02 g (89%) of product after drying. An analytical sample was obtained by recrystallization from HOAc, mp 295° C. (dec).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]([CH3:10])=C.C([OH:14])C=C.O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:10]=[O:14]
Reactant: C=C(C)OC1CCCCO1
Reactant: C=CCO
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=CCOC1CCCCO1

Procedure:
2-(Tetrahydro-2-pyranyloxy)-propene (20 g, 0.14 mole) was dissolved in dichloro-methane (250 ml). Ozone was bubbled into the solution at -78° C. for about 3 hours until the solution turned blue. Warmed to room temperature and zinc powder (20 g) was added. Acetic acid (20 ml) and water (3 ml) were added slowly with cooling in ice bath. The reaction mixture was further stirred for 2 hours at room temperature and then extracted with dichloromethane. The extract was washed with sodium bicarbonate aqueous solution (10 ml×2), dried over anhydrous magnesium sulfate, concentrated. The crude product was distilled under vacuum (62°-64° C./2 mmHg) gave colorless oil (13.72 g, 68%). 2-(Tetra-hydro-2-pyranyloxy)-propene was directly prepared from allyl alcohol and dihydropyran in the presence of a small amount of p-toluenesulfonic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:9]2[CH2:14][CH2:13][N:12](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.OC1C=CC(C(O)=O)=CC=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1
Agent: Br
Agent: O=C(O)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.8 %

Procedure:
370 g (0.839 mole) of levorotatory (-)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine (prepared in Example 3.A1) and 405 g of 4-hydroxybenzoic acid are added to 1 liter of a 30% solution of hydrobromic acid in acetic acid. The suspension is stirred for 17 hours at 25° C. 2 liters of water are then added thereto and the suspension is cooled in an ice bath. The precipitate which forms is filtered and washed with 750 ml of water. 2 liters of toluene and 0.9 liters of a 50% aqueous solution of sodium hydroxide are then added to the filtrate. The organic phase is decanted off and washed with 100 ml of water and then once again with 1 liter of a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and the solvent evaporated off under reduced pressure. The residue is recrystallized from 600 ml of boiling hexane. The solution is filtered while hot, so as to remove any slightly insoluble material and the filtrate is then allowed to crystallize, first at ambient temperature, and then for 24 hours in an ice bath. The crystals are filtered off, washed with hexane and dried under vacuum at 40° C. 204.15 g of levorotatory (-)-1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31]CN(C(OC(C)(C)C)=O)CC4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.FC1C=C2C(C(C3C=NNC=3)=CN2S(C2C=CC=CC=2)(=O)=O)=CC=1.CS(OCC1C[N:71]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:70]1)(=O)=O>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][N:71]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH2:70]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Product: CC(C)(C)OC(=O)N1CC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)C1
Yield: 76 %

Procedure:
Following the general method as outlined in Intermediate 20, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 1.22 g; 3.56 mmol) and tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (1.40 g; 5.28 mmol), 1.37 g (76%) of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])[C:2]1C=CC=CC=1>C(O)C.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[C:13]([CH:17]=1)[C:14]([NH2:16])=[O:15])[CH3:2]
Reactant: NC(=O)c1cc(OCc2ccccc2)ccc1NCCN1CCN(c2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(NCCN2CCN(c3ccccc3)CC2)c(C(N)=O)c1
Yield: 45.4 %

Procedure:
5-Benzyloxy-2-(2-[4-phenyl-1-piperazinyl]ethylamino)benzamide (1.8 g) in 35 ml ethanol was hydrogenated using 1 g 5% Pd-C catalyst. The mixture was heated to boiling and filtered. The filtrate was cooled and the solid filtered and washed to give 0.7 g product, m.142-3°.