Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19](C(N)=O)[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].IC.[Cl-].[NH4+].[CH3:31][N:32]([CH:34]=[O:35])[CH3:33]>>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:34]([N:32]([CH3:33])[CH3:31])=[O:35])[S:20][CH:21]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C=O
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2C1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Product: COc1nccc2c1c(-c1csc(C(=O)N(C)C)c1)nn2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(1-Cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (51.0 mg) was added to a solution of sodium hydride (60% dispersion in mineral oil, 30.0 mg) in DMF (10 ml), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added iodomethane (0.023 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (55.0 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.C[S-:27].[Na+]>CN(C)C=O>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([SH:27])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: C[S-]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(S)c2c1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (1.5 g, 4 mmol, prepared in analogy to the one in Example 17-1) in dry N,N-dimethylformamide (100 mL) was added sodium methanethiolate (1.4 g, 20 mmol) under argon protection. The reaction was stirred at 130° C. for 16 hours. The reaction mixture was cooled to 50° C. and concentrated in vacuo. The residue was dissolved in cooled water (150 mL) and carefully acidified with 20% of hydrochloric acid to pH 4˜5 under argon atmosphere. The resultant solution was extracted with cooled dichloromethane (150 mL×3). The combined organic layer was washed with cooled brine (100 mL×2) and concentrated in vacuo at room temperature to afford the crude product, which was used for next step without further purification.
Reaction SMILES: COC[O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][N:9]=[CH:8][C:7]=1Br.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][CH2:21][C:20]([N+:28]([O-:30])=[O:29])=[CH:19]2>>[CH3:27][O:26][C:25]1[CH:24]=[C:23]2[C:18](=[CH:17][C:16]=1[O:15][CH3:14])[C@@H:19]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH3:12])[C:6]=1[CH2:5][OH:4])[C@H:20]([N+:28]([O-:30])=[O:29])[CH2:21][CH2:22]2
Reactant: COc1cc2c(cc1OC)CCC([N+](=O)[O-])=C2
Reactant: COCOCc1c(C)cncc1Br
Product: COc1cc2c(cc1OC)[C@@H](c1cncc(C)c1CO)[C@H]([N+](=O)[O-])CC2

Procedure:
The compound of step 14c was condensed with 1,2-dihydro-6,7-dimethoxy-3-nitronaphthalene according to the procedure of Example 13c. The protecting methoxymethyl group was removed from the intermediate by a standard hydrolysis method (HCl, ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:6]([N:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:6]([N:24]([CH3:25])[CH3:26])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Yield: 98.5 %

Procedure:
A solution of methyl[4,6-bis(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (5.00 g, 13.39 mmol) in methanol (150 mL) was treated with palladium on charcoal (10% Pd, 0.50 g) and the resulting black suspension was stirred under a blanket of hydrogen gas at room temperature for 10 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give methyl[2-(4-aminobenzyl)-4,6-bis(dimethylamino)pyrimidin-5-yl]acetate (4.53 g, 98%).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[Cl:18][C:19]1[N:24]=[C:23]([NH2:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH3:27].CCN(CC)CC>ClCCl>[Cl:18][C:19]1[N:24]=[C:23]([NH:25][C:14]([C:11]2([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]2)=[O:15])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH3:27]
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: Cc1cc(N)nc(Cl)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (676 mg, 2.6 mmol) and 6-chloro-4,5-dimethylpyridin-2-amine (314 mg, 2.0 mmol), dichloromethane (7.0 mL) and Et3N (835 μL, 6 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with 1N HCl (3×) and saturated aqueous NaHCO3 (3×). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (560 mg, 73%). ESI-MS m/z calc. 380.07. found 381.3 (M+1)+. Retention time 2.18 minutes.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.F[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Temperature: 120 °C
Yield: 64.3 %

Procedure:
To a solution of 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (69.8 mg, 0.25 mmol) in DMF (1.0 mL) was added 4-fluorobenzotrifluoride (32 μL, 41 mg, 0.25 mmol) and potassium carbonate (69.1 mg, 0.5 mmol) and the resulting mixture heated at 120° C. overnight. The resulting mixture was then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=60:40) afforded the title compound (68 mg, 64%) which was obtained as an off-white solid. MS: m/e=424.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.Cl[C:46]1[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[CH:48][CH:47]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:46]2[N:51]=[C:50]([NH2:52])[C:49]([N+:53]([O-:55])=[O:54])=[CH:48][CH:47]=2)=[N:6]1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Fc1ccccc1Cn1nc(I)c2cccnc21
Agent: CCCC[Sn](CCCC)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h

Procedure:
200 mg (0.57 mmol) of the compound from example 33A were initially charged in dimethylformamide (5.3 ml) under argon, then 0.43 ml (0.85 mmol) of hexabutylditin and 160 mg (0.92 mmol) of 6-chloro-3-nitropyridin-2-amine were added, and the reaction mixture was purged with argon for 10 min. Subsequently, 231 mg (0.28 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (1:1) were added and the reaction mixture was stirred at 110° C. overnight. The mixture was then cooled to RT, saturated aqueous sodium hydrogencarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was extracted by stirring in dichloromethane/methanol (1:1), and the solids were filtered off and dried under high vacuum. This gave 95 mg (54% purity, 15% of theory) of the title compound. The filtrate was chromatographed on silica gel (eluent: 20:1 cyclohexane/ethyl acetate) and the product fractions were concentrated. The residue was suspended in methanol, the solids were filtered off and drying under high vacuum afforded a further 30 mg (15% of theory) of the title compound in solid form. The fractions were combined and converted without further purification (purity approx. 60%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]1([C:13]2[CH:17]=[C:16]([NH2:18])[NH:15][N:14]=2)[CH2:12][CH2:11]1.[Na+].[I-].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:18][C:16]2[NH:15][N:14]=[C:13]([CH:10]3[CH2:12][CH2:11]3)[CH:17]=2)[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To the solution of 2,4-dichloro-6-methylpyrimidine (1.63 g) and 3-cyclopropyl-1H-pyrazol-5-amine (1.24 g) in DMF (20 ml) was added NaI (1.49 g) and DIEA (1.72 ml). And the mixture was stirred at 80° C. overnight. The mixture was concentrated to remove DMF. The residue was suspended into EtOAc. The insoluble material was filtered off and washed with EtOAc. The filtrate was concentrated and the residue was pufiried with silica gel column chromatography (eluent: CHCl3/MeOH=98/2˜90/10) to give 2-chloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-6-methylpyrimidin-4-amine (1054 mg) as a pale pink solid.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[CH3:15]I>O1CCCC1.[Ag]=O>[CH3:15][O:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: CI
Reactant: NC(=O)CC1CCC(O)c2sccc21
Agent: O=[Ag]
Solvent: C1CCOC1
Product: COC1CCC(CC(N)=O)c2ccsc21
Reaction time: 8 h
Yield: 95 %

Procedure:
Eight g (37.86 mm) of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-ylacetamide and methyl iodide (28 ml, 0.45 M) are stirred in tetrahydrofuran (160 ml). The suspension is treated with silver oxide (60 g, 0.259 M) added in portions over a period of 5 hours. The reaction mixture is stirred overnight, filtered through celite, the cake is washed with tetrahydrofuran (2 × 100 ml) and dichloromethane (100 ml) and the filtrate evaporated to afford the crude title compound as a yellow-orange solid (8.1 g, 95% Y) m.p. 108° C-113° C dec. Two recrystallizations from acetone/hexane afford the analytical specimen, m.p. 124° C-126° C dec.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][NH:11][S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:9][C:3]1[C:2](/[CH:16]=[CH:15]/[S:12]([NH:11][CH3:10])(=[O:14])=[O:13])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: C=CS(=O)(=O)NC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)/C=C/c1cc(Cl)cnc1N
Temperature: 25 °C
Yield: 25 %

Procedure:
A mixture of 3-bromo-5-chloro-2-pyridinamine (414 mg, 2 mmol), N-methyl ethene sulphonamide (266 mg, 2.2 mmol) and triethylamine (555 μl, 4 mmol), palladium acetate (18 mg, 0.08 mmol) and tri-o-tolylphosphine (50 mg, 0.16 mmol) in DMF (0.5 ml) in a Teflon™ pressure vessel was microwaved for 30 sec (full power), allowed to cool to RT and irradiated for a further 30 sec. After allowing to cool, the reaction mixture was diluted with water, extracted with EtOAc and the organic phase washed with saturated brine, dried over MgSO4, and concentrated to a brown semi-solid. Purification by column chromatography on silica gel eluting with methylene chloride—methanol (95:5), and then crystallisation from methanol gave the title compound (130 mg, 0.5 mmol):
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:56])([CH3:55])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:54])([C@@:20]4([CH3:53])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][NH:40][S:41]([C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=2)(=[O:43])=[O:42])[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.CO>O1CCOCC1.O>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([CH3:56])([CH3:55])[C@H:16]3[C@:29]([CH3:32])([CH2:30][CH:31]=2)[C@@H:28]2[C@:19]([CH3:54])([C@@:20]4([CH3:53])[C@H:25]([CH2:26][CH2:27]2)[C@H:24]2[C@H:33]([C:36]([CH3:38])=[CH2:37])[CH2:34][CH2:35][C@:23]2([CH2:39][NH:40][S:41]([C:44]2[CH:52]=[CH:51][C:47]([C:48]([OH:50])=[O:49])=[CH:46][CH:45]=2)(=[O:42])=[O:43])[CH2:22][CH2:21]4)[CH2:18][CH2:17]3)=[CH:10][CH:9]=1)([OH:7])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNS(=O)(=O)c3ccc(C(=O)O)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(CNS(=O)(=O)c3ccc(C(=O)O)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 70 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
4-(N—(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(tert-butoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl)sulfamoyl)benzoic acid (10 mg, 0.013 mmol) from Step 1 was dissolved in dioxane (1 ml) and MeOH (5 ml) sodium hydroxide (10.20 mg, 0.255 mmol) (powder) was added followed by 5 drops of water. The resulting suspension was stirred at 70° C. for 6 h. After the reaction was completed, all volatile material was removed in vacuo. The residue was re-dissolved in MeOH and purified by prep. HPLC to afford 4-(N—(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-carboxyphenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl)sulfamoyl)benzoic acid as a white solid (1.8 mg, 18.4%). LCMS: m/e 728.2 (MH+), 2.11 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 8.24 (m, J=8.5 Hz, 2H), 8.01 (m, J=8.5 Hz, 2H), 7.94 (m, J=8.3 Hz, 2H), 7.24 (m, J=8.3 Hz, 2H), 5.31 (d, J=4.3 Hz, 1H), 4.70 (d, J=2.3 Hz, 1H), 4.59 (s, 1H), 3.05 (s, 1H), 2.62 (d, J=13.1 Hz, 1H), 2.37 (br. s., 1H), 2.11 (m, 1H), 1.76-2.01 (m, 4H), 1.65-1.76 (m, 6H), 1.53-1.65 (m, 4H), 1.44 (br. s., 5H), 1.31 (d, J=2.8 Hz, 6H), 1.03 (s, 6H), 1.01 (s, 3H), 0.99 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CN1CCC(=O)CC1
Solvent: C1CCOC1
Product: CN1CCC(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a solution of (S)-(−)-N-Boc-3-aminopyrrolidine (500 mg, 2.68 mmol) and 1-methyl-4-piperidone (0.34 mL, 2.95 mmol) in THF (10 mL) MP-(OAc)3BH resin (Argonaut; 2.55 mmol/g; 2.63 g, 6.71 mmol) was added and the reaction mixture was agitated at room temperature for 18 hours. Then, 1-methyl-4-piperidone (0.28 mL, 2.42 mmol) was added and the reaction mixture was agitated for 24 hours more. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 12% MeOH in CH2Cl2 as eluent to afford (S)-3-(1-methyl-piperidin-4-ylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (750 mg, 99%) as an orange oil.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].Cl[C:10]1[N:15]2[N:16]=[C:17]([CH3:28])[C:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[C:14]2[N:13]=[C:12]([CH3:29])[CH:11]=1>CS(C)=O>[CH2:4]([CH:5]([O:8][C:10]1[N:15]2[N:16]=[C:17]([CH3:28])[C:18]([C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[C:14]2[N:13]=[C:12]([CH3:29])[CH:11]=1)[CH2:6][CH3:7])[CH3:3]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)Oc1cc(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Temperature: 88 °C

Procedure:
To a suspension of 60% Sodium hydride in oil (160 mg) in 4 ml of DMSO was added 3-pentanol (853 mg), and then 7-chloro-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (580 mg) at room temperature. The mixture was heated at 88° C. overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated and purified through silica gel column chromatography using 10% hexane in chloroform as eluent to give the title compound as an orange oil. 1H NMR (CDCl3) ä 6.96(s, 2H), 5.95(s, 1H), 4.52(m, 1H), 2.48(s, 3H), 2.33(s, 3H), 2.27(s, 3H), 2.03(s, 6H), 1.75-2.00(m, 4H), 1.08(t, 6H)ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC=C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(C)[CH:24]=C(C)C=C(C)[CH:20]=1>>[CH2:24]([C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[OH:15])[CH:19]=[CH2:20]
Reactant: C=CCOc1ccc(OCc2ccccc2)cc1
Reactant: Cc1cc(C)cc(C)c1
Product: C=CCc1cc(OCc2ccccc2)ccc1O
Temperature: 165 °C
Yield: 85 %

Procedure:
1-Benzyloxy-4-allyloxy-benzene (20.4 g, 84.9 mmol) dissolved in mesitylene (150 ml) was heated at 165° C. for 48 hr under an argon atmosphere. After cooling to ambient temperature the resulting brown oil was chromatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-nHexane (1:9) to afford 2-allyl-4-benzyloxy-phenol (17.45 g, 72.6 mmol, 85%) as a pale yellow oil MS m/e=240.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH2:11]>>[CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:11])[C:7]=1[CH3:8]
Reactant: O
Reactant: Cc1ccc(C)c(O)c1C
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 2 h
Yield: 28.5 %

Procedure:
13.6 g (0.1 mole) of 2,3,6-trimethylphenol was pulverized and dispersed in 40 g of water. Then, oxidation reaction was conducted in the same manner as in Example 4. The reaction proceeded so late that 2 hours were required at a room temperature. After conducting stream distillation, the same treatment as in Example 1 (B) was effected to obtain 4.28 g (28.6 percent in yield) of 2,3,6-trimethyl-p-benzoquinone.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[S:23]([C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
3-Hydroxy-Cbz-(R)-pyrrolidine (13.7 g, 0.06 mol) was dissolved in CH2Cl2 (250 mL) and cooled to 0° C. p-Toluenesulfonyl chloride (14.16 g, 0.07 mol), and triethylamine (20.7 mL, 0.15 mol) were added and the resulting solution was stirred for 4 h at 0° C. The solution was washed with 1 M HCl, saturated NaHCO3, and brine. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with ethyl acetate/hexanes (3/1, v/v) to afford 20.4 g (88% yield) of the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:26][CH2:27][CH2:28][OH:29].[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:3]=1[O:4][C:5]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:8]([C:9]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:10])=[CH:7][C:6]=1[O:26][CH2:27][CH2:28][OH:29]
Reactant: Nc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(=O)O)cc(OCCO)c2Oc2cc(OC)ccc2Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(=O)Nc3ccccc3)cc(OCCO)c2Oc2cc(OC)ccc2Cl)cc1

Procedure:
Analogously to Example 74, by condensing 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonylamino)-benzoic acid with aniline there was obtained 4-(2-chloro-5-methoxy-phenoxy)-3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonylamino)-N-phenyl-benzamide.
Reaction SMILES: C1(O)OC2O[CH:8]([OH:12])[CH:9](O)OC2OC1O.[C:15]1([CH2:21][NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>Cl>[C:15]1([CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[C:8](=[O:12])[CH2:9]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: OC1OC2OC(O)C(O)OC2OC1O
Reactant: c1ccc(CNCCNc2ccccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1CN(Cc2ccccc2)CCN1c1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
Glyoxal trimeric dihydrate (15.8 g, 75 mmol) was added to a mixture of N-phenylmethyl-N′-(2-pyridinyl)-1,2-ethanediamine (Description 146, 5.7 g, 25 mmol) and hydrochloric acid (2N, 100 mL) and the mixture was stirred at room temperature for 24 hours. Further glyoxal trimeric dihydrate (5.3 g, 25 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was basified with aqueous sodium hydroxide (4M) and extracted with ethyl acetate (2×200 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with isohexane/EtOAc (40:60 increasing to 30:70), to give the title compound as a light brown oil (3.6 g, 54%). m/z (ES+) 268 (M+1).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:37]2[CH2:36][CH2:35][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[F:27])[CH2:39][CH2:38]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: Fc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3F)CC2)c(Oc2ccccc2)nc1C
Yield: 72 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(2-fluorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.