Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C(O)CCC>[CH2:21]([N:23]([CH2:24][CH3:25])[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1)[CH3:22]
Reactant: CCNCC
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Solvent: CCCCO
Product: CCN(CC)c1nc2cc(C)nn2c2c1cnc1c2cnn1CC
Reaction time: 10 h
Yield: 82.5 %

Procedure:
8.6 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine (0.03 mol) and 7.2 g of diethylamine are suspended in 50 ml of butyl alcohol and heated with stirring in an autoclave for 10 hours at 150°. After this time, the solvent is removed, the residue is treated with water and filtered off. Recrystallization from alcohol yields 8 g (83%) of N,N,8-triethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine; m.p. 106°-108°.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([N:51]2[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][CH2:52]2)[CH:9]=[CH:10][C:11]=1[N:12](C(OC(C)(C)C)=O)[C:13]1[CH:18]=[C:17]([N:19]([CH3:43])[C:20]([N:22]([C:31]2[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=2[Cl:42])COCC[Si](C)(C)C)=[O:21])[N:16]=[CH:15][N:14]=1)(=[O:4])[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>C(Cl)Cl>[Cl:37][C:36]1[C:35]([O:38][CH3:39])=[CH:34][C:33]([O:40][CH3:41])=[C:32]([Cl:42])[C:31]=1[NH:22][C:20](=[O:21])[N:19]([C:17]1[N:16]=[CH:15][N:14]=[C:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([N:51]3[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]3)=[CH:7][C:6]=2[NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH:18]=1)[CH3:43]
Reactant: C=CC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N(C(=O)OC(C)(C)C)c1cc(N(C)C(=O)N(COCC[Si](C)(C)C)c2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cc(N2CCNCC2)ccc1Nc1cc(N(C)C(=O)Nc2c(Cl)c(OC)cc(OC)c2Cl)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.2 %

Procedure:
tert-butyl 4-(3-acrylamido-4-((tert-butoxycarbonyl)(6-(3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)ureido)pyrimidin-4-yl)amino)phenyl)piperazine-1-carboxylate (59 g, 0.06 mmol) was stirred in DCM (2.0 ml). TFA (97 μl, 1.3 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated. The remaining residue was dissolved in DCM and washed with saturated NaHCO3, dried over MgSO4 and evaporated. The resulting material was dissolved in THF (2.0 ml) and NH4OH (74 μl, 1.9 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was evaporated to obtain the title compound (34 mg, yield: 90%) which was taken to the next step without further purification. 1H-NMR (400 MHz, DMSO-d) δ 2.62 (br. s., 4H) 3.08-3.27 (m, 7H) 3.77-4.03 (m, 6H) 5.72 (d, 1H) 6.11-6.34 (m, 2H) 6.40-6.62 (m, 1H) 6.70-6.98 (m, 2H) 7.22-7.37 (m, 2H) 8.32 (s, 1H) 8.70 (s, 1H) 9.58 (br. s., 1H) 12.06 (s, 1H); ESI-MS: 601 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:22]=[CH:21][CH:20]=[C:14]2[C:15]([O:17][C:18](=O)[C:13]=12)=[O:16])([O-:11])=[O:10].O>C(O)(=O)C>[N+:9]([C:12]1[CH:22]=[CH:21][CH:20]=[C:14]2[C:15]([N:1]([C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)[C:18](=[O:17])[C:13]=12)=[O:16])([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1c1ccc(O)cc1
Yield: 78.3 %

Procedure:
The starting material used in the above example can be prepared as follows: 34.3 g (0.31 mol) of 4-aminophenol and 59.9 g (0.31 mol) of 3-nitrophthalic anhydride in 600 ml of acetic acid are refluxed for 6 hours and the mixture is then stirred into 3,000 ml of water. The product which has precipitated is washed with water and dried for 24 hours at 70° C./30 mm Hg. 69 g (78% of theory) of 4-(3-nitrophthalimidyl)-phenol are obtained; melting point 202° C. IR spectrum (KBr): 1785 cm-1 and 1725 cm-1 (CO--N--CO); 1550 and 1350 cm-1 (NO2).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)O.[CH3:12][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]([CH2:20][CH2:21][CH2:22][CH:23]([CH2:25][CH2:26][CH2:27][C:28]([OH:32])([CH:30]=[CH2:31])[CH3:29])[CH3:24])[CH3:19])[CH3:14].C1(C)C=CC=CC=1>C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:10][C:4]1[C:3]([OH:11])=[C:2]([CH3:1])[C:8]2[CH2:31][CH2:30][C@:28]([CH2:27][CH2:26][CH2:25][C@@H:23]([CH2:22][CH2:21][CH2:20][C@@H:18]([CH2:17][CH2:16][CH2:15][CH:13]([CH3:12])[CH3:14])[CH3:19])[CH3:24])([CH3:29])[O:32][C:6]=2[C:5]=1[CH3:9]
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 99.2 %

Procedure:
Suspended in 20 ml of ethyl acetate were 10.0 g (65.8 mmol) of trimethylhydroquinone (TMH) and 0.32 g (0.658 mmol) of scandium trifluoromethanesulfonate, followed by heating under reflux for 10 minutes under an argon gas stream. After a solution of 20.3 g (68.4 mmol) of isophytol in 20 ml of ethyl acetate was added dropwise over 30 minutes under heating and reflux, TMH and isophytol were reacted for 3 hours. The reaction mixture was cooled, to which 100 ml of toluene were added. The resulting mixture was washed twice with 200-ml portions of water and then concentrated under reduced pressure. The residue was added with 100 ml of toluene and 100 ml of 2-butanone. The organic layer was washed twice with 200-ml portions of a 1N aqueous solution of sodium hydroxide and then with 200 ml of a saturated aqueous solution of sodium chloride. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent: n-hexane-diethyl ether system), whereby 28.1 g of the title compound were obtained in the form of a brown oil. (Yield: 99%, GLC purity: 95%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH3:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18].[OH-].[Na+]>C(O)C.O>[Cl:10][C:11]1[CH:32]=[CH:31][CH:30]=[CH:29][C:12]=1[CH2:13][C:14]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:20](=[O:22])[CH:21]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=1)[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)C(CCC(=O)O)(Cc1ccccc1Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCC(Cc1ccccc1Cl)(C(=O)C=Cc1cccc(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
m-Chlorobenzaldehyde (3.5 g., 0.025 mole) in ethanol (10 ml.) is added to a solution of levo-4-(o-chlorobenzyl)-4-phenyl-5-oxohexanoic acid (4.89 g., 0.015 mole) and sodium hydroxide (0.8 g., 0.02 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (300 ml.), and extracted with ether to remove the excess m-chlorobenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the off-white solid that precipitates is filtered and air-dried. Several recrystallizations from n-butyl chloride yields 3.15 g. of material with m.p. 170°-172°C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([C:12]3[C:20]4[O:19][CH2:18][O:17][C:16]=4[CH:15]=[CH:14][C:13]=3[NH2:21])=O)[C:4]=2[O:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:29])[C:25](=O)[CH2:26][CH3:27].S(=O)(=O)(O)O>C(O)(=O)C>[O:3]1[C:6]2[CH:7]=[CH:8][C:9]([C:10]3[C:12]4[C:13](=[CH:14][CH:15]=[C:16]5[O:17][CH2:18][O:19][C:20]5=4)[N:21]=[C:25]([C:24]([O:23][CH3:22])=[O:29])[C:26]=3[CH3:27])=[CH:4][C:5]=2[O:1][CH2:2]1
Reactant: CCC(=O)C(=O)OC
Reactant: Nc1ccc2c(c1C(=O)c1cccc3c1OCO3)OCO2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1nc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C)OCO3
Yield: 75.2 %

Procedure:
5-Amino-1,3-benzodioxole-4-yl 1,3-benzodioxole-4-yl ketone (2.7 g) and 2-ketobutyric acid methyl ester (1.9 g) were dissolved in acetic acid (30 ml), followed by addition of sulfuric acid (0.3 ml). The mixture was refluxed for 1.5 hours and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and water successively, dried over magnesium sulfate and concentrated under reduced pressure to yield the title compound as yellow crystals (2.6 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([OH:16])=O)=[C:6]([CH3:8])[N:7]=1.C(CC1NC(C2C(C)=CC(C)=C(C=2)C(O)=O)=C(C)N=1)#N.Cl.[NH:41]1[CH2:44][CH:43]([C:45]2[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=2)[CH2:42]1.Cl.FC1(C2C=CC(C#N)=CC=2)CNC1>>[OH:1][CH2:2][C:3]1[NH:4][C:5]([C:9]2[C:10]([CH3:19])=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=2)[C:14]([N:41]2[CH2:44][CH:43]([C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=3)[CH2:42]2)=[O:16])=[C:6]([CH3:8])[N:7]=1
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)O
Agent: Cc1cc(C)c(-c2[nH]c(CC#N)nc2C)cc1C(=O)O
Agent: Cl
Agent: N#Cc1ccc(C2(F)CNC2)cc1
Product: Cc1cc(C)c(-c2[nH]c(CO)nc2C)cc1C(=O)N1CC(c2ccc(C#N)cc2)C1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 222, except 5-(2-(hydroxymethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.5) was used in place of 5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.6) and 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2) was used in place of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4). m/z (ES+) 401 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:5](COCC[Si](C)(C)C)[C:6]=1[Cl:7].Cl.C(OCC)(=O)C>C(O)C>[Cl:7][C:6]1[N:5]=[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:3][C:2]=1[Cl:1]
Reactant: CCOC(=O)c1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(Cl)c(Cl)[nH]1
Yield: 64.1 %

Procedure:
Ethyl 4,5-dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-carboxylate obtained in Example (7b) (0.61 g, 1.79 mmol) was dissolved in ethanol (3 mL). A 4 N hydrochloric acid/ethyl acetate solution (15 mL) was added, and the mixture was heated under reflux for one hour. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 1/1) to obtain 0.24 g of the title compound as a pale yellow oily substance (65%).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][S@@](C(C)(C)C)=O)[CH3:10])=[C:5]([F:18])[CH:4]=1.Cl.C(OCC)C>O1CCOCC1>[F:19][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([F:18])[CH:4]=1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc(C(F)F)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@H](N)c1ccc(C(F)F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To (R)—N—((S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (160 mg, 0.545 mmol) was added 4M HCl in dioxane (409 μL) to give a yellow solution. The resulting mixture was stirred at room temperature for ˜1 hour. To the mixture was added slowly diethylether (˜20 mL). The solids were filtered off, suspended in diethylether, filtered off and rinsed with diethylether, dried under reduced pressure providing (S)-1-(4-(difluoromethyl)-2-fluorophenyl)ethanamine (103 mg) as an off-white solid, which was used without further purification. LCMS m/z 190.1 (M+H)+, Rt 0.42 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][C@H:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NC3CCc4ccccc43)c2CC1)C(F)(F)F
Yield: 63.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.5 mmol) with (R)-1-aminoindan (188 mg, 1.4 mmol) in toluene (5 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give 7-chloro-6-(indan-1-ylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (129 mg, 67%). GC-MS m/z: 408 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([CH2:27][CH3:28])[CH3:26])=[CH:21][CH:20]=1)=[O:17]>CCO>[CH:25]([C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:13]=[C:6]2[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)=[CH:20][CH:21]=1)([CH2:27][CH3:28])[CH3:26]
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(C)c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Yield: 80.6 %

Procedure:
4-methyl-3-nitrobenzaldehyde (0.246 g, 1.50 mmol) and anhydrous CuCl2 (0.400 g, 3.00 mmol) were added to a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (0.400 g, 1.50 mmol) in anhydrous EtOH (15 mL). After heating at reflux temperature for 2 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 60% EtOAc in heptane, afforded 3-(4-sec-butylphenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.500 g, 81%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C@@H:24]([CH3:28])[C:25]([OH:27])=O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([O:23][C@@H:24]([CH3:28])[C:25]([NH2:30])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(=O)O)cc1OCC2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O[C@@H](C)C(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.3 %

Procedure:
To a solution of (S)-2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-propionic acid (115 mg, 0.28 mmol) in DMF (3 mL) was added HATU (128 mg, 0.34 mmol), ammonium chloride (23 mg, 0.42 mmol) and triethylamine (674, 0.42 mmol) and the reaction mixture stirred at room temperature (RT) for 5 hours. Further quantities of HATU (106 mg, 0.28 mmol), ammonium chloride (15 mg, 0.28 mmol) and triethylamine (21 μL, 0.28 mmol) were added and the reaction stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 426 as a white solid (68 mg, 58%). LCMS: RT=3.07 min, [M+H]+=384; 1H NMR (400 MHz, d6-DMSO) 9.05 (1H, s), 7.87 (1H, s), 7.86 (1H, s), 7.38 (1H, s), 7.05 (1H, s), 6.41 (1H, s), 5.87 (1H, sept, J=6.6 Hz), 5.17 (1H, q, J=6.9 Hz), 4.59-4.43 (4H, m), 1.47-1.37 (9H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15].[Cl-].CN(C=O)C>[Cu].CO>[Cl:8][C:6]1[CH:5]=[C:4]([Cl:9])[C:3]2[S:10](=[O:12])(=[O:11])[N:13]=[C:18]([NH:17][CH:14]([CH3:16])[CH3:15])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)cc(Cl)c1S(N)(=O)=O
Reactant: CC(C)N=C=S
Agent: [Cu]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)NC1=NS(=O)(=O)c2c(Cl)cc(Cl)cc2N1
Temperature: 100 °C

Procedure:
A mixture of 2-amino-4,6-dichlorobenzenesulfonamide (1.0 g), isopropyl isothiocyanate (0.84 g), copper(l) chloride (0.4 g), and DMF (1.5 ml) was heated at 100° C. for 2 h. Then 5 ml of methanol was added and the precipitated material was removed by filtration. Evaporation of the solvent in vacuo and subsequent treatment of the residue with 25 ml of ethyl acetate gave a yellow precipitate, which was collected by filtration and recrystallized from ethanol to give the title compound as white crystals; m.p. 291-293° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[N:6]2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:17](=[N:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]([C:12]([CH3:13])([CH3:15])[CH3:14])=[N:6]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N
Reactant: O=Cc1ccccc1
Product: Cn1nc2nc(C(C)(C)C)[nH]c(=O)c2c1N=Cc1ccccc1

Procedure:
3-Amino-2-methyl-6-(1,1-dimethylethyl)-2,5-dihydropyrazolo[3,4-d]pyrimidin-4-one (2.2 g) prepared as in Example 1 was heated under reflux in benzaldehyde (6.6 ml) for 11/2 hours. The solution was cooled to precipitate the product (2.4 g), m.p. 250°-253° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=2)[N:8]=1)(=O)=O.[C:30]1(B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33][CH2:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]1([C:7]2[C:15]3[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:25])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[N:8]=2)[CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: COc1nccc2c(OS(=O)(=O)C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nccc2c(C3=CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Yield: 45.6 %

Procedure:
A solution of 7-methoxy-1-(4-sulfamoylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate (59 mg), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.3 mg), tetrakis(triphenylphosphine)palladium(0) (7.5 mg) and 2M aqueous sodium carbonate solution (0.33 mL) in DME (5 mL) was stirred under argon atmosphere at 100° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed 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 (22 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:25])[CH2:6]1)[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:26]OC(OC)(C)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:25])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([CH:15]=[C:16]([O:24][CH3:26])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@H]12
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 5 h

Procedure:
10.0 g of 15α-acetoxy-4-androstene-3,17-dione is stirred under reflux with 60 ml of dimethoxypropane and 1.0 g of pyridinium-4-toluenesulfonate. After 5 hours, 1 ml of pyridine is added, the mixture is diluted with ethyl acetate, washed neutral with water, and dried. The crude product is recrystallized from hexane/acetone. Yield: 9.6 of 15α-acetoxy-3-methoxyandrosta-3,5-dien-17-one, mp 209° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH2:13])=[N:2]1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27](O)=[O:28])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([NH:10][CH2:11][CH2:12][NH:13][C:27]([CH:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:22]2)=[O:28])=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: NCCNc1nsc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)NCCNc2nsc3ccccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine (600 mg, 3.11 mmol), 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (854 mg, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (585 mg, 3.7 mmol) and triethylamine (577 μL, 3.7 mmol) in dichloromethane (40 mL) was allowed to stir at room temperature overnight. The reaction mixture was washed successively with 1N aqueous hydrochloric acid, saturated sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure. Purification by flash column chromatography, on silica gel, eluting with a mixture of 25% ethyl acetate in hexanes gave fractions that were combined and concentrated under reduced pressure to yield tert-butyl 3-(2-(benzo[d]isothiazol-3-ylamino)ethylcarbamoyl)piperidine-1-carboxylate as a white solid, (325 mg). 1H NMR (300 MHz, DMSO-d6): 8.1 (m, 2H), 7.92 (m, 3H), 7.9 (d, 1H), 7.5 (m, 1H), 7.3 (m, 1H), 3.9 (m, 2H), 3.5 (m, 2H), 3.3 (m, 2H), 2.8 (m, 2H), 2.2 (m, 1H), 1.8 (m, 1H), 1.6 (m, 3H), 1.3 ppm (s, 9H). MW=405 confirmed by LC-MS, tr=3.81 min (Method B) MH+=406.