Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]2[O:15][CH:3]12)=[N:10][O:11][N:12]=3.[NH3:17].CCO>>[CH3:1][C:2]1([CH3:16])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:17])[CH:3]1[OH:15])=[N:10][O:11][N:12]=3
Reactant: N
Reactant: CC1(C)Oc2cc3nonc3cc2C2OC21
Solvent: CCO
Product: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Yield: 87 %

Procedure:
0.82 g (3.8 mmol) of 7,8-dihydro-6,6-dimethyl-7,8-epoxy-6H-pyrano[2,3-f]benzo-2,1,3-oxadiazole were dissolved in 25 ml of 16.7% NH3 -EtOH and reacted for at 60° C. for 48 hours in a pressure glass tube. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate-methanol=5:1) to obtain 0.77 g of the intended compound as a brown solid. (yield: 87%) A part of the product was recrystallized from ethanol to obtain pure colorless crystals of the intended compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.C(OC(=O)C)(=O)C.[OH:16][C:17]1[CH2:22][CH:21]([C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[CH2:20][C:19](=[O:32])[C:18]=1[C:33](=[O:36])[CH2:34][CH3:35]>O>[OH:32][C:19]1[CH2:20][CH:21]([C:23]2[CH:24]=[C:25]3[O:31][CH2:30][O:29][C:26]3=[CH:27][C:28]=2[N+:1]([O-:4])=[O:2])[CH2:22][C:17](=[O:16])[C:18]=1[C:33](=[O:36])[CH2:34][CH3:35]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)OCO3)CC1=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2cc3c(cc2[N+](=O)[O-])OCO3)CC1=O

Procedure:
A solution consisting of fuming nitric acid (0.84 g), glacial acetic acid (0.54 g) and acetic anhydride (0.54 g) was added to a mixture of 3-hydroxy-5-(3,4-methylenedioxyphenyl)-2-propionylcyclohex-2-en-1-one (2.60 g) and acetic anhydride (1.62 g) at 0° C. The mixture was stirred at 0°-3° C. for 1.5 hours with addition of extra portions of acetic anhydride when necessary to aid the stirring. The mixture was poured into water and the precipitate was collected and dried giving 3-hydroxy-5-(2-nitro-4,5-methylenedioxyphenyl)-2-propionylcyclohex-2-en-1-one as a yellow solid, mp 139° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH2:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[CH:20]=[O:21])=[CH:14][CH:13]=1
Reactant: Cc1ccc(/C=C/CO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(/C=C/C=O)cc1

Procedure:
Following General Procedure H, oxalyl chloride (7.1 ml, 14.2 mmol, 2 M in CH2Cl2), DMSO (1.3 ml, 18.9 mmol), (E)-3-(4-methylphenyl)prop-2-en-1-ol (Compound 41, 1.4 g, 9.5 mmol) and triethylamine (4.4 ml, 31.4 mmol) in CH2Cl2 (5 ml) were reacted to obtain the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH3:11]OC(OC)OC.[I:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[NH2:22]>>[I:18][C:19]1[CH:20]=[C:21]([NH:22][CH:11]=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1I
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(OC)OC
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1I
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (203 g, 1.4 mol) and trimethoxymethane (1.51) was heated to reflux for 1 h, then the 3-iodo-4-methoxy-aniline (349.2 g, 1.402mol) was added portionwise. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature. The resulting precipitate was filtered off, washed with diisopropyl ether and dried to give the title compound as a beige powder (485 g, 85.9%)
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31](=O)[C:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)([CH3:34])[CH3:33].C(N(CC)CC)C>CN1CCCC1=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=3)([CH3:34])[CH3:33])[CH:30]=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cccc(C(C)(C)C(=O)C=CN(C)C)c1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: CN1CCCC1=O
Product: COc1cccc(C(C)(C)c2ccnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)n2)c1
Reaction time: 2.5 h

Procedure:
The title compound was prepared in analogous manner as described in example 4c) from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate, 1-dimethylamino-4-(3-methoxy-phenyl)-4-methyl-pent-1-en-3-one and triethylamine using 1-methyl-pyrrolidinone as the solvent. The reaction was performed in a microwave at 200° C. for 2.5 h. The title compound was isolated as a brown viscous oil in 44% yield.
Reaction SMILES: [NH2:1][C@H:2]([CH2:11][OH:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[CH2:16][O:17][C:18](Cl)=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[CH3:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[CH2:16][O:17][C:18]([NH:1][C@H:2]([CH2:11][OH:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:19]
Reactant: N[C@H](CO)Cc1ccc(O)cc1
Reactant: Cc1ccccc1COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccccc1COC(=O)N[C@H](CO)Cc1ccc(O)cc1
Yield: 72.9 %

Procedure:
In a mixture of 10 ml of water and 20 ml of ethyl acetate, 1.6 g of tyrosinol was dissolved. To the solution were added dropwise 2 g of 2-methylbenzyloxycarbonyl choride and 10 ml of an aqueous solution containing 1.3 g of sodium carbonate alternately with stirring while cooling with ice. After stirring for two hours at room temperature, the ethyl acetate layer was collected and washed with 5% hydrochloric acid and then with water. The layer was dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give 2.2 g of N-(2-methylbenzyloxycarbonyl)-tyrosinol with a mp. 78°-81° C in a yield of 70%. Analysis, calculated for C18H21O4N C 68.55, H 6.72. N 4.44, found C 68.88, H 6.84, N 4.42. According to the same procedure as used in Example 38, the following tyrosinol derivatives were prepared from the corresponding chlorides.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:23]CC5C=CC=CC=5)[CH:17]=4)[NH:12][C:11]=3[C:10]([O:31][CH2:32][CH3:33])=[CH:9][C:8]=2[C:6]1=[O:7].[H][H]>C(O)(=O)C.[C].[Pd]>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([OH:23])[CH:17]=4)[NH:12][C:11]=3[C:10]([O:31][CH2:32][CH3:33])=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: CCOc1cc2c(c3c1[nH]c1ccc(OCc4ccccc4)cc13)C(=O)N(CCN(C)C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOc1cc2c(c3c1[nH]c1ccc(O)cc13)C(=O)N(CCN(C)C)C2=O
Yield: 80.3 %

Procedure:
In 10 ml of acetic acid was dissolved 31 mg of N-(2-dimethylaminoethyl)-6-benzyloxy-1-ethoxycarbazole-3,4-dicarboximide. Thereto was added 30 mg of 5% palladium-carbon. The mixture was subjected to catalytic reduction in a hydrogen atmosphere at room temperature at atmospheric pressure. The resulting insoluble material was removed by filtration. The filtrate was subjected to distillation under reduced pressure to remove the solvent. The residue was mixed with 50 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethanol to obtain 20 mg (yield: 80%) of N-(2-dimethylaminoethyl)-1-ethoxy-6-hydroxycarbazole-3,4-dicarboximide as orange crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.Cl.[O:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:33][C@H:30]2[CH2:31][CH2:32][O:28][CH2:29]2)[CH2:13][CH2:14]1
Reactant: N[C@H]1CCOC1
Reactant: Fc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccc(OC2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 70.5 %

Procedure:
To a mixture of 3-chloro-2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)pyrido[3,4-b]pyrazine (2.5 g, 6.64 mmol) in DMF (30 mL) was added (S)-tetrahydrofuran-3-amine hydrochloride (4.10 g, 33.2 mmol) and Et3N (9.25 mL, 66.4 mmol) at room temperature. The reaction mixture was stirred at 70° C. for 14 h then cooled to room temperature and diluted with EtOAc (80 mL), washed with water (30 mL) and brine (2×30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, then the residue was purified by column chromatography (petroleum ether:EtOAc from 10:1 to 1:1) on silica gel to give the title compound as a yellow solid (2.0 g). ESI-MS m/z [M+H]+ 428.1.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:20].Cl>O1CCCC1.CN(C)C=O>[C:3]([O:7][C:8]([N:10]([CH3:20])[C@@H:11]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CC[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.5 %

Procedure:
To a stirred suspension of sodium hydride (89 mg, 2.24 mmol) in tetrahydrofuran (10 mL) and dimethyl formamide (10 mL) cooled in an ice bath was added (1S,3R)-3-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (427 mg, 1.86 mmol, WO2006/011035) and iodomethane (128 microL, 2.05 mmol). The mixture was allowed to warm to room temperature and stirred for 20 h. Sodium hydride (178 mg, 4.474 mmol) and idomethan (256 microL, 4.102 mmol) were added, and the reaction mixture was stirred at 20 h at room temperature. Reaction mixture was acidified to pH 3.5 with 1 mol/L hydrochloric acid and extracted with ethyl acetate. Organic layer was dried over sodium sulfate and concentrated under reduced pressure. Crude material was purified by column chromatography (50% ethyl acetate in hexane containing 1.5% acetic acid) to give the desired compound as a colorless solid (138.0 mg, 31%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].S(Cl)(Cl)=O.[Cl:17][S:18](O)(=[O:20])=[O:19]>O>[Cl:17][S:18]([C:10]1[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7])(=[O:20])=[O:19]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCOc1ccc(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.9 %

Procedure:
Molten 2-ethoxybenzoic acid (25.0 g, 0.150 mol) was added to a stirred, ice-cooled mixture of thionyl chloride (11 ml, 0.151 mol) and chlorosulphonic acid (41.3 ml, 0.621 mol), whilst maintaining the temperature of the reaction mixture below 25° C. The resulting mixture was stirred at room temperature for 18 hours and then poured into a stirred mixture of ice (270 g) and water (60 ml) to give an off-white precipitate. Stirring was continued for 1 hour, then the product was collected by filtration, washed with water and dried under vacuum to provide the title compound (36.08 g). A reference sample, m.p. 115-116° C., was obtained by crystallisation from hexane:toluene. Found: C,41.02; H,3.27. C9H9ClO5S requires C,40.84; H,3.43%. δ (CDCl3): 1.64(3H,t), 4.45(2H,q), 7.26(1H,d), 8.20(1H,dd), 8.80(1H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14](=[O:38])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][NH:29]C(OC(C)(C)C)=O)=[O:22])=[C:17]([Cl:37])[CH:16]=3)[CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14](=[O:38])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][NH2:29])=[O:22])=[C:17]([Cl:37])[CH:16]=3)[CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)butyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.06 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O2 (488.42); mass spectrum: (M+H)+=488/490/492 (chlorine isotope).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([N:13]1C(=O)C2C(=CC=CC=2)C1=O)[C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[NH2:26]N>C(O)C>[C:6]1([C:5]2[NH:26][N:2]=[CH:3][C:4]=2[NH2:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)N1C(=O)c2ccccc2C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Nc1cn[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 250 ml round-bottomed flask is charged at RT with 20.5 g of a mixture of the E and Z isomers of 2-[1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl]-1H-isoindole-1,3(2H)dione in 75 ml of ethanol. 7.8 ml of hydrazine hydrate are added. The suspension is stirred at RT for 1 h 30 min and then heated to reflux. After 1 h 30 min of heating, a thickening of the mixture may be observed, and it takes on a yellow colour. The suspension is filtered off hot with suction on a frit and the precipitate is washed with ethanol. The filtrate is concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with DCM and with a DCM/methanol mixture (95/5 by vol.), to give 9.45 g of 5-phenyl-1H-pyrazol-4-amine (brown solid). LC-MS-DAD-ELSD: 163 (+)=(M+H)(+).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:14][C@H:15]([CH2:19][OH:20])[CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH3:12][N:11]1[C:3]2[C:2]([NH:14][CH:15]([CH:16]([CH3:18])[CH3:17])[CH2:19][OH:20])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:13])=[N:10]1
Reactant: CC(C)[C@H](N)CO
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC(CO)C(C)C)c2c(n1)c(C)nn2C
Reaction time: 50 h
Yield: 45.6 %

Procedure:
A mixture of 8 g (0.04 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 3), 4.5 g (0.045 mol) of L-valinol (2-amino-3-methyl-1-butanol) and 8 ml of triethylamine in 50 ml of dimethylformamide is stirred at 50°-55° C. for 50 hours and evaporated in vacuo. The residue is dissolved in methylene dichloride, washed with a saturated solution of sodium bicarbonate, dried over MgSO4, and evaporated in vacuo. The residue is stirred in pet ether to give 4.8 g (45%) of 2-[1,3,5-trimethyl-1H-pyrazolo[4,3-d]-pyrimidine-7-yl]amino-3-methyl-1-butanol, mp 166°-168° C. from acetonitrile.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([O:20]CC)=[O:19])[N:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[OH-].[Na+]>CO>[C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([OH:20])=[O:19])[N:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)Cn1nc(C(=O)C(C)C)c2ccc(OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(C(=O)C(C)C)nn(CC(=O)O)c2c1

Procedure:
Dissolve 1.68 g ethyl (3-isobutyryl-6-methoxy-1H-indazol-1-yl)acetate in 50 mL MeOH at 45° C. Add 10 mL water and 1.5 mL 5 N NaOH solution. The resulting mixture was heated overnight and evaporated to dry. The residue was taken up in water, acidified with 0.8 mL concentrated HCl, and extracted with 3×50 mL EtOAc. The combined organic extract was washed with water and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the title compound as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.27 (d, 8.9 Hz, 1H), 7.01 (dd, 2.1 & 8.9 Hz, 1H), 6.69 (d, 2.1 Hz, 1H), 5.23 (s, 2H), 3.91 (s, 3H), 3.85 (heptet, 6.9 Hz, 1H), 1.28 (d, 7.1 Hz, 6H). In NOE difference spectrum, irradiation of the 5.23 ppm singlet showed positive NOE at the 6.69 ppm doublet. LC-MS: 2.94 min. (m/Z=277.0, 299.0).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[N-:34]=[N+:35]=[N-:36].[Na+].CCN(C(C)C)C(C)C.C(OCC)(=O)C>CN(C=O)C>[N:34]([CH2:2][C:3]1[S:7][C:6]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:10][CH:9]=2)=[N:5][CH:4]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CCl)s2)nn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-c2ncc(CN=[N+]=[N-])s2)nn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
To a stirring solution of t-butyl 6-(5-(chloromethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (60.7 g, 124 mmol) in DMF (800 mL) was added sodium azide (22.2 g, 341 mmol) and DIPEA (31.1 mL, 171 mmol). The reaction was heated to 60° C. and stirred for 1 h. The reaction was poured into ethyl acetate (2000 mL), washed with water (3×400 mL), and the combined organic layers were separated, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (EtOAC/hexanes) to afford 20.0 g of t-butyl 6-(5-(azidomethyl)thiazol-2-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate as a yellow oil.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1.Br[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:15][CH2:14][CH2:13][CH:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][NH:2]1
Reactant: C1=CC2(CCC1)CCCNC2
Reactant: OCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: OCCC1NCCCC12C=CCCC2
Yield: 72 %

Procedure:
A mixture of 2-azaspiro-[5.5]-undec-7-ene (30.2 g.; 0.20 mole), 2-bromoethanol (25 g.; 0.20 mole) and triethylamine (20.2 g.) in toluene (250 ml.) is heated under reflux for 5 hours. The solution is cooled, filtered to remove triethylamine hydrobromide and the filtrate concentrated under reduced pressure. The residual liquid is distilled under reduced pressure to afford 28 g. (72% yield) of 2-hydroxyethyl-2-azaspiro-[5.5]-undec-7-ene, b.p. 90°-91° C./0.45 mm.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:21][CH:20]3[CH:15]([CH2:16][CH2:17][C:18]4[C:25]([O:26]C)=[C:24]([O:28]C)[CH:23]=[CH:22][C:19]=43)[CH2:14]2)=[CH:6][CH:5]=1.B(Br)(Br)[Br:31].CO>C(Cl)Cl>[BrH:31].[BrH:31].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:21][CH:20]3[CH:15]([CH2:16][CH2:17][C:18]4[C:25]([OH:26])=[C:24]([OH:28])[CH:23]=[CH:22][C:19]=43)[CH2:14]2)=[CH:6][CH:5]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc2c(c1OC)CCC1CN(CCCc3ccc(N)cc3)CC21
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: Br
Product: Nc1ccc(CCCN2CC3CCc4c(ccc(O)c4O)C3C2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of the compound of example 16 (0.41 g, 0.92 mmole) in CH2Cl2 (9.2 mL) was stirred under N2 at -78° C. as a solution of BBr3 (0.37 mL, 3.9 mmole) in 2.1 mL of CH2Cl2 was added dropwise. The reaction mixture was stirred for 1 hour at -78° C., 21/4 hr at 0°, and 21/4 hr at room temperature, then was cooled again to -78° as MeOH (7.3 mL) was added slowly. The reaction mixture was allowed to warm to room temperature overnight. The precipitate was filtered, washed with Et2O, and dried (in-vacuo) to yield 0.30 g light yellow powder; mp 290°; M+ 338.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[I:14]Cl>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([I:14])=[C:10]([Cl:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClI
Reactant: CC(=O)N1CCc2ccc(Cl)cc21
Solvent: CC(=O)O
Product: CC(=O)N1CCc2cc(I)c(Cl)cc21
Yield: 38.6 %

Procedure:
1-Acetyl-6-chloroindoline (0.3 g, 1.53 mmol) and iodine monochloride (2.48 g, 15.3 mmol) in acetic acid (25 ml) were heated under reflux for 48 hours. After cooling the mixture was partitioned between ethyl acetate and 10% aqueous NaOH. The organic extract was washed with aqueous Na2 SO3 dried (Na2SO4) & evaporated to dryness under reduced pressure. Chromatography on silica gel using dichloromethane afforded the title compound (0.19 g, 39%).
Reaction SMILES: C([NH:4][OH:5])(=O)C.C([O-])([O-])=O.[K+].[K+].F[C:13]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[C:26](=[O:43])[N:27]([C:30]4[CH:35]=[CH:34][C:33]([N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][C:37]5=[O:42])=[CH:32][CH:31]=4)[CH2:28][CH2:29][C:24]=3[C:23]([C:44]([F:47])([F:46])[F:45])=[N:22]2)=[CH:17][C:14]=1[C:15]#[N:16].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[NH2:16][C:15]1[C:14]2[CH:17]=[C:18]([N:21]3[C:25]4[C:26](=[O:43])[N:27]([C:30]5[CH:35]=[CH:34][C:33]([N:36]6[CH2:41][CH2:40][CH2:39][CH2:38][C:37]6=[O:42])=[CH:32][CH:31]=5)[CH2:28][CH2:29][C:24]=4[C:23]([C:44]([F:46])([F:45])[F:47])=[N:22]3)[CH:19]=[CH:20][C:13]=2[O:5][N:4]=1
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)ccc1F
Reactant: CC(=O)NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1noc2ccc(-n3nc(C(F)(F)F)c4c3C(=O)N(c3ccc(N5CCCCC5=O)cc3)CC4)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
Acetohydroxamic acid (54 mg, 0.72 mmol) and K2CO3 (0.2 g, 1.45 mmol) were added to 8 mL of DMF and 4 mL of H2O. The mixture was stirred at rt for 15 min, followed by addition of a solution of 2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7,-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile (0.12 g, 0.24 mmol) in DMF (2 mL). The mixture was stirred at rt overnight. The mixture was then partitioned between ethylacetate (40 mL) and water (20 mL), washed with H2O (20 mL×3) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. HPLC C18 RP, 0.5% TFA, H2O/MeCN gradient) purification gave 100 mg (67% yield) of the title compound as its TFA salt. LRMS (ESI−): 623.4 (M+TFA-H)−. 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.34-7.24 (m, 4H), 4.16 (t, 2H), 3.98 (br, 2H), 3.61 (br, 2H), 3.20 (t, 2H), 2.60 (br, 2H), 1.98-1.89 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[CH2:8]([NH2:11])[CH:9]=[CH2:10]>>[CH2:8]([NH:11][CH2:2][CH:3]([OH:7])[CH2:4][CH:5]=[CH2:6])[CH:9]=[CH2:10]
Reactant: C=CCC(O)CCl
Reactant: C=CCN
Product: C=CCNCC(O)CC=C
Temperature: 90 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
A mixture of 1-chloropent-4-en-2-ol (23.40 g, 194.06 mmol, 1.00 Eq) and prop-2-en-1-amine (33.00 g, 578.03 mmol, 2.98 Eq) was stirred at 90° C. for 16 hr. The mixture was cooled to 25° C. and concentrated in reduced pressure at 60° C. The residue was poured into ice-water (w/w=1/1) (150 mL) and stirred for 20 min. The aqueous phase was extracted with EA. The combined organic phase was washed with saturated brine (200 mL*2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (DCM:MeOH=30/1 to 10/1) to afford 1-(allylamino)pent-4-en-2-ol (16.00 g, 113.31 mmol, 58.39% yield) as yellow oil.