Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1>C1COCC1.O=[Mn]=O>[CH:2]([C:3]1[S:7][C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)(=[O:27])=[O:28])[CH2:22][CH2:21]2)=[CH:5][CH:4]=1)=[O:1]
Reactant: NC(=O)c1cc(-c2ccc(CO)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(C=O)s2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 734.4 %

Procedure:
To a solution of 5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(4-morpholinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (82.5 mg, 0.015 mmol) in THF (10 mL) was added MnO2 (391 mg, 4.5 mmol). The reaction mixture was stirred at room temperature overnight and filtered through a pad of celite after that. The filtrate was collected and concentrated at reduced pressure to give the crude product (60 mg, 73%), which was used in the next step without further purification.
Reaction SMILES: [Br-].[F:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C@H:45]3[CH2:50][CH2:49][C@H:48]([CH:51]=O)[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1)#[N:32]>C1COCC1>[F:2][CH2:3][CH2:4]/[CH:5]=[CH:51]/[C@H:48]1[CH2:49][CH2:50][C@H:45]([C@H:42]2[CH2:43][CH2:44][C@H:39]([C:36]3[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=3)[CH2:40][CH2:41]2)[CH2:46][CH2:47]1
Reactant: FCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](C=O)CC3)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H]([C@H]3CC[C@H](/C=C/CCF)CC3)CC2)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A mixture of (3-fluoropropyl)triphenylphosphonium bromide (15.0 g, 37.2 millimols) with THF (75 ml) was cooled down to -20° C., followed by adding t-BuOK (4.2 g, 37.2 millimols) to the mixture, stirring for one hour, dropwise adding to the mixture, a THF (100 ml) solution of trans-4-(trans-4-(4-cyanophenyl)cyclohexyl)cyclohexanecarbaldehyde (10.0 g, 37.2 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 3, to obtain raw (E)-4-(trans-4-(trans-4-(4-fluorobutenyl)cyclohexyl)cyclohexyl)benzonitrile (9.9 g).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH2:20]1>CCCCCC.CS(C)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:36][N:34]([CH3:35])[C:31]1[CH:30]=[CH:29][C:28]([CH2:27][CH2:26][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:33][CH:32]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CN(C)c1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(CCN2CCCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Sodium hydride (67 mg, 1.68 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (300 mg, 1.53 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. A solution of (R)-3-chloro-1-(4-dimethylaminophenethyl)homopiperidine (470 mg, 1.68 mmol) in dimethyl sulfoxide (5 ml) was added dropwise into the obtained solution, and they were stirred at 50° C. for 3 hours. The reaction liquid was distributed in saturated aqueous sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduce pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and ethyl acetate (10:1), then with hexane and ethyl acetate (4:1) and finally with hexane and ethyl acetate (1:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-5,11-dihydro-5-[1-(4-dimethylaminophenethyl) piperidine-2-ylmethyl] dibenzo[b,e][1,4]oxazepine in the form of a light yellow solid (224 mg, 33%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([O:13]C(C2CC2)=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:20])[C:8]=2[F:19])[N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:20])[C:8]=2[F:19])[N:3]=1
Reactant: Cc1nc2ccc(F)c(F)c2c(OC(=O)C2CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2ccc(F)c(F)c2c(O)c1C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
2,3-Dimethyl-4-cyclopropanecarbonyloxy-5,6-difluoroquinoline (1.5 g) prepared as described in Example 4 was dissolved in 15 ml of methanol. A 10% aqueous sodium hydroxide solution (15 ml) was added to the solution, and the mixture was stirred at 50° C. for 1.5 hr. The reaction mixture was allowed to stand for cooling, was then poured into 50 ml of water, and was neutralized with 1 N hydrochloric acid, and the precipitate was then collected by filtration to give 1.1 g of 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline. In 5 ml of dimethyl formamide was suspended 11.5 mg of 60% sodium hydride. Separately, 50 mg of 2,3-dimethyl-4-hydroxy-5,6-difluoroquinoline (starting material 1) prepared above was suspended in 5 ml of dimethyl formamide, and this suspension was added dropwise to the above suspension under ice cooling. After stirring for one hr, 20 mg of acetyl chloride (starting material 2) was added thereto, and the mixture was stirred at room temperature for 15 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under the reduced pressure. The crude product thus obtained was purified on Wako Gel C-200 (100 ml; elution solvent=n-hexane-ethyl acetate (10:1)) to give 54.2 mg of 2,3-dimethyl-4-acetoxy-5,6-difluoroquinoline (compound 44). 1H-NMR data are shown in Table 3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].C1COCC1.[Br:40][C:41]1[CH:46]=[C:45]([Cl:47])[CH:44]=[C:43](F)[C:42]=1[Cl:49]>CS(C)=O>[Br:40][C:41]1[C:42]([Cl:49])=[C:43]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:44]=[C:45]([Cl:47])[CH:46]=1
Reactant: Fc1cc(Cl)cc(Br)c1Cl
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2Cl)c1F
Temperature: 110 °C
Yield: 50.6 %

Procedure:
6-chloro-2-fluoro-3-methylphenol (3.3 g, 20.55 mmol) and 18-crown-6 (1.086 g, 4.11 mmol) were dissolved in dry DMSO (50 mL) and treated with 20% potassium t-butoxide in THF (11.50 g, 20.55 mmol) for 15 minutes at room temperature. 1-bromo-2,5-dichloro-3-fluorobenzene (7.21 g, 29.6 mmol) was added in one portion and the reaction mixture heated at 110° C. for 3 days at which time LC-MS indicated nearly complete consumption of phenol and formation of a major new product. Addition of water to the reaction mixture resulted in a brown gummy oil which was extracted with EtOAc. The organic phase was isolated, washed with brine four times, dried over MgSO4, filtered and concentrated to dryness to give a brown syrup. This material was filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized from EtOH and a few drops of water. This mixture was cooled in an ice bath, filtered, and the precipitate washed with three portions of cold EtOH to give 2-[(3-bromo-2,5-dichlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (4.0 g, 10.40 mmol, 50.6% yield) as a cream solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (s, 1H), 7.29-7.47 (m, 2H), 6.81 (s, 1H), 2.29 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[K].[O-2].[O-2].[O-2].[O-2].[O-2].[V+5:19].[V+5].[OH-].[K+:22].OO.N1C=CC=[CH:27][C:26]=1C1C=CC=CN=1.[K]>O.C(O)C>[V+5:19].[N:1]1[C:2]2[C:3](=[CH:26][CH:27]=[C:12]3[C:7]=2[N:8]=[CH:9][CH:10]=[CH:11]3)[CH:4]=[CH:5][CH:6]=1.[K+:22]
Reactant: c1ccc(-c2ccccn2)nc1
Agent: [V+5]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1cnc2c(c1)ccc1cccnc12

Procedure:
For potassium (2,2'-bipyridine) oxodiperoxovanadium (V), vanadium pentoxide (0.91 g) and potassium hydroxide (0.65 g) are dissolved in water (10 ml), cooled, and, if necessary, the dissolution is completed with a small amount of hydrogen peroxide. To the clear, cooled solution, hydrogen peroxide (10 ml) and 2,2'-bipyridine (1.6 g) dissolved in ethanol (7-8 ml) are added. Pure crystals are obtained as described for the analogous oxalato-derivative of potassium. Potassium (1,10-phenanthroline) vanadium (V) can be obtained similarly.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH2:4][CH:5]=C.[CH2:14]1[CH:18]2[CH:19]3[CH:23]=[CH:22][CH:21]([CH:17]2[CH:16]=[CH:15]1)[CH2:20]3>>[F:1][C:2]([F:12])([F:13])[C:3]([CH:4]1[CH2:5][CH:14]2[CH2:15][CH:16]1[CH:17]1[CH:18]2[CH:19]2[CH2:20][CH:21]1[CH:22]=[CH:23]2)([C:8]([F:10])([F:9])[F:11])[OH:7]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CCC(O)(C(F)(F)F)C(F)(F)F
Product: OC(C1CC2CC1C1C3C=CC(C3)C21)(C(F)(F)F)C(F)(F)F
Temperature: 190 °C
Yield: 22.2 %

Procedure:
A 500 ml autoclave was charged with 230 g of 1,1-bis(trifluoromethyl)-3-butenol, 73 g of dicyclopentadiene, and 0.15 g of 2,6-di-t-butylparacresol, and the mixture was heated at 190° C. for 12 hours. The reaction solution was cooled to room temperature and purified by distillation to obtain 40 g of 8-(2,2,2-trifluoro-1-trifluoromethyl-1-hydroxyethyl)tetracyclo[4.4.0.12,5.17,10]dodec-3-ene of the following formula (13).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[CH:31]=[CH:32][CH:33]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: CC(=O)Nc1cccc(NN)c1
Product: CC(=O)Nc1cccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and N-(3-hydrazino-phenyl)-acetamide according to the method described for example 91. MS: M=456.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:20][C:21]([O:23]CC)=[O:22].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:20][C:21]([OH:23])=[O:22]
Reactant: CCCCCOc1c(OC)ccc2c(Cl)c(NC(=O)OCC)cnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCOc1c(OC)ccc2c(Cl)c(NC(=O)O)cnc12
Yield: 80.5 %

Procedure:
Ethyl 4-chloro-7-methoxy-8-pentyloxyquinoline-3-carbamate (311 mg, 0.84 mmol), ethanol (3 ml) and a 1N aqueous sodium hydroxide solution (3 ml) were mixed, and this solution was refluxed under heating for 0.5 hour. Ethanol was evaporated under reduced pressure, and conc. hydrochloric acid was added to make the reaction mixture acidic. THF (10 ml) and ethyl acetate (10 ml) were added to dissolve the precipitated crystals. The organic layer was separated, washed 3 times with saturated brine (10 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give 4-chloro-7-methoxy-8-pentyloxyquinoline-3-carbamic acid (229 mg, 80%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[C:18](/[CH:19]=[CH:20]/[C:21](OCC)=[O:22])=[CH:17][N:16]=[C:15]([S:26][CH3:27])[N:14]=1)[CH2:9][CH2:8]2.N12CCCN=C1CCCCC2>CN1CCCC1=O.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([N:12]1[C:13]3[N:14]=[C:15]([S:26][CH3:27])[N:16]=[CH:17][C:18]=3[CH:19]=[CH:20][C:21]1=[O:22])[CH2:9][CH2:8]2
Reactant: CCOC(=O)/C=C/c1cnc(SC)nc1NC1CCc2cccc(OC)c21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc2c1C(n1c(=O)ccc3cnc(SC)nc31)CC2
Temperature: 120 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-ethyl 3-(4-(7-methoxy-2,3-dihydro-1H-inden-1-ylamino)-2-(methylthio)pyrimidin-5-yl)acrylate (0.30 g, 0.78 mmol) in N-methylpyrrolidinone (1.8 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL, 0.35 g, 2.29 mmol) and the reaction was stirred for 4 h at 120° C. The reaction mixture was poured onto ice water and diluted with ethyl acetate (8 mL) and saturated brine solution (2.5 mL). The two phases were separated, and the organic layer was washed with 1 M hydrochloric acid (1×7 mL), water (1×7 mL), dried over sodium sulfate, filtered and evaporated to 8-(7-methoxy-2,3-dihydro-1H-inden-1-yl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one as a brown oil (0.40 g, 1.18 mmol, quant.). ESMS m/z 340 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.B.CSC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
To a solution of 5-bromopyridin-2-carboxylic acid (8 g, 42.1 mmol) in THF (100 ml) was added borane-dimethylsulphide (16 ml, 168.30 mmol) dropwise at 0° C. After warming-up to ambient temperature stirring was continued for 24 hours. The solution was cooled again to 0° C., quenched with MeOH and refluxed for 1 h. Solvents were removed and the residue was treated with water. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried, filtered and concentrated under reduced pressure to afford 4.76 g (64%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:23][CH2:22][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[C:20]([F:21])=[C:12]3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[CH:44][N:43]=2)[C:27]1=[O:48].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[F:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]2[CH2:22][CH2:23][N:10]([C:6]3[N:5]=[CH:4][CH:3]=[C:2]([C:30]4[CH:29]=[C:28]([NH:41][C:42]5[CH:47]=[CH:46][N:45]=[CH:44][N:43]=5)[C:27](=[O:48])[N:26]([CH3:25])[CH:31]=4)[C:7]=3[CH:8]=[O:9])[C:11](=[O:24])[C:12]=12
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccncn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccncn2)c1=O
Temperature: 100 °C
Yield: 26.5 %

Procedure:
A round-bottomed flask was charged with 146a (200 mg, 0.58 mmol), 1-methyl-3-(pyrimidin-4-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 143a (227 mg, 0.69 mmol), PdCl2(dppf) (47 mg, 0.06 mmol), K3PO4 (244 mg, 1.15 mmol), NaOAc (94 mg, 1.15 mmol), acetonitrile (30 mL), and H2O (3 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified on flash column chromatography eluting with 1:20 methanol/dichloro-methane to afford 146b as a red solid (79 mg, 27%). LCMS: [M+H]+ 514
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CO.Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:15][OH:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(C=NO)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
4-Nitrobenzaldehyde (40 g, 264.49 mmol) was added to MeOH (100 ml) followed by hydroxylamine hydrochloride (22.9 g, 330.9 mmol) in H2O (100 ml). The solution was then cooled to 0° C. Sodium carbonate (16.9 g, 159.5 mmol) in H2O (100 ml) was added and the reaction was allowed to stir overnight. The MeOH was removed under vacuum and then H2O (400 ml) was added. The precipitate was filtered and dried under vacuum to yield the product (39.65 g, 238.68 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][N:6]=[C:7]([CH3:9])[CH3:8])=[O:4].C(O)(=O)C>C(O)C>[CH3:1][O:2][C:3]([NH:5][NH:6][CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: COC(=O)NN=C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)NNC(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.6 %

Procedure:
N′-Isopropylidene-hydrazine-carboxylic acid methyl ester (6.45 g) were dissolved in ethanol (50 mL) and acetic acid (50 mL) PtO2 (0.231 g) was added, and reaction was stirred at room temperature for 22 hours under an atmosphere of hydrogen. Mixture was evaporated under vacuum, giving N′-Isopropyl-hydrazine-carboxylic acid methyl ester (5.08 g, 77%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:29]=[C:17]2[N:18]=[C:19]([N:23]([CH3:28])[CH2:24][CH2:25][NH:26][CH3:27])[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1.CCN(CC)CC>CC#N>[O:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[N:29]=[C:17]2[N:18]=[C:19]([N:23]([CH3:28])[CH2:24][CH2:25][N:26]([CH3:27])[CH2:2][C:3]3[CH:7]=[C:6]([CH3:8])[O:5][N:4]=3)[N:20]=[C:21]([NH2:22])[N:16]2[N:15]=1
Reactant: Cc1cc(CCl)no1
Reactant: CNCCN(C)c1nc(N)n2nc(-c3ccco3)nc2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(CN(C)CCN(C)c2nc(N)n3nc(-c4ccco4)nc3n2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloromethyl-5-methyl-isoxazole (1.5 eq.) was directly added to a solution of 2-furan-2-yl-N5-methyl-N5-(2-methylamino-ethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine (0.14 mmol) and Et3N (0.3 mmol), in 3 mL of CH3CN. The resulting reaction mixture was stirred at room temp for 18 hours. It was then concentrated and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (DMSO-d6) δ 7.90 (br s, 2H), 7.80 (d, J=1.0 Hz, 1H), 7.05 (d, J=3.6 Hz, 1 H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 6.30 (s, 1H), 3.65 (m, 2H), 3.20-2.75 (m, 4H), 2.5 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H) ppm. MS: m/z: 385 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH2:3][CH2:4][C:5]([CH3:8])(O)[CH3:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]([Cl:10])([Cl:9])[CH2:3][CH2:4][C:5]([CH3:8])=[CH2:6]
Reactant: CC(C)(O)CCC(Cl)(Cl)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=C(C)CCC(Cl)(Cl)Cl
Yield: 9.3 %

Procedure:
Then, to 732 g of 1,1,1-trichloro-4-methyl-4-pentanol was added 7.3 g of p-toluenesulfonic acid and the mixture was heated at 155°-160° C. for 1.5 hours, the byproduct water being azeotropically removed. The reaction mixture was as such distilled under a reduced pressure of 200 mmHg and the distillate was dried over sodium sulfate and fractionally distilled. By the above procedure was obtained 62 g of 1,1,1-trichloro-4-methyl-4-pentene as a fraction boiling at 73°-74° C. (20 mmHg), together with 536 g of 1,1,1-trichloro-4-methyl-3-pentene as a fraction boiling at 74°-77° C. (20 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH3:27][C@H:28]1[NH:33][CH2:32][CH2:31][N:30]([C:34](=[O:36])[CH3:35])[CH2:29]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[CH2:1]([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13]([Cl:17])[N:14]=[C:15]([N:33]3[CH2:32][CH2:31][N:30]([C:34](=[O:36])[CH3:35])[CH2:29][C@H:28]3[CH3:27])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Reactant: CC(=O)N1CCN[C@H](C)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2nc(Cl)nc3c2CN(Cc2ccccc2)CC3)[C@H](C)C1
Temperature: 80 °C

Procedure:
A mixture of 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (0.655 g, 1.89 mmol), (R)-1-(3-methylpiperazin-1-yl)ethanone 2,2,2-trifluoroacetate (1 g, 2.84 mmol) and DIEA (2.65 mL, 15.2 mmol) in i-PrOH (25 mL) was heated to 80° C. for 48 h. The reaction mixture was then diluted with EtOAc, and washed successively with sat aq NaHCO3 and brine. The organic layer was then dried over Na2SO4, filtered and concentrated. The resulting residue was diluted with DCM and filtered to remove solid. The filtrate was concentrated and purified by FCC (0-5% MeOH in DCM) to provide (R)-1-(4-(6-benzyl-2-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethanone. MS (ESI+) m/z 400.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13].CN(C)N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([C:11]1[C:10](=[O:15])[CH:11]=[C:12]([CH3:13])[O:14][C:12]=1[CH3:13])=[O:15]
Reactant: CC(=O)CC(=O)Nc1c(C)cccc1Cl
Agent: CN(C)N
Product: Cc1cc(=O)c(C(=O)Nc2c(C)cccc2Cl)c(C)o1
Yield: 45 %

Procedure:
The title compound was prepared from N-(2-chloro-6-methylphenyl)-3-oxo-butanamide and N,N-dimethylhydrazine as the raw materials in a similar manner to the method described in Example 2. (Yield: 45%).