Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=O.P(Cl)(Cl)(Cl)=O.[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([NH2:32])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]>O1CCOCC1>[N+:14]([C:17]1[N:21]([CH3:22])[C:20]([C:23]2[N:27]3[N:28]=[C:29]([N:32]=[CH:1][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=2)=[N:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=CN1CCCCC1
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N=CN3CCCCC3)nn12
Reaction time: 1.5 h

Procedure:
2.85 ml. N-formyl-piperidine in 10 ml. dioxan were stirred with 2.4 ml. phosphorus oxychloride, which was introduced portionwise at 35° - 40° C., for 30 minutes at this temperature, then 1.5 g. crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[4,3-b]pyridazine was added and the reaction mixture was stirred for 1.5 hours at 35° - 40° C. The solution obtained was now poured into 75 ml. ice water, filtered with suction and the clear filtrate was rendered alkaline (about pH 10) with concentrated aqueous ammonia, cooled, left to stand for some time and the resultant crystals (1.28 g.) filtered off with suction and recrystallized from 25 ml. isopropanol, with the addition of charcoal, 0.82 g. of the desired 3-(5-nitro-1-methyl-2 -imidazolyl)-6-(1-piperidinyl-methyleneamino)-s-triazolo[4,3-b]pyridazine thereby being obtained in the form of yellowish-white crystals which melt at 187° - 189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[NH:12][C:11](=S)[CH:10]([CH2:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:33][NH2:34].C[C:36]([CH3:42])(C)C([O-])([O-])[O-].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:36]([CH3:42])=[N:33][N:34]=[C:11]3[CH:10]([CH2:22][C:23]([NH:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:24])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=NC(CC(=O)NC1CCCCC1)C(=S)N2
Reactant: NN
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=NC(CC(=O)NC1CCCCC1)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
To a solution of Intermediate 8 (420 mg, 0.9 mmol) in MeOH (40 mL) at 0° C. was added hydrazine monohydrate (0.22 mL, 4.6 mmol). After 15 min at 0° C., the reaction mixture was allowed to warm RT for 1 h and a further 2.5 equiv. of hydrazine hydrate before being heated to 40° C. for 15 min. The mixture was then concentrated to half volume and water was added. The aqueous layer was extracted with DCM (×2) and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was then dissolved in MeOH (30 mL) and trimethylorthoacetate (0.17 mL, 1.3 mmol) and PPTS (45 mg, 0.18 mmol) were added. The reaction mixture was refluxed for 45 min before being concentrated under reduced pressure. The crude mixture was dissolved in DCM and washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was then purified by flash chromatography on silica gel to give the title compound (70 mg, 16% yield over two steps) as a white solid. Rf=0.5 (DCM/MeOH:90/10). Mp >260° C. LC/HRMS (M+H)+ calculated for C26H2835ClN5O2 478.2010. Found 478.1968. Rt 2.76 min.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH:18]([OH:21])[CH2:19][CH3:20])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(N(CC)CC)C>CCO>[OH:21][CH:18]([C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:16])[CH3:17])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=3)[N:27]=[CH:26][N:25]=2)[C:3]1=[O:22])[CH2:19][CH3:20]
Reactant: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CCC(Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A solution of (S)-3-amino-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (47.6 mg, 0.153 mmol) in EtOH (3 mL) was charged with 4-chloro-6-(trifluoromethyl)quinazoline (46.3 mg, 0.2 mmol) and triethylamine (0.064 mL, 0.46 mmol). The mixture was heated for 30 min at 100° C. in the microwave oven. Solvent was evaporated off, and the residue was purified by flash chromatography on silica gel with elution by 0.8:7.2:92 cNH4OH—MeOH—CH2Cl2 to afford the titled compound 1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (47.3 mg) as a solid. MS found: (M+H)+=508.3
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].ClCCCl.[N:16]1([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:20]=[CH:19][CH:18]=[CH:17]1>ClC(Cl)C>[C:1]([C:20]1[N:16]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1cccc(-n2cccc2C(C)=O)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Acetic anhydride (1.3 ml) was added to a mixture of aluminum chloride (2.7 g) and 1,2-dichloroethane (10 ml) under ice-cooling and the mixture was stirred for 20 minutes at the same temperature. To the mixture was added dropwise a mixture of methyl 3-(pyrrol-1-yl)benzoate (2.0 g) in dichloroethane (3 ml) for 10 minutes at 0° to 5° C., and the mixture was stirred for 3 hours at the same temperature. The reaction mixture was poured into an ice-water and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give methyl 3-(2-acetylpyrrol-1-yl)benzoate (0.94 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(=O)([O-])O.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:19][CH:18]([O:21][CH2:22][CH3:23])[O:17][CH2:15][CH3:16])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Cl
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(CNc1ccc(C)c(Cl)c1)OCC
Yield: 26.2 %

Procedure:
3-Chloro-4-methylaniline (10.26 g, 72.5 mmol), sodium hydrogen carbonate (9.1 g, 108 mmol) and bromoacetaldehyde diethyl acetal (13.1 ml, 87.1 mmol) were stirred at reflux under Ar in ethanol (150 ml) for 6 days. The mixture was then evaporated to dryness, partitioned between ether and water, and separated. The organic portion was washed with brine, dried (Na2SO4) and evaporated to a black oil. Bulb to bulb distillation of this crude material (oven temperature 175° C., ca 0.1 mmHg) then gave the title compound (4.90 g, 26%) as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([CH3:33])[O:32][CH2:31][CH2:30][O:29]3)=[CH:24][C:23]=2B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([CH3:33])[O:29][CH2:30][CH2:31][O:32]3)=[CH:24][C:23]=2[C:2]2[C:3]3[NH:10][C:9]([CH3:11])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(Cl)ncnc12
Reactant: CC1(c2ccc(OCC3CC3)c(B3OC(C)(C)C(C)(C)O3)c2)OCCO1
Product: CCOC(=O)c1c(C)[nH]c2c(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-chloro-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A4) and 2-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (example B.c13) the title compound is obtained as off-white solid.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>C1C=CC=CC=1.CN(C)C=O>[O:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CC(N)=O
Reactant: BrCCCCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CC(=O)NCCCCOc1ccccc1
Yield: 81.7 %

Procedure:
Added to 20 ml of N,N-dimethylformamide were 1.34 g of acrylic amide and 3.4 g of (4-bromobutoxy)benzene. With stirring, 0.88 g of flaky potassium hydroxide which had been ground in a mortar was added. Phenothiazine was added in an amount of 0.5% based on the acrylic amide. After they were reacted at 0°-5° C. for 6 hours, insoluble matter was filtered off from the liquid reaction mixture. The solvent and unreacted raw materials were distilled off from the filtrate. The residue was extracted with benzene-water, thereby obtaining the intended product in the benzene layer. Benzene was then driven off from the benzene layer to obtain 2.66 g of N-(4-phenoxybutyl)acrylic amide (yield: 81%). It was purified further with column chromatography in which silica gel and benzene were used as an adsorbent and developer respectively. Its melting point was measured and its elementary analysis was also conducted. The following results were obtained. Melting point: 46°-47° C. Elementary analysis data: C, 71.29% (Calculated: 71.19%); H, 7.31% (7.82%); N, 6.15% (6.38%).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH:29]([C:31]1[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:2]1[C:29]([C:31]2[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[CH:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Reactant: COC(=O)c1cc(C=O)n(C)c1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2ccnc3ccc(Cl)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 535.05 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[C:3]=1[O:12][CH2:13][C:14]([CH3:16])=[CH2:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1.C(O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[Br:8][C:6]1[CH:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[C:3]2[O:12][CH2:13][C:14]([CH3:16])([CH3:15])[C:2]=2[CH:7]=1
Reactant: C=C(C)COc1c(Br)cc(Br)cc1C(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O=CO
Product: CC(C)c1cc(Br)cc2c1OCC2(C)C

Procedure:
Following general procedure C and using 1,5-dibromo-3-isopropyl-2-(2-methyl-allyloxy)-benzene (Compound 6, 28.45 g, 82 mmol), palladium(II)acetate (0.808 g, 3.5 mmol), triphenyl phosphine (1.02 g, 3.5 mmol), 7.7 mL of piperidine and 21 mL of 98% formic acid in a total volume of 1L of anhydrous N,N-dimethylformamide, the title compound was obtained as a colorless oil (1.6 g, 7.3%). 1H NMR (300 MHz, CDCl3): δ 7.12 (d, 1H, J=2.2 Hz), 7.03 (d, 1H, J=2.2 Hz), 4.21 (s, 2H), 3.06 (heptet, 1H, J=6.9 Hz), 1.32 (s, 6H), 1.22 (d, 6H, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[NH:17][CH:16]=[C:15]2[CH3:23].[H-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1.Cl.[CH3:37][NH:38][CH3:39]>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:37][N:38]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:17]2[CH:16]=[C:15]([CH3:23])[C:14]3[C:19](=[CH:20][CH:21]=[C:12]([C:3]4[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=4[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[CH:13]=3)[C:18]2=[O:22])=[CH:30][CH:29]=1)[CH3:39]
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]cc(C)c3c2)c1
Reactant: ClCc1ccc(CCl)cc1
Reactant: CNC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-c2ccc3c(=O)n(Cc4ccc(CN(C)C)cc4)cc(C)c3c2)c1
Reaction time: 0.33 h

Procedure:
A solution of the product of Example 93 step ii) in DMF (10 mL) was treated with 60% sodium hydride in mineral oil (0.12 g) and the mixture was stirred at room temperature under a nitrogen atmosphere for 20 mins before the addition of 1,4-di(chloromethyl)benzene (0.74 g). After stirring for a further 20 mins the reaction was treated with dimethylamine hydrochloride (0.98 g), followed by triethylamine (5 mL). Stirring was continued for 16 hours before being diluted with ethyl acetate (150 mL) and washing with water (150 mL). The organic layer was dried with anhydrous sodium sulphate and concentrated in vacuo to give a brown oil, which was purified (SiO2, eluting with ethyl acetate containing 2.5% MeOH and 0.25% triethylamine) to give the sub-titled compound (0.25 g).
Reaction SMILES: [Si]([O:18][C:19]1[C:24]([CH3:25])=[C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C(O)=[C:21]([O:57][CH3:58])[C:20]=1[O:59][CH3:60])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:61]([O:68][C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])(OC(C)(C)C)=O.C(N(CC)CC)C>ClCCl>[C:72]([O:71][C:69]([O:68][C:61]1[C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[C:24]([CH3:25])[C:19]([OH:18])=[C:20]([O:59][CH3:60])[C:21]=1[O:57][CH3:58])=[O:70])([CH3:73])([CH3:74])[CH3:75]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1c(O)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(OC(=O)OC(C)(C)C)c1OC
Temperature: 40 °C
Reaction time: 16 h
Yield: 150.3 %

Procedure:
A mixture of 4-tert-butyldiphenylsilyloxy-2,3-dimethoxy-5-methyl-6-(10-trityloxydecyl)phenol (8 g), di-tert-butyl dicarbonate (3 g), triethylamine (1 g) and dichloromethane (20 ml) was stirred at 40° C. for 16 hours. After concentration under reduced pressure, the residue was dissolved in tetrahydrofuran (30 ml). Tetrabutylammonium fluoride trihydrate (2 g) was added, and the mixture was stirred at room temperature for 15 minutes. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (7:3) to obtain the desired compound (10 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:32](OCC)=[O:33])=[N:4][C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][Si](C(C)(C)C)(C)C)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].NC1C(C(OCC)=O)=NC(NC2C=CC=CC=2O)=NC=1NC1C=CC=C[C:46]=1[O:51]C.[Si](Cl)(C(C)(C)C)(C)C.[NH:74]1C=CN=C1>C(Cl)Cl>[OH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:5]1[N:6]=[C:7]2[C:2]([NH:1][C:46](=[O:51])[N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:3]([C:32]([NH2:74])=[O:33])[N:4]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2O)nc(Nc2ccccc2OC)c1N
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)c1nc(Nc2ccccc2O[Si](C)(C)C(C)(C)C)nc(Nc2ccccc2OC)c1N
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(Nc3ccccc3O)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Ethyl 5-amino-2-(2-(tert-butyldimethylsilyloxy)phenylamino)-6-(2-methoxyphenyl amino)pyrimidine-4-carboxylate. Ethyl 5-amino-2-(2-hydroxyphenylamino)-6-(2-methoxy phenylamino)pyrimidine-4-carboxylate (184 mg, 0.465 mmol) was dissolved in methylene chloride (5 mL) and tert-butyldimethylsilyl chloride (77 mg, 0.512 mmol) and imidazole (38.0 mg, 0.558 mmol) were added. The reaction mixture was stirred overnight at room temperature. Solvent was removed under reduced pressure and crude was purified by column chromatography (20% ethyl acetate in hexanes). Fractions containing product were combined and the solvent evaporated to provide the title compound (232.6 mg, 0.456 mmol, 98% yield) as a yellow solid. MS (ESI) m/z 510.5 [M+1]+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[CH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]Br.C(N(CC)CC)C>C(Cl)(Cl)Cl.O1CCCC1>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([Br:14])[C:8]2=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: BrBr
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1C=C(Br)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To N-phenylmaleimide (2 g, 11.50 mmol) in chloroform (15 mL) was added bromine (0.65 mL, 12.70 mmol) dropwise in chloroform (5 mL). The reaction mixture was refluxed for 1 hour, and then allowed to cool to room temperature. The precipitate was filtered off and washed with chloroform (50 mL). This solid (2.70 g, 8.10 mmol) was dissolved in tetrahydrofuran (50 mL) and to this was added dropwise dropwise a solution of triethylamine (1.2 mL, 8.9 mmol) in tetrahydrofuran (10 mL) at 0° C. and the mixture was stirred for 2 hours. The mixture was allowed to warm to room temperature and solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with H2O (50 mL) brine (50 mL) and dried (Na2SO4). Solvent was removed in vacuo to afford the desired compound as a pale yellow solid (1.80 g, 7.14 mmol) in 62% yield. Data matched literature: Sahoo et al., Synthesis, 2003, 346
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][CH2:23][CH2:22]1.C(Cl)[Cl:32]>O1CCOCC1>[ClH:32].[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]([CH2:12][C:10]([OH:11])([CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:19][CH3:20])([CH3:18])[CH3:17])[C:13]([F:16])([F:15])[F:14])[CH2:23][CH2:22]1
Reactant: ClCCl
Reactant: c1ccc2c(c1)NCCO2
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Solvent: C1COCCO1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCOc2ccccc21)C(F)(F)F
Product: Cl

Procedure:
A mixture of 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-trifluoromethyloxirane (see Example 1) (0.139 g) and 3,4-dihydro-2H-benzo[1,4]oxazine (0.76 g) was dissolved in approximately 5 mL of methylene chloride and 0.55 g of flash silica gel was added. The volatiles were removed in vacuo and the residue was microwaved for 60 seconds at 150° C. and applied to a column of flash silica gel. Elution with EtOAc-hexanes (1:10) and concentration in vacuo of the product-rich fractions provided a residue which was dissolved in diethyl ether. HCl in dioxane was added. The volatiles were removed in vacuo and the residue triturated with diethyl ether. The resulting solid was dried in vacuo to provide the title compound, m.p. 98° C.-99° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:34])[N:7]3[CH2:15][CH:14]([CH3:16])[N:13](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.N1CCCCC1>C(Cl)Cl.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:34])[N:7]3[CH2:15][CH:14]([CH3:16])[NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1Cn2c(nc3cc(Br)ccc3c2=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC1Cn2c(nc3cc(Br)ccc3c2=O)CN1

Procedure:
A solution of (9H-fluoren-9-yl)methyl 9-bromo-3-methyl-6-oxo-3,4-dihydro-1H-pyrazino[2,1-b]quinazoline-2(6H)-carboxylate (2 g, 3.9 mmol, 1 equiv) and piperidine (4 mL) in DCM (50 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:17]=[C:4]2[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]2)[CH:19]=1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Reactant: Nc1cccnc1
Agent: [I-]
Solvent: c1ccncc1
Product: c1cncc(N=C2SC[C@@H]3Cc4ccccc4CN23)c1
Reaction time: 24 h
Yield: 79.7 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (36.3 g.) is added, a little at a time, to a solution of 3-aminopyridine (15 g.) in pyridine (1 liter). The suspension gradually passes into solution. After 24 hours at a temperature of about 20° C., the solution is concentrated to dryness under reduced pressure (25 mm. Hg.). The residue is dissolved in a mixture of methylene chloride (250 cc.), 2N sodium hydroxide solution (200 cc.) and water (200 cc.). The organic phase is decanted, dried over magnesium sulphate, filtered and then concentrated under reduced pressure (30 mm. Hg) at 40° C. The residue is recrystallised from acetonitrile (150 cc.) to give (S)-3-(pyrid-3-ylimino)-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinoline (22.4 g.) in the form of white crystals which melt at 111° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:21][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:21])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoic acid (3.0 g, 8.67 mmol) in a mixture of THF (15 ml) and MeOH (5 ml) was added (trimethylsilyl)diazomethane (5.63 ml, 2 M in Hexanes, 11.3 ml). After stirring for 4 h, the reaction was quenched with AcOH and diluted with EtOAc (100 ml). The organic solution was washed with H2O (50 ml) and brine (50 ml), dried over Na2SO4 and concentrated to dryness to give 2.83 g (91%) of methyl 5-bromo-3,4-difluoro-2-(2-fluorophenylamino)benzoate as a light yellow solid.
Reaction SMILES: CC(=CCCC(C=C)=C)CCC=O.[CH3:14]/[C:15](/[CH2:23][CH2:24]/[CH:25]=[C:26](/[CH:28]=[O:29])\[CH3:27])=[CH:16]\[CH2:17]/[CH:18]=[C:19](/[CH:21]=[CH2:22])\[CH3:20]>>[CH3:14]/[C:15](/[CH2:23][CH2:24]/[CH:25]=[C:26](/[CH:28]=[O:29])\[CH3:27])=[CH:16]\[CH2:17][CH2:18][C:19]([CH:21]=[CH2:22])=[CH2:20]
Reactant: C=C/C(C)=C/C/C=C(\C)CC/C=C(\C)C=O
Agent: C=CC(=C)CCC=C(C)CCC=O
Product: C=CC(=C)CC/C=C(\C)CC/C=C(\C)C=O

Procedure:
4-Methyl-8-vinyl-4,8-nonadienal was used in place of 4-methyl- 8-vinyl-4,7-nonadienal in the reaction described in Example 1 (d). for preparing α-sinensal. The resulting aldehyde, ⃝-sinensal, was obtained in comparable yields and had the same constants as the product obtained according to Example 4 (d).