Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][NH2:19])=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].C(O)(=O)C>CO>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][O:18][N:19]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[CH3:10])=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: CC(=O)c1ccc(CO)cc1
Reactant: NOCc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NOCc1ccc(Cl)c(C(F)(F)F)c1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-(4-hydroxymethyl-phenyl)-ethanone (1 eq) in methanol is added O-(4-chloro-3-trifluoromethyl-benzyl)-hydroxylamine (1 eq) followed by the addition of acetic acid (0.05 eq). The mixture is stirred at room temperature for 5 hours. After concentrated, the residue is purified by column chromatography (30% EtOAc in hexane) to give 1-(4-hydroxymethyl-phenyl)-ethanone O-(4-chloro-3-trifluoromethyl-benzyl)-oxime as an oil [MS: (ES+) 358.1 (M+1)+].
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][CH2:16][CH2:17][CH:18]=[C:19]([F:21])[F:20])(=[O:14])=[O:13])=[CH:8][CH:7]=1>C(O)C>[F:20][C:19]([F:21])=[CH:18][CH2:17][CH2:16][NH:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC=C(F)F)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: NC(=S)NCCC=C(F)F
Yield: 174.8 %

Procedure:
Thiourea (0.29 g) and 4,4-difluorobut-3-enyl 4-methyl-benzenesulfonate (1 g) were heated together under reflux in ethanol (20 cm3) for 24 hours. The reaction mixture was cooled and the solvent evaporated under reduced pressure to give an oil which slowly crystallised. Trituration with hexane gave (4,4-difluorobut-3-enylthiourea as its 4-methyl-benzenesulfonate salt (1.14 g). MH+ (FAB)=167; 1H NMR (DMSO-d6): δ 2.48(3H,s); 2.46-2.58(2H,m); 3.42(2H,t); 4.66-4.84(1H,m); 7.32(2H,d); 7.68(2H,d); 9.10-9.40(3H,br)
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([NH2:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](OC)(OC)OC>C1COCC1.C(O)(C(F)(F)F)=O>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:17]=[N:16][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)nc1N
Reactant: COC(OC)OC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reaction time: 24 h
Yield: 81.1 %

Procedure:
To a solution of 6-(benzyloxy)pyridine-2,3-diamine (19.31 g, 89.71 mmol) in THF (300 mL) was added trimethyl orthoformate 99% (99.16 ml, 897.1 mmol) and TFA (345 μL, 4.49 mmol) at room temperature. After stirring for 24 h the solvent was removed under reduced pressure. The residue was taken up in 2 M HCl and EtOAc. The two layers were separated. The organic layer was washed with 2 M HCl and the combined aqueous layers were then made basic by the careful addition of 2 N NaOH. The precipitate was collected by vacuum filtration to give the title compound as a white solid (16.39 g). LCMS m/z=226.3, [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 5.40 (s, 2H), 6.91 (d, J=9.1 Hz, 1H), 7.32 (m, 1H), 7.38 (m, 2H), 7.48 (m, 2H), 8.09 (d, J=9.1 Hz, 1H), 8.79 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13](N)=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].N1C=CC=CC=1.N([O-])=O.[Na+].[FH:29]>>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[C:13]([F:29])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: F
Reactant: CCOC(=O)[C@H]1CC[C@H](c2cccnc2N)CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1CC[C@H](c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-4-(2-amino-pyridin-3-yl)-cyclohexanecarboxylic acid ethyl ester (0.25 g, 1.0 mmol) in 70% hydrogen fluoride in pyridine (2.4 ml, 92 mmol) was added solid sodium nitrite (0.076 g, 1.1 mmol) at 0-5° C. The cooling bath was removed after 30 minutes and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was partitioned between an ice-water mixture (50 ml) and tert-butyl methyl ether (50 ml). The organic layer was collected. The aqueous layer was extracted with one 100-ml portion of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness. Flash-chromatography with n-heptane/ethyl acetate as eluent gives the title compound (0.11 g, 44%) as light yellow oil. MS m/e: 252 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.Cl.[CH3:53][N:54]1[CH2:57][CH:56]([N:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]([N:61]3[CH2:62][CH2:63][N:58]([CH:56]4[CH2:55][N:54]([CH3:53])[CH2:57]4)[CH2:59][CH2:60]3)=[O:14])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)=[O:49])[CH2:39][CH2:38]1)=[O:36]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN1CC(N2CCNCC2)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.2 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (79.4 mg), triethylamine (0.125 ml) and water (0.10 ml), followed by stirring at room temperature for 6 hr. To the reaction mixture were added 1-(1-methylazetidin-3-yl)piperazine trihydrochloride (19.9 mg) and triethylamine (0.032 ml), followed by stirring at room temperature for 2 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, ethyl acetate:methanol=20:1 then 10:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (19.7 mg, 43.4%).
Reaction SMILES: C(O[C:4]1[CH2:9][O:8][CH:7]([CH3:10])[C:6](=[O:11])[CH:5]=1)C.[NH3:12]>>[NH2:12][C:4]1[CH2:9][O:8][CH:7]([CH3:10])[C:6](=[O:11])[CH:5]=1
Reactant: N
Reactant: CCOC1=CC(=O)C(C)OC1
Product: CC1OCC(N)=CC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 88A was treated with ammonia saturated ethanol (60 mL), stirred at ambient temperature for 16 hours and concentrated to provide the title compound (0.98 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8][NH:9][C:10]2=O)=[CH:5][CH:4]=1.O.[OH-].[Na+].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(-c3ccccc3)n[nH]c(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(-c3ccccc3)nnc(Cl)c2c1
Temperature: 80 °C

Procedure:
7-Methoxy-4-phenyl-2H-phthalazin-1-one (740 mg, 2.9 mmol) is dissolved in 7 mL of phosphoryl chloride. The solution is heated at 80° C. for 2 hours. The reaction medium is cooled to room temperature and then poured slowly into 200 mL of water with stirring. The mixture is then stirred at 5° C., basified with 35% sodium hydroxide solution and then extracted with dichloromethane. The organic phase is washed with water and then with brine and dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure, 750 mg of product are obtained in the form of a beige-coloured powder.
Reaction SMILES: CNN.O=C1C2C(=CC=CC=2)C(=O)[N:6]1[N:15]([CH2:23][CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH2:23]([N:15]([C:16]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:22])[NH2:6])[CH3:24]
Reactant: CCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: C1CCOC1
Product: CCN(N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
Methylhydrazine (1.415 mL, 26.9 mmol) was added to a solution of tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (example 74A, 5.2 g, 17.91 mmol) in THF (40 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. A white precipitate formed and was filtered off through a pad of Celite, The filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with 1N HCl (3×30 ml), the acid layer was washed with ethyl acetate (50 ml) and basified to pH 10 by addition of 20% NaOH. The basic solution was then extracted with ethyl acetate (3×50 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl 1-ethylhydrazinecarboxylate (2.5 g, 87% yield) as colorless oil.
Reaction SMILES: [OH-].[K+].Cl.[OH:4][C:5]1[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:13]I.Cl>CS(C)=O>[OH:12][CH2:11][C:6]1[C:5]([O:4][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CI
Reactant: OCc1ncccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccnc1CO
Yield: 31.3 %

Procedure:
Potassium hydroxide (41.66 g ,0.744 mol) was ground under nitrogen and stirred in DMSO (130 ml, anhydrous) for 20 min. 3-Hydroxy-2-hydroxymethyl pyridine hydrochloride [Aldrich] (47 g, 0.248 mol) was added and stirred for 30 rain in an ice bath. Methyl iodide (35.2 g, 0.248 mol, 15.43 ml) in DMSO (20 ml) was added dropwise to the solution and then allowed to stir overnight at room temperature. 5N HCl was added to pH 1 and the solution was extracted with dichloromethane (5×500 ml). The aqueous was then basified with 5N NaOH to pH 14 and extracted with dichloromethane (3×500 ml). The organics (base wash) were dried over sodium sulfate, and concentrated leaving tan colored crystals. The solid was recrystallized (50% ethyl acetate/hexanes) providing 10.8 g (32%) of the titled product as light tan crystals:
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH:5]([C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1)=O>C1C=CC=CC=1>[N:9]1[CH:8]=[C:7]([CH2:5][NH:3][CH2:2][CH2:1][NH2:4])[CH:12]=[N:11][CH:10]=1
Reactant: NCCN
Reactant: O=Cc1cncnc1
Solvent: c1ccccc1
Product: NCCNCc1cncnc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
Ethylenediamine (60 g) was dissolved in benzene (200 ml), and 5-formylpyrimidine (21.6 g) was added at room temperature. Subsequently, the mixture was heated, and refluxed for 3 hours while removing water as an azeotrope. After the reaction, benzene and the excess of ethylenediamine were distilled off under reduced pressure. The residue was dissolved in ethanol (200 ml). Sodium borohydride (8.4 g) was added portionwise to this solution at room temperature, and subsequently the mixture was stirred at room temperature for 5 hours. Ethanol was distilled off under reduced pressure. Dichloromethane (100 ml) was added to the residue, and a dichloromethane-soluble portion was separated. Dichloromethane was distilled off from the dichloromethane layer under reduced pressure to give N-(5-pyrimidinylmethyl)ethylenediamine (25.8 g) as a colorless oil. nD25 =1.5532.
Reaction SMILES: [C:1](=[O:11])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:2][CH3:3].[C:12]1(O)[CH:17]=[CH:16]C=[CH:14][CH:13]=1.C(=O)(OC)OC>CO>[C:1](=[O:11])([O:2][C:3]1[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=1)[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Oc1ccccc1
Reactant: COC(=O)Oc1ccccc1
Solvent: COC(=O)OC
Solvent: CO
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
In a column apparatus as described in Example 15, in which, instead of the 10-tray sieve-plate column, a 10-tray bubble-cap tray column, isothermically thermostatted to 183° C., of length 72 cm and internal diameter 4.75 cm was used, there was reacted, under the conditions described there, a mixture of 150 g/h of methyl phenyl carbonate, 350 g/h of phenol and 6.25 g/h of octylstannonic acid. After establishment of constant conditions, at the head of the apparatus, 365 g/h of a mixture of 1.3% by weight of methanol, 8.5% by weight of dimethyl carbonate and 90.2% by weight of phenol was continuously withdrawn and, at the foot of the column, 135 g/h of a mixture of 6.2% by weight of phenol, 14.0% by weight of methyl phenyl carbonate and 79.8% by weight of diphenyl carbonate were continuously withdrawn. This represents a space-time yield for the formation of diphenyl carbonate of 0.085 g·ml-1· h-1, based on the reactor volume. 16.6% of the methyl phenyl carbonate used reacted with phenol with transesterification to form diphenyl carbonate. The selectivity of the formation of diphenyl carbonate was >99%, that is no by-products could be detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[N:37]1([CH2:43][CH2:44]CO)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][CH2:44][CH2:43][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: OCCCN1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCN4CCCCC4)c(C)c3C)c2cc1OC
Yield: 81.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 3-piperidino-1-propanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (62 mg, yield 73%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@@H:11]([CH3:13])[NH:10][CH2:9][C@@H:8]2[CH3:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([C:33](Cl)=[O:34])=[CH:30][C:29]=2[CH:36]=1>C(Cl)Cl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]2[O:32][C:31]([C:33]([N:10]3[CH2:9][C@@H:8]([CH3:14])[N:7]([CH2:6][C:5]4[CH:15]=[CH:16][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:12][C@@H:11]3[CH3:13])=[O:34])=[CH:30][C:29]=2[CH:36]=1
Reactant: O=C(Cl)c1cc2cc(Cl)ccc2o1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2cc3cc(Cl)ccc3o2)[C@@H](C)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To an ice cold solution of (trans)-1-(4-fluorobenzyl)-2,5-dimethylpiperazine (712 mg, 3.2 mmol) and triethylamine (506 mg, 5 mmol) in CH2Cl2 (5 mL) a solution of the 5-chloro-1-benzofuran-2-carbonyl chloride (4.2 mmol) in CH2Cl2 (2 mL) was dropwise added. The reaction mixture was stirred at room temperature over night and washed with 0.5 M aqueous NaOH. The organic layer was dried, concentrated and submitted to flash column chromatography (CHCl3/MeOH; 1:0→10:1) to yield 1.05 g (82%) of the title compound.
Reaction SMILES: [C:1]1(=NO)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-2].[Ca+2].[CH:11]#[CH:12].[CH3:13][N:14]([CH3:23])P(N(C)C)(N(C)C)=O>>[CH:11]([N:14]1[C:23]2[CH2:5][CH2:4][CH2:3][CH2:2][C:1]=2[CH:6]=[CH:13]1)=[CH2:12]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: C#C
Reactant: ON=C1CCCCC1
Agent: [Ca+2]
Agent: [O-2]
Product: C=Cn1ccc2c1CCCC2
Yield: 30 %

Procedure:
5 g of cyclohexanone oxime, 0.5 g of calcium oxide in 50 ml of hexamethyltriamidophosphate are heated with a 3-fold molar excess of acetylene (with reference to the stoichiometric amount thereof) to the temperature of 170° C in a one-liter rotary autoclave (maximal pressure is 30 atm). The cooled mixture is extracted with vinyl butyl ether and the extract is distilled to give 1.8 g (yield of 30%) of 1-vinyl-4,5,6,7-tetrahydroindole.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1SC.[N+:17]([O-])([O-:19])=[O:18].[K+].C([O:24]CC)C>S(=O)(=O)(O)O>[OH:24][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([N+:17]([O-:19])=[O:18])=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=1
Reactant: CCOCC
Reactant: CSc1nc(-c2ccncc2)cc(=O)n1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cn1c(O)nc(-c2ccncc2)c([N+](=O)[O-])c1=O
Temperature: 70 °C

Procedure:
To a stirring solution of 3-methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one (15.5 mmol) in 40 mL sulfuric acid was added potassium nitrate (62.1 mmol). The reaction was heated to 70° C. for 3 h. Reaction was then added to stirring diethyl ether (400 mL), and precipitate collected by filtration. The precipitate was suspended in water and the pH was adjusted to 3 using sodium hydroxide. The solid was collected by filtration. M+1=249.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[C:14]([CH3:16])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[CH3:9][C:10]1[CH:11]=[C:12]([C:2]2[C:7]([C:12]3[CH:13]=[C:14]([CH3:16])[CH:15]=[C:10]([CH3:9])[CH:11]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: Clc1nccnc1Cl
Reactant: Cc1cc(C)cc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(C)cc(-c2nccnc2-c2cc(C)cc(C)c2)c1
Reaction time: 1 h
Yield: 44 %

Procedure:
First, 5.00 g of 2,3-dichloropyrazine, 10.23 g of 3,5-dimethylphenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes to be heated. Here, into the flask were further put 2.55 g of 3,5-dimethylphenylboronic acid, 1.80 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile, and irradiation with microwaves (2.45 GHz, 100 W) was performed again for 60 minutes so that heating was performed. Then, water was added to this solution and the organic layer was extracted with dichloromethane. The obtained organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated brine, and was dried with magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and the obtained residue was purified by flash column chromatography using hexane and ethyl acetate as a developing solvent in a ratio of 5:1. The solvent was distilled off, and the obtained solid was purified by flash column chromatography using dichloromethane and ethyl acetate as a developing solvent in a ratio of 10:1, so that Hdmdppr (abbreviation), which was the pyrazine derivative to be produced, was obtained as a white powder in a yield of 44%. Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, manufactured by CEM Corporation). A synthesis scheme of Step 1 is shown in (e-1).
Reaction SMILES: [CH2:1]([O:3]C(C1C([N+]([O-])=O)=C(NC2C=CC=CC=2OC)N=C(Cl)N=1)=O)C.C(OC([N:32]1[CH2:36][CH2:35][C@H:34]([NH:37][C:38]2[N:43]=[C:42]([C:44](OCC)=[O:45])[C:41]([N+:49]([O-])=O)=[C:40]([NH:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[O:59][CH3:60])[N:39]=2)[CH2:33]1)=O)(C)(C)C.C([N:68]1CCC(N)C1)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:60][O:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[N:52]1[C:1](=[O:3])[NH:49][C:41]2[C:40]1=[N:39][C:38]([NH:37][C@H:34]1[CH2:35][CH2:36][NH:32][CH2:33]1)=[N:43][C:42]=2[C:44]([NH2:68])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CCOC(=O)c1nc(Cl)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Reactant: CCOC(=O)c1nc(N[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(Nc2ccccc2OC)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(N[C@H]3CCNC3)nc21
Yield: 134.7 %

Procedure:
(S)-Ethyl 2-(1-(tert-butoxycarbonyl)pyrrolidin-3-ylamino)-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate Ethyl 2-chloro-6-(2-methoxyphenylamino)-5-nitropyrimidine-4-carboxylate (See Example 30.A) (0.300 g, 0.852 mmol), (S) 1-boc-3-aminopyrrolidine (0.190 g, 1.022 mmol) and diisopropylethylamine (0.164 g., 1.27 mmol) were reacted according to General Procedure C, except at room temperature and in dimethylformamide (5 ml). The crude reaction mixture was condensed and purified using Biotage chromatography (0-100% ethyl acetate in hexanes) to afford the title compound (0.424 g, 99%). MS (ESI) m/z 503 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][CH3:13])[O:11][CH2:10]1.B(F)(F)F.C[CH2:19][O:20]CC.[CH2:23](O)[CH:24]=C>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:11][CH2:10][CH:23]=[CH2:24])([CH2:12][CH3:13])[CH2:19][OH:20]
Reactant: CCOCC
Reactant: CCC1(c2ccc(Cl)cc2Cl)CO1
Reactant: C=CCO
Agent: FB(F)F
Product: C=CCOC(CC)(CO)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 108.1 %

Procedure:
8.68 g (38 mmoles) of 2-(2,4-dichlorophenyl)-1,2-epoxybutane of 95% purity are added dropwise at 7°-8° C. to a solution of 5.67 g (40 mmoles) of boron trifluoride-etherate in 23.2 g (400 mmoles) of allyl alcohol. The mixture is kept at 20° C. overnight in a water bath, and the solution is extracted with chloroform and water. Drying the organic phase with Na2SO4 and removing the solvent on a rotary evaporator gives 11.3 g of crude product, which is purified by column chromatography (silica gel; mobile phase: 4 parts of petroleum ether/1 part of ethyl acetate). The yield of pure product is 5.28 g (50.5% of theory) of a colourless oil. Refractive index n50D =1.5291. 60 MHz-1H-NMR(DCCl3): δ=7.1-7.6 ppm (m, 3H, aromatic); 5.0-6.5 ppm (m, 3H; olefinic): 3.8-4.4 ppm (m, 4H; 2× OCH2) 1.5-2.5 ppm (m; 3H CH2CH3, OH); 0.67 ppm (t, 3H, CH2CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[C:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)(=[O:24])[CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:22](=[O:24])[CH3:23])[CH:30]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4cccc(C(C)=O)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-acetylphenylboronic acid (139 mg, 0.85 mmol) the subtitle compound was obtained (89 mg, 26%). 1H NMR (DMSO) δ 8.75(d, 1H), 8.46(dd, 1H), 8.23(t, 1H), 7.98–7.96(m, 2H), 7.69–7.56(m, 3H), 7.27(d, 1H), 4.08(s, 3H), 2.68(s, 3H).