Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N+:6]([C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]>N1C=CC=CC=1.C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[S:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1)(=[O:16])=[O:17])[CH3:2]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
Diethylamine (2.4 g) was dissolved in pyridine (15 ml) and 3-nitrobenzenesulfonyl chloride (6.7 g) was added, followed by stirring at 50° C for 2 hours. The residue obtained by an evaporation of pyridine under a reduced pressure was dissolved in methylene chloride (150 ml), washed with water, 1 N hydrochloric acid, water, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N,N-diethyl-3-(nitro)benzenesulfonamide (4.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(CO)c(N)n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CSc1ncc(C=O)c(N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 4-amino-5-hydroxymethyl-2-(methylthio)pyrimidine (1-1; 1.0 g, 5.84 mmol) in CHCl3 (100 mL) was added MnO2(2.5 g, 29.2 mmol, 5 equiv). The suspension was stirred at rt overnight. The mixture was filtered through celite and washed with CHCl3. The combined filtrate was concentrated to give the titled compound (1-2). 1H-NMR (500 MHz, CDCl3) δ 9.78 (s, 1H), 8.42 (s, 1H), 8.20 (broad, 1H), 5.74 (broad, 1H)), 2.55 (3, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]=2[C:3]=1[F:15].[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[C:6]3[N:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]=2[C:3]=1[F:15]
Reactant: Fc1c(Cl)ncc2[nH]c3ncccc3c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c2cnc(Cl)c(F)c2c2cccnc21
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A suspension of 6-chloro-5-fluoro-9H-dipyrido[2,3-b;4′3′-d]pyrrole (9 g, 40.6 mmol) in DMF (90 mL) was placed in a cold water bath and treated portionwise with sodium hydride (60% suspension in mineral oil) (1.94 g, 48.5 mmol) keeping the internal temperature at 20-25° C. When gas evolution ceased (ca. 1 hour) the mixture was treated dropwise with 2-(trimethylsilyl)ethoxymethyl chloride (8.1 g, 8.7 mL, 48.5 mmol) keeping the internal temperature at 25-30° C. After stirring for a further 1 hour the mixture was partitioned between ethyl acetate and ice-cold 1N hydrochloric acid. The aqueous phase was further extracted with ethyl acetate and the combined organic phase was washed with water, aqueous potassium carbonate solution, water, and brine, dried (Na2SO4), filtered and evaporated in-vacuo. The residue was triturated with pentane:diethyl ether (ca. 20:1) to afford the title compound as a beige solid (11.4 g, 80%). The trituration liquors were evaporated and purified by chromatography to afford a second crop of title compound (0.85 g, 6%). Total yield=12.3 g, 86%. 1H NMR (400 MHz, CDCl3): 8.68-8.68 (m, 2H), 8.52 (dd, J=7.8, 1.7 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.95 (s, 2H), 3.59 (t, J=8.2 Hz, 2H), 0.92 (t, J=8.2 Hz, 2H), −0.09 (d, J=0.5 Hz, 9H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1([CH3:25])[CH2:14][O:13][C:12]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]=[O:18])=[N:11]1>C(OCC)C.C(Br)C.BrCCBr>[CH3:9][C:10]1([CH3:25])[CH2:14][O:13][C:12]([C:15]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=2[CH:17]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[OH:18])=[N:11]1
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C=O)c1
Reactant: Brc1ccccc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: CCBr
Product: COc1ccc(C2=NC(C)(C)CO2)c(C(O)c2ccccc2)c1
Temperature: 25 °C
Yield: 107.8 %

Procedure:
Magnesium turnings for Grignard (0.12 g, 4.71 mmoles) in ethyl ether (8 ml) were put under N2 and stirring at room temperature. Ethyl bromide (2 drops) and then, slowly, bromobenzene (0.52 ml, 4.93 mmoles) in ethyl ether (10 ml) and 1,2-dibromoethane (2 drops) were added. The temperature arose to reflux and was kept as such for 1 hour. The mixture was treated with 2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-benzaldehyde (1 g, 4.29 mmoles), prepared as described in example 2, and kept at reflux for a further hour, then cooled, poured into water/ice and extracted more times with ethyl acetate. The organic phases were washed with water, anhydrified and brought to dryness to give 1.44 g of the title compound (yield: 98%).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:33])([CH3:32])[CH3:31]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(O)CCCCCBr
Reactant: CCCCn1cnc2c1c(=O)[nH]c(=O)n2CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1cnc2c1c(=O)n(CCCCCC(C)(C)O)c(=O)n2CC

Procedure:
4.7 g of 7-butyl-3-ethylxanthine, 2.8 g of potassium carbonate, and 4.4 g of 1-bromo-6-hydroxy-6-methylheptane are stirred in 100 ml of dimethylformamide at 120° C. for 7 hours. The mixture is filtered hot with suction, the filtrate is concentrated under reduced pressure, the residue is taken up in chloroform, washed first with 2 N sodium hydroxide solution and then with water until neutral and dried over sodium sulphate, the solvent is distilled off under reduced pressure whereupon an oily crude product in virtually quantitative yield is obtained which can advantageously be purified by filtration over a silica gel column using a chloroform/methanol (10:1) mixture as mobile phase, followed by a final recrystallization from diisopropylether with addition of petroleum ether.
Reaction SMILES: BrC1C=CC2C(=N)NC[CH2:9][O:10]C=2C=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([F:23])[CH:16]=1.C[O-].[Na+]>CO>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:10][CH3:9])=[C:17]([F:23])[CH:16]=1
Reactant: N=C1NCCOc2cc(Br)ccc21
Reactant: N#Cc1ccc(Br)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1ccc(Br)cc1F

Procedure:
Scheme 13 shows an alternative synthesis of 8-bromo-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-imine 33 from 4-bromo-2-fluorobenzonitrile 11. Reaction of 11 with sodium methoxide in methanol gives methyl 4-bromo-2-fluorobenzimidate 35. Alkylation of 35 with 2-aminoethanol gives 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzimidamide 36, followed by cyclization to 33.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[N:4]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:19]=[C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:17][C:16]=3[S:24]([NH:27]C(C)(C)C)(=[O:26])=[O:25])[CH:12]=[CH:13][CH:14]=2)[C:3]1=[O:32].B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:49]([O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[O:50].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:52]([O:51][C:49]([NH:27][S:24]([C:16]1[S:17][C:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:19][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:4]2[C:5](=[O:7])[CH2:6][N:2]([CH3:1])[C:3]2=[O:32])[CH:10]=1)(=[O:26])=[O:25])=[O:50])[CH2:53][CH2:54][CH3:55]
Reactant: CC(C)Cc1cc(-c2cccc(CN3C(=O)CN(C)C3=O)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(CN2C(=O)CN(C)C2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 3-[3-(3-methylimidazolidine-2,5-dione-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (42.1 mg, 0.088 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water, and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (26.1 mg, 0.176 mmol) and butyl chloroformate (112.0 μL, 0.88 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (3:97) as eluent and then with LCMS (30-100% CH3CN in water) to give the title compound in 80% yield, over two steps, (36.6 mg, 0.702 mmol).