Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH2:21][CH2:20]1>O1CCCC1>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[C:13](=[O:14])[C:12](=[CH:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1
Reactant: O=C1CNC(=O)N1Cc1ccc(Cl)cc1
Reactant: CN1CCN(c2ccccc2C=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccccc2C=C2NC(=O)N(Cc3ccc(Cl)cc3)C2=O)CC1

Procedure:
Under a nitrogen atmosphere in a flame-dried flask, sodium hydride (43 mg, 1.07 mmol, 60% oil dispersion) was washed with hexanes and then treated with tetrahydrofuran (THF) (8 mL), followed by 3-(4-chlorobenzyl)-imidazolidine-2,4-dione (235 mg, 1.04 mmol) and 2-(4-methylpiperazin-1-yl)-benzaldehyde (209 mg, 1.02 mmol), and an additional 2 mL of THF. After refluxing the mixture overnight, the solvent was removed and the residue was treated with aqueous ammonium chloride and aqueous sodium bicarbonate to a pH of 8, then extracted with methylene chloride. The organic extracts were washed with aqueous sodium chloride, dried and concentrated in vacuo to a yellow foam. The foam was crystallized from hot ethyl acetate: hexanes to give a solid, 240 mg (57%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCOCC1>C1COCC1.CO.[Ni]>[CH2:1]([NH:8][C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N)c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N-Benzyl-5-(4-methylpiperazin-1-yl)-2-nitroaniline E-1.1′ (5.000 g; 15.319 mmol) is dissolved in THF (50.000 ml) and filled into a Büchi autoclave. RaNi (500.000 mg) is added and hydrogenated at 6 bar overnight (pressure after 16 h=0.5 bar). The autoclave is filled again with 6 bar H2 and stirred for 5 hours at rt. The reaction mixture is filtered through a plug of celite and HCl in dioxane (4 M, 4.000 ml; 16.000 mmol) is added. The filtrate is concentrated under reduced pressure to give a residue, which is dissolved in the smallest possible amount of MeOH and sonicated for few minutes. Precipitation of the product occurs and the product is filtered off. The product is washed with a very small amount of MeOH and 50 ml of isopropyl ether and then dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([O:11][CH:12]([O:16][CH2:17][CH3:18])[CH2:13]CN)[CH3:10].CC[N:21](CC)CC>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:21][CH2:13][CH:12]([O:16][CH2:17][CH3:18])[O:11][CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCN(CC)CC
Reactant: CCOC(CCN)OCC
Solvent: CCO
Product: CCOC(CNc1ccnc(Cl)n1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of 2,4-dichloropyrimidine (A-1) (20 g, 134 mmol), 3,3-diethoxypropan-1-amine (19.6 g, 147 mmol) and Et3N (20.5 mL, 147 mmol) in ethanol (250 mL) is stirred at RT for 24 h. The mixture is concentrated in vacuo and the residue is purified by flash column chromatography to afford the 2-chloro-N-(2,2-diethoxyethyl)pyrimidin-4-amine (A-2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](O)[CH:2]=1.CN([CH:11]=[O:12])C.C[C:14](C)([O-:16])C.[K+].COCCl>C1COCC1>[CH3:14][O:16][CH2:11][O:12][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1cccnc1
Reactant: CN(C)C=O
Agent: COCCl
Agent: [K+]
Solvent: C1CCOC1
Product: COCOc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Pyridinol (1 eq.) was taken up in a 2:1 (v/v) mixture of DMF:THF (0.9 M). To this was then added, at −15° C., potassium tert-butoxide (1.1 eq.) and the resulting suspension was stirred at −15° C. for 25 min before chloromethyl methyl ether (1.1 eq.) was added dropwise over 15 min. The mixture was then warmed to RT over 1 h and allowed to stir at RT for another 2 h. The reaction mixture was then concentrated in vacuo and the resulting residue partitioned between EtOAc and water. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered through a short plug of SiO2 and the filtrate concentrated in vacuo to afford the title compound as a colorless oil.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=S)[NH2:21]>CO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([NH:2][NH2:3])=[NH:21]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(N)=S)c1Cl
Reactant: NN
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=N)NN)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Hydrazine hydrate (430 μl) is added dropwise to a room temperature solution of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzene thioamide (1.71 g, 5.48 mmol) in 30 ml of methanol. The solution is stirred at room temperature under nitrogen for five hours, then concentrated in vacuo to half its original volume. This material is chromatographed, eluting with ethyl acetate:hexane (gradient of 1:1 to 3:1) to give 1.15 g (68%) of a glassy pale yellow solid. This material darkens and softens after two days at room temperature.
Reaction SMILES: [P:1]([CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2].C(N(CP(O)(O)=O)[CH2:14][C:15]([OH:17])=[O:16])=O>>[P:1]([CH2:5][N:6]([CH2:14][C:15]([OH:17])=[O:16])[CH2:7][C:8]([OH:10])=[O:9])([OH:4])([OH:3])=[O:2]
Reactant: O=C(O)CNCP(=O)(O)O
Reactant: O=CN(CC(=O)O)CP(=O)(O)O
Product: O=C(O)CN(CC(=O)O)CP(=O)(O)O

Procedure:
The percent selectivity to N-phosphonomethylglycine was determined by dividing the moles of N-phosphonomethylglycine and N-formyl-N-phosphonomethylglycine produced by the total moles of N-phosphonomethyliminodiacetic acid consumed and multiplying by 100. The percent conversion of N-phosphonomethyliminodiacetic acid was determined by dividing the moles of N-phosphonomethyliminodiacetic acid that were reacted by the total moles of starting N-phosphonomethyldiacetic acid and multiplying by 100.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](Br)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=1.Br[C:25]1[C:34]2[C:29](=CC=CC=2)[C:28]([NH2:35])=C[CH:26]=1.FC1C=CC(C)=C(S([Cl:46])(=O)=O)C=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[ClH:46].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([S:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:34]3[CH2:29][CH2:28][NH:35][CH2:26][CH:25]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(Br)c2ccccc12
Reactant: Nc1ccc(Br)c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(F)cc1S(=O)(=O)Nc1ccc(C2=CCNCC2)c2ccccc12
Reaction time: 16 h

Procedure:
5-Fluoro-2-methyl-N-[4-bromo-1-naphthyl]benzenesulfonamide—4-Bromo-1-naphthylamine (0.96 g, 4.33 mmol) was dissolved in DCM (10 mL) before pyridine (1 mL) was added. 5-Fluoro-2-methylbenzenesulfonyl chloride was added neat and the reaction mixture was stirred for 16 h. HCl (1 M, 1 mL) was added to the reaction mixture. The organic phase was filtered through a Silica plug using DCM as eluent. The solvent was evaporated. The obtained crude product was purified by flash-chromatography using MeOH (10%) in pentane, to give the desired product as a tar. To increase the purity, the product was purified by recrystallising (EtOAc/hexanes). This gave the product with a purity of 95%. 1H NMR (270 MHz, CDCl3) δ 8.22 (d, J=8.98 Hz, 1H), 7.92 (d, J=7.92 Hz, 1H), 7.64-7.51 (m, 4H), 7.25-7.23 (m, 1H), 7.21-7.05 (m, 2H), 6.84 (br.s, 1H, N—H), 2.55 (s, 3H); MS (ESI+) for C17 H13 Br F N O2 S m/z 394.263 (M+H)+.
Reaction SMILES: CS(Cl)(=O)=O.C(Cl)Cl.O[CH2:10][CH2:11][CH2:12]/[C:13](=[CH:23]\[S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)/[C:14](=[S:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[I-].[Na+]>O.C(N(CC)CC)C>[C:25]1([S:24]/[CH:23]=[C:13]2/[C:14](=[N:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)/[S:22][CH2:10][CH2:11][CH2:12]/2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C(\Sc1ccccc1)=C1\CCCS\C1=N/c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
0.48 g of methanesulfonyl chloride was added to 20 ml of methylene chloride solution including 0.4 g of (E)-5-hydroxy-N-phenyl-2-(phenylthiomethylene) pentanethioamide, 0.46 g of triethylamine and 0.69 of sodium iodide. The resulting solution was stirred at room temperature for 3 hours, and added with water, extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.23 g of the title compound.
Reaction SMILES: [S:1]1[C:5]([NH:6][CH:7]=[C:8]2[C:13](=[O:14])OC(C)(C)OC2=O)=[CH:4][C:3]2[CH2:18][CH2:19][CH2:20][C:2]1=2.ClCCl.CO>O(C1C=CC=CC=1)C1C=CC=CC=1>[C:4]12[C:13]([OH:14])=[CH:8][CH:7]=[N:6][C:5]=1[S:1][C:2]1[CH2:20][CH2:19][CH2:18][C:3]2=1
Reactant: CC1(C)OC(=O)C(=CNc2cc3c(s2)CCC3)C(=O)O1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: Oc1ccnc2sc3c(c12)CCC3
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A solution of 5-[([4H,5H,6H-cyclopenta[b]thiophen-2-yl]amino)methylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (540 mg, 1.84 mmol, 1.00 equiv) in phenoxybenzene (5 mL) was heated at 220° C. for 30 min under nitrogen. After cooling to room temperature, the residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give the desired 7-thia-9-azatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-ol (0.28 g, 80%) as a brown solid. MS (ES): m/z 192 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:18]=[C:17]2[C:19]([CH3:31])([CH3:30])[C:20]3[CH:28]=[C:27](Br)[CH:26]=[C:22]4[C:23]([CH3:25])([CH3:24])[C:13]5[C:14]6[N:15]([C:21]=34)[C:16]2=[C:7]([C:8]([CH3:33])([CH3:32])[C:9]=6[CH:10]=[CH:11][CH:12]=5)[CH:6]=1.CN(C)[CH:36]=[O:37]>[Cu]I>[CH3:1][O:2][C:5]1[CH:18]=[C:17]2[C:19]([CH3:31])([CH3:30])[C:20]3[CH:28]=[C:27]([O:37][CH3:36])[CH:26]=[C:22]4[C:23]([CH3:25])([CH3:24])[C:13]5[C:14]6[N:15]([C:21]=34)[C:16]2=[C:7]([C:8]([CH3:33])([CH3:32])[C:9]=6[CH:10]=[CH:11][CH:12]=5)[CH:6]=1
Reactant: CN(C)C=O
Reactant: CC1(C)c2cccc3c2N2c4c1cc(Br)cc4C(C)(C)c1cc(Br)cc(c12)C3(C)C
Reactant: C[O-]
Agent: [Cu]I
Agent: [Na+]
Product: COc1cc2c3c(c1)C(C)(C)c1cc(OC)cc4c1N3c1c(cccc1C4(C)C)C2(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
A flame-dried 50 mL Schlenk flask was equipped with sodium methanolate (1.90 g, 35.1 mmol, 6.5 mL; 5.4 M in MeOH), copper(I) iodide (0.77 g, 4.05 mmol) and 2,6-dibromo-4,4,8,8,12,12-hexamethyl-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine (0.21 g, 0.40 mmol), suspended in N,N-dimethylformamide (12.4 mL) and degassed with argon for 30 min. This mixture was stirred under an atmosphere of argon at 100° C. overnight. The reaction was stopped by addition of aqueous NH4Cl solution and the resulting mixture was extracted with CH2Cl2 (3×). The combined organic fractions were dried with MgSO4, filtered and the solvents were evaporated. The crude product was purified by column chromatography (silica, n-hexane/EtOAc 8:1) yielding 2,6-dimethoxy-4,4,8,8,12,12-hexamethyl-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine as a greenish oil (0.12 g, 70%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C:15](=[CH:16][C:17]3[C:22]2=[N:21][C:20]([Cl:27])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])(C)(C)C.CN(C)[CH:30]=[O:31]>>[Cl:27][C:20]1[N:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:30]=[O:31])=[C:15]1[N:23]2[C@H:24]([CH3:26])[CH2:25][N:13]([C:11]([OH:10])=[O:12])[CH2:14]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3ccc(Cl)nc3n21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@@H]1CN(C(=O)O)Cc2c(C=O)c3ccc(Cl)nc3n21
Yield: 55.2 %

Procedure:
N,N-Dimethylformamide (10 ml) was cooled to 1 deg C. and treated dropwise with 5.1 ml (56.0 mmol) phosphorus oxychloride. After the addition the temperature was again cooled to 1 deg C. and a solution of 1.0 g (3.11 mmol) (R)-6-chloro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in (Example 2, intermediate a) in 10 ml N,N-dimethylformamide was added. The cooling bath was removed and after 1.5 h at room temperature the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to yield the desired compound as a yellow foam (55.2%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][O:14][CH3:15]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][CH2:12][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]1
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCn1ccc([N+](=O)[O-])n1
Yield: 84.7 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 300 mg, 2.65 mmol) was dissolved in anhydrous N,N-dimethylformamide (6.6 mL) and a 60% dispersion of sodium hydride in mineral oil (106 mg, 2.66 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min, 1-bromo-2-methoxy-ethane (250 μL, 2.66 mmol) was added. The reaction continued to stir under nitrogen for 16 h. The solution was diluted with ethyl acetate (100 mL), washed with 1.0 M aqueous hydrochloric acid solution (25 mL), water (25 mL), saturated aqueous brine solution (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) afforded 1-(2-methoxy-ethyl)-3-nitro-1H-pyrazole (384 mg, 85%) as a white solid: H1-NMR (400 MHz, CDCl3) δ 3.34 (3H, s), 3.77 (2H, t, J=4.4 Hz), 4.36 (2H, t, J=4.8 Hz), 6.87 (1H, d, J=2.8 Hz), 7.54 (1H, d, J=2.4 Hz).
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18])([O-:13])=[O:12].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[N+:11]([C:14]1[CH:15]=[C:16]([C:17]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[O:18])[CH:20]=[CH:21][CH:22]=1)([O-:13])=[O:12]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: NS(=O)(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc([N+](=O)[O-])c1

Procedure:
Benzenesulphonamide (9.4 g, 60 mmol), 3-nitrobenzoic acid (10.0 g, 60 mmol), 4-dimethylaminopyridine (7.32 g, 60 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (11.48 g, 60 mmol) were stirred in anhydrous dichloromethane (400 ml) for 2 hours. The reaction mixture was extracted with 1M sodium hydroxide solution (300 ml), aqueous separated then re-acidified to pH=3 with 5M hydrochloric acid. 3-Nitro-(phenylsulphonylaminocarbonyl)benzene was isolated as a colourless solid (16.0 g, 87%), mp 186°-188° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=1.[NH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:24][C:25]3[N:26]=[C:27]([CH3:30])[S:28][CH:29]=3)[N:3]=[CH:4][C:5]=2[C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=2)[N:10]=1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Cc1nc(N)cs1
Reactant: Cc1ncc(Br)cn1
Product: Cc1ccc2c(-c3cnc(C)nc3)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=349.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 5-bromo-2-methylpyrimidine and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1.CC(O)=O>CN(C=O)C>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:4]1[N:3]=[C:2]([NH:36][C:33]2[CH:34]=[CH:35][NH:31][N:32]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)nc1
Reactant: Nc1cc[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Fc1ccc(C(F)(F)c2nc(Nc3cc[nH]n3)c3ccccc3n2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazoline (100 mg, 0.32 mmol) was added a solution of KI (20 mg, 0.12 mmol), DIEA (0.068 mL, 0.39 mmol), and 1H-pyrazol-3-amine (40 mg, 0.48 mmol) in DMF (2 mL). The mixture was stirred overnight at rt. AcOH (0.14 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(1H-pyrazol-3-yl)quinazolin-4-amine (15 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 12.52 (br s, 1H), 10.82 (br s, 1H), 8.53-8.86 (m, 2H), 7.77-8.13 (m, 4H), 7.57-7.74 (m, 2H), 6.50 (br s, 1H); LC-MS (ESI) m/z 357 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(N(CC)CC)C.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23]>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][C:22](=[O:23])[NH:14][N:13]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NNC(=O)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccc3ccccc3c2)o1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To a stirred mixture of naphthalene-2-carboxylic acid hydrazide (2.0 g, 10.7 mmol, pre pared as described in example 1) and triethylamine (1.1 g, 10.7 mmol) in dry tetrahydrofuran (40 ml) was added carbonyl diimidazole (2.2 g, 13.4 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 17 h. The resulting reaction mixture was evaporated in vacuo and to the residue was added water (50 ml) and ethyl acetate (50 ml). The phases were separated and the organic phase was washed with saturated aqueous sodium chloride (2×25 ml), dried (MgSO4) and filtered and evaporated in vacuo affording 2.2 g of crude product which was recrystallised from a mixture of ethyl acetate and heptane 1:1 (60 ml) affording after drying in vacuo at 50° C. 1.2 g (52%) of the title compound as a solid.
Reaction SMILES: [CH:1]1([C@@H:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[S:29]>>[ClH:17].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[N:27]=[C:28]1[N:9]([C@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[S:29]1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Reactant: C[C@H](NCC(C)(C)O)C1CCCCC1
Product: C[C@@H](C1CCCCC1)N1CC(C)(C)SC1=Nc1ccc(Cl)cc1Cl
Product: Cl

Procedure:
(1S)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1S)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1S)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,4-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,4-dichlorophenylimino)-3-((1S)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH3:26])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:27](O)C.CC[O-].[Na+].CCO>O>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Reactant: CCO
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 72 h
Yield: 70 %

Procedure:
Methyl [1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in, absolute ethanol (10 mL and a catalytic amount of 21% NaOEt/EtOH was added. The reaction was stirred without temperature control for 72 hours, then water (10 mL) was added. The product crystallized, the suspension was cooled to 0° C. and held for 30 minutes. The product was filtered, washed with water (5 mL) and dried to yield 0.071 g (70%) of a white solid: Mass Spectrum: MH+=406. Anal. Calc'd for C18H16N3O4ClS: C, 53.27; H, 3.97; N, 10.3; Cl, 8.74; S, 7.90. Found: C, 53.04; H, 4.00; N, 10.27; Cl, 8.609; S, 7.97.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:29][C:24]3[C:23]([N:30]=2)=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: Nc1ccccc1N
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CO
Product: O=c1[nH]c2ccccc2nc1-c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A mixture of 396.0 mg of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 137.6 mg of 1,2-phenylenediamine is heated to 120° for 60 minutes. Thereafter, the mixture is suspended in methanol, filtered under suction and recrystallized from N,N-dimethylformamide/water. There is obtained 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone of m.p. >300°.
Reaction SMILES: ClC1C=CC=C(F)C=1COC1N(C2C=CC=CC=2C(F)(F)F)C(SCC2C(F)=CC=CC=2Cl)=NN=1.[Cl:36][C:37]1[CH:38]=[C:39]([N:43]2[C:47]([S:48][CH2:49][C:50]3[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][C:51]=3[Cl:57])=[N:46][N:45]=[C:44]2[OH:58])[CH:40]=[CH:41][CH:42]=1.Br[CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[C:62]=1[F:68].C[O-].[Na+]>CN(C=O)C>[Cl:36][C:37]1[CH:38]=[C:39]([N:43]2[C:44]([O:58][CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[C:63]([F:67])[C:62]=3[F:68])=[N:45][N:46]=[C:47]2[S:48][CH2:49][C:50]2[CH:55]=[CH:54][C:53]([Cl:56])=[CH:52][C:51]=2[Cl:57])[CH:40]=[CH:41][CH:42]=1
Reactant: Oc1nnc(SCc2ccc(Cl)cc2Cl)n1-c1cccc(Cl)c1
Reactant: Fc1cccc(CBr)c1F
Agent: C[O-]
Agent: Fc1cccc(Cl)c1COc1nnc(SCc2c(F)cccc2Cl)n1-c1ccccc1C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(COc2nnc(SCc3ccc(Cl)cc3Cl)n2-c2cccc(Cl)c2)c1F

Procedure:
4-(3-chlorophenyl)-3-((2,4-dichlorobenzyl)thio)-5-((2,3-difluorobenzyl)oxy)-4H-1,2,4-triazole (599) was prepared in a similar manner as that described for the synthesis of compound 598 using 4-(3-chlorophenyl)-5-((2,4-dichlorobenzyl)thio)-4H-1,2,4-triazol-3-ol (50 mg, 0.129 mmol), 1-(bromomethyl)-2,3-difluorobenzene (40 mg, 0.194 mmol), sodium methoxide (17.4 mg, 0.322 mmol), and DMF (1.0 mL). 1H NMR (400 MHz, CDCl3) δ: 7.40-7.39 (m, 2H), 7.34-7.31 (m, 2H), 7.25-7.05 (m, 6H), 5.11 (s, 2H), 4.24 (s, 2H). LC-MS ESI m/z; found 512.0 [M+H]+.