Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.[CH3:14][N:15](C)C=O>>[C:14]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1)#[N:15]
Reactant: CN(C)C=O
Reactant: CC1(C)C(=O)Oc2ccc(Br)cc21
Product: CC1(C)C(=O)Oc2ccc(C#N)cc21
Yield: 45 %

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethylbenzofuran-2-one (39.2 g, 0.162 mole) was treated with cuprous cyanide (17.9 g, 0.2 mole) in dimethyl formamide (40 ml) (as in example 2). Recrystallisation (twice) of the product from ethanol yielded 14 g (45%) title product m.p. 138°-140° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C([O:10][C@H:11]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C:13](=[CH:14][C:15](=[O:38])[C@@H:16]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:37])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@H:21]([CH3:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12]1)(=O)C.N#N>CO>[OH:10][C@H:11]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C:13](=[CH:14][C:15](=[O:38])[C@@H:16]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:37])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[C@H:21]([CH3:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:12]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
To a suspension of finely ground K2CO3 (3.45 g, 25 mmoles) in 250 ml of methanol was added methyl 3β-acetoxy-7-oxochol-5-en-24-oate (1) (11.1 g, 25 mmoles). After stirring at 45° for 15 minutes in a N2 atmosphere, most of the methanol was removed in vacuo from the clear brown reaction mixture. The residue was suspended in H2O and extracted three times with CH2Cl2. The combined extracts were washed with H20 twice and saturated brine and dried with MgSO4. Evaporation in vacuo gave 10.1 g of nearly pure 2 as a pale yellow solid. The nuclear magnetic resonance data for this and subsequent Examples was taken at 400 MHz in CDCl3 : δ0.68 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.21 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 3.68 (m, 1H, 3-H); 5.70 (s, 1H, 6-H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16](/[C:17](=[CH:7]/[C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)/[C:18]#[N:19])[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COc1ccc(CC#N)cc1OC
Product: COc1ccc(/C(C#N)=C/c2cccc([N+](=O)[O-])c2)cc1OC
Yield: 96.9 %

Procedure:
3-Nitrobenzaldehyde (3.02 g) and 3,4-dimethoxybenzyl cyanide (3.54 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce the target product (6.01 g, yield: 97%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][Br:10])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)cnc1Cl
Yield: 48 %

Procedure:
A suspension of 2-chloro-3-fluoro-5-methylpyridine (5.1 g, 35 mmol), N-bromosuccinimide (6.1 g, 35 mmol) and benzolyperoxide (0.16 g, 0.66 mmol) in carbon tetrachloride (100 mL) was refluxed overnight. Upon cooling down, the solid was filtered off and the filtrate was concentrated and loaded onto a silica gel column eluted with 5% EtOAc in hexane to give 3.77 g of the desired 2-chloro-3-fluoro-5-bromomethylpyridine as colorless oil in 48% yield. GC-MS calcd. for C6H4BrClFN: 224.46. Found: 224.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].Cl.[CH3:16][NH:17][O:18][CH3:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH3:14])[N:8]=[C:7]([N:17]([CH3:16])[O:18][CH3:19])[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCNc1ncnc(NCCC)n1
Reactant: CNOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCNc1nc(NCCC)nc(N(C)OC)n1
Temperature: 60 °C
Yield: 90 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (10.00 g, 43.53 mmol), N,O-dimethylhydroxylamine hydrochloride (8.49 g, 87.06 mmol) and NaOH (3.13 g, 78.35 mmol) in 1,4-dioxane (120 mL) and water (30 mL) was heated at 60° C. for 6 h, after which the volatiles were removed under reduced pressure. Saturated NaHCO3 solution (500 mL) was added to the residue and the mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were washed with water (300 mL), then with a brine solution (300 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the resultant residue was filtered through silica gel using eluent CH2Cl2/EtOH (9/1 v/v) to yield N-(4,6-bis-n-propylamino[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXXV) (9.96 g, 90% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:36])[CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:11][O:12][C:13](=[O:36])[CH2:14][CH:15]1[CH2:16][CH2:17][CH:18]([C:21]2[CH:22]=[CH:23][C:24]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:25][CH:26]=2)[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc([N+](=O)[O-])cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of 2-bromo-5-nitropyridine (0.81 g, 4.0 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (1.5 g, 4.0 mmol, 1.05 equiv) in 20 Ml DME was added 2 Ml saturated potassium carbonate solution followed by 50 mg Pd(PPh3)4 catalyst. The reaction was then heated to 80° C. over the weekend. Removal of volatiles in vacuo followed by silica gel chromatography (20% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.06 (m, 1 H) 1.00 (dd, J=12.76, 2.15 Hz, 2 H) 1.30-1.42 (m,J=12.82, 12.60, 12.60, 2.91 Hz, 2 H) 1.65 (br. S., 2 H) 1.68 (d, J=3:54 Hz, 3 H) 2.11 (d, J=6.82 Hz, 2 H) 3.46 (s, 3 H) 7.27 (d, J=8.34 Hz, 2 H) 7.98 (d, J=8.34 Hz, 2 H) 8.08 (dd, J=8.84, 0.51 Hz, 1 H) 8.47 (dd, J=8.84,2.78 Hz, 1 H) 9.27 (d, J=2.27 Hz, 1 H) (M+H)+ 355.1.
Reaction SMILES: [C:1]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[OH:14])(=O)[CH2:2][CH2:3][CH3:4].[H][H]>Cl(O)(=O)(=O)=O.[Pt]=O.C(O)(=O)C>[CH2:1]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[OH:14])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCC(=O)c1c(C)cc(C)cc1O
Agent: O=[Pt]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCc1c(C)cc(C)cc1O

Procedure:
10 g. of 2-butyryl-3,5-dimethyl-phenol are dissolved in 100 ml. of glacial acetic acid. After the addition of 3 drops of perchloric acid, the solution is hydrogenated under normal conditions in the presence of 0.5 g. of platinum oxide. After the uptake of 3.0 l. of hydrogen, the hydrogenation is stopped. The catalyst is filtered off. The filtrate is extracted with ether. The ether extract is washed with water to neutral reaction, dried over sodium sulfate and evaporated. There is obtained 2-butyl-3,5-dimethylphenol, which melts at 65°-67° C. after absorption on silica gel, using methylene chloride/hexane 1:1 parts by volume as the eluent.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[C:15]([CH:18]=O)=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.[C:63]([Cl:67])(Cl)(Cl)[Cl:64]>CN(C)C(=O)C.[Zn]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[CH:14]([C:20]([O:22][CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:21])[C:15]([CH:18]=[C:63]([Cl:67])[Cl:64])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(C=C(Cl)Cl)=CS[C@H]12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Zinc powder (78.4 g) was added to a solution of benzhydryl 7-phenylacetamido-3-formyl-2-cephem-4-carboxylate (102.4 g) and triphenylphosphine (367.2 g) in a mixture of carbon tetrachloride (800 ml) and N,N-dimethylacetamide (200 ml) at ambient temperature and the mixture was stirred at 60° C. for 30 minutes. After being cooled, the mixture was added to ethyl acetate (20 l) and the resulting precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give benzhydryl 7-phenylacetamido-3-(2,2-dichlorovinyl)-2-cephem-4-carboxylate (15.26 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl[C:21]1C=CC(C(C2C=CC(Cl)=CC=2)CC(O)=O)=C[CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][C:10]([O:12][CH2:21][CH3:22])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Prepared in a similar manner from 3,3-bis(p-chlorophenyl)acrylic acid was 3,3-bis(p-chlorophenyl)propionic acid, m.p. 190°-193° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[CH3:27][O:26][C:24]([N:1]1[C:5]([C:6]2[C:11](=[O:12])[N:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]3=[N:8][CH:7]=2)=[N:4][N:3]=[N:2]1)=[O:25]
Reactant: O=c1c(-c2nnn[nH]2)cnc2ccccn12
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)n1nnnc1-c1cnc2ccccn2c1=O

Procedure:
A mixture of 1.07 g (0.005 moles) of 3-(1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine; 45 ml of dimethylformamide, 0.75 g (0.0055 moles) of anhydrous potassium carbonate and 0.76 ml (0.01 moles) of methyl chloroformate was stirred at 80°-90° C. for 6 hours. The hot reaction mixture was filtered; the crystals precipitating from the filtrate were collected to obtain 0.32 g (23.5%) of the 1:1 ratio mixture of the title compounds, which on crystallization from ethanol gave the 3-(1-methoxycarbonyl-1H-tetrazol-5-yl)-4-oxo-4H-pyrido[1,2-a]pyrimidine, m.p.: 182°-183° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[C:18]3[CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].C(O)C.C(OCC)(=O)C>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[C:18]3[CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN1CCC(c2cccc3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCC(c2cccc3ccc(Nc4ncccc4N)cc23)CC1
Reaction time: 4 h

Procedure:
A mixture of the product from Example 58 (0.18 g, 0.5 mmol) and 10% palladium on carbon (0.04 g)in ethanol (35 mL) and ethyl acetate (15 mL) was hydrogenated at 45 psi for 4 hours. The mixture was filtered through celite and concentrated to give 7-(3-amino-2-pyridylamino)-1-(1-methyl-4-piperidinyl)-naphthalene which was suitable for further reaction; 1H NMR δ 8.07 (d, J=2 Hz, 1 H), 7.89 (dd, J=1.5, 5 Hz, 1 H), 7.79 (d, J=9 Hz, 1 H), 7.64 (d, J=7.5 Hz, 1 H), 7.45 (dd, J=2, 9 Hz, 1 H), 7.36-7.26 (m, 2H with CHCl3 from NMR solvent overlapping), 7.07 (dd, J=1.5, 7.5 Hz, 1 H), 6.82 (dd, J=5, 7.5 Hz, 1 H), 6.51 (br s, 1 H), 3.49 (br s, 2 H), 3.18 (tt, J=4, 12 Hz, 1H), 3.03 (long range coupled d, J=13.5 Hz, 2 H), 2.39 (s, 3 H), 2.23 (dt, J=2.5, 11.5 Hz, 2H), 2.08-1.87 (m, 4 H). HRMS m/e calculated for C21H24N4 : 332.1996. Observed m/e 332.2003.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](O)(=O)=O)=CC=1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH:12]1([C:4]2[S:7][CH:1]=[CH:6][CH:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Solvent: Cc1ccccc1
Product: c1csc(C2CCCCC2)c1

Procedure:
Synthesis substrates 4H-indeno[1,2-c]thiophen-4-one and 4H-indeno [1,2-c]thiophene and their derivatives are prepared in accordance with MacDowell and Jefferies, J. Org. Chem., 35, 871 (1970). Wherein treatment of 4-bromo-3-thienyllithium with a commonly available lower alkyl substituted cyclohexanone or cyclohexanone, such as 4-methylcyclohexanone, at -65° to -75° C. yields the corresponding cyclohexanol derivative which is dehydrated with para-toluenesulfonic acid in refluxing benzene or toluene to yield a cyclohexylthiophene product such as 3-bromo-4-(4-methyl-1'-cyclohexenyl)thiophene. Dehydrogenation with tetrachlorobenzoquinone in refluxing xylene for 8-24 hours yields the corresponding 3-bromo-4-phenylthiophene, e.g., 3-bromo-4-(4'-methylphenyl)thiophene. After purification by sublimation and/or chromatography over alumina, the bromide is subjected to halogen-metal exchange at -65° to -75° C. with n-butyllithium in ether, followed by carbonation with carbon dioxide. The isolated 3-phenyl-thiophene-4-carboxylic acid derivative, e.g., 3-(4'-methylphenyl)thiophene-4-carboxylic acid, is converted with thionyl chloride to the acid halide. Ring closure to the ketone via heating the aroyl chloride and aluminum chloride in carbon disulfide for 18-36 hours yields the corresponding ketone, such as 6-methyl-8H-indeno[1,2-c] thiophen-8-one. This 8-one derivative, which may be further derivatized according to Method V, is converted (in accordance with Method I) into a hydantoin derivative. Wolff-Kishner reduction (Method VIII) of the 8-one derivative (and optional derivatization according to Method V) and spiro-derivatization in accordance with Methods II, III and IV yields the corresponding spiro-thiazolidinedione, spiro-oxazolidinedione and spiro-succinimide derivatives respectively. These spiro-derivatives may be further derivatized according to Method VI.
Reaction SMILES: [CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][N:22]=[CH:21]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O-:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([N:4]([CH3:27])[C:5]2[C:6]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][N:22]=[CH:21]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: CN(c1nc2cc(C(=O)[O-])ccc2nc1-c1ccc2[nH]ncc2c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 3-(cyclopropyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylate (40.0 mg, 0.11 mmol,) in methanol (15 mL) and water (1 mL) was added a solution of NaOH (20 mg, 0.50 mmol). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (5 mL) and adjusted to pH 6 with hydrochloric acid (3N). The solids were collected by filtration to afford 3-(cyclopropyl(methyl)amino)-2-(1H-indazol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (18.2 mg, 47%).
Reaction SMILES: C([C:6]([CH:22](OCC)OCC)([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:31][C:32]([NH2:34])=[NH:33]>C(O)C>[NH2:34][C:32]1[N:33]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:22][N:31]=1
Reactant: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Reactant: N=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(3,4,5-trimethoxyphenyl)propionitrile (7.9 g, 0.02 mol) and an equivalent amount of potassium hydroxide in ethanol (50 ml) was heated at reflux for one hour. A solution of guanidine (0.07 mol) in ethanol (50 ml) was added, and reflux was resumed. Some ethanol was allowed to boil off bringing the reaction temperature up to 85°. After about 20 hours at reflux the mixture was allowed to cool, and the product was filtered and washed with ethanol. The crude product was purified by treating with hot aqueous acetic acid and reprecipitation with ammonium hydroxide. The yield of purified trimethoprim (m.p. 197°-198°) was 3.6 g (62%), its identity being confirmed by an NMR spectrum.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Clc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1Cl
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Product: COCC(=O)N(c1ccc(Cl)c(Cl)c1)C1CCN(Cc2ccccc2)CC1

Procedure:
12 mmol of methoxyacetyl chloride are added to 12 mmol of 1-benzyl-4-[(3,4-dichlorophenyl)amino]piperidine obtained in the preceding stage in 50 ml of anhydrous tetrahydrofuran (THF). The mixture is brought to reflux for 3 hours. After cooling, the expected product is obtained by filtering the precipitate, which is washed with THF and dried.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:10][C:11]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=1>C1COCC1>[CH:1]1([O:6][CH2:10][C:11]2[C:15]([C:16]([O:18][CH:19]3[CH2:3][CH2:2][CH2:1][CH2:5]3)=[O:17])=[C:14]([CH:20]([CH3:22])[CH3:21])[O:13][N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: COC(=O)c1c(CBr)noc1C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1onc(COC2CCCC2)c1C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
A solution of cyclopentanol (0.44 mL, 4.8 mmol), in THF (10 mL), was stirred at 0° C. as sodium hydride 60% oil dispersion (192 mg, 4.8 mmol) was added. The solution was allowed to stir for 30 minutes. A solution of methyl 3-(bromomethyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (500 mg, 1.91 mmol), in THF (5 mL) was then added and the resulting solution was allowed to warm to room temperature and stir for 3 hours. The solution was then partitioned between brine and ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated. The residue purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated to yield cyclopentyl 3-[(cyclopentyloxy)methyl]-5-(1-methylethyl)-4-isoxazolecarboxylate (94 mg, 15%). 1H NMR (400 MHz, DMSO-d6): δ 5.29-5.26 (m, 1H), 4.54 (s, 2H), 3.98 (m, 1H), 3.64 (septet, 7 Hz, 1H), 1.85 (m, 2H), 1.72-1.56 (m, 12H), 1.47-1.40 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 322 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-])=O.[K+].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[F:21][C:22]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:23]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([C:23]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:22]=1[F:21])[CH3:3])[CH3:9]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)c1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
To an oven-dried flask was added potassium ethyl malonate (3.66 g, 21.5 mmol) and freshly distilled acetonitrile (70 mL). The mixture was cooled to 10° C. to 15° C. and stirred under an atmosphere of nitrogen and to it added anhydrous magnesium chloride (2.44 g, 25.7 mmol) and triethylamine (2.05 g, 20.3 mmol). The mixture was then stirred at room temperature under nitrogen for 2.5 hours. The resultant white slurry was recooled to 0° C. and 2,4,5-trifluorobenzoyl chloride was added over a period of 15 minutes, followed by more triethylamine (0.23 g, 2.3 mmol). The mixture was then stirred at room temperature overnight under nitrogen. Acetonitrile was then removed in vacuo and toluene (30 mL) was added. The mixture was reconcentrated and more toluene (60 mL) then added. Hydrochloric acid (1.5 M, 40 mL) was cautiously added, ensuring that the temperature did not exceed 25° C., and the aqueous layer separated. The organic fraction was washed with 1.5 M HCl (2×25 mL) and water (2×25 mL), dried over MgSO4, and solvent removed in vacuo to afford 3-oxo-3-(2,4,5-trifluoro-phenyl-propionic acid ethyl ester as a pale orange solid (2.35 g, 9.55 mmol, 94%). Rf 0.55 (CH2C2), mp 57-59° C. FTIR, νmax/cm −1 3088, 2990, 1735, 1687, 1514, 1429, 1321, 1205, 1140, 1055, 897, 807. 1 H NMR (CDCl3, 250 MHz), δ/ppm [12.69 (s), 5.81 (s) and 3.92 (d, J=3.9 Hz)] (2 H, keto-enol tautomers); 7.74 (1 H, m, Ar H); 6.98 (1 H, m, Ar H); 4.24 and 4.17 (2 H, both q, 3J=7.1 Hz); 1.31 and 1.24 (3 H, both t, 3J=7.1 Hz). 13C{1 H}NMR (CDCl3, 63 MHz), δ/ppm 187.8 (C=O); 173.0 (—HC=C); 166.9 (CO2Et); 163.7, 159.8, 155.9, 151.8, 149.0, 145.3, 120.9 (quat. Ar C); 118.7, 106.6 (Ar C—H); 92.9 (HC=C); 61.4 and 60.6 (—OCH2); 49.4 (—OCCH2CO—); 14.0 (—CH3). 19FNMR (CDCl3, 235 MHz) δ/ppm −110.6 and −111.7 (m, Ar F); −123.5 and −129.0 (m, Ar F); −140.5 and −141.7 (m, Ar F). λmax/nm (δ/dm3mol−1cm−1) 295 (4781), 281 (3962), 240 (5191). HRMS (EI), M+/z C11H9F3O3 (M−) requires 246.0504; found 246.0514.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([N+:10]([O-])=O)[C:6](=[O:9])[NH:7][CH:8]=1)#[CH:2]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:10][C:5]1[C:6](=[O:9])[NH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH3:13]
Reactant: C#Cc1c[nH]c(=O)c([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1c[nH]c(=O)c(N)c1C

Procedure:
A mixture of 5-ethynyl-4-methyl-3-nitro-2-pyridone (0.18 g, 0.6 mmol) and 10% Pd/C (0.02 g) in ethanol/ethyl acetate (50 mL, 1/1) was hydrogenated at 35 psi in a Parr apparatus overnight. The catalyst was removed by filtration, and the solvents were evaporated to give 3-amino-5-ethyl-4-methyl-2-pyridone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[S:11]1[C:15]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:18])=[O:17])=[C:4]([NH:10][S:16]([C:15]2[S:11][C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH:14]=2)(=[O:17])=[O:18])[CH:3]=1
Reactant: Nc1cc(F)c(Cl)cc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: O=S(=O)(Nc1cc(F)c(Cl)cc1NS(=O)(=O)c1cc2ccccc2s1)c1cc2ccccc2s1
Yield: 59.2 %

Procedure:
N,N′-(4-chloro-5-fluoro-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (0.108 g) was prepared by using 4-chloro-5-fluoro-benzene-1,2-diamine (0.054 g, 0.33 mmol) and Benzo[b]thiophene-2-sulfonyl chloride (0.157 g, 0.67 mmol), following the procedure as in Example 32.