Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)([O-])=O.C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1.C(Cl)Cl.CCOC(C)=O>C1COCC1>[O:31]=[C:30]1[N:7]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:6][C:5]2[C:4](=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:1]1
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2[N+](=O)[O-])CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Reaction time: 16 h
Yield: 24.4 %

Procedure:
To a solution of tert-butyl 4-(2-nitrobenzylamino)piperidine-1-carboxylate (13.2 g, 43.2 mmol) in THF (400 ml) was added a solution of CDI (7.7 g, 47.5 mmol) in 1:1 DCM:THF (100 ml) dropwise over 1 hour followed by stirring the reaction mixture for a further 16 hours. The reaction mixture was evaporated to give an oil that, when treated with EtOAc, precipitated the desired product. The precipitate was washed with cold EtOAc and dried to give a yellow solid (3.5 g). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=332; tR=3.01.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:12]3)[N:7]([CH2:25][C:26]#[C:27][CH3:28])[C:6]=2[C:5](=[O:29])[NH:4][C:3]1=[O:30].[O:31]1[CH:35]=[CH:34][C:33]([CH2:36]O)=[CH:32]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[O:31]1[CH:35]=[CH:34][C:33]([CH2:36][N:4]2[C:5](=[O:29])[C:6]3[N:7]([CH2:25][C:26]#[C:27][CH3:28])[C:8]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:12]4)=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:30])=[CH:32]1
Reactant: OCc1ccoc1
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)[nH]c(=O)n2C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(Cc1ccoc1)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 300 mg of 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine, 95 μl furan-3-yl-methanol, 302 mg triphenylphosphine and 226 μl diisopropyl azodicarboxylate in 4 ml tetrahydrofuran is stirred overnight at ambient temperature. For working up the reaction mixture is combined with saturated potassium carbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate and evaporated down. The flask residue is chromatographed over a silica gel column with cyclohexane/ethyl acetate (1:1 to 3:7).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[CH2:16])[C:12]([O:14]C)=[O:13]>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[CH2:16])[C:12]([OH:14])=[O:13]
Reactant: C=C(C(=O)OC)c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=C(C(=O)O)c1ccccc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.3 %

Procedure:
765 ml of an aqueous solution (0.33M) of potassium hydroxide were added to a solution of 21 g of the product of Step B in 1 liter of tetrahydrofuran and the mixture was stirred for 48 hours at ambient temperature. The tetrahydrofuran was evaporated off and the aqueous phase was cooled and acidified with 2N hydrochloric acid. Separation was carried out, then washing with water and drying to obtain 16.8 g of the product which was used as is for the following step. An analytical sample was prepared by hot and cold crystallization of 1.6 g of product from 30 ml of isopropyl ether to obtain 0.8 g of the product melting at 146° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[OH:10].[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[CH:14][N:13]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:10][C@@H:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]2[CH3:3])[N:15]=[CH:14][N:13]=1
Reactant: C[C@@H]1CCCC[C@H]1O
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Temperature: 0 °C
Yield: 39.4 %

Procedure:
In 4 ml of tetrahydrofuran was suspended 0.11 g of sodium hydride (60% in oil), to which 1 ml of a tetrahydrofuran solution containing 0.25 g of trans-2-methylcyclohexanol was slowly added dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 10 minutes, to which 1 ml of a tetrahydrofuran solution containing 0.3 g of 4,6-dichloropyrimidine was added at 0° C., followed by further stirring at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.18 g of 4-chloro-6-(trans-2-methylcyclohexyloxy)pyrimidine.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]#[N:15])=[CH:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:23]>O>[N+:1]([C:4]1[O:8][C:7]([C:9]2[C:13]([C:14]([NH2:15])=[O:23])=[CH:12][N:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Solvent: O
Product: NC(=O)c1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 40 °C
Yield: 98 %

Procedure:
Add 29.4 g of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carbonitrile to 59 ml of concentrated sulfuric acid while stirring and maintaining the temperature at 40° C for 5 hours. Pour the solution onto 500 g of ice and water. Seperate the formed precipitate by vacuum filtration and wash it with water until it is neutral to obtain a 98% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxamide [m.p. 236° to 238° C (from dimethylformamide/methanol)].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].I[CH3:13]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH3:13])=[N:6][CH:7]=1
Reactant: OCc1ccc(Br)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Br)cn1
Temperature: 60 °C
Yield: 65 %

Procedure:
To a stirred solution of 5-bromo-2-(hydroxymethyl)pyridine (150 mg, 0.798 mmol) in THF (8 mL) under nitrogen at r.t. was added sodium hydride (60% dispersion in oil, 64 mg, 1.60 mmol). After 30 minutes iodomethane was added and the reaction mixture was heated to 60° C. for 3 h, then cooled to r.t. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL); the organic fraction was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo to give the title compound (70 mg, 65%) as 70% pure material. LCMS (ES+) 202.0 (M+H)+, RT 2.40 minutes (Method 1).
Reaction SMILES: [CH3:1][C:2]([OH:13])([C:4]#[C:5]C1C=CC=C(N)C=1)[CH3:3].NC#CC1C=CC=CC=1.NC1C=C(C#C)C=CC=1.Br[C:33]1[CH:34]=[C:35]([N+:39]([O-:41])=[O:40])[CH:36]=[CH:37][CH:38]=1.CC(O)(C#C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.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>[CH3:1][C:2]([OH:13])([C:4]#[C:5][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1)[CH3:3]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CC(C)(O)C#Cc1cccc(N)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#CC(C)(C)O
Agent: C#Cc1cccc(N)c1
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1cccc([N+](=O)[O-])c1

Procedure:
Sabourin, Prepr. Div. Pet. Chem., Am. Chem. Soc., vol. 24, pp. 233-239 discloses the preparation of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol (an aminophenylacetylene) and 3-aminophenylacetylene in two and three steps, respectively, from 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol. In the first step, 3-bromonitrobenzene and 2-methyl-3-butyn-2-ol were reacted in the presence of a catalyst system of bis(triphenylphosphine)palladium dichloride, additional triphenylphosphine, and cuprous iodide in triethylamine solvent at the reflux temperature to obtain 2-methyl-4-(3-nitrophenyl)-3-butyn-2-ol. In the second step, this nitrophenylacetylene was hydrogenated in isopropanol in the presence of a Ru/Al2O3 catalyst to obtain 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol. This reference states that is essential to stop the hydrogenation reaction at the stoichiometric point because reduction of the triple bond ensues. In the third step, this aminophenylacetylene was heated in toluene in the presence of sodium hydroxide pellets, with removal of the acetone co-product by distillation, to obtain 3-aminophenylacetylene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.[CH3:14][S-:15].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([S:15][CH3:14])[N:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(OC)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)nc(SC)c1
Reaction time: 18 h

Procedure:
To a stirred solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (8.5 g, 42 mmol) in DMF (100 mL) was added sodium thiomethoxide (3.22 g, 41.6 mmol), resulting in a yellow colored solution. After 18 hours, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to afford 2-methoxy-6-methylsulfanyl-isonicotinic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.Cl[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[O:20][N:19]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:17][C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[O:20][N:19]=3)=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: ClCc1cc(-c2ccc(Cl)cc2)on1
Solvent: CC#N
Product: COC(=O)Cc1coc2cc(OCc3cc(-c4ccc(Cl)cc4)on3)ccc12
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A solution of (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (0.41 g, 2.0 mmol) and commercially available 3-(chloromethyl)-5-(4-chlorophenyl)isoxazole (0.46 g, 2.0 mmol) were combined in 15 ml of acetonitrile. The mixture was stirred at room temperature for 64 hours and filtered. The insoluble material was washed on the funnel several times with fresh acetonitrile. The bulk of the solvent was evaporated, and the residue was partitioned between 200 ml of ethyl acetate and 150 ml of brine. The layers were separated, and the aqueous layer was extracted with fresh ethyl acetate (2×100 ml). The combined organic layers were back-washed with brine (2×150 ml), then dried over anhydrous sodium sulfate and concentrated. The crude product was purified by normal phase chromatography. mp 136–137° C.; MS m/z 397 (M−1).
Reaction SMILES: O.[OH-].[Li+].[C:4]1([S:10]([CH2:13][C:14]2[C:19]([C:20]([O:22]C)=[O:21])=[C:18]([CH2:24][CH3:25])[C:17]([C:26]3[CH:30]=[CH:29][O:28][CH:27]=3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O1CCOCC1.O>[C:4]1([S:10]([CH2:13][C:14]2[C:19]([C:20]([OH:22])=[O:21])=[C:18]([CH2:24][CH3:25])[C:17]([C:26]3[CH:30]=[CH:29][O:28][CH:27]=3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Temperature: 150 °C
Yield: 30.5 %

Procedure:
Lithium hydroxide monohydrate (0.075 g) was added to a solution of methyl 6-(benzenesulphonylmethyl)-2-ethyl-3-(furan-3-yl)benzoate (Intermediate 152, 0.092 g) in dioxane (1 ml) and water (1 ml) and the resultant solution was stirred and heated in the microwave at 150° C. for 4.5 hours. Ethyl acetate and water were added and the organic layer was separated, then acidified with concentrated hydrochloric acid. The mixture was extracted with ethyl aceate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness then azeotroped with toluene. The residue was triturated with ether and the solid was collected by filtration and dried to give 6-(benzenesulphonylmethyl)-2-ethyl-3-(furan-3-yl)benzoic acid (0.027 g) as a white solid.
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:8]([CH3:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]=1.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1.C(N(CC)CC)C>C(O)C>[CH3:14][C:15]1[N:20]=[C:19]([S:21][CH2:3][C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[N:5]=2)[N:18]=[C:17]([OH:22])[CH:16]=1
Reactant: Cn1c(CBr)nc2ccccc21
Reactant: Cc1cc(O)nc(S)n1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2nc3ccccc3n2C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
A mixture of 2-(bromomethyl)-1-methyl-benzimidazole hydrobromide (6.8 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (740 mg, 5.2 mmol), and triethylamine (4 mL, 28.7 mmol) in absolute ethanol (30 mL) was stirred at room temperature overnight. The mixture was recovered, evaporated, and then co-evaporated with EtOAc (20 mL). The solid residue was treated with water (200 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (2×20 mL), and hexanes (2×20 mL), and then dried in vacuo, affording 6-methyl-2-{[(1-methyl-1H-benzimidazol-2-yl)methyl]sulfanyl}pyrimidin-4-ol (1.3 g, 90% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 3.83 (s, 3H), 4.70 (s, 2H), 6.02 (s, 1H), 7.19 (m, 2H), 7.53 (m, 2H); M+287. The product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=C[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.BrC1C=[N:19]C(C#N)=NC=1.BrC1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[N:12][C:11]([C:14]#[N:15])=[N:19][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cn1
Reactant: N#Cc1ccc(-c2ccc(Br)cc2)cn1
Agent: OB(O)c1ccc(Br)cc1
Product: N#Cc1ncc(-c2ccc(Br)cc2)cn1
Yield: 58 %

Procedure:
The same procedure described for 5-(4′-bromophenyl)-2-pyridinecarbonitrile was used by employing 5-bromo-2-cyanopyrimidine and 4-bromophenylboronic acid to furnish 84 in 58% yield; mp 202-204° C. 1H NMR (DMSO-d6): δ 7.79 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 9.39 (s, 2H).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25]Br)=[CH:19][CH:18]=1.Cl>C(O)C>[CH2:11]([O:10][C:2]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[CH:19][CH:18]=1)=[O:9])[CH3:12]
Reactant: BrCCCc1ccc(CCCBr)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccc(CCCC(C(=O)OCC)C(=O)OCC)cc1)C(=O)OCC
Temperature: 0 °C
Yield: 99.1 %

Procedure:
First, to 483 mg of metallic sodium dissolved in 21 ml of absolute ethanol, 6.72 g of diethyl malonate was added dropwise, and the mixture was refluxed for 5 minutes. After cooling, to the solution was added dropwise a mixture of 3.2 g of 1,4-bis(3-bromopropyl)benzene and diethyl malonate over 5 minutes, and the mixture was refluxed for 40 minutes to obtain a white suspension. After cooling and addition of 21 ml of ice water, the mixture was adjusted to pH 7.0 with 1N hydrochloric acid, and ethanol was removed under a reduced pressure to obtain an aqueous layer, which was then twice extracted with 100 ml of benzene each time. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated under a reduced pressure to remove the solvent, and then to remove any unreacted diethyl malonate under a reduced pressure at 140° C. to obtain 4.74 g of the title compound as a colorless liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)([O-])=O.C([O-])=O.[NH4+].O1CCOCC1>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1ccc2[nH]c(=O)sc2c1
Reaction time: 24 h

Procedure:
The compound obtained in Step A (0.036 mol) is dissolved in 90 ml of methanol, and then 2.5 g of palladium-on-carbon and 18 g of ammonium formate are added in succession and the mixture is heated at reflux for 18 hours. 40 ml of dioxane are added and refluxing is continued for 24 hours. The palladium-on-carbon is then filtered off. The reaction mixture is concentrated, the resulting precipitate is filtered off, and the filtrate is evaporated under reduced pressure. The resulting residue is taken up in a 1N hydrochloric acid solution and extracted twice with 50 ml of ethyl acetate each time. The aqueous phase is rendered alkaline with a 10% potassium carbonate solution and extracted twice with 50 ml of ethyl acetate each time. The organic phase is dried and then evaporated under reduced pressure, and the resulting precipitate is recrystallised from acetonitrile.
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH:12]12[CH2:17][CH:16]1[C:15](=[O:18])[O:14][C:13]2=[O:19]>C(O)C>[CH2:1]([N:6]1[CH2:7][CH2:8][N:9]([C:15]([CH:16]2[CH2:17][CH:12]2[C:13]([OH:19])=[O:14])=[O:18])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1CCNCC1
Reactant: O=C1OC(=O)C2CC12
Solvent: CCO
Product: CCCCCN1CCN(C(=O)C2CC2C(=O)O)CC1

Procedure:
To 100 mL of ethanol is added 1-pentylpiperazine (15.6 g, 0.1 mol) and 11.2 g (0.1 mol) of 3-oxabicyclo[3.1.0]-hexane-2,4-dione. Reflux the reaction and monitor by thin-layer chromatography. Upon completion remove the solvent in vacuo to obtain the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C2CCCCCCCC2)BCCCCCCC1.[OH-:35].[Na+].OO>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:35])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: C=CCCCOc1ccc(C(C)(C)C)cc1
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCCCCCO)cc1
Temperature: 25 °C

Procedure:
The 5-(p-tert-butylphenoxy)-1-pentene (10.5 g) was treated with 115 ml 0.5 M 9-borabicyclononane in tetrahydrofuran and the reaction mixture was stirred at reflux for one hour. The solution was cooled to room temperature and treated with 25 ml 3 N sodium hydroxide, then 10 ml 30% hydrogen peroxide. After the bubbling ceased the reaction mixture was partitioned between 150 ml ether-150 ml water. The ether layer was removed, dried (MgSO4), and evaporated to a yellow oil which was chromatographed through 300 g, 90 to 200 mesh silica gel (2% MeOH/CH2Cl2 eluent) yielding a yellow oil which was vacuum distilled (126° C./0.75 mm) to a clear, colorless oil, 5-p-t-butylphenoxy-1-pentanol, 1.7 g.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:32][C:33]1[S:37][C:36]([C:38](Cl)=[O:39])=[CH:35][CH:34]=1.[N:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH2:75][CH2:74][C:50]3([CH2:55][CH2:54][N:53]([C:56]([C:58]4[N:59]=[C:60]5[CH2:65][N:64](C(OC(C)(C)C)=O)[CH2:63][CH2:62][N:61]5[CH:73]=4)=[O:57])[CH2:52][CH2:51]3)[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>C(Cl)Cl>[Cl:32][C:33]1[S:37][C:36]([C:38]([N:64]2[CH2:63][CH2:62][N:61]3[CH:73]=[C:58]([C:56]([N:53]4[CH2:52][CH2:51][C:50]5([CH2:74][CH2:75][N:47]([C:44]6[CH:43]=[CH:42][N:41]=[CH:46][CH:45]=6)[CH2:48][CH2:49]5)[CH2:55][CH2:54]4)=[O:57])[N:59]=[C:60]3[CH2:65]2)=[O:39])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)nc2C1
Reactant: O=C(Cl)c1ccc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cn2c(n1)CN(C(=O)c1ccc(Cl)s1)CC2)N1CCC2(CC1)CCN(c1ccncc1)CC2
Reaction time: 0.5 h
Yield: 11 %

Procedure:
EDCl (1.29 mmol, 1.5 equiv.), HOBt (1.29 mmol, 1.5 equiv.) and DIPEA (3.44 mmol, 4 equiv.) were added at 0° C. to a solution of 5-chlorothiophene-2-carbonyl chloride (0.86 mmol, 1.0 equiv.) in DCM (20 ml), and the mixture was stirred for 30 min. A solution of tert-butyl 2-(9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (0.86 mmol, 1.0 equiv.) in DCM (5 ml) was then added, the ice bath was removed, and stirring was carried out for 16 h at 25° C. The reaction mixture was diluted with dichloromethane (100 ml) and washed with sat. sodium carbonate solution (65 ml), sat. ammonium chloride solution (65 ml), water (50 ml) and sat. sodium chloride solution (50 ml), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (8% methanol in DCM) and the desired product was thus obtained in the form of a white solid. Yield: 11%. MS, Rt=2.7 min; m/z=525.2 [MH]+
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1CCc2cc(O)ccc21

Procedure:
To a solution of 5-methoxy-1-indanone (2 g, 12.3 mmol) in benzene (50 ml) was added AlCl3 (4 g, 31 mmol). The mixture was heated at reflux for 5 hours and extracted with ethyl acetate. The organic phase was evaporated and purified by flash chromatography, eluting with CH2Cl2 /CH3CN (90/10) to give 5-hydroxy-1-indanone as a yellow solid (1.65 g; 90%).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]([NH:13][CH3:14])([C:10]([NH2:12])=[O:11])[CH2:6][CH2:5]1)(C)C.C(N1CCC(NC)(C(N)=O)CC1)C1C=CC=CC=1>>[CH3:14][NH:13][C:7]1([C:10]([NH2:12])=[O:11])[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]1
Reactant: CNC1(C(N)=O)CCN(C(C)C)CC1
Agent: CNC1(C(N)=O)CCN(Cc2ccccc2)CC1
Product: CNC1(C(N)=O)CCNCC1

Procedure:
The 1-isopropyl-4-(methylamino)piperidine-4-carboxamide used as starting material was prepared as follows: 1-benzyl-4-(methylamino)piperidine-4-carboxamide (J Med Chem., 1998, 41(25), 5084) may be deprotected by hydrogenation using an analogous method to that described for the equivalent step in Example 74 to give 4-(methylamino)piperidine-4-carboxamide; 1H NMR Spectrum: 1.35 (m, 2H); 1.68 (m, 2H); 1.93 (brs, 1H); 2.06 (s, 3H), 2.59 (m, 2H); 2.71 (m, 2H); 6.81 (s, 1H); 7.14 (s, 1H).
Reaction SMILES: C([N:3]1[C:8]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH2:15][C:7]=2[N:6]2[C:16](Cl)=[C:17]([C:19]([O-:21])=[O:20])[N:18]=[C:5]2[C:4]1=[O:23])C.[ClH:24]>>[Cl:24][C:11]1[CH:12]=[CH:13][C:14]2[CH2:15][C:7]3[N:6]4[CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=[C:5]4[C:4](=[O:23])[NH:3][C:8]=3[C:9]=2[CH:10]=1
Reactant: CCn1c2c(n3c(Cl)c(C(=O)[O-])nc3c1=O)Cc1ccccc1-2
Reactant: Cl
Product: O=C(O)c1cn2c3c([nH]c(=O)c2n1)-c1cc(Cl)ccc1C3

Procedure:
0.58 g of ethyl-chloro-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-2-carboxylate in suspension in 10 ml of 6N hydrochloric acid is heated to reflux for 24 hours. After cooling to a temperature close to 20° C., the insoluble matter is filtered off, washed with water and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 45° C. 0.38 g of 7-chloro-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazine-2-carboxylic acid is thus obtained in the form of a beige powder whose melting point is higher than 260° C. (analysis C14H10ClN3 O4 ; % calculated C: 52.60, H: 3.15, Cl: 11.09, N: 13.14; % found C: 52.9, H: 3.3, Cl: 10.8, N: 12.9); 1H spectrum in DMSO, T=300K, δ in ppm (300 MHz): 4.02 (2H, s, CH2), 7.37 (1H, d, J=7 Hz, CH arom.), 7.60 (1H, d, J=7 Hz, CH arom.), 7.92 (1H, s, CH arom.), 8.52 (1H, s, CH arom.), 12.45 (1H, s, NH)).