Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([OH:31])=O)[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:28][C:29]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:31])[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][C@H:16]([CH3:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:14][C@H:13]2[CH3:27])=[O:11])=[N:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
To a solution of N-[(5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-pyridin-3-yl)-acetic acid (0.045 g, 0.10 mmol) in dichloromethane (2 mL) was added 4-dimethylaminopyridine (0.018 g, 0.15 mmol), and 1,3-dicyclohexylcarbodiimide (0.023 g, 0.11 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, and then treated with methanesulfonamide (0.011 g, 0.12 mmol). The reaction was stirred at ambient temperature for 18 hours, filtered through a pad of celite and the resulting filter cake was washed with dichloromethane. The combined organics were concentrated in vacuo and purified by silica gel chromatography followed by trituration with dichloromethane to give the title compound (0.037 g, LRMS: 525.3, 527.2).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].C([O-])(O)=O.[Na+].O1CCOCC1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>CCOC(C)=O.O>[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([NH:5][NH:4][C:1](=[O:3])[CH3:2])=[O:23]
Reactant: CC(=O)NN
Reactant: O=C(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)NNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107 %

Procedure:
To a mixture of acetic hydrazide (2.63 g) and NaHCO3 (3.44 g) in a solution of dioxane (40 ml) and H2O (4 ml) was added dropwise 2-thiophenecarbonyl chloride (4.00 g) with ice-cooling. After stirring for 2 hours at ambient temperature, the mixture was diluted with AcOEt and filtered. After concentration of the filtrate, the obtained residue was crystallized from a mixture of AcOEt and hexane to give 5.38 g of N-(2-thienylcarbonylamino) ethanamide.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])=[N:6][N:5]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.[Cl-].[Na+]>O1CCCC1.CN(P(N(C)C)(N(C)C)=O)C>[O:20]1[CH2:19][CH:18]1[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[O:8][C:4]([CH3:3])=[N:5][N:6]=1
Reactant: BrCC1CO1
Reactant: Cc1nnc(-c2ccccc2O)o1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccccc2OCC2CO2)o1
Temperature: 25 °C
Reaction time: 32 h

Procedure:
1.6 g of sodium hydride, in the form of a 55% strength suspension in paraffin oil (0.036 mole) are introduced into 70 ml of anhydrous tetrahydrofuran and 6.3 g (0.036 mole) of ortho-(5-methyl-1,3,4-oxadiazol-2-yl)-phenol, dissolved in 50 ml of tetrahydrofuran, are added dropwise. 5 g (0.036 mole) of epibromohydrin are then introduced dropwise, 10 ml of hexamethylphosphorotriamide are added to the reaction mixture, and the whole is stirred for 32 hours at room temperature. Thereafter, the reaction mixture is poured into 500 ml of aqueous sodium chloride solution and repeatedly extracted by shaking with diethyl ether. The combined ether extracts are dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil. This crystallizes on triturating with a toluene/hexane mixture. 5.5 g (66% of theory) of colorless crystals are obtained; melting point 38°-40° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[F:20].[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:21][C:22]3=[CH:26][CH:25]=[N:24][N:23]23)=[CH:14][C:13]=1[F:20]
Reactant: O=Cc1ccc(Cl)c(F)c1
Reactant: Nc1cc[nH]n1
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(Cl)c(F)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 4-chloro-3-fluorobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [NH3:1].[C:2]([CH2:4][C:5]([O:7]C)=O)#[N:3].[C:9]([O:15]C)(=O)[CH2:10][C:11]([CH3:13])=O.Cl>O>[C:2]([C:4]1[C:5](=[O:7])[NH:1][C:9]([OH:15])=[CH:10][C:11]=1[CH3:13])#[N:3]
Reactant: N
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: O
Product: Cc1cc(O)[nH]c(=O)c1C#N
Temperature: 25 °C

Procedure:
24 Parts of 28% aqueous ammonia, 20 parts of methyl cyanoacetate (reagent), 23 parts of methyl acetoacetate (reagent) and 40 parts of water were mixed and reacted at 100° C. for 6 hours. Thereafter, the suspension was left to cool to room temperature. 50 Parts of 35% hydrochloric acid was added thereto, and crystals were collected by filtration and washed with water, followed by drying under reduced pressure to obtain 21 parts of 3-cyano-4-methyl-6-hydroxypyridone.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:14]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[O:17][N:16]=[C:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:14]=1
Reactant: COC(=O)CCCCc1noc(-c2ccccc2OC)n1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCc1noc(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Add boron tribromide (4.9 mL, 51.7 mmol) dropwise to a stirred solution of methyl 5-[5-(2-methoxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (3.0 g, 10.3 mmol) in methylene chloride (70 mL) at 0° C. under nitrogen. Allow to warm to room temperature and stir for 5 hours. Cool the mixture to 0° C., 1 add methanol (20 mL) dropwise and allow to warm to room temperature. Remove the solvents under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:9), to provide methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate, which is used without further purification. Add a solution of sodium hydroxide (800 mg, 20 mmol) in water (15 mL) to a solution of methyl 5-[5-(2-hydroxyphenyl)[1,2,4]oxadiazol-3-yl]pentanoate (2.6 g, 9.4 mmol) in methanol (30 mL) at room temperature and stir the mixture for 2 hours. Adjust the pH of the mixture to 2 with 1 N HCl and extract with ethyl acetate (2×150 mL). Wash the combined organic extracts with water (3×150 mL), dry over sodium sulfate and remove the solvent under reduced pressure. Triturate the residue with hexanes/ethyl acetate and collect the solids by vacuum filtration to afford the title compound (2.4 g, 89% over two steps). APCI MS m/z 261 [C13H14N2O4−H]−.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:9]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]#[CH:29])[CH:26]=3)=[N:8][C:7]=2[N:6]([CH2:30][CH2:31][CH3:32])[C:5]1=[O:33])[CH2:2][CH3:3].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C=O.[CH3:43]S(C)=O>O.[Cu]I>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:43][C:29]#[C:28][CH2:27][N:25]2[CH:26]=[C:22]([C:9]3[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:21])[CH3:19])[C:11]4[C:12](=[O:13])[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:33])[N:6]([CH2:30][CH2:31][CH3:32])[C:7]=4[N:8]=3)[CH:23]=[N:24]2)[CH2:37][CH2:36]1
Reactant: CS(C)=O
Reactant: C#CCn1cc(-c2nc3c(c(=O)n(CCC)c(=O)n3CCC)n2COCC[Si](C)(C)C)cn1
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: C=O
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#CCN4CCN(C)CC4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 30 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
A mixture of 1,3-dipropyl-8-(1-prop-2-ynyl-1H-pyrazol-4-yl)-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.1 g, 0.212 mmol), N-methyl piperazine (0.025 g, 0.254 mmol), formaldehyde (0.08 ml), CuI (0.008 g), and DMSO (2 ml) was stirred at 30° C. for 72 hours. The mixture was cooled to 25° C. and the residue was diluted with water (10 ml) and extracted with ethylacetate (2×10 ml). The organic layer was washed with saturated brine solution (50 ml) and dried over Na2SO4. The solvent was evaporated to obtain pure 8-{1-[4-(4-Methyl-piperazin-1-yl)-but-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.105 g, 85%).
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH3:3].[C:6]([Mg]Br)#[C:7][CH3:8].O1CCCC1.C(=O)(O)[O-].[K+].Cl.[NH:22]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][OH:32])=[CH:26][CH:25]=1)[NH2:23]>CCOCC.C(O)C>[CH2:7]([C:6]1[CH:1]=[C:2]([CH3:3])[N:22]([C:24]2[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][OH:32])=[CH:28][CH:29]=2)[N:23]=1)[CH3:8]
Reactant: CCC(=O)Cl
Reactant: CC#C[Mg]Br
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc(C)n(-c2ccc(CCO)cc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27 %

Procedure:
To a stirred solution of propionyl chloride (0.87 mL, 10 mmol) in ether (10 mL) was added a propynylmagnesium bromide 0.5 M solution in tetrahydrofuran (22 mL, 11 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h and then potassium bicarbonate was added. After filtered, ethanol (30 mL) and 2-(4-hydrazinophenyl)ethanol hydrochloride (490 mg, 2.5 mmol) were added. The mixture was heated under reflux overnight. After removal of the solvent, the resulting residue was partitioned between dichloromethane and water. Organic phase was washed with brine and dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 155 mg (27%) of the title compound as yellow oil: MS (EI) m/z 230 [M]+, 1H-NMR (CDCl3) δ 7.37-7.30 (4H, m), 6.02 (1H, s), 3.87 (2H, br.s), 2.91 (2H, br.s), 2.67 (2H, q, 6.5 Hz), 2.30 (3H, s), 1.27 (3H, t, 6.5 Hz).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.[C:9]1([C@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)(C)C>[CH3:1][C@@H:2]1[O:3][CH2:4][C@H:5]([OH:6])[C@@H:7]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH2:8]1
Reactant: C[C@@H](N)c1ccccc1
Reactant: C[C@H]1CC2OC2CO1
Solvent: CC(C)O
Product: C[C@H](N[C@H]1C[C@H](C)OC[C@@H]1O)c1ccccc1
Temperature: 85 °C

Procedure:
A mixture of (4S)-4-methyl-3,7-dioxabicyclo[4.1.0]heptane (˜3 mL dichloromethane solution, 10 mmol) and (R)-1-phenylethanamine (2.4 g, 20 mmol) in isopropyl alcohol (20 mL) was stirred at 85° C. for 1 week. After that, the solution was cooled to room temperature and purified by prep-HPLC to get the title compound (more polar, 120 mg, 10% for 2 steps) as a yellow solid and a side product (less polar, 400 mg, 32% for 2 steps) as a white solid. MS (ES+) C14H21NO2 requires: 235, found: 236 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:26]([O:28][CH2:29][CH3:30])=[CH2:27])CCC>O1CCOCC1.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>[CH2:29]([O:28][C:26]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1)=[CH2:27])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(Br)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Yield: 77.1 %

Procedure:
To a solution of 1,1-dimethylethyl {(1S)-1-[(4-bromophenyl)methyl]-3-hydroxypropyl}carbamate (20 g, 58 mmol) in dioxane (500 mL) was added tributyl[1-(ethyloxy)ethenyl]stannane (39 mL, 116 mmol) and PdCl2(PPh3)2. The resulting solution was heated at 100° C. for 5 h. The reaction was then concentrated and the residue purified by flash chromatography (47.5% EtOAc, 47.5% hexanes, 5% triethylamine) to give 15 g (77%) of 1,1-dimethylethyl [(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate as a brown solid.
Reaction SMILES: [Li]CCCC.C(#N)C.[Li].C(#N)C.[CH3:13][C:14]1([S:17][CH2:16]1)[CH3:15].[OH-:18].[Na+].[O:20]1[CH2:24][CH2:23]CC1>O.C(O)C>[SH:17][C:14]([CH3:13])([CH3:15])[CH2:16][CH2:23][C:24]([OH:20])=[O:18]
Reactant: C1CCOC1
Reactant: CC1(C)CS1
Reactant: [OH-]
Agent: [Li]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: CC(C)(S)CCC(=O)O
Temperature: -78 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
A 500 mL flask was equipped with a stir bar and a 150 mL addition funnel. The system was placed under an argon atmosphere. 150 mL of anhydrous tetrahydrofurane (THF) and 75 mL of 2.5 M n-BuLi in hexanes (18.7 mmol) were added via a cannula and the solution was cooled in a −78° C. dry ice/acetone bath. Acetonitrile (7.3 g, 9.4 mL, 18 mmol) was added drop-wise via a syringe over approximately 5 min. The reaction was stirred for 30 min, while white lithium-acetonitrile precipitate was formed. Isobutylene sulfide (15 g, 17 mmol) was dissolved in 100 mL of anhydrous THF and added drop wise over approximately 30 min via the addition funnel. The cooling bath was removed and the reaction was allowed to stir for 3 hours. The flask was cooled in an ice/water bath as 38 mL of 0.5 M HCl was added drop-wise. The THF layer was retained and the aqueous layer was washed twice with 75 mL of ethyl acetate. The THF and ethyl acetate layers were combined, dried over approximately 20 g of anhydrous sodium sulfate and transferred to a 250 mL flask. Solvent was removed by rotary evaporation under vacuum to give crude 6. Ethanol (30 mL) and a stir bar were added. The contents were stirred as a solution of 8.0 g NaOH in 30 mL deionized water was slowly added. The flask was equipped with a reflux condenser and placed under an argon atmosphere. The reaction was refluxed overnight then cooled to room temperature. Deionized water (60 mL) was added and the mixture was extracted twice with 25 mL portions of a 2:1 mixture of ethyl acetate and hexane. The aqueous layer was acidified to pH 2 with concentrated HCl then extracted three times with 75 mL portions of ethyl acetate. The organic layers were dried over anhydrous Na2SO4 and solvent was removed by rotary evaporation under vacuum to give 10 g of product 7 (39% yield). Material was used without further purification. 1H NMR (CDCl3): δ1.38 (6H, s), 1.87-1.93 (2H, m), 2.08 (1H, s), 2.51-2.57 (2H, m).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35]C)=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].CO.C(=O)([O-])[O-].[NH4+:44].[NH4+]>ClCCl.C(O)C>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:44])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 87 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide and methanolic hydrochloric acid, methanol, and ammonium carbonate. Yield: 87% of theory, C27H28N6O3 (484.6); Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=485; (M+2H)++=243; (M+H+Na)++=254.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1.CCN(CC)CC.[CH3:20][C@H:21]1[CH2:26][O:25][CH2:24][CH2:23][NH:22]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][C@@H:21]2[CH3:20])[C:5]2[S:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)CCCS2
Reactant: C[C@H]1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1SCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine (500 mg, 2.26 mmol) and Et3N (457 mg, 4.52 mmol) in DMF (5.0 mL) at 0° C. was added 3-(S)-methylmorpholine (252 mg, 2.49 mmol) dropwise. The reaction was stirred overnight at rt, then the solvent removed under vacuum to give a residue which was partitioned between water and ethyl acetate. The organic layer was separated, dried and concentrated to give the crude product which was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=10/1) to give 2-chloro-7,8-dihydro-4-((S)-3-methylmorpholino)-6H-thiopyrano[3,2-d]pyrimidine (380 mg, 87%) as a light yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.C(O[C:15](=O)[NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH3:27])[CH:20]=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[I-].[K+].[CH3:37][N:38](C)[CH:39]=[O:40]>>[ClH:1].[F:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH2:2][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][NH:16][CH2:15][C:39]([NH:38][CH3:37])=[O:40])=[CH:20][C:21]=1[O:26][CH3:27]
Reactant: Fc1cccc(CCl)c1
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CNC(=O)CNCCc1ccc(OCc2cccc(F)c2)c(OC)c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
34.6 g (0.23 mol) of 1-chloromethyl-3-fluoro-benzene in 50 ml of dry dimethylformamide were added to a suspension of 55.9 g (0.209 mol) of [2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-carbamic acid tert-butyl ester, 43 g of K2CO3 and 3.4 g of potassium iodide in 400 ml of dry dimethylformamide. The reaction was stirred at room temperature overnight. Solvent was removed, water was added to the residue and the product was extracted with ethyl acetate. The crude oil obtained was triturated with diethyl ether. The solid was filtered and 58.2 g (74% yield) of the title product were obtained.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[C:9]([C:13]([OH:15])=[O:14])=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6].[CH3:16]O>>[CH3:16][O:14][C:13]([C:9]1[C:8]([N+:5]([O-:7])=[O:6])=[CH:12][NH:11][N:10]=1)=[O:15]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
Thionyl chloride (2.90 ml, 39.8 mmol) is slowly added to a mixture of 4-nitro-3-pyrazolecarboxylic acid (5.68 g, 36.2 mmol) in methanol (100 ml) at ambient temperature and the mixture is stirred for 48 hours. The mixture is reduced in vacuo and dried through azeotrope with toluene to afford the 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][C:17]([O:19]CC)=[O:18])[C:10]=3[N:9]([CH:22]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)[CH2:23][CH2:24][CH3:25])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][CH2:12][CH:11]([CH2:16][C:17]([OH:19])=[O:18])[C:10]=3[N:9]([CH:22]([C:26]3[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=3)[CH2:23][CH2:24][CH3:25])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(c1ccc(C(F)(F)F)cc1)n1cc(-c2ccccc2)c2c1C(CC(=O)OCC)CCC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(c1ccc(C(F)(F)F)cc1)n1cc(-c2ccccc2)c2c1C(CC(=O)O)CCC2
Yield: 5.5 %

Procedure:
To a stirred solution of ethyl (3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetate (107 mg, 2.2 mmol) in dioxane (5 ml) and water (0.5 ml) was added lithium hydroxide (900 mg, 22.0 mmol) and the reaction heated to reflux for 16 h. After cooling, the reaction was diluted with ethyl acetate and acidified with 2N HCl. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers dried over sodium sulfate and concentrated in vacuo. The product was purified by mass directed HPLC to give (3-phenyl-1-{1-[4-(trifluoromethyl)phenyl]butyl}-4,5,6,7-tetrahydro-1H-indol-7-yl)acetic acid (55.1 mg, 55%), a colourless foam as a 1:1 mixture of diastereomers A and B; 1H NMR δ (ppm) (CDCl3): 7.59 (2 H, d, J=8.2 Hz, A/B), 7.53 (2 H, d, J=8.1 Hz, A/B), 7.47 (2 H, d, J=8.1 Hz, A/B), 7.35 (4 H, t, J=7.3 Hz A+B), 7.21-7.13 (4 H, m, A+B), 7.06 (1 H, s, A), 6.95 (1 H, s, B), 5.19-5.11 (2 H, m, A+B), 3.39 (1 H, d, J=9.0 Hz, B), 3.06 (1 H, s, A), 2.79-2.65 (5 H, m, A+B), 2.37-2.19 (2 H, m, A+B), 2.14-2.08 (4 H, m, A+B), 2.00 (1 H, s, A/B), 1.90-1.78 (6 H, t, J=13.5 Hz, A+B), 1.74-1.70 (4 H, m, A+B), 1.42 (1 H, t, J=6.1 Hz, A/B), 1.38-1.30 (1 H, m A/B), 1.03 (3 H, t, J=7.3 Hz, A/B), 0.95 (3 H, t, J=7.3 Hz, A/B); m/z (ES−) 454 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:5]2.[Cl-].C[Al+]C.[CH3:23][CH:24]1[CH2:29][C:28](=[O:30])[O:27][C:26](=[O:31])[CH2:25]1>C(Cl)Cl.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:5]2[C:28](=[O:30])[CH2:29][CH:24]([CH3:23])[CH2:25][C:26]([OH:31])=[O:27]
Reactant: CCCCCCCc1cc2cc(Cl)ccc2n1C
Reactant: CC1CC(=O)OC(=O)C1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCCCc1c(C(=O)CC(C)CC(=O)O)c2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-heptyl-1-methyl-1H-indole in methylene chloride at 0° C. was added dimethyl aluminum chloride solution in hexane. The reaction mixture was stirred for 30 minutes. To this solution 4-methyl-dihydro-pyran-2,6-dione was added at 0° C. and the reaction mixture was stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product was purified by column chromatography.