Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14](=[O:16])[CH3:15])=[CH:4][CH:3]=1.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.[Br:41]Br>C(Cl)(Cl)Cl>[Br:41][CH2:15][C:14]([C:9]1[N:10]([CH3:13])[N:11]=[N:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nnn1C
Reactant: BrBr
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: ClC(Cl)Cl
Product: Cn1nnc(-c2ccc(F)cc2)c1C(=O)CBr
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A solution of 1-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-ethanone (4.02 g, 18.34 mmol) was dissolved in chloroform (18 mL) and acetic (0.36 mL) was heated to reflux and then a solution of bromine (1.04 mL, 20.17 mmol) in chloroform (9 mL) was added dropwise within 10 min at and after 1 h bromine (0.10 mL, 2.02 mmol) was added and heated under reflux for 1 h. After cooling to room temperature the mixture was poured onto ice-water and the mixture extracted with dichloromethane. The combined organic extracts were washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (3.48 g, 63%) as a light red solid. MS: m/e=298.1/300.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([OH:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14](=O)[CH2:15][CH3:16].C[Si]([O:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:27][C:26]([F:29])([F:28])[S:23]([O:25]/[C:11](=[C:10]1/[CH:14]([CH2:15][CH3:16])[O:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)/[CH3:12])(=[O:24])=[O:22]
Reactant: CCC=O
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC#CCCC(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCC1OC(c2ccccc2)CC/C1=C(/C)OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and propionaldehyde (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. At the same temperature, the reaction solution was stirred for 1 hour, and then slowly heated to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[NH+]1C=CC=CC=1>ClCCl.C1(C)C(S([O-])(=O)=O)=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1COC1CCCCO1
Reaction time: 12 h
Yield: 62.3 %

Procedure:
A magnetically stirred solution of 4-chloro-2-nitrobenzyl alcohol (25.0 g, 133 mmol) and 3,4-dihydro-2H-pyran (118.2 mL, 16.8 g, 200 mol) in anhydrous dichloromethane (250 mL) was treated at 25° C. with pyridinium (toluenesulfonate (PPTS, 50 mg). The solution was stirred for 12 h, washed with 1 N NaOH (250 mL), brine (250 mL), dried (K2CO3), filtered, and concentrated in vacuo. Silica gel chromatography (4:1 hexane:ethyl acetate) of the concentrate gave 22.5 g (62%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=[CH:9][C:10]=1[F:11])([F:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[F:4][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[CH:23]=[C:24]([CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[C:30]3[CH3:34])[N:25]=[N:26][CH:27]=2)[CH:8]=[CH:9][C:10]=1[F:11])([F:1])[CH3:3]
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC(F)(F)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Product: Cc1nccn1Cc1cc(-c2ccc(F)c(C(C)(F)F)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=333.3 (M+H+), was prepared from 2-[3-(1,1-difluoro-ethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: Cl[C:2]1[C:3]2[N:17]=[CH:16][CH:15]=[CH:14][C:4]=2[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:7]=1.[CH3:18][C@H:19]1[NH:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1>C(Cl)Cl>[CH3:18][C@H:19]1[N:24]([C:2]2[C:3]3[N:17]=[CH:16][CH:15]=[CH:14][C:4]=3[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[N:6][N:7]=2)[CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:20]1
Reactant: Clc1nnc(-c2ccccc2)c2cccnc12
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(-c2ccccc2)c2cccnc12
Temperature: 130 °C

Procedure:
8-chloro-5-phenylpyrido[3,2-d]pyridazine 71 (374 mg, 1.548 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (1240 mg, 6.19 mmol) were combined in a reaction vial and heated to 130° C. for 3 h. After cooling to room temperature, the resulting solid was dissolved in 100 mL of CH2Cl2 and washed with 1×10 mL of saturated NaHCO3, followed by 1×10 mL of brine. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification by column chromatography afforded pure (R)-tert-butyl 3-methyl-4-(5-phenylpyrido[3,2-d]pyridazin-8-yl)piperazine-1-carboxylate 74. 1H-NMR (400 MHz, CDCl3): δ 9.08 (dd, J=4.3, 1.6 Hz, 1H), 8.32 (dd, J=8.2, 1.6 Hz, 1H), 7.70 (m, 2H), 7.67 (dd, J=8.6, 4.3 Hz, 1H), 7.53 (m, 3H), 4.70 (m, 1H), 4.30-3.67 (series of m, 2H), 3.66 (ddd, J=13.3, 12.1, 3.5 Hz, 1H), 3.35 (m, 2H), 1.51 (s, 9H), 1.36 (br d, J=6.3 Hz, 3H). MS 405.2 (calc'd) 406.1 (M+H, found).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C
Yield: 67.5 %

Procedure:
In a manner similar to that of Example 1(e), starting with 125 g (410 mmol) of tert-butyl (3-bromo benzyl)-N-methylcarbamate (prepared in Example 1(b)) and 82 g (510 mmol) of 4-formylbenzene boronic acid, 90 g (67%) of the desired product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27].[NH4+].[Cl-]>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[OH:27]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cccc(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(OC)c1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 22.8 g of 1,3-dimethoxy benzene in THF (150 ml) was added dropwise a solution of 1.59 mol/L n-butyl lithium in an n-hexane solution (104 ml) over 30 minutes under ice cooling, and the reaction mixture was stirred at room temperature for one hour. The solution was cooled by ice again, 10.0 g of 5-chloroisatin and was added, and the reaction mixture was stirred at room temperature for two hours. An aqueous solution of saturated NH4Cl was added to the solution and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=50/1 to 10/1; v/v) to obtain 14.2 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].C(O[C:10]([C:12]1[C:13]([CH:18]([F:20])[F:19])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])C.Cl[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:2]([CH:5]1[CH:23]2[C:22]3[C:27]([CH:26]1[CH2:25][CH2:24]2)=[CH:18][CH:13]=[CH:12][C:16]=3[NH:15][C:10]([C:12]1[C:13]([CH:18]([F:19])[F:20])=[N:14][N:15]([CH3:17])[CH:16]=1)=[O:11])([CH3:3])[CH3:1]
Reactant: CCOC(=O)c1cn(C)nc1C(F)F
Reactant: Clc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: CC(C)C1C2CCC1c1c(NC(=O)c3cn(C)nc3C(F)F)cccc12
Temperature: 95 °C
Reaction time: 20 h

Procedure:
6.2 g of 9-isopropyl-5-amino-benzonorbornene (Comp. No. Z3.11, syn/anti ratio 90:10; mmol, 1.05 equivalents) and 1.6 g of potassium tert-butoxide (14.7 mmol, 0.5 equivalent) are added to a solution of 6 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (29 mmol) in 60 ml of chlorobenzene. The reaction mixture is heated to 95° C. and the chlorobenzene solvent is completely removed in vacuo. The reaction mixture is heated to 120° C. and stirred for 20 hours. 30 ml of chlorobenzene are then added. The organic phase is extracted twice with water, first at low pH, then at high pH. The organic phase is concentrated by distilling off chlorobenzene. 8 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (9-isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-yl)-amide are obtained in the form of a brown oil (crude yield: 33%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][N:17]=[CH:18]2)=[CH:13][C:12]=1F.[Cl-].[Na+].C[N:25]([CH:27]=O)C>C(OCC)(=O)C>[Cl:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][N:17]=[CH:18]2)=[CH:13][C:12]=1[O:7][CH:1]1[CH2:6][CH2:5][C:4]([CH2:27][NH2:25])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: CN(C)C=O
Reactant: Fc1cc2ccncc2cc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NCC1(c2ccccc2)CCC(Oc2cc3ccncc3cc2Cl)CC1
Reaction time: 0.33 h

Procedure:
123.3 mg of 4-aminomethyl-4-phenyl)-cyclohexanol were dissolved in 4 mL of dry DMF and 60 mg of sodium hydride were added. The mixture was allowed to stir for 20 minutes, then 91 mg of 7-Chloro-6-fluoro-isoquinoline (4) were added. Stirring at room temperature was continued until conversion was complete. Ethyl acetate and saturated sodium chloride solution were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, concentrated and the resultant residue was purified via preparative HPLC. The obtained TFA salt was dissolved in 2 N HCl and evaporated. After dissolving the residue in water and lyophilization, the title compound was isolated as the hydrochloride. Rt=0.97 min (Method B). Detected mass: 367.2 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: C1CCNCC1
Product: CC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-8-(methyloxy) -2-{[(1S)-1-methylpropyl]oxy}-9H-purin-6-amine and piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][OH:10])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.ClCCl.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][O:10][C:21](=[O:23])[CH3:22]
Reactant: COc1cccc(CO)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cccc(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-methoxy-phenyl)-methanol (14.15 g, 102.4 mmol) and triethylamine (32.8 mL, 235.6 mmol) in dry dichloromethane (45 mL) dimethylaminopyridine (1.3 g, 10.2 mmol) and acetic anhydride (11.1 mL, 118.0 mmol) was added at 0° C. and the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed with 1N HCl solution. The organic solution was dried over Na2SO4, evaporated in vacuo and purified by column chromatography (ethyl acetate:hexane; 5:95) to give the acetic acid 3-methoxy-benzyl ester as a slightly yellow oil (17.84 g, 96%). 1H NMR (CDCl3, 400 MHz) 2.08 (s, 3H), 3.78 (s, 3H), 5.06 (s, 2H), 6.85 (d, J=8.0 Hz, 1H), 6.89 (s, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 13C NMR (CDCl3, 100 MHz) 20.6, 54.8, 65.7, 113.30, 113.32, 120.0, 129.2, 137.1, 159.4, 170.4.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1

Procedure:
7.8 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin--10-yl)-piperazine are treated, together with 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide and 100 ml of toluene, with 8.22 g of N-(β-chloroethyl)--oxazolidinone and the mixture is heated under reflux for 22 hours. Then the mixture poured on to water and the organic phase washed with saturated soda solution and water, dried over sodium sulphate and concentrated under reduced pressure. There is obtained crude liquid 3-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone. The maleate is prepared by treatment with maleic acid in ethanol/ether; melting point 173°-175° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:13]([C:14](Cl)=[C:5]2[C:4]([CH3:16])=[N:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CS(C)=O>O>[CH3:1][N:2]1[C:6]2=[N:7][C:8]3[C:13]([C:14]([NH:24][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:5]2[C:4]([CH3:16])=[N:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Cc1nn(C)c2nc3ccccc3c(Cl)c12
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1nn(C)c2nc3ccccc3c(NCc3ccccc3)c12
Temperature: 25 °C

Procedure:
A mixture of 1,3-dimethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.2 g, 0.005 mol), benzylamine (1.2 ml) and DMSO (3 ml) is heated at 80°-90° C. for 3-4 hours. The reaction mixture is cooled to room temperature and then is poured into water. The mixture is extracted with CH2Cl2 (3×50 ml) and then the CH2Cl2 layers are combined and evaporated. The residue is purified by column chromatography on silca gel eluting with ethyl acetate to afford the product which is crystallized from ether/hexane to afford 1.2 g of 1,3-dimethyl-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, as a yellow solid, m.p. 105° C.
Reaction SMILES: N[C:2](N)=[S:3].Cl[CH2:6][C:7]1[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=1.[CH2:18](O)C>>[C:12]1([C:9]2[CH:8]=[C:7]3[CH2:6][S:3][CH2:2][CH2:18][N:11]3[N:10]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCO
Reactant: NC(N)=S
Reactant: ClCc1cc(-c2ccccc2)n[nH]1
Product: c1ccc(-c2cc3n(n2)CCSC3)cc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
4.42 g (58 mmol) of thiourea are added to a solution of 5.59 g (29 mmol) of 5-(chloromethyl)-3-phenyl-1H-pyrazole in 200 ml of ethanol. The mixture is stirred at 20° C. for 2 days. Most of the solvent is then removed from the mixture, and 10-20 ml of dichloromethane are added. After brief stirring, the precipitate is filtered off with suction and dried. This gives 6.3 g of a product mixture which is used further without further purification. 4.19 g of this mixture are taken up again in 140 ml of N,N-dimethylformamide. 4.55 g of dried potassium carbonate and 4.74 ml of 1,2-dibromoethane are added to this mixture. The mixture is then stirred at 60° C. for 18 h. The reaction mixture is then carefully stirred into water. The aqueous phase is then decanted off, and ethyl acetate is added to the oily residue. The organic phase is dried over Na2SO4 and concentrated. Purification is carried out by silica gel chromatography (cyclohexane/ethyl acetate). This gives 620 mg of the desired product; log P(HCOOH): 2.46; 1H-NMR (ppm): δ (DMSO-d6)=3.20 (t, 2H), 3.94 (s, 2H), 4.32 (t, 2H), 6.54 (s, 1H), 7.31 (t, 1H), 7.40 (t, 2H), 7.65 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][N:12]1[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]1=[O:20].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:21]1([NH:24][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH2:23][CH2:22]1
Reactant: CCCC1CC(=O)N(Cn2cnc3c(Cl)ncnc32)C1
Reactant: NC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC1CC(=O)N(Cn2cnc3c(NC4CC4)ncnc32)C1
Yield: 54 %

Procedure:
A mixture of 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x166 (250 mg, 0.85 mmol, 1 eq) and cyclopropylamine (1 ml) is heated at 50° C. during 24 hours in THF. After cooling, a saturated aqueous solution of NaHCO3 is added and the aqueous phase is extracted with AcOEt. The combined organic layers are dried on anhydrous MgSO4, filtered of and evaporated under reduced pressure. The crude mixture is purified by preparative HPLC to yield 1-{[6-(cyclopropylamino)-9H-purin-9-yl]methyl}-4-propylpyrrolidin-2-one 285.
Reaction SMILES: [Si]([N:8]1[C@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@@H:10]([C@H:29]([OH:31])[CH3:30])[C:9]1=[O:32])(C(C)(C)C)(C)C.Cl>CO.O.C(OCC)(=O)C>[OH:31][C@@H:29]([C@@H:10]1[C@@H:11]([CH2:12][C:13](=[O:28])[CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[O:16])[NH:8][C:9]1=[O:32])[CH3:30]
Reactant: C[C@@H](O)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-hydroxyethyl]-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidin-2-one (1.0 mmol) in 20 ml of 9:1 (v/v) methanol-water is cooled to 0° C. Concentrated hydrochloric acid (0.34 ml) is added and the resulting solution is stirred at 0° C. for 15 min., then allowed to warm to room temperature. After 2.5 hrs, at room temperature the reaction mixture is diluted with ethyl acetate (25 ml), washed with water (10 ml) and brine, dried over magnesium sulfate and concentrated in vacuo to yield (3S, 4R)-3-[(R)-1-hydroxyethyl]-4-(3-p-nitrobenzyloxycarbonyl-2-oxopropyl)-azetidin-2-one.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C>[CH3:15][N:14]([CH3:16])[CH:13]=[C:8]([C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#CCc1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C=C(C#N)c1ccncc1
Temperature: 110 °C

Procedure:
To a solution of 4-pyridylacetonitrile hydrochloride (155 mg, 1 mmol) in DMF (0.5 mL) was added dimethylformamide dimethylacetal (2 mL) and triethylamine (0.15 mL, 1.1 eq). The mixture was heated at 110° C. for 9 hours and then concentrated to give 3-dimethylamino-2-pyridin-4-ylacrylonitrile (3, Ar=4-Py) as dark brown crystals and used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].I[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:13]([O-:15])=[O:14])[CH2:17][CH2:18][C:19](=[O:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C(CCI)CCc1ccccc1
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CC(CCC(=O)CCc2ccccc2)[N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a solution of 36 g (0.17 mole) of 2-(3,4-dimethoxyphenyl)-1-nitroethane in 300 mL of dry tetrahydrofuran was added 71 g (0.17 mole) of 40% Triton B. The solution was stirred at room temperature for 10 min. 55.3 g (0.19 mole) of 1-iodo-5-phenyl-3-pentanone in a minimum amount of dry tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 30 min, at 50° C. for 3 hrs., then allowed to stir at room temperature overnight. Solvent was removed in vacuo and the residue taken up in ether and extracted twice with water. The organic layer was dried over anh.MgSO4, and concentrated at reduced pressure to give 71.5 g of crude oil. This crude material was passed through HPLC to give 46.4 g of purified material.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[C:4]([F:19])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si](C=[N+]=[N-])(C)(C)[CH3:22]>C1COCC1.CO>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[C:3]([F:20])=[C:4]([F:19])[C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid (17.4 g, 48.1 mmol) in THF-MeOH (100 mL-30 mL) was added TMSCHN2 (31.0 mL, 62.0 mmol, 2M solution in hexanes) at room temperature. The resulting mixture was stirred for 2 hours, quenched with AcOH, and diluted with EtOAc. The organic layer was washed with water, saturated NaHCO3 (2×), and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give the crude product (18.0 g, 99%) that was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+]>O.Cl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1/[CH:5]=[CH:13]/[C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: COc1ccc(OC)c(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OC)c(/C=C/C(C)=O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 16.6 g (0.1 mol) of 2,5-dimethoxybenzaldehyde in 21 ml (0.28 mol) of acetone and 10 ml of water was treated with 2.5 ml of 3N sodium hydroxide solution. The temperature of the reaction mixture should not exceed 30°. The mixture was stirred at room temperature for 20 hours, diluted with water and 3N hydrochloric acid was added to produce a strongly acidic reaction. The aqueous phase was extracted twice with methylene chloride. The combined organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained (E)-4-(2,5-dimethoxyphenyl)but-3-en-2-one as a yellow oil.