Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]([NH:12][CH2:13][CH:14](OC)OC)=[S:11])=[CH:4][C:3]=1[F:19]>S(=O)(=O)(O)O.O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[CH:14]=[CH:13][N:12]=[C:10]2[SH:11])=[CH:4][C:3]=1[F:19]
Reactant: COC(CNC(=S)Nc1cc(F)c(N)c(F)c1)OC
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1c(F)cc(-n2ccnc2S)cc1F

Procedure:
A solution of 4-amino-3,5-difluorophenyl isothiocyanate in trichloromethane is treated with an equimolar amount of aminoacetaldehyde dimethyl acetal. The solvent is evaporated, and the residue is recrystallized from ethanol to yield N-(4-amino-3,5-difluorophenyl)-N'-(β,β-dimethoxyethyl)thiourea. A suspension of this thiourea in concentrated sulfuric acid and water (1:4) was refluxed for three hours. The mixture then is cooled and the solid that forms is filtered, washed with water, and dried. Recrystallization from ethanol yields 1-(4'-amino-3',5'-difluorophenyl)imidazole-2-thiol.
Reaction SMILES: C([Si]([O:8][C@H:9]1[CH2:13][CH2:12][C:11]([C:14]([CH3:16])=[CH2:15])=[CH:10]1)(C)C)(C)(C)C.[F-].C([NH3+])(C)(C)C>C1COCC1>[C:14]([C:11]1[CH2:12][CH2:13][C@H:9]([OH:8])[CH:10]=1)([CH3:16])=[CH2:15]
Reactant: C=C(C)C1=C[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: CC(C)(C)[NH3+]
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(C)C1=C[C@@H](O)CC1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
A solution of compound (6a) (402.8 mg; 1.689 mmol) in THF (34 mL) was cooled to 0° C. and treated with 1.0 M tert-Butylammonium floride (2.55 mL, 2.55 mmol). The next 3½ hours the reaction mixture was stirred at room temperature and then quenched with saturated aqueous NH4Cl. The resulting solution was extracted with DCM (3×) and AcOEt (1×), dried (Na2SO4) and concentrated in vacuo. Purification by chromatography (pentane/ether 3/1 to 2/1) provided 190.4 mg of compound (7a) as clear yellow oil with 95% yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([O:22]C)=[O:21].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH:19]([CH2:24][CH2:25][CH3:26])[C:20]([OH:22])=[O:21]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1cccs1)CCC3
Temperature: 100 °C
Yield: 72.5 %

Procedure:
To a solution of methyl [2-methyl-4-(2-thienyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.249 g, 0.646 mmol) in methanol (6.5 mL) was added a solution of sodium hydroxide 10 N (0.65 ml) and the mixture was heated at 100° C. for 18 h in a sealed tube. After cooling, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.174 g (72%) of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=1.[I-].[Na+].[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>CC(C)=O>[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][N:19]([CH2:2][CH2:3][CH2:4][C:5]2[CH:13]=[CH:12][C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=2)[CH2:18]1
Reactant: CC1CNCC(C)C1
Reactant: N#CCc1ccc(CCCCl)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1CC(C)CN(CCCc2ccc(CC#N)cc2)C1
Reaction time: 1 h

Procedure:
In a 250 ml round bottom flask 5.3 g of 4-(3-chloropropyl)benzylcyanide, 4.4 g of sodium iodide, 62.2 g of 3,5-dimethylpiperidine and 32.9 ml of acetone are mixed together and boiled for 1 hour at reflux.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1.[CH3:15][C:16]1[C:21](/[CH:22]=[CH:23]/[N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:22]([C:21]3[C:16]([CH3:15])=[C:17]([NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:18]=[CH:19][CH:20]=3)[CH2:23][N+:24]([O-:26])=[O:25])=[CH:11][NH:12]2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc2cc[nH]c2c1
Reactant: Cc1c(/C=C/[N+](=O)[O-])cccc1NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1ccc2c(C(C[N+](=O)[O-])c3cccc(NC(=O)OCc4ccccc4)c3C)c[nH]c2c1
Yield: 62.1 %

Procedure:
6-(2-Methoxyethoxy)-1H-indole (1.461 g, 88% purity, 6.72 mmol) and (E)-benzyl 2-methyl-3-(2-nitrovinyl)phenylcarbamate (1.75 g, 5.60 mmol) were dissolved in THF (50 mL). The solution was then concentrated under vacuum to dryness. The solid mixture was melted at 125° C. and heated at this temperature for 16 hr. The mixture was subjected to ISCO (220 g silica gel, solid loading, 25-65% ethyl acetate/hexane) to afford the desired product (1.75 g, 3.48 mmol, 62% yield) as a beige solid.
Reaction SMILES: Cl.[C:2]([Si:6]([CH3:17])([CH3:16])[O:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:27][C:28]([O:31][C:32]([N:34]1C(C2C=CC(C#N)=CC=2)O1)=[O:33])([CH3:30])[CH3:29]>ClCCl>[C:28]([O:31][C:32](=[O:33])[NH:34][N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][CH2:8][O:7][Si:6]([C:2]([CH3:3])([CH3:5])[CH3:4])([CH3:17])[CH3:16])[CH2:11][CH2:12]1)([CH3:30])([CH3:29])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NN1CCC(CCO[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
4-[2-(t-Butyl-dimethyl-silanyloxy)-ethyl]-piperidine hydrochloride (1:1) (300 mg, 1.07 mmol) was combined with dichloromethane (15 mL) to give a light yellow suspension. N,N-Diisopropylethylamine (166 mg, 225 μl, 1.29 mmol) was added at 0° C. Subsequently 3-(4-cyanophenyl)-2-oxaziridinecarboxylic acid 1,1-dimethylethyl ester (238 mg, 965 μmol) in dichloromethane (10 mL) was added during 20 min at 0° C. and the reaction mixture was stirred for 1 h at 0° C. Afterwards the reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in n-heptane) to deliver an oil contaminated with 4-cyano-benzaldehyde. This material was purified by a second chromatography (aminophase 10 g, ethyl acetetate/n-heptane 1/1) to give the title compound (0.23 g, 60%) as a white solid; LC-MS (ESI) 94.9%, 359.2710 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]=O.[CH3:13][NH2:14].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:11][NH:14][CH3:13]
Reactant: CN
Reactant: O=Cc1oc2ccccc2c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1oc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
To a solution of 3-chlorobenzofuran-2-carboxaldehyde (1.62 g, 8.9 mmol) in methanol (50 mL) is added N-methylamine (33% solution in ethanol, 1.11 g, 35.9 mmol) and stirred overnight at room temperature. The mixture is concentrated in vacuo, re-solvated in methanol (50 mL) and cooled in an ice bath. Sodium borohydride (407 mg, 10.8 mmol) is added in portions and the mixture stirred at room temperature for 4 h. The mixture is concentrated in vacuo, re-solvated in 1.3M sodium hydroxide solution, stirred for 20 min, extracted with ethyl acetate, dried with sodium sulfate and concentrated. Purification by column chromatography (silica, CH2Cl2/MeOH, 9/1) gave title compound (1.43 g, 82%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6) δ 7.55-7.63 (m, 2H), 7.33-7.42 (m, 2H), 3.93 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([OH:18])[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]([O:31][C@@H:32]1[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[C@@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[O:34][C@@H:33]1Br)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(#N)C>O>[C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([O:18][C@@H:33]4[O:34][C@H:35]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[C@@H:36]([O:45][C:46](=[O:51])[C:47]([CH3:48])([CH3:49])[CH3:50])[C@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:32]4[O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])[C:10]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1n[nH]c2nccc(CCc3ccccc3)c12
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccccc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
A mixture of 4-(2-phenylethyl)-1H-pyrazolo[3,4-b]-pyridin-3-ol (0.59 g), potassium carbonate (0.68 g), 2,3,4,6-tetra-O-pivaloyl-α-D-glucopyranosyl bromide (1.71 g) and acetonitrile (10 mL) was stirred at 50° C. overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-1/1) to give the title compound (0.22 g).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[Cl:11][C:7]1[CH:6]=[C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])[CH:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1cccc(Cl)c1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1cccc(Cl)c1

Procedure:
The title compound was prepared with 2-amino-2-(3-chlorophenyl)ethanol (Galley, G.; et al., WO 2008092785) and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an white solid (1.44 g, 99%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.66-7.53 (m, 3H), 7.25-7.08 (m, 2H), 6.77 (dd, J=8.6, 6.3 Hz, 4H), 6.70-6.61 (m, 4H), 6.58 (dd, J=6.4, 2.2 Hz, 1H), 6.49 (d, J=7.8 Hz, 1H), 5.18-4.95 (m, 1H), 3.43 (dd, J=11.3, 3.9 Hz, 1H), 3.31 (dd, J=11.3, 4.6 Hz, 1H); ESIMS m/z 534 ([M+H]+).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH2:5])[CH:2]=[CH2:3].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][C:20](=[O:21])[NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH2:3]
Reactant: O=C=NCc1ccccc1
Reactant: C=CCN(N)CC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCN(CC(=O)OCC)NC(=O)NCc1ccccc1
Yield: 73.6 %

Procedure:
To the solution of ethyl 2-(1-allylhydrazinyl)acetate (Compound XV-1) 6.9 g (44 mmol) in tetrahydrofuran 40 ml, benzyl isocyanate 6.1 g (46 mmol) was added at 0° C. and at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate 150 ml and washed with water 75 ml and brine 75 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound 9.43 g (75%).
Reaction SMILES: [N:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:8])[CH2:2]2.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[C:10]1([CH:9]=[C:2]2[C:3](=[O:8])[CH:4]3[CH2:7][N:1]2[CH2:6][CH2:5]3)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CN2CCC1C2
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccccc2)N2CCC1C2

Procedure:
A mixture of 1-azabicyclo[2.2.1]heptan-3-one (2.65 g), benzaldehyde (3.64 ml) and sodium hydroxide (1.15 g) in ethanol (25 ml) was heated at reflux for 40 min. After cooling the solvent was removed in vacuo and the residue partitioned between dichloromethane (300 ml) and water (300 ml). The aqueous layer was further extracted with dichloromethane (2×300 ml). The organic extracts were combined, backwashed with brine (100 ml), dried and concentrated in vacuo to give an orange oil (5.84 g). The oil was purified by FCC, using gradient elution with petrol/ethyl acetate 6:1 to 3:1 to give the title compound as a yellow solid (3.80 g). m.p. 61-63°.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[Cl:12][C:13]1[C:18](I)=[C:17]([CH3:20])[N:16]=[C:15]([NH2:21])[N:14]=1>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>[NH2:21][C:15]1[N:14]=[C:13]([Cl:12])[C:18]([C:3]#[C:2][CH2:1][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[C:17]([CH3:20])[N:16]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1nc(N)nc(Cl)c1C#CCNC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
tert-Butyl prop-2-ynylcarbamate (3.11 g), 4-chloro-5-iodo-6-methylpyrimidin-2-amine (1.8 g) and bis(triphenylphosphine)palladium(II) chloride (0.469 g) were combined in TEA (100 mL). The reaction mixture was purged with nitrogen gas for 3 min then copper(I) iodide (0.254 g) added. The resulting mixture was stirred at 70° C. for 16 h, then cooled to rt and filtered. The filtrate was washed with water and brine, dried and the solvents evaporated. The crude material was dissolved in MeOH (20 mL), acidified with acetic acid (1 mL) and purified by SCX and further purified by chromatography eluting 10% MeOH and 0.25% Ammonia (7N) in DCM to afford the subtitle compound 0.93 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:12])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1.[F:13][C:14]([F:18])([F:17])CO>>[CH3:12][C:5]1[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=[C:3]([O:2][CH2:1][C:14]([F:18])([F:17])[F:13])[N:4]=1
Reactant: OCC(F)(F)F
Reactant: COc1cnc(C(=O)O)c(C)n1
Product: Cc1nc(OCC(F)(F)F)cnc1C(=O)O

Procedure:
The title compound was synthesized according to Intermediate 13, using 2,2,2,-trifluoroethanol (Aldrich) in Step 4. MS m/z=237 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7].C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:26])C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([OH:26])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[F:17])([CH3:8])[CH3:7]
Reactant: COC(=O)CCC(C)(C)c1cccc(OC)c1F
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(O)CC(C)(C)c1cccc(OC)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
19.58 g (77 mmol) of 4-(2-fluoro-3-methoxyphenyl)-4-methylpentanoic acid methyl ester is introduced into 245 ml of tetrahydrofuran, and the reaction mixture is cooled to −70° C. Within one hour, 220.7 ml of a 0.5 molar solution of potassium-bis-(trimethylsilylamide) in toluene is added in drops, and the reaction mixture is then stirred for 45 more minutes at −70° C. 28.3 g (107.79 mmol) of Davis reagent, dissolved in 245 ml of tetrahydrofuran, is now added in drops within 40 minutes. After two hours of stirring at −70° C., 250 ml of saturated ammonium chloride solution is slowly added in drops, and in this case, the batch is brought to room temperature. After extraction with methyl tert-butyl ether, the combined organic extracts are treated as usual with water and brine. After the solvent is spun off, the residue is chromatographed several times on silica gel (mobile solvent ethyl acetate/hexane). 12.14 g (58.3%) of the desired compound is ultimately isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.O[CH2:14][CH2:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][CH:16]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:17]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(CCO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CCOc2ccc(Br)cc2C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
4-Bromo-2-(trifluoromethyl)phenol (3 g), tert-butyl 3-(2-hydroxyethyl)azetidine-1-carboxylate (2.81 g) and triphenylphosphine (3.92 g) were dissolved in DCM (25 ml). The reaction mixture was placed under a nitrogen atmosphere and cooled to 0° C. then DIAD (2.94 ml) was added dropwise. The mixture was stirred at room temperature for 16 hours then solvent evaporated under reduced pressure. The resulting residue was dissolved in ether (10 ml), heptane (15 mL) was then added and the suspension stirred for 45 minutes. The mixture was filtered (solid was washed with 3:2 heptane/ether) and the filtrate washed with NaOH (1M, 2×40 mL). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to yield crude product as a clear oil (6.05 g). Purification by flash chromatography (100 g silica column, 10% to 25% EtOAc in heptane gradient) afforded tert-butyl 3-(2-(4-bromo-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (52.6% yield) as a clear oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=2)[C:10]=1[N+:30]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-].CO.O>C1COCC1.[Fe]>[NH2:30][C:10]1[C:11]([NH:15][C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH:19]=[CH:20][CH:21]=2)=[N:12][CH:13]=[N:14][C:9]=1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2N)c1
Temperature: 50 °C
Yield: 46 %

Procedure:
To a solution of tert-butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenylcarbamate (2) (9.2 g, 17.5 mmol) in 100 mL THF were added Fe powder (9.8 g, 175 mmol), NH4Cl (18.7 g, 350 mmol), 100 mL MeOH and 20 mL H2O. The reaction mixture was heated at 50° C. for 7 hrs under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was concentrated to 100 mL, and extracted with EtOAc (80 mL×3). The combined organic layer was washed with water (100 mL×2) and brine (100 mL×1), dried over Na2SO4, then concentrated to dryness in vacuo. The residual was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenylcarbamate (3) (4.0 g, 46.1%) as a brown solid. LC-MS (ESI): m/z (M+1) 497.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH-:20].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1nn(-c2c(Cl)cccc2Cl)c(N)c1C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Amino-1-(2,6-dichlorophenyl)-3-isopropyl-1H-pyrazole-4-carbonitrile (15 g, 50 mmol) was taken up in conc. H2SO4 (45 mL) and stirred at room temp for 16 h. The reaction was then poured onto 3 N NaOH (850 mL) at 0° C. The resulting solid was then filtered and washed with H2O (1 L). The product was then dried under vacuum to yield the desired ariide (14 g, 88%).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[CH:8]=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=1)[CH3:6])C.Cl.[NH2:26][OH:27].[OH-].[K+]>CO>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[NH:10][N:9]=[CH:8][C:7]=2[CH:5]([CH3:6])[C:4]([NH:26][OH:27])=[O:3])=[CH:13][CH:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: NO
Reactant: CCCCCCc1ccc(-c2[nH]ncc2C(C)C(=O)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCc1ccc(-c2[nH]ncc2C(C)C(=O)NO)cc1
Temperature: -5 °C
Reaction time: 24 h

Procedure:
10 g 5-(4-n-hexylphenyl)-1H-pyrazol-4-yl-propionic acid ethyl ester dissolved in 40 ml methanol are added rapidly to a solution of 4.2 g hydroxylamine hydrochloride and 5 g KOH in 40 ml methanol, pre-cooled to -5° C. After reaching room temperature, the reaction mixture is stirred for 24 hrs. The mixture is filtered and the solvent concentrated under vacuum. The residue is dissolved in ethyl acetate, washed with water, dried with Na2SO4 and solvent removed by evaporation under vacuum. The title compound is crystallised from ethyl ether/hexane: m.p.=150°-155° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[S:25])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: Nc1ncccc1OCc1ccc(Cl)cc1
Reactant: S=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(4-chlorobenzyloxy)pyridine (3.37 g, 0,014 mol), phenyl isothiocyanate (2.33 g, 0,017 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 4.36 g (82%), m.p. 162°-164 ° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:4]2[C:3](=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[S:8][CH2:9][CH2:10]1
Reactant: CC(C)=CCSc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C)CCSc2c(Br)cccc21

Procedure:
26.00 g (102.0 mmol) of 2-bromo-1-(3-methylbut-2-enylthio)benzene, 180 ml of toluene and 23.20 g (122.0 mmol) of para-toluenesulphonic acid are introduced into a three-necked flask. The reaction mixture is heated at reflux for four hours and is evaporated to dryness. The residue is taken up in an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate and the organic phase is separated by settling, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column eluted with heptane. 20.00 g (76%) of the expected compound are collected in the form of an orangey oil.