Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][N:12]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.ClCCl.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][C:33]=1[F:41]>CCOCC>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:9][CH2:10][CH2:11][N:12]([CH2:14][C@H:15]([O:20][C:39](=[O:40])[NH:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[C:33]([F:41])[CH:34]=3)[C:16]([F:18])([F:19])[F:17])[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=Nc1ccc(Cl)c(F)c1
Reactant: O[C@@H](CN1CCOC(c2cccc(Cl)c2)C1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: Cl
Product: O=C(Nc1ccc(Cl)c(F)c1)O[C@@H](CN1CCO[C@H](c2cccc(Cl)c2)C1)C(F)(F)F
Temperature: 50 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
In a 50 mL round-bottom flask, (2S)-3-(2-(3-chlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (218 mg, 704 μmol) was combined with dichloromethane (12 ml) to give a colorless solution. triethylamine (71.2 mg, 98.1 μl, 704 μmol) was added. 1-chloro-2-fluoro-4-isocyanatobenzene (157 mg, 915 μmol) was added. The reaction mixture was heated to 50° C. and stirred for 3 h and filtered. The solid was washed with dichloromethane (2×). The combined filtrate and washes were concentrated to a reduced volume and loaded onto a silica column. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 20% EtOAc in hexanes gradient). The fractions that contained product were re-purified by flash chromatography (silica gel, 40 g, 10% to 20% (2:1 dichlormethane:EtOAc) in hexanes gradient). The front peak was collected and pooled and concentrated in vacuo. TLC corresponded to the free base of (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride prepared in Example 6. The resulting colorless film was dissolved in 2:1 hexanes ether and treated with 1M HCl in ether (1 mL). The resulting sticky solid was concentrated in vacuo to afford the salt, which was foamed to a white solid with ether to give 107 mg of (4-chloro-3-fluoro-phenyl)-carbamic acid (S)-1-[(R)-2-(3-chlorophenyl)-morpholin-4-ylmethyl]-2,2,2-trifluoro-ethyl ester hydrochloride. LCMS: M+1=481; 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.83 (br. s., 1H) 3.03 (br. s., 1H) 3.16 (br. s., 1H) 3.48 (t, J=6.99 Hz, 1H) 3.68 (br. s., 2H) 4.21 (d, J=11.71 Hz, 1H) 4.52 (br. s., 1H) 5.61 (br. s., 1H) 5.71 (br. s., 1H) 7.17 (d, J=7.55 Hz, 1H) 7.29-7.45 (m, 5H) 7.50 (d, J=10.58 Hz, 1H) 8.83 (br. s., 1H).
Reaction SMILES: C([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([C:13]#N)=[CH:11][C:10]=1[F:18])C1C=CC=CC=1.S(=O)(=O)(O)O.[CH3:24][OH:25].[OH2:26]>>[F:18][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([F:17])[C:9]=1[OH:8])[C:13]([O:25][CH3:24])=[O:26]
Reactant: N#Cc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(O)c(F)c1

Procedure:
4-Benzyloxy-3,5-difluorobenzonitrile and 15 ml of concentrated sulfuric acid were added to 100 ml of methanol and the mixture was heated under reflux for 5 days. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 4.5 g of methyl 3,5-difluoro-4-hydroxybenzoate represented by the formula:
Reaction SMILES: [NH2:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].Cl>C(OCC)(=O)C>[C:39]([NH:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[N:4]2[N:3]=1)(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 58 %

Procedure:
A mixture of the compound obtained in Example 40 (60 mg), pyridine (600 μL) and acetic anhydride (200 μL) was stirred at 100° C. for 3 days. After cooling to room temperature, to the reaction mixture was added an aqueous 1N HCl and ethyl acetate and the mixture was stirred. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on NH-silica gel (Chromatorex NH-silica gel/Fuji Silicia Chem., solvent; hexane/ethyl acetate=90/10 to 50/50) to give 2-acetylamino-6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (38.2 mg; yield: 58%) as a pale yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][S:4][C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)=[N:2]1.S(Cl)(Cl)=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][S:4][C:3]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:12])=[N:2]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cccc(C2=NOCCS2)c1
Solvent: O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccc1)c1cccc(C2=NOCCS2)c1

Procedure:
3-(5,6-Dihydro-1,4,2-oxathiazine-3-yl)benzoic acid (15 g, 0.07 mol) was suspended in methylene chloride (200 ml). Thionyl chloride (10 ml) was added and the reaction was refluxed until homogenous and all gassing had ceased. The solvent was removed, the remaining oil was taken up in methylene chloride and treated portionwise with aniline (12.5 g, 0.12 mol). An exotherm was observed. After several hours, water was added, the organic material separated, washed successively with water, aqueous bicarbonate, dilute hydrochloric acid, water and then dried over anhydrous magnesium sulphate. Evaporation of the solvent left a solid which was recrystallised from ethanol to give crystals of 3-(5,6-dihydro-1,4,2-oxathiazin-3-yl)-N-phenylbenzamide, mp 149°-150° C. (Found: C,64.65; H,4.92; N,9.65. C16H14N2O2S requires C,64.42; H,4.73; N,9.39).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[C:16]2[CH:17]=[CH:18][C:19]([NH:21][CH:22]=O)=[CH:20][C:15]=2[O:14][N:13]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C(Cl)Cl>[N+:21]([C:19]1[CH:18]=[CH:17][C:16]2[C:12]([N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[N:13][O:14][C:15]=2[CH:20]=1)#[C-:22]
Reactant: O=CNc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [C-]#[N+]c1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
1-5 (150 mg, 0.480 mmol) was suspended in CH2Cl2 (10 mL) and cooled to 0° C. To the mixture were added triphosgene (87.0 mg, 0.290 mmol) followed by Et3N (0.140 mL, 0.980 mmol). The mixture was stirred at room temperature for 2 h. The mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, brine and dried over Na2SO4. The residue was triturated with hexane to give 115 mg (82%) of 1-6 as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 8.34 (1H, br s), 8.09 (2H, m), 8.04 (1H, dd, J=8.4, 0.8 Hz), 8.00 (2H, m), 7.68 (1H, dd, J=8.4, 1.6 Hz); ESI-MS m/z 290 [C16H7N3O3]+.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][Br:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>C(#N)C>[Br-:15].[NH2:24][C:25]1[CH:30]=[CH:29][N+:28]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([O:9][CH2:8][CH:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:12]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccncc1
Reactant: BrCc1ccc(OCC(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Nc1cc[n+](Cc2ccc(OCC(c3ccccc3)c3ccccc3)cc2)cc1
Product: [Br-]

Procedure:
7-5 (100 mg, 0.27 mmol) was reacted with 4-aminopyridine 7-6 (28 mg, 0.30 mmol) in acetonitrile (3 ml) as in Example 6, Step E. The white solid product 7-7 was obtained.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:21][N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[O:26])=[CH:21][N:20]=4)[C:15](=[O:33])[N:14]([CH3:34])[N:13]=3)[CH:10]=[CH:9][N:8]=1)[N:44]=[CH:43]2)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: Cn1nc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A mixture of 116e (150 mg, 0.20 mmol) and lithium hydroxide (85 mg, 2.0 mmol) in THF/i-propanol (5/3 mL) and water (2 mL) was stirred at 30° C. for 1 h. The mixture was evaporated under reduce pressure and the residue was extracted with ethyl acetate (3×20 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 116 (80 mg, 80%) as a white solid. MS-ESI: [M+H]+ 641.3. 1H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 8.75 (d, J=5.0 Hz, 1H), 8.47 (s, 1H), 8.45 (d, J=2.0 Hz, 1H), 8.34 (d, J=3.0 Hz, 1H), 7.79 (dd, J=2.0, 8.0 Hz, 1H), 7.64 (d, J=4.5 Hz, 1H), 7.57 (s, 1H), 7.52 (dd, J=1.5, 12.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.57-4.55 (m, 2H), 3.94 (s, 3H), 3.81-3.75 (m, 6H), 1.64-1.62 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[CH:19][N:18]=4)[N:14]=[CH:15][C:10]=3[C:9]([CH3:29])=[C:8]([C:30]([O:32]CC)=[CH2:31])[C:7]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>ClCCl.C(OCC)C.C([O-])(O)=O.[Na+]>[C:30]([C:8]1[C:7](=[O:35])[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]2[N:12]=[C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:19][N:18]=3)[N:14]=[CH:15][C:10]=2[C:9]=1[CH3:29])(=[O:32])[CH3:31]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCOCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (0.490 g, 1.03 mmol) was dissolved in dichloromethane (5 mL). 2 N HCl in diethyl ether (3 mL) was added and the resulting mixture was stirred at room temperature for 4 hours. Then, additional 2 N HCl in diethyl ether (2 mL) was added and the mixture was stirred for an additional 12 hours. The reaction mixture was diluted with dichloromethane and aqueous NaHCO3. The layers were separated and the organic layer was dried over MgSO4, filtered, and the solvent evaporated to give a yellow solid. The solid was recrystallized from a mixture of hexanes, ethyl acetate and dichloromethane to give 6-acetyl-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a yellow solid (0.280 g, 60.7%). MS (APCI); M++1: Calc'd, 449.2. Found 449.2. 1H NMR δ(400 MHz, DMSO-d6) 8.79 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.31 (dd, J=2.9, 9.0 Hz, 1H), 5.86 (m, 1H), 3.88 (m, 4H), 3.15 (m, 4H), 2.54 (s, 3H), 2.36 (s, 3H), 2.32 (m, 2H),2.05 (m, 2H), 1.87 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: IC1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=O)C(C)(C)C.Cl[CH2:16][CH2:17][CH2:18][C:19]#[CH:20].O.C(OCC)(=O)C>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:17]1[C:18]2=[CH:19][C:20]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]2[CH2:9][CH2:16]1
Reactant: C#CCCCCl
Reactant: CC(C)(C)C(=O)Nc1cnccc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1cc2cc3n(c2cn1)CCC3
Yield: 56.7 %

Procedure:
A mixture of 0.2885 g bis(triphenylphosphine) palladium dichloride and 0.1565 g copper (I) iodide in 200 mL triethylamine was heated to reflux for 20 min. To the resulting solution was added at room temperature 25.00 g N-(4-iodo-3-pyridinyl)-2,2-dimethyl-propanamide and 25.3 g 5-chloro-1-pentyne and the mixture was heated to reflux for 30 min. The reaction mixture was distributed between water and ethyl acetate, the phases were separated and the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was taken up in 200 mL tert-butanol and 18.45 g powdered potassium hydroxyde was added. The mixture was heated to reflux for 30 min. The reaction mixture was distributed between water and ethyl acetate, the phases were separated and the organic phase was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with ethyl acetate:methanol=7:3 to yield 7.37 g 2,3-Dihydro-1H-3a,5-diaza-cyclopenta[a]indene as slightly yellow solid melting at 90-91° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][C@H:30]([CH2:41][CH3:42])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[OH:29][C@H:30]([CH2:41][CH3:42])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: CC[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC[C@@H](O)C(=O)Nc1ccc(C)cn1
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (3.21 g, 10.19 mmol) was added to a stirred solution of (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-N-(5-methylpyridin-2-yl)butanamide (Step 2) (2.00 g, 6.79 mmol) in THF (20 mL). The reaction mixture was kept at ambient temperature for 2 hrs. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted with EtOAc. The organic extracts were combined and washed with water, dried over MgSO4 and concentrated in vacuo. The residue was recrystallised from diethyl ether to give the title compound as colourless crystals (1.14 g).
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].C([Li])CCC.CN(C)CCN(C)C.[C:25]([C:29]1[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:32]2[O:33][P:34](Cl)[O:35][C:36]3[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:40][C:39]([C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:38][C:37]=3[C:31]=2[CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>CCCCCC.O1CCCC1>[C:46]([C:39]1[CH:40]=[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]2[O:35][P:34]([C-:1]3[CH:5]=[CH:4][CH:3]=[CH:2]3)[O:33][C:32]3[C:51]([C:53]([CH3:55])([CH3:54])[CH3:56])=[CH:52][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][C:31]=3[C:37]=2[CH:38]=1)([CH3:49])([CH3:48])[CH3:47].[C-:6]1([P:34]2[O:35][C:36]3[C:41]([C:42]([CH3:43])([CH3:44])[CH3:45])=[CH:40][C:39]([C:46]([CH3:48])([CH3:49])[CH3:47])=[CH:38][C:37]=3[C:31]3[CH:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:52]=[C:51]([C:53]([CH3:56])([CH3:55])[CH3:54])[C:32]=3[O:33]2)[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c2op(Cl)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Reactant: c1cc[cH-]c1
Agent: [Fe+2]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(C)(C)C)c2op(-[c-]3cccc3)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
To a solution of 9.5 g (50 mmol) of ferrocene in 250 mL of hexane is added dropwise 67 mL of a 1.6M solution of n-butyl lithium at ambient temperature. The reaction mixture is stirred for 20 minutes and then to the resultant red suspension is added 12.0 g (103 mmol) of N,N,N',N'-tetramethylethylenediamine. A slight exotherm of 10° C. is observed. The reaction mixture is then heated at reflux for two hours during which time an orange suspension forms. The reaction mixture is cooled to room temperature and 100 mL of tetrahydrofuran is then added. The reaction mixture is cooled to -40° C. Then to the cooled reaction mixture is added dropwise a solution of 51.8 g (109 mmol) of 2,4,8,10-tetrakis(tert-butyl)-6-chloro-dibenzo[d,f][1,3,2]dioxaphosphepin in 100 mL of tetrahydrofuran. The reaction mixture is allowed to warm to ambient temperature after the addition is complete. The reaction mixture is then heated at reflux for six hours. After cooling, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue formed is triturate with 150 mL of hexane. The resultant solid is recrystallized from acetonitrile/tetrahydrofuran mixture to give 25 g (47% yield) of a light brown solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=4)[NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][NH:34][CH3:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:24]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][N:34]([CH3:35])[CH3:33])=[CH:27][CH:26]=4)[NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3[nH]2)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3[nH]2)cc1
Reaction time: 0.08 h

Procedure:
A mixture of 220 mg (0.5 mmol) crude (4-benzyloxy-phenyl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine in 15 ml absolute ethanol is treated with 0.8 ml (5 mmol) of a 33% solution of dimethylamine in ethanol (Fluka, Buchs, Switzerland) and then heated under reflux for 1 h. The resulting solution is cooled and the solvent evaporated. The residue is dissolved in a mixture of dichloromethane and ethanol (95:5), washed with water, dried over sodium sulfate and the solvent evaporated. The solid material is then suspended in ether stirred for 5 min and filtered. Purification of the crude material through flash chromatography using dichloromethane/ethanol 9:1 plus 1% conc. ammonia gives the title compound; m.p. 272-274° C.; MS-ES+: (M+H)+=450.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[N:5]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:8]=[CH:7][N:6]([CH3:9])[N:5]=1
Reactant: [I-]
Reactant: Cn1cnc(SCCl)n1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1cnc(SCI)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 3-chloromethylthio-1-methyl-1,2,4-triazole (981 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 3-iodomethylthio-1-methyl-1,2,4-triazole (1.50 g) as yellow oil.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17])[CH:12]=O.C([O-])(=O)C.[NH4+]>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]2)[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[OH:17]
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)N1

Procedure:
A solution containing 0.65 g of hydantoin, 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.15 g of ammonium acetate in 15 ml of acetic acid was refluxed overnight. The product was filtered and washed with acetic acid and 2-propanol. Yield 0.56 g (42%), mp>350° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)([OH:3])=O.Cl.[CH2:23]([NH:25][CH:26]([CH3:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[CH2:23]([N:25]([CH:26]([CH3:35])[C:27](=[O:28])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1)=[O:3])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: CCNC(C)C(=O)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)C(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
tert-Butyl 4-(4-carboxythiazol-2-yl)piperidine-1-carboxylate (6.5 mmol; 2.03 g) is dissolved in 40 ml of anhydrous dimethylformamide and placed under an inert atmosphere, and 2-(ethylamino)propiophenone hydrochloride (1 eq.; 6.5 mmol; 1.39 g), HBTU (1 eq.; 6.5 mmol; 2.47 g) and N-ethyldiisopropylamine (3.5 eq.; 22.75 mmol; 3.97 ml) are then added. The reaction medium is stirred at room temperature overnight. The reaction medium is evaporated to dryness and then taken up in dichloromethane and washed with saturated potassium carbonate (K2CO3) solution, citric acid solution and water (twice). The organic phase is dried over sodium sulfate and then evaporated to dryness. The crude product is chromatographed on silica, using a 1/1 ethyl acetate/hexane mixture as eluent (Rf=0.55) to give 2.6 g of expected product in the form of an oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:11])[NH:9][CH3:10].[S:12](N1C=CN=C1)(N1C=CN=C1)(=[O:14])=[O:13]>O>[CH3:10][N:9]1[CH:8]([NH2:11])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][S:12]1(=[O:14])=[O:13]
Reactant: CNC(=N)c1ccccc1O
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Solvent: O
Product: CN1C(N)c2ccccc2OS1(=O)=O
Yield: 33.8 %

Procedure:
0.18 g (1.20 mmol) of 2-hydroxyl-N-methylbenzenecarboximidamide is stirred with 0.48 g (2.42 mmol) of 1,1′-sulphonyldiimidazole at 120° C. for 18 hours. Cooling is followed by stirring the mixture with water and then decanting off from the water. The remaining residue is chromatographed on silica gel (450 g, 40-63 μm) with dichloromethane/methanol=99/1. 87 mg of product are isolated.