Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: COc1ccc(C(=O)O)nc1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: COc1ccc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)nc1

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-methoxy-pyridine-2-carboxylic acid (CAS 29082-92-6) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=377.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:16][CH2:15][N:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[C:7](=[O:13])[C:8]2=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrCCC1CCCCC1
Reactant: COc1ccc2c(c1)NC(=O)C2=O
Product: COc1ccc2c(c1)N(CCC1CCCCC1)C(=O)C2=O

Procedure:
The title compound was prepared as a red solid, using 6-methoxy-isatin prepared as described in Pavlidis et al. and 1-Bromo-2-cyclohexylethane following Method B. Pavlidis, V. H., et al., The Synthesis of a Novel Series of Substituted 2-Phenyl-4H-3,1-benzoxazin-4-ones, Synthetic Communications, 1994, 24:4, 533-548.
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]([N:15](CC)[CH2:16][CH3:17])[CH3:14].ClC(OCC)=O.C(NCC)C>CC(C)=O.C(Cl)(Cl)Cl.O>[CH2:13]([N:15]([CH2:16][CH3:17])[C:10]([C:7]1[CH:8]=[C:9]2[O:1][CH:2]=[CH:3][C:4]2=[N:5][CH:6]=1)=[O:12])[CH3:14]
Reactant: O=C(O)c1cnc2ccoc2c1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CCN(CC)C(=O)c1cnc2ccoc2c1
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
To a suspension of furo[3,2-b]pyridine-6-carboxylic acid (3.26 g, 20 mmol) in dry acetone (40 mL), under a nitrogen atmosphere and cooled in an ice bath, was added dropwise triethylamine (3.1 mL, 22.3 mmol). After 15 minutes, a solution of ethyl chloroformate (2.1 mL, 22.3 mmol) in dry acetone (12 mL) was added dropwise. This solution was stirred for two hours and then diethylamine (4.2 mL, 40.6 mmol) was added. After another hour the reaction mixture was diluted with chloroform/water and the chloroform layer separated and washed with sodium carbonate solution and then 10% hydrochloric acid. The chloroform solution was dried over anhydrous sodium sulfate, filtered through a charcoal pad and evaporated to give crude oily product (4.2 g). This material was purified by fractional distillation to give 2.42 g (55.5% yield) of oil, bp: 155°-156° C./1.2 mmHg.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]([F:36])([F:35])[C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:34]=[CH:33][C:24]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:22]=3)=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][N:2]([CH3:7])[S:3]([N:30]1[CH2:31][CH2:32][N:27]([C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:14]3[C:13]4[C:18](=[CH:19][C:10]([C:9]([F:8])([F:35])[F:36])=[CH:11][CH:12]=4)[N:17]=[CH:16][CH:15]=3)=[CH:34][CH:33]=2)[CH2:28][CH2:29]1)(=[O:5])=[O:4]
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Reaction time: 19 h
Yield: 88.3 %

Procedure:
Dimethylsulfamoyl chloride (0.72 g, 0.54 ml, 0.005 mol) is added dropwise to a solution of 2.00 g (0.005 mol) of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine and 2 ml of triethylamine in 20 ml of dimethylformamide. The reaction is stirred for 19 hours and then partitioned with chloroform-aqueous sodium carbonate. The organic phase is dried over anhydrous sodium sulfate, concentrated, and chromatographed with methylene chloride to 1% methanol/chloroform on silica gel to give 2.24 g of 1-[(dimethylamino)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine. This is crystallized from methylene chloride-cyclohexane to give 1.60 g of 1-[(dimethylamino)sulfonyl]-4-[4-[[-7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 223°-224.5° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1O[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[OH:22][N:21]1[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=[C:3]1[CH2:2][OH:1]
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2cn(O)c(CO)cc2=O)cc1
Temperature: 85 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
To a stirred solution of 2-(hydroxymethyl)-5-[(4-methoxybenzyl)oxy]-4H-pyran-4-one (Intermediate 289, 101.7 g, 0.388 mol) in pyridine (1.35 L) was added hydroxylamine hydrochloride (134.7 g, 1.94 mol). The reaction mixture was heated at 85° C. for 4 hours, then evaporated to dryness and triturated with water (700 mL). The precipitate was collected by filtration and washed with water (250 mL). The solids were then stirred in isopropanol (100 mL) for 12 hours, collected by filtration and dried under vacuum to afford the title compound as a white solid (41.2 g, 38%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].Cl>[OH-].[Na+]>[CH2:17]([O:16][C:14]([NH:1][C@H:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C[C@H](N)c1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
To a cooled (0° C.) mixture of 4-[(1S)-1-aminoethyl]benzoic acid (Chem. Eur. J. 1999, 5, 1095, 16.2 g, 98 mmol) and 2 N sodium hydroxide aqueous solution (100 mL) was added benzyl chloroformate (20.5 g, 120 mmol) dropwise over 30 min period followed by the addition of additional 2 N sodium hydroxide aqueous solution (70 mL). The reaction mixture was stirred overnight at room temperature and then acidified to pH 1 with concentrated hydrochloric acid. The resulting precipitate was filtered, washed with water (100 mL), and then vacuum dried to yield 26 g (88%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 7.95 (2H, d, J=8.1 Hz), 7.40–7.15 (7H, m), 5.12–4.94 (3H, m), 4.82 (1H, br.s), 1.40 (3H, d, J=7.0 Hz); MS (ESI) m/z 300 (M+H)+, 298 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][C@@H:14]([C:16]([OH:18])=[O:17])[NH:13][CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:52](O)[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:12][NH:13][C@H:14]([C:16]([O:18][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[O:17])[CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=[N:35]2)[C:23]([F:25])([F:24])[F:26])[N:3]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Temperature: 25 °C

Procedure:
To a flask equipped with a Dean Stark trap were added (2S)-8-[2-amino-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2-carboxylic acid (1 g, 1.78 mmol), toluene (25 mL), and p-toluene sulfonic acid monohydrate (336 mg, 1.77 mmol), and n-octanol (690 mg, 5.30 mmol). The reaction mixture was heated to reflux for 48 h, cooled to RT, and concentrated in vacuo. Purification on a 120 g Isco RediSep silica cartridge (CH2Cl2/MeOH/NH4OH) provided the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:27])[C:15](=[O:26])[C:16]([CH3:25])=[C:17]([NH:18]C4C=CC=CC=4)[C:12]=3[C:11](=[O:28])[N:10]([CH:29]3[CH2:31][CH2:30]3)[C:9]2=[O:32])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:13]2[N:14]([CH3:27])[C:15](=[O:26])[C:16]([CH3:25])=[C:17]3[C:12]=2[C:11](=[O:28])[N:10]([CH:29]2[CH2:31][CH2:30]2)[C:9](=[O:32])[N:18]3[NH:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:6][CH:7]=1
Reactant: Cc1c(Nc2ccccc2)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(=O)n(C)c(Nc2ccc(Br)cc2)c2c(=O)n(C3CC3)c(=O)n(Nc3ccccc3)c12
Temperature: 25 °C
Reaction time: 10 h
Yield: 57.2 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 41 (78 mg) obtained in Step 7 was added chloroform-methanol [1:1 (volume ratio), 2.0 ml], potassium carbonate (22 mg) was added, and the mixture was stirred at room temperature for 10 hrs. The mixture was further stirred under reflux for 3 hrs, and allowed to cool to room temperature. The mixture was concentrated under reduced pressure and purified by column chromatography (chloroform:acetone=50:1) to give 5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H-pyrido[4,3-d]pyrimidine-2,4,7-trione 42 (23 mg, yield 26%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.FC(F)(F)S(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:19][C:18]([F:21])([F:20])[CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.2 %

Procedure:
A mixture of 1-(4-hydroxyphenyl)ethanone (0.5 g, 3.67 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.58 mL, 4.04 mmol) and cesium carbonate (2.39 g, 7.34 mmol) in DMF (10 mL) is stirred at rt for 2.5 hours. The reaction mixture is poured into saturated aqueous sodium hydrogen carbonate (10 mL) and extracted with EtOAc (30 mL). The organic layer is washed with saturated aqueous sodium hydrogen carbonate (10 mL×2) and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo to give 0.65 g (81% yield) of the title compound as white solid. This material is used for the next reaction (Step-2) without further purification.
Reaction SMILES: CN(C)C=O.[I:6]N1C(=O)CCC1=O.[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][N:16]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C>[NH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([I:6])=[CH:17][N:16]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(I)cn1
Reaction time: 8 h
Yield: 74.9 %

Procedure:
N,N-Dimethylformamide (47 ml) and N-iodosuccinimide (10.7 g, 47.6 mmol) were added to 2-amino-4-chloropyridine (4.72 g, 36.7 mmol); and the reaction mixture was stirred overnight. An aqueous solution of sodium thiosulfate and ethyl acetate were added thereto; the organic layer was separated, concentrated, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure; a solvent mixture (ether: hexane=1:1) was added to the residue; and the solid was filtered off to yield the title compound (7.0 g, 27.5 mmol).
Reaction SMILES: [F:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[F:31])=[C:19]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[N:18]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1>[C].[Pd].C(OCC)(=O)C>[F:1][CH:2]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[F:31])=[C:19]([CH2:32][C:33]([CH3:34])([CH3:36])[CH3:35])[N:18]=1)[CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C=Cc1cccc(CC(F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(CC(F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Under a hydrogen atmosphere, a mixture of ethyl 3-(3-(2-fluoro-2-(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)ethyl)phenyl)acrylate (119 mg), 10% palladium-carbon (50 mg) and ethyl acetate (2.0 mL) was stirred at room temperature for 1 hr. The catalyst was removed by filtration, and the filtrate was evaporated under reduced pressure to give the title compound (90 mg) as a colorless oil.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[F:23].[Br:24]Br>>[Br:24][C:19]1[C:18]([F:23])=[C:17]([Cl:16])[CH:22]=[CH:21][N:20]=1
Reactant: BrBr
Reactant: Fc1cnccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Product: Fc1c(Cl)ccnc1Br
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (25 g, 190 mmol) in hexanes (100 mL) cooled over dry ice acetone bath for 5 minutes was added 1.6M n-butyl lithium in hexanes (121 mL, 194 mmol) over 5 minutes. After the addition was complete, the reaction mixture was placed in an ice bath and the mixture was allowed to stir at 0° C. for 20 minutes as a white solid formed. The suspension was re-cooled over dry ice/acetone bath for 5 minutes and then treated with a solution of 4-chloro-3-fluoropyridine (25 g, 190 mmol) in hexanes (50 mL) over 5 minutes and this mixture was stirred over dry ice/acetone bath for additional 10 minutes. After this time, this mixture was treated with bromine (30.4 mL, 190 mmol) and stirred over dry ice/acetone bath for 15 minutes. After this time, the reaction mixture was stirred for 30 minutes at 0° C. and then allowed to warm to room temperature. The reaction mixture was re-cooled over wet ice bath and quenched with water (200 mL) and extracted with ether (3×300 mL). The combined organic extracts were washed with water, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by chromatography using 330 g silica gel cartridge and eluting with a gradient of 20-100% CH2Cl2 in hexanes to provide the title compound. 1H NMR (CDCl3) δ=8.13 (d, 1H, J=5.1 Hz) and 7.35 (dd, 1H, J=5 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20].[CH3:24][Si:25]([CH3:28])([CH3:27])Cl.N1C=CN=C1.N1C=CC=CC=1>C(OCC)C>[CH3:1][C:2]1([CH3:23])[C:10]2([CH3:11])[CH:5]([C:6](=[O:12])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][C:19]([CH3:21])([O:22][Si:25]([CH3:28])([CH3:27])[CH3:24])[CH3:20]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(O)CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(CCCOCCC1CC2C(=O)CCCC2(C)C1(C)C)O[Si](C)(C)C
Yield: 78.9 %

Procedure:
201 mg (0.62 mmol) of 50 is reacted with 205 mg (1.86 mmol) of trimethylchlorosilane, 167 mg (2.42 mmol) of imidazole and 0.25 ml of pyridine in 15 ml of diethyl ether analogously to 33., and 194 mg of the title compound is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:19]([CH:21]1[CH2:25][CH2:24][CH2:23][NH:22]1)[CH3:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][CH2:25][CH:21]2[CH2:19][CH3:20])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCC1CCCN1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Product: CCC1CCCN1c1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Yield: 32 %

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) and 2-ethylpyrrolidine (84 mg, 0.848 mmol) were combined and purified as per Preparation Hd to give two pairs of racemic diasteriomers 2-chloro-4-(2-ethylpyrrolidin-1-yl)-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. (Hf1, Diastereomer 1, racemic, first to elute) (77 mg, 0.223 mmol, 32% yield) LC-MS (M+H)+=346. (Hf2, Diastereomer 2, racemic, second to elute) (80 mg, 0.232 mmol, 33% yield); LC-MS (M+H)+=346.2. The relative stereochemistry for Hf1 and Hf2 was not determined
Reaction SMILES: Br[C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[C:16]([O:22][CH3:23])(=[O:21])[CH2:17][CH2:18][C:19]#[CH:20]>C(Cl)Cl>[CH3:23][O:22][C:16]([CH2:17][CH2:18][C:19]#[C:20][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)=[O:21]
Reactant: C#CCCC(=O)OC
Reactant: COC(=O)c1cc(C(=O)OC)c(Br)cn1
Solvent: ClCCl
Product: COC(=O)CCC#Cc1cnc(C(=O)OC)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
546 mg of dimethyl 5-bromo-dicarboxylate (from Example 3) and 269 mg of methyl 4-pentinoate are dissolved in methylene chloride in a flask flushed with argon, and 840 μl of triethylamine are added dropwise. The mixture is stirred at room temperature for 15 minutes, 28 mg of ((C6H5)3P)2PdCl2 and 4 mg of CuI are added and the mixture is boiled under reflux for 18 hours. After cooling, the mixture is diluted with methylene chloride and washed with water and sodium chloride solution and the combined organic phases are dried over potassium carbonate. After evaporation and chromatography on silica gel, 460 mg of a white solid remain.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[C:4]([NH:6][CH:7]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:5]>CO.[Pt]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:7]([NH:6][C:4](=[O:5])[C:3]2[C:22]([Cl:26])=[CH:23][CH:24]=[CH:25][C:2]=2[Cl:1])[C:8]([O:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Pt]
Solvent: CO
Product: COC(=O)C(Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
Methyl 2-[(2,6-dichlorobenzoyl)amino]-3-(4-nitrophenyl)propanoate 7 (7 g) is solubilized in CH3OH in presence of Pt(S)/C (5% in weight). H2 pressure is then applied at RT for 2 h. The catalyst is filtered over celite and the solvent is evaporated to give methyl 3-(4-aminophenyl)-2-[(2,6-dichlorobenzoyl)amino]propanoate 8.
Reaction SMILES: [CH3:1][S:2][C:3](=[N:6][N+:7]([O-:9])=[O:8])[NH:4][CH3:5].CC#N.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>N1C=CC=CC=1>[C:13]([N:4]([CH3:5])[C:3](=[N:6][N+:7]([O-:9])=[O:8])[S:2][CH3:1])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CNC(=N[N+](=O)[O-])SC
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CSC(=N[N+](=O)[O-])N(C)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 83.6 %

Procedure:
A mixture of S,N-dimethyl-N'-nitroisothiourea (0.5 g), CH3CN (6 ml) and pyridine (1 ml) was cooled to 0° C. To the cooled mixture was added benzoyl chloride (1 g) dropwise in 5 minutes under stirring. After stirring at the same temperature for 1 hour, benzoyl chloride (0.4 g) was added to the mixture which was stirred at room temperature for 1 hour. The reaction mixture was poured into 50 ml of 2N hydrochloric acid and the resulting mixture was extracted with CHCl3. The extract was dried over MgSO4 and evaporated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with hexane-AcOEt (5:1) to afford 0.71 g of crude N-benzoyl-S,N-dimethyl-N'-nitroisothiourea as an oil. To the solution of the product (0.636 g) in CH3CN (4 ml) was added a solution of 2-chloro-5-thiazolylmethylamine (0.37 g) in CH3CN (2 ml) dropwise at 0° C. over 5 minutes. After stirring at the same temperature for 25 minutes, precipitates were collected by filtration and the product was applied to column chromatography on silica gel. The column was eluted with CH2Cl2 -MeOH (20:1) to afford 0.344 g of 1-benzoyl-3-(2-chloro-5-thiazolylmethyl)-l-methyl-2-nitroguanidine (Compound No. 15) as a crystal, m.p. 170°-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.C(N(CC)C(C)C)(C)C.Br[CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][CH:17]([NH:20][CH2:31][CH2:32][O:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:42])[F:43])[CH:35]=4)[CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2sc(NC(=O)N3CC[C@H](N)C3)nc12
Reactant: FC(F)(F)c1cccc(OCCBr)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncnc2sc(NC(=O)N3CCC(NCCOc4cccc(C(F)(F)F)c4)C3)nc12
Temperature: 80 °C
Reaction time: 1 h
Yield: 7.8 %

Procedure:
A mixture of (S)-3-amino-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (300 mg, 0.74 mmol) in N,N-dimethylformamide (5 mL) was treated with N,N-diisopropylethylamine (285 mg, 2.20 mmol) and 1-(2-bromoethoxy)-3-(trifluoromethyl) benzene (220 mg, 0.81 mmol). The reaction mixture was allowed to stir at 80° C. for 1 h. At this time, the reaction was poured into water. The aqueous layer was extracted with ethyl acetate. The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Preparative high pressure liquid chromatography afforded 3-[2-(3-trifluoromethyl-phenoxy)-ethylamino]-pyrrolidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (28 mg, 8%) as a light brown solid; LRMS for C20H21F3N6O3S (M+H)+ at m/z=482. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19]Br>C(O)=O.CCOC(C)=O.[Fe]>[CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[Br:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc(OCC2CCCCC2)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CCCCC2)c(Br)c1
Reaction time: 1 h

Procedure:
A solution of 23-2 (26.3 g, 106 mmol) was warmed on a steam bath in 110 mL of HCOOH with 592 mg (10.6 mmol) of Fe powder. Bromine (7.6 mL, 147.4 mmol) in 50 mL of HCOOH was added by dropping funnel over a period of 10 min. The reaction mixture was stirred an additional 1 h , cooled and poured onto ice. The resulting gum was taken up in 500 mL of EtOAc and washed with sat'd Na2S2O3 (2×150 mL), water (5×100 mL), sat'd NaHCO3 (3×100 mL) and brine (50 mL), dried (MgSO4) and concentrated to afford product 23-3 as a white solid.