Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=4)=[O:3])([CH2:11][CH2:10]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Nc1ccc(CCO)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(CCO)cc3)(CC1)CC2
Yield: 52 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-(4-aminophenyl)ethanol (47.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-[4-(2-hydroxyethyl)phenyl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (35.6 mg).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1.Cl>N1C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(Br)n1
Temperature: 25 °C

Procedure:
10 g (53.8 mmol) of 6-bromo-pyridine-2-carbaldehyde were dissolved in 70 ml of pyridine and 6.73 g (64.5 mmol) of malonic acid and 457 mg (5.4 mmol) of piperidine were added. The reaction mixture was boiled under reflux for 6 h. The solution was cooled to room temperature and then poured onto ice. Concentrated hydrochloric acid was added until pH=5, whereupon the product precipitated. The product was isolated by filtration and dried under reduced pressure. Yield: 9.85 g.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH2:14][CH3:15]>C(OCC)C>[CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][C:13]([CH2:14][CH3:15])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)CC(=O)CC
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: CCOCC
Product: CCOC(=O)C=C(CC)NCCc1ccc2c(c1)OCO2
Reaction time: 12 h

Procedure:
In a manner similar to that described in Example IV, 5.0 grams (30 millimoles) of 4-(3,4-methylenedioxyphenethylamine is added dropwise with stirring at ambient temperature to 4.5 grams (31 millimoles) of ethyl propionylacetate and the stirring continued for about 12 hours at ambient temperature. Thereafter, the mixture is diluted with 250 milliliters of diethyl ether and the resulting ether solution washed with 50 milliliters of brine and then dried over sodium sulfate. The ether is vaporized off of the dried and filtered solution to obtain ethyl 3-[2-(3,4-methylenedioxyphenyl)ethyl]amino-2-pentenoate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](S(C)=O)[N:22]=3)=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:30])#[N:2].C(C1C=C(C=CC=1)CN1CC[C@H](NS(C2SC(C3C=CN=C(S(C)(=O)=O)N=3)=CC=2)(=O)=O)[C:41]1=[O:64])#N>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][CH:33]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[S:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([O:64][CH3:41])[N:22]=3)=[CH:19][CH:20]=2)(=[O:15])=[O:14])[C:8]1=[O:30])#[N:2]
Reactant: CS(=O)c1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1
Solvent: CO
Product: COc1nccc(-c2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)s2)n1

Procedure:
A mixture of [5-(2-methylsulfinyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide and [5-(2-methylsulfonyl-pyrimidin-4-yl)-thiophene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxo-pyrrolidin-3-(S)-yl]-amide (0.19 g, 0.37 mmol) is dissolved in 10 mL of MeOH and 1 mL of CH2Cl2 and NH3 gas is bubbled through the solution for 5 minutes. The resulting mixture is heated at reflux for 4 hours. After this time, the solution is concentrated in vacuo to give the title compound (0.17 g, 0.36 mmol) as a solid.
Reaction SMILES: [CH3:1][C:2](Br)([CH3:17])[C:3]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:1][CH:2]([CH3:17])[C:3]([C:5]3[CH:16]=[CH:15][C:8]([O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: COC(=O)COc1ccc(C(=O)C(C)(C)Br)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: COC(=O)COc1ccc(C(=O)C(C)CN2CCN(c3ccncc3)CC2)cc1

Procedure:
A stirred mixture of methyl 4-(2,2-dimethylbromoacetyl)phenoxyacetate (3.15 g), and 1-(4-pyridyl)piperazine (3.26 g) in acetonitrile (200 ml) was heated at reflux temperature for 4 days. The solvent was removed in vacuo and the residue partioned between dichloromethane/water. The organic phase was dried (MgSO4), evaporated and then purified by flash chromatography on silica, eluting with 2 to 5% v/v methanol/dichloromethane. Further purification by flash chromatography on neutral alumina, eluting with dichloromethane, gave the title compound, 350 mg, as a clear oil: NMR (d6DMSO) δ 8.12 (2H, d), 7.98 (2H, d), 7.Q4 (2H, d), 6.75 (2H, d), 4.92 (2H, s), 3.86 (1H,m), 3.71 (3H, s), 3.19 (4H, t), 2.70 (1H, q), 2.49 (DMSO+4H), 2.36 (1H, q), 1.09 (3H, s), trace of dichloromethane; m/e 398 (M+H)+ ; calculated for C22 H27N3O4.0.1 CH2Cl2 : C, 65.3; H, 6.7; N, 10.3. found: C, 65.1; H, 6.9; N, 10.1%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N+:33]([O-])=O)[C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)#[N:2].[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[CH2:18]([C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:2][N:38]=[N:37][N:36]=3)=[CH:14][CH:13]=2)[C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[N:33]=1)[CH2:19][CH2:20][CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cc(C(=O)OC)ccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 120 h
Yield: 39.8 %

Procedure:
A mixture of methyl 4-[N-(2'-cyanobiphenyl-4-yl)methyl-N-valerylamino]-3-nitrobenzoate (1.7 g), sodium azide (3.9 g) and ammonium chloride (3.2 g) in DMF (17 ml) was stirred at 115 ° C. for 5 days. To the reaction mixture was added water and the mixture was neutralized with 1N-HCl, followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated to dryness. The concentrate was purified by column chromatography on silica gel to give crude crystals. Recrystallization from ethyl acetate gave colorless needles (0.67 g, 34%), m.p. 134-136° C.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:11]1([C@@H:9]([OH:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Solvent: O
Product: O[C@@H](CCc1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
Washed phaseolus aureus L (green grams) 50 g. were taken into a conical flask and allowed to soak in deionised water (400 ml) for a period of 24 hr. Chalcone (0.500 g; 0.0024 moles) (V) was added to the soaked phaseolus aureus L (green grams) in the above water, covered and allowed to shake for 24 hr at 15–20° C. Then the green grams were filtered off and washed with deionised water (3×100 ml). The combined filtrate was extracted with chloroform (3×500 ml). The chloroform layer was dried and the crude product obtained (240 mg). Pure 1,3-diphenyl-(1S)-propan-1-ol (VI) was obtained after column chromatography with silica gel using chloroform as eluent.
Reaction SMILES: BrCC1C=CC(C(OC)=O)=CC=1.[CH3:13][S:14]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1)(=[O:16])=[O:15].[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CS(CC1C=CC(C(O)=O)=CC=1)(=O)=O>>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:22](=[O:24])[C:21]2[CH:20]=[CH:19][C:18]([CH2:17][S:14]([CH3:13])(=[O:15])=[O:16])=[CH:27][CH:26]=2)=[CH:31][C:30]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: COC(=O)c1ccc(CBr)cc1
Agent: CS(=O)(=O)Cc1ccc(C(=O)O)cc1
Product: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
1 g of methyl 4-(bromomethyl)benzoate was reacted via Procedure O. 2.77 g of methyl 4-(methylsulfonylmethyl)benzoate was hydrolyzed via Procedure M. 1 g of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1.15 g of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was subjected to basic workup and recrystallized with 1:1 Ratio of Isopropylacetate and Ether to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 401 (M)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:28][CH:27]([OH:29])[CH:26]=[CH:25]4)[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.C(Cl)(=[O:38])C>CN(C)C1C=CN=CC=1.ClCCl>[C:1]1([CH:7]2[CH2:9][CH:8]2[NH:10][C:11]2[C:12]3[N:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][CH:27]([OH:29])[CH:28]4[OH:38])[C:13]=3[N:14]=[C:15]([S:17][CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3C=CC(O)C3)c2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CCC(O)C3O)c2n1
Reaction time: 3 h

Procedure:
To a solution of the product of step d) (0.78 g), pyridine (0.43 ml) and 4-dimethylaminopyridine (1 mg) in dichloromethane (15 ml) was added acetyl chloride (0.16 ml). The solution was stirred for 3 hours and then concentrated in vacuo. The residue was purified by chromatography (SiO2, ethyl acetate:hexane 1:1 as eluant) to afford the sub-title compound (0.75 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=1.N1C=CC=CC=1.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[S:44](Cl)(=[O:46])=[O:45])(=[O:37])=[O:36]>C1CCCCC1.C(OCC)(=O)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([NH:19][S:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[S:35]([CH3:34])(=[O:37])=[O:36])(=[O:46])=[O:45])[CH:17]=2)[N:12]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:11]=1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc(N)ccc21
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: c1ccncc1
Product: C[Si](C)(C)CCOCn1nc(-c2nc3ccccc3[nH]2)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Yield: 94 %

Procedure:
N-[3-(1H-Benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide can be obtained as described in Example 2 from 130 mg of 3-(1H-benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-ylamine, 5 ml of pyridine and 87 mg of 2-methylsulfonylbenzenesulfonyl chloride. 192 mg of N-[3-(1H-benzimidazol-2-yl)-1-(2-trimethylsilanylethoxymethyl)-1H-indazol-5-yl]-2-methylsulfonylbenzenesulfonamide are thus obtained in the form of an orange lac (Rf=0.53, silica gel thin layer chromatography, eluent: cyclohexane/ethyl acetate (50/50 by volume), mass analysis: Cl: m/z 598 (M+H)+.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15](COCC[Si](C)(C)C)[CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(C#Cc2cn(COCC[Si](C)(C)C)c3ncnc(N)c23)cc(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#Cc2c[nH]c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A solution of 5-((3,5-dimethoxyphenyl)ethynyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (4.27 g) obtained in Step 3 in methylene chloride (20 ml) was cooled to 0° C., and TFA 10 ml was added thereto. The reaction mixture was stirred at room temperature for 5 hours, and the solvent was distilled off under reduced pressure. THF (50 ml) was added to the residue, and the mixture was cooled to 0° C. 4N aqueous sodium hydroxide (12.5 ml) was added thereto, and the mixture was stirred at room temperature overnight. The result was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was distilled off under reduced pressure, and chloroform was added to the resulting residue. The mixture was subjected to filtration to obtain the title compound as a white solid (2.60 g). Physical properties: m/z [M+H]+ 295.3
Reaction SMILES: C([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:36])[C:26]([CH3:35])([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH3:27])=[C:9]12)C1C=CC=CC=1.C(O)C.[H][H]>C1COCC1.[Pd]>[CH3:20][C:11]1([CH3:21])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:36])[C:26]([CH3:27])([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[CH3:35])=[C:9]2[NH:8][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12]1
Reactant: [H][H]
Reactant: Cc1ccc(C(C)(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)C(=O)c2cnn3c2NC(c2ccccc2)CC3(C)C)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
To 0.060 g (0.126 mmol) of 6 dissolved in 4 mL of 1:1 THF:ethanol was added 0.080 g of 10% palladium on carbon. The reaction vessel was capped with a rubber septum and charged with hydrogen via a balloon. After 1 h, the catalyst was removed via filtration and the filtrate concentrated to a cream colored solid. Purification by flash chromatography eluting with 90% hexanes/ethyl acetate gave 0.041 g (84%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.49 (s, 3H), 1.54 (s, 9H), 2.04-2.11 (m, 2H), 2.32 (s, 3H), 4.63 (dd, J=4.1, 10.7 Hz, 1H), 6.66 (s, 1H), 7.12-7.26 (m, 5H), 7.31-7.44 (m, 5H). MS Calcd.: 387. Found: 388 (M+H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]([Cl:22])([Cl:21])[C:11]([CH:13]=[C:14]1[CH2:18][O:17]C(C)(C)O1)=[O:12]>>[OH:17][CH2:18][C:14]1[CH2:13][C:11]([C:10]([Cl:22])([Cl:21])[Cl:9])([OH:12])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: NNc1ccccc1
Reactant: CC1(C)OCC(=CC(=O)C(Cl)(Cl)Cl)O1
Product: OCC1=NN(c2ccccc2)C(O)(C(Cl)(Cl)Cl)C1

Procedure:
The procedure is as described in example 2 but using phenylhydrazine and 1,1,1-trichloro-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)acetone.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2].[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>O>[C:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]1[NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([CH3:16])([CH3:15])[S:17]1)([OH:3])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O
Product: CC1(C)SC(c2ccccc2C(=O)O)N[C@H]1C(=O)O
Reaction time: 3 h

Procedure:
A mixture containing 6 g (30 mmoles) of 2-carboxybenzaldehyde and 6 g (30 mmoles) of D-penicillamine in 44 ml of water is stirred for 3 hours. The precipitate is filtered out and washed with aqueous methanol to given the crude title acid in a yield of 9.86 g (82.6%) which can be recrystallized from methanol containing water, m.p.: 185°-186° C. [α]D18 =+385° (c=0.51, methanol).
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=O.N[C:15]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=C[NH:17][N:16]=1>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:17]3[N:16]=[CH:15][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]3[N:2]=[CH:3][CH:4]=2)=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: CN(C)C=CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccncc3)ccnc12

Procedure:
A mixture of 3.52 g. of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one and 3.10 g. of ethyl 3-aminopyrazole-4-carboxylate in 50 ml. of glacial acetic acid is refluxed for 15 hours. The solvent is removed and the residue worked up as for Example 53 to give 3.0 g. of crystals, m.p. 209°-210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH:30]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:37][CH2:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Reactant: NCC1CCCCC1
Solvent: ClCCl
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(NCC3CCCCC3)nc2N1c1ccccc1
Yield: 94.2 %

Procedure:
A solution of 100 mg (0.22 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 285 μl (2.2 mmol) of cyclohexylmethylamine in 2 ml of dichloromethane was stirred at room temperature overnight. The mixture was diluted with 10 ml of dichloromethane, washed with 10 ml of 2M hydrochloric acid and with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. 100 mg (94%) of 3-(2,6-dichlorophenyl)-7-(cyclohexylmethylamino)-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one were isolated as a white foam of melting point 229-233° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH:40](Br)[CH3:41])(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH:40]([O:39][C:36](=[O:38])[CH3:37])[CH3:41])=[O:23])=[C:15](/[CH:18]=[CH:19]/[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OC(C)Br
Reactant: CC/C=C/C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C/C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(E)-1-butenyl]-3-cephem-4-carboxylic acid (130 mg, 0.3 mmole) and K2CO3 (55 mg, 0.4 mmole) in DMF (2.5 ml) was added at 5° C. 1-bromoethyl acetate (67 mg, 0.4 mmole). The mixture was stirred at 5° C. for 1 hour, diluted with ethyl acetate (25 ml), washed successively with water and an aqueous NaCl solution, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column with 1% methanol in CHCl3. The desired fractions were combined and concentrated in vacuo to yield 77 mg (49%) of the title compound. Estimated purity 90% (by HPLC). Mp. 110°-115° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:18][CH3:19])[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][S:14][C:15](N)=[C:11]2[S:10][C:9]1=[S:17])[CH3:2].N([O-])=O.[Na+].[I-:25].[K+].CCCCCC>Cl.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:18][CH3:19])[CH2:6][CH2:7][N:8]1[C:12]2=[N:13][S:14][C:15]([I:25])=[C:11]2[S:10][C:9]1=[S:17])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)C(CC)CCn1c(=S)sc2c(N)snc21
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(CC)CCn1c(=S)sc2c(I)snc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 6.1 %

Procedure:
Compound 43 (280 mg, 0.925 mol) was suspended in 270 μl HCl (12 M) and water (400 μl). After stirring for 15 minutes the solution was cooled to 0° C. and sodium nitrite (127.6 mg, 1.85 mmol), dissolved in 1 ml water, was added dropwise. Stirring was continued for additional half an hour while maintaining the temperature below −5° C. Potassium iodide (307 mg, 1.85 mmol) dissolved in 1 ml water was added to the resulting mixture, which then turned dark brown. The reaction mixture was allowed to warm to 25° C. and stirring was continued overnight. Ethyl acetate was thereafter added, the phases were separated and the aqueous phase was further extracted with ethyl acetate. The combined organic phase was dried over Na2SO4, and the solvent was evaporated under reduced pressure to give 450 mg of the crude product. Purification by column chromatography using fine silica and a 4:1 hexane:ethyl acetate mixture as eluent gave 50 mg of Compound 44 (13% yield) as a white solid.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]2=[N:17][CH:18]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>CN(C)C=O>[CH2:1]([NH:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:21]=[CH:20][NH:19][C:16]2=[N:17][CH:18]=1)=[O:11])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NCCc3ccccc3)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Product: O=C(NCCc1ccccc1)Nc1cnc2[nH]ccc2n1
Yield: 26.8 %

Procedure:
A solution of 1-phenethyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.22 g, 0.53 mmol), tetrabutylammonium fluoride (1 M in THF, 3 mL, 3 mmol) and ethylene diamine (0.3 mL, 5 mmol) in 5 mL of N,N-dimethylformamide was stirred at 80° C. for 14 h, then concentrated. The resulting residue was triturated with methanol then ether to afford 0.040 g (26%) of 1-phenethyl-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].N1C=CN=C1.[Si:24](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].O>CN(C)C=O.CO.C(Cl)(Cl)Cl>[Si:24]([O:14][CH2:13][C@H:12]1[O:15][C@@H:7]([N:6]2[CH:16]=[C:2]([F:1])[C:3](=[O:18])[NH:4][C:5]2=[O:17])[C@H:8]([OH:9])[C@@H:10]1[OH:11])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)[C@H](O)[C@@H]1O
Reaction time: 15 h
Yield: 82.2 %

Procedure:
A 1.50 g quantity of 5-fluorouridine (5.72 mmoles) was dissolved in 5 ml of N,N-dimethylformamide. To the solution were added 520 mg (7.64 mmoles) of imidazole and 633 mg (4.20 mmoles) of tert-butyldimethylsilyl chloride, and the reaction was conducted at room temperature for 15 hours. -The reaction mixture was ice-cooled, and 40 ml of water was added thereto. The reaction mixture was extracted three times with 40 ml of ethyl acetate. The organic layers were combined, washed three times with 50 ml of water and washed three times with 50 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (chloroform: methanol=20:1). The eluate was concentrated and the residue was recrystallized from ether, giving 1.3 g of the title compound as white crystals. Yield: 60%.